Organ Procurement and Preservation (Vademecum)

v a d e m e c u m

Organ Procurement and Preservation Goran B. Klintmalm, M.D., Ph.D. Marlon F. Levy, M.D. Baylor University Medical Center Dallas, Texas, U.S.A.

LANDES BIOSCIENCE

GEORGETOWN, TEXAS U.S.A.

v a d e m e c u m

Organ Procurement and Preservation

Goran B. Klintmalm, M.D., Ph.D. Marlon F. Levy, M.D. Baylor University Medical Center Dallas, Texas, U.S.A.

L ANDES B I O S C I E N C E

AUSTIN, TEXAS U.S.A.

VADEMECUM Organ Procurement and Preservation LANDES BIOSCIENCE Austin Copyright © 1999 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publishers: Landes Bioscience, 810 S. Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 ISBN: 1-57059-498-8

Library of Congress Cataloging-in-Publication Data Organ procurement and preservation / [edited by] Goran B. Klintmalm, Marlon F. Levy. p. cm. "Vademecum." Includes bibliographical references and index. ISBN 1-57059-498-8 (alk. paper) 1. Procurement of organs, tissues, etc. 2. Preservation of organs, tissues, etc. I. Klintmalm, Goran B. II. Levy, Marlon F. [DNLM: 1. Organ Procurement. 2. Organ Preservation. WO 660 06567 1998] RD129.5.0747 1998 362.1'783--dc21 DNLM/DLC 98-55261 for Library of Congress CIP While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication To all organ donors and their families for their wonderful, selfless gifts.

Contents 1. Principles of Brain Death Diagnosis ................................... 1 Marwan S. Abouljoud, Marlon F. Levy Introduction .................................................................................................. 1 Historical Background .................................................................................. 1 Clinical Diagnosis of Brain Death ................................................................ 4 Confirmatory Tests for Brain Death ............................................................. 8 Conclusion ................................................................................................... 12

2. Approaching the Family ..................................................... 14 Jerome Menendez, Tammie S. Peterson, Alison B. Smith Approaching the Family ............................................................................. 14 Phase 1–Identification and Referral of the Potential Donor .................... 15 Phase 2–Predonation Family Evaluation ................................................... 16 Phase 3–Understanding Brain Death ......................................................... 18 Phase 4–The Grieving Process .................................................................... 20 Phase 5–Presenting The Option ................................................................. 23 Phase 6–Aftercare of the Family ................................................................. 27

3. Physiologic Consequences of Brain Death ....................... 31 Dimitri Novitzky Introduction ................................................................................................ 31 Histological Changes ................................................................................... 35 Endocrine Changes ..................................................................................... 38 The Impact of Brain Death on the Hemodynamic and Metabolic Functions, the Role of Hormonal Replacement ............ 39 Hormonal Therapy in the Brain Dead Organ Donors .............................. 43 Discussion .................................................................................................... 43

4. Assessing Suitability of the Cadaver Donor ..................... 47 Giuliano Testa, Goran B. Klintmalm Introduction ................................................................................................ 47 Defining the Donor ..................................................................................... 48 Living Donors .............................................................................................. 48 The Cadaveric Donor .................................................................................. 50 The Marginal Donor ................................................................................... 58 Non-Heart-Beating Donors ........................................................................ 59

5. Organ Preservation ............................................................ 63 James H. Southard Introduction ................................................................................................ 63 Brief Historical Perspective on Organ Preservation .................................. 63 Principles of Organ Preservation ............................................................... 66 Delayed Graft Function and Chronic Rejection ........................................ 73 Future of Organ Preservation ..................................................................... 74

6. Optimal Management for Abdominal Organ Donation ........................................ 80 Allan M. Roza, Christopher A. Johnson, Mark B. Adams Introduction ................................................................................................ 80 Hemodynamic Monitoring ......................................................................... 81 Management of Hypertension .................................................................... 81 Management of Hypotension ..................................................................... 82 Management of Electrolyte Disorders ....................................................... 85 Management of Coagulopathy ................................................................... 86 Management of Hypothermia .................................................................... 87 Management of Hypoxemia ....................................................................... 88 Management of Arrhythmias ..................................................................... 88 Management of Hyperglycemia ................................................................. 89 Nutritional Support of the Abdominal Organ Donor .............................. 89 Modulation of the Inflammatory Response in the Abdominal Organ Donor .............................................................. 89 Organ Specific Issues .................................................................................. 90 Conclusion ................................................................................................... 92

7. Optimal Thoracic Organ Donor Management ................. 94 Dan M. Meyer, Michael A. Wait, Michael E. Jessen, W. Steves Ring Donor Selection (General) ......................................................................... 96 Donor Selection (Organ Specific) ............................................................ 101 Donor Preoperative Management ............................................................ 105

8. Surgical Technique for Multiple Organ Recovery .......... 113 Osman Abbasoglu, Marlon F. Levy The Role of the Anesthesiologist in Organ Procurement ....................... 114 Liver Procurement ..................................................................................... 114 Kidney Procurement ................................................................................. 120 Pancreas Procurement .............................................................................. 122 Small Bowel Procurement ........................................................................ 124 Summary ................................................................................................... 126

9. Surgical Technique for Thoracic Organ Recovery .......... 128 Michael A. Wait, Dan M. Meyer, Michael E. Jessen, W. Steves Ring Thoracic Organ Procurement Technique ................................................ 128 Isolated Donor Cardiectomy .................................................................... 129 Combined Donor Cardiectomy and Pneumonectomy ........................... 131 Principles of Lung Preservation ............................................................... 134 Perfusate Composition ............................................................................. 134 Prostaglandins ........................................................................................... 136 Preservation Temperature, Ventilation Volume and Composition ........ 136 Bronchial Arterial Perfusion ..................................................................... 137 Retrograde vs. Antegrade Flush Administration ..................................... 137 Principles of Myocardial Preservation ..................................................... 138 Cardiopulmonary Bypass and Procurement ........................................... 139

Adenosine .................................................................................................. 140 Impact of Brain Death on the Heart ........................................................ 141 Reimplantation-Reperfusion .................................................................... 142 Summary ................................................................................................... 142

10. The Role of the Recovery Services Coordinator ............. 147 Cindy Morphew-Magie, Alison B. Smith Interviewing/Hiring .................................................................................. 148 Training ...................................................................................................... 149 Referral Process ......................................................................................... 149 Evaluation Process ..................................................................................... 150 Consent ...................................................................................................... 151 Medical/Social History .............................................................................. 151 Medical Examiner Release ........................................................................ 152 Saying Good-Bye ....................................................................................... 152 Donor Management .................................................................................. 153 UNOS ........................................................................................................ 153 Organ Placement ....................................................................................... 154 Organ Allocation ....................................................................................... 155 Operating Room ....................................................................................... 156 Arranging Transportation ......................................................................... 157 Marketing Department ............................................................................. 157 Donor Family Follow-Up ......................................................................... 157 Other Job Duties ....................................................................................... 158 Conclusion ................................................................................................. 158

11. Ethical Issues in Organ Donation ................................... 159 L.S. Rothenberg Introduction .............................................................................................. 159 Methods of Obtaining Natural Organs for Transplantation .................. 160 Special Issues Concerning Living Donors ................................................ 164 Special Issues Concerning the Determination of Death ......................... 165 Artificial Organs and Other Body Parts ................................................... 167

Index ........................................................................................ 171

Editors Goran B. Klintmalm, M.D., Ph.D. Director, Transplantation Services Baylor University Medical Center Dallas, TX, USA Chapter 4

Marlon F. Levy, M.D. Assistant Director Transplantation Services Baylor University Medical Center Dallas, TX, USA Chapters 2, 9

Contributors Osman Abbasoglu, M.D. Baylor Unviersity Medical Center and Haceteppe University School of Medicine Department of General Surgery Sihhiye, Ankara, Turkey Chapter 8 Marwan S. Abouljoud, M.D. Division of Transplantation Surgery Henry Ford Hospital Detroit, MI, USA Chapter 1 Mark B. Adams, M.D. Medical College of Wisconsin Department of Transplant Surgery Milwaukee, WI, USA Chapter 6 Michael E. Jessen, M.D. University of Texas Southwestern Medical School Dallas, TX, USA Chapters 7, 9 Christopher P. Johnson, M.D. Medical College of Wisconsin Department of Transplant Surgery Milwaukee, WI, USA Chapter 6

Cindy Morphew-Magie, RN, CPTC Southwest Transplant Alliance Dallas, TX, USA Chapter 10 Jerome Menendez, R.N., CPTC Southwest Transplant Alliance Dallas, TX, USA Chapter 3 Dan M. Meyer, M.D. University of Texas Southwestern Medical School Dallas, TX, USA Chapters 7, 9 Dimitri Novitzky, M.D. Division of Cardiothoracic Surgery University of South Florida Tampa, FL, USA Chapter 3 Tammie S. Peterson, R.N., CPTC Southwest Transplant Alliance Dallas, TX, USA Chapter 2 W. Steves Ring, M.D. University of Texas Southwestern Medical School Dallas, TX, USA Chapters 7, 9

L.S. Rothenberg, M.D. Division of Medical Genetics UCLA Department of Medicine Los Angeles, CA, USA Chapter 11

James H. Southard, Ph.D. Department of Surgery University of Wisconsin Madison, WI, USA Chapter 5

Allan Roza, M.D. Medical College of Wisconsin Department of Transplant Surgery Milwaukee, WI, USA Chapter 6

Giuliano Testa, M.D. Universitäts Klinikum Essen Zentrum für Chirurgie Germany Chapter 4

Alison B. Smith, R.N., CPTC Regional Organ Bank of Illinois Chicago, IL,USA Chapters 2, 10

Michael A. Wait, M.D. University of Texas Southwestern Medical School Dallas, TX, USA Chapters 7, 9

Preface Over the past 20 years, organ transplantation has developed from a work of love by dedicated individuals taking care of patients brave enough to seek transplantation as a cure for their illnesses, to a discipline where patients with endstage organ failures are routinely referred for transplantation. As a result, we have seen an increasing demand for organ retrieval, sharing, and distribution. This change has caused an enormous development in the techniques of retrieval, organ donor management, and how organs are distributed for transplantation. Organ retrieval now involves and affects, not only the transplant professionals, but also the lives and professions of many others, such as staff at intensive care units and emergency rooms. There, not only physicians and surgeons are drawn into the recovery process, but also nurses, ministers, administrators, and others. Many questions on organ recovery are now asked with no one available to answer those questions. The purpose of this handbook is to be a readily available source of answers for most of those questions. We hope it will provide information, not only for trained professionals, but also for those in training, such as residents and nurses. The handbook has been formatted to provide easy access to the readers’ questions. We would like to thank all of those who participated in the development of this handbook. They have been generous with their time and expertise and willing to share it with all readers. Organ retrieval is an extremely difficult field in which to work and we are slowly improving our ways of approaching not only the social/ethical difficulties for a higher consent rate, but also our abilities to more perfectly preserve the organs we retrieve. It is our desire that this handbook will be able to communicate these developments that have resulted in today’s high level of success.

Goran Klintmalm, M.D., Ph.D. Marlon Levy, M.D.

Principles of Brain Death Diagnosis

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Principles of Brain Death Diagnosis Marwan S. Abouljoud, Marlon F. Levy Introduction ............................................................................................................ 1 Historical Background ............................................................................................ 1 Clinical Diagnosis of Brain Death .......................................................................... 4 Confirmatory Tests for Brain Death ....................................................................... 8 Conclusion ............................................................................................................ 12

INTRODUCTION The concept and understanding of brain death have evolved significantly over the past few decades. This entity has become more recognized as our ability to provide prolonged cardiovascular support to brain injured patients became more sophisticated. In parallel with these developments, organ transplantation became a reality with wider applications resulting in significant increase in demand for potentially transplantable organs. Quite likely, the availability of organs for transplantation was fueled by the broadened application of brain death laws. Achieving a uniform definition of brain death and establishing methods for prompt brain death diagnosis (prior to the onset of hemodynamic and cardiovascular collapse) is a sine qua non in the field of modern organ transplantation. Therefore, it was of great importance to achieve a uniform definition of brain death and establish methods for prompt diagnosis prior to the development of hemodynamic instability which culminates in cardiovascular collapse. The concept of brain death is confusing for many in the medical community as well as in the lay public. The purpose of this chapter is to outline the legislative and clinical background of current definitions, describe a systematic process for the evaluation of the brain injured patient, and to arrive at the diagnosis of brain death.

HISTORICAL BACKGROUND

EVOLUTION OF A CONCEPT For many centuries death was determined based on cessation of cardiorespiratory function. Advances in medical technology have allowed for cardiac and respiratory functions to be maintained artificially even in the presence of irreversible loss of brain function. As early as 1959, published reports described clinical Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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conditions similar to what we currently view as brain death.1,2 Mollaret and Goulon1 coined the term “coma dépassé” (state beyond coma) to describe a neurological state associated with deficits beyond what has been previously described as coma. Such patients were unresponsive, had no brainstem reflexes and showed progressive hemodynamic collapse. The authors reflected on the prognosis of such a condition but did not equate it to death nor did they recommend withdrawal of ventilatory support. During the same year, a second group2 described “death of the central nervous system”. These patients also lacked brainstem reflexes, were apneic in spite of hypercapnea and had an electrically silent electroencephalogram (EEG) with scalp and deep thalamic electrodes. The authors concluded that in such conditions recovery was not possible and that respiratory support was to be discontinued. These early reports were followed by several studies that attempted to define clinical criteria for brain death and methods for diagnosis. As investigators moved toward more objective evidence and supportive studies, the concept of brain death became somewhat blurred with an evolution toward a more clinical approach in determining brain death and efforts to accept brain death as patient death. In 1968, the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain death published its report, “A Definition of Irreversible Coma”.1 Its primary purpose was to define irreversible coma as a new criterion for death. The definition included the criteria of coma, absence of spontaneous respirations and movements, unresponsiveness, dilated pupils, loss of cephalic and deep tendon reflexes and absence of postural responses. A flat or isoelectric EEG was considered of “great confirmatory value”. Testing was to be repeated at least 24 hours later with no change. The final diagnosis of brain death was dependent on the exclusion of hypothermia (temperature below 32.2°C) and presence of central nervous system depressants (e.g., barbiturates). The authors failed to describe what would happen if mechanical ventilation was discontinued. In 1971, Mohandas and Chou1 formulated criteria for brain death based on clinical grounds. The authors did not feel an EEG was mandatory and repeat examinations could be performed at 12 hours. However, patients should have had irreparable brain lesions “with presently available means”. The proposed criteria emphasized the clinical diagnosis of brain death and set the foundation for more modern criteria for determining brain death which included: 1) defining a clear irreparable etiology for brain death, 2) emphasis on brainstem death with loss of brainstem reflexes, 3) questioning the value of an EEG in that setting. In 1976, the Conference of Royal Colleges and Faculties of the United Kingdom endorsed a document outlining the diagnostic criteria for determining brain death.1 The criteria were also based purely on clinical grounds with strong emphasis on brainstem death. Included was a detailed outline of preconditions and cautionary notes while considering brain death. This became known as the “UK code” and was discussed in much greater detail by Pallis.2 The author emphasized the conceptual evolution from classical death to brain death as an initial step and subsequently from total brain death to brain stem death.

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In 1981, the President’s Commission for the Study of Ethical Problems in Medicine published its report “Guidelines for the Determination of Death”1 (Table 1.1). The Commission stated that “an individual with irreversible cessation of the entire brain, including the brain stem, is dead.” The report was similar in many ways to the UK code and also outlined complicating conditions that may affect the accuracy and reliability of brain death diagnosis. The emphasis was on cessation of cerebral and brain stem functions, establishment of irreversibility and evaluation for complicating conditions. Confirmatory studies, such as EEG or cerebral blood-flow, were suggested when criteria were not met as outlined. These criteria subsequently became the text for brain death legislation in all 50 states. LEGISLATIVE BACKGROUND Acceptance of brain death as clinical death was dependent on the integration of both medical and legal criteria. “Death” has long been accepted as meaning “cessation of respiratory and cardiac functions”. Yet, while such functions can be replaced by machines and to some extent pharmacologic agents, those of the brain cannot. Therefore, the evolution into brain death as an acceptable diagnosis of death was a natural one. Although earlier reports1 have described this condition with its eventual outcome, it was not until 1971 in Finland that brain death was first legally accepted as death.1 In the United States, legislative activity in support of organ donation and brain death diagnosis started at the state level. The Uniform Anatomical Gift Act (UAGA) of 1968 established the legality of anatomical gifts after death, the organ donor card and also prohibited the sale of organs. By 1972, the UAGA had been adopted in all 50 states. However, without brain death laws, removal of organs was possible

Table 1.1. President’s commission criteria for brain death 1. Absence of: a) Cerebral functions: deep coma b) Brain stem function: pupillary, corneal, oculovestibular, gag, cough, respiratory (apnea) reflexes 2. Irreversibility: a) Cause of coma is established b) Possibility of recovery of any brain function is excluded c) Findings confirmed on a second exam after an appropriate period of observation 3. Complicating conditions: a) Drug and metabolic intoxication b) Hypothermia: below 32.2oC core temperature c) Children: younger than 5 years require longer periods of observation and supportive studies d) Shock 4. Confirmatory studies: Not required. EEG or blood-flow study may be used as indicated by medical circumstances.

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only after a prolonged period of circulatory ischemia. In 1970, Kansas became the first state to adopt a brain death statute.3 By 1977, 12 states had enacted laws to accept brain death as sufficient for declaration of a patient’s death. In 1978, The National Conference of Commissioners on Uniform State Laws drafted and established the Uniform Brain death Act.3 This act expanded the traditional definition of death (cardiopulmonary) to include brain death. The Uniform Determination of Death Act was introduced in 1978 and approved in 1980. Today, all states have adopted some form of brain death legislation.

CLINICAL DIAGNOSIS OF BRAIN DEATH With increased reliance on clinical criteria for determining brain death, the approach to this diagnosis should be in a stepwise and systematic fashion. The clinical diagnosis of brain death involves three steps that are outlined below. Adherence to this logical and stepwise process assures that clinical testing is applied to properly selected patients; in pooled series, there have been no survivors among patients fulfilling these criteria.3 PRECONDITIONS The patient must be in deep coma on the ventilator. Structural damage to the brain should be firmly established either clinically (open brain injury) or radiographically, usually by computerized tomography (CT) or magnetic resonance imaging (MRI) of the head. Once the cause of coma is established, irreversibility of brain damage must be ascertained. This involves vigorous efforts to treat or remedy the condition with potential reversal or improvement; such therapies may range from evacuation of intracranial hematoma to control of cerebral edema. A certain period of time may be needed on the ventilator to assure irreversibility. Usually a period of 12 hours is adequate; on occasions a longer period may be needed, although at times a period as short as 6 hours may suffice. During this period of observation, the patient should undergo aggressive resuscitation and correction of potential underlying metabolic abnormalities. Restoration of normal arterial oxygenation is essential. Hemodynamic instability can have potentiating effects on findings of brain dysfunction. Therefore, one should aim for a systolic blood pressure greater than 90 mm Hg. An unhurried and disciplined approach is the best safeguard against premature or unjustified diagnosis of brain death. EXCLUSIONS Drug intoxication can present a serious hindrance to the determination of death. Cessation of brain functions can be caused by barbiturates, benzodiazepines and anesthetics. The influence of anticonvulsants, alcohol and neuromuscular blockade must also be excluded. Other causes of total paralysis and areflexia must also be excluded. In addition to a waiting period until such intoxicants are me-

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tabolized, in the absence of identified structural brain damage, confirmatory cerebral blood-flow studies may be essential. Other conditions that may cause deep coma include hypoglycemia, uremia, hepatic failure, Reye’s syndrome, hyponatremia, hyperosmolar coma, hypercalcemia, panhypopituitarism, myxedema and adrenocortical failure. Before any attempt at determining brain death these conditions must be excluded and remedied if established. Shock (systolic blood pressure less than 90 mm Hg) or low cardiac output may also cause reversible suppression of cerebral function because of reduced cerebral blood flow. Hypothermia (below 90°F/32.2°C) can also mimic brain death and can protect against neurological damage due to hypoxia. CLINICAL EXAMINATION Once preconditions and exclusions have been rigorously refuted, clinical testing for absence of brainstem reflexes and total apnea can then be performed and brain death can be established with certainty. The examination is fairly simple and follows a logical and stepwise process looking for total absence of response to various testing maneuvers. BRAINSTEM REFLEXES There are six brainstem reflexes that need to be tested as part of brain death determination; all reflexes should be absent. Pupillary response to light This test should be performed under dim lights or darker surroundings. Both eyes should be closed initially to exclude a consensual response, minimizing the constrictor response. One eye is opened and a bright focused light is directed into the eye being tested. The light should be very bright; old household torches and ophthalmoscopes are not acceptable. The pupil is observed for a minute to allow time for a slow response to become evident. The procedure is then repeated for the opposite eye. The pupils are not invariably dilated during brain death, but fixation with no response to light is mandatory for this diagnosis. One should be aware of drugs that may have been used that may influence pupil size and response to light. In addition, prior ocular surgery and pathology, such as a cataract, may complicate this examination. Corneal reflexes During the initial examination, corneal reflexes are tested by touching the cornea with a wisp of cotton wool. If this fails to elicit a response, firmer pressure needs to be applied with sterile throat swab. Both eyelids need to be observed for any response as the cornea is being stimulated.3 Oculo-vestibular reflex (caloric response) The external auditory canals should be wax-free prior to this test. A soft catheter is inserted into the canal which is slowly irrigated with at least 50 mL of iced water while the eyes are held open by an assistant. The stimulus should not elicit any movement whatsoever in either eye within one minute of completion of the test. Any movement of one or both eyes excludes the diagnosis of brain death. The

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test cannot be performed as described with a perforated eardrum or with a basal skull fracture and cerebrospinal fluid leak from the auditory meatus. Certain drugs can diminish or abolish this response and these include sedatives, aminoglycosides, anticholinergics, anti epileptics and some chemotherapeutic agents. Facial motor response Painful stimuli applied as firm pressure over the supraorbital groove (trigeminal nerve sensation) should not result in any facial grimacing (facial nerve response). A painful stimulus applied to the limbs (pressing a pencil firmly over fingernail or toenail) also should result in no grimacing. However, a peripheral pain stimulus may elicit dramatic and disturbing limb movements called the Lazarus sign.3 These complex movements, which may resemble decerebrate or decorticate posturing, are spinal reflexes that may persist in the absence of all brain functions. Oculocephalic reflex (doll’s eye phenomenon) The examiner holds the patient’s eyes open and turns the head suddenly 90° from the starting position. The head is then turned briskly to the opposite side. Each position should be briefly held while eye position is observed. The reflex is absent when the eyes move with the head and do not move within the orbits. When the reflex is intact, the eyes turn opposite to the side of the movement as if lagging behind and may then turn gradually to the starting position. When testing brainstem reflexes to confirm brain death, any eye movement excludes the diagnosis.12 Care must be taken in performing this test in patients with suspected cervical spine injury. Gag reflex and cough reflex The gag reflex is tested with a tongue depressor by stimulating each side of the oropharynx. The patient is observed for any pharyngeal or palatal movement. Presence or absence of the cough reflex is frequently noted by the nursing staff. A suction catheter is passed down the trachea through the endotracheal or tracheostomy tube and the carina is deliberately stimulated. The patient must be observed closely for any cough response or movement of the chest or diaphragm.12 APNEA TESTING Apnea testing seeks to establish lack of respiratory efforts or movements, in the presence of a powerful respiratory stimulus (hypercapnea with PaCO2 > 60 mm Hg) while avoiding hypoxemia during the testing period. The patient will need to be disconnected from the ventilator for this test. In order to avoid hypoxemia, the patient is ventilated with 100% oxygen for 10 minutes before the apnea test (preoxygenation). When the patient is disconnected from the ventilator 100% oxygen is delivered through a tracheal catheter delivering oxygen at 6 L/min. This method (apneic oxygenation) produces full oxygen saturation for at least 45 minutes in man.3 Arterial CO2 is expected to rise through endogenous metabolism, and should reach or exceed 60 mm Hg before the patient is reconnected to the ventilator. The rate of CO2 rise varies among patients and averages 3.0-3.5 mm Hg/min,3 but can be as high as 6.7 mm Hg/min.4 Ventilation is adjusted during preoxygenation to bring the PaCO2 to 40 mm Hg or

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greater.16 An end-tidal CO2 monitor may help guide the examiner when to begin the apnea test (ETCO 2 > 40 mm Hg) and when to end the test (ETCO 2 > 60 mm Hg). If there are no respirations for 3 minutes or the ETCO2 is greater than 60 mm Hg, arterial blood is sent for blood gas determination and the patient is placed back on the ventilator. The PaCO2 must be greater than 60 mm Hg to assure maximal stimulation of the medullary respiratory centers. A certain degree of respiratory acidosis is expected during this test.14,16 If hypotension or arrhythmias develop during the test, the patient is placed immediately back on the ventilator. One should safeguard against many potential pitfalls during this test. Absence of neuromuscular blockade must be assured. Patients with chronic obstructive pulmonary disease may have CO2 retention and be dependent on hypoxic stimulation for breathing. In the presence of acute lung pathology, patients may remain hypoxemic in spite of maximal oxygenation efforts. Such patients are not good candidates for the apnea test and death determination will require other criteria.12 Repeat testing, as recommended by the President’s Commission, is necessary to establish irreversibility of brain death. The interval between examinations is frequently set at 6 hours.7 However, this interval may vary among institutions and may be made shorter for significant structural brain damage and extended for nonstructural brain damage and in children less than 5 years of age. Confirmatory tests of brain death have been utilized in certain instances to shorten this interval especially when hemodynamic stability is imminent. When transplantation of potential organs is being considered, members of the transplant team must not be involved in brain death determination. Finally, brain death examination must be made by two different physicians, both of whom must be qualified to perform this exam. Frequently, these may be neurologists, neurosurgeons, anesthesiologist or intensivists. DETERMINATION OF BRAIN DEATH IN CHILDREN Though controversial, it has generally been assumed that children’s brains are more resistant than those of adults to insults leading to death. The report published by the President’s Commission7 outlined brain death criteria valid in children older than 5 years. The criteria outlined are useful in determining brain death in infants and children.3 In full term newborns the criteria are applicable 7 days after the neurologic insult. Determination of brain death should always begin with an accurate clinical history and examination. It is most important to determine the cause of coma and eliminate remediable or reversible conditions. The Task Force guidelines for the determination of brain death are outlined in Table 1.2. In general, more confirmatory tests are desirable in younger children and neonates. The interval between examinations depends on the cause of death and the age of the child. Generally, the interval is longer with patients of a younger age as outlined in Table 1.2. Current knowledge of the epidemiology, diagnosis and management of pediatric brain death has been well summarized in a recent report.3

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Table 1.2. Guidelines for the determination of brain death in children 1. History a) Determination of the cause of coma b) Eliminate remediable causes 2. Physical examination criteria a) Coma and apnea b) Absence of brainstem function c) Absence of hypotension (for age) and hypothermia d) Flaccid tone and absence of spontaneous or induced movements e) Examination remains consistent with brain death throughout the observation and testing period 3. Observation period and confirmatory testing a) 7 days to 2 months: two examinations and EEGs at least 48 hours apart b) 2 months to 1 year: two examinations and EEGs at least 24 hours apart. Absence of cerebral blood flow on radionuclide angiography obviates the need for the second examination and EEG. c) Over 1 year: two examinations at least 12 hours apart, 24 hours for hypoxicischemic brain damage. EEG and cerebral flow study not required but may shorten observation period.

CONFIRMATORY TESTS FOR BRAIN DEATH Examination for brain death can be frequently completed based on the clinical criteria outlined above without the need for confirmatory testing. In published reports on adult patients diagnosed as brain dead using these criteria there have been no survivors.11 However, in a significant number of patients where these criteria are not met (hypoxic brain injury, chronic obstructive pulmonary disease, young children), there may be an indication to shorten the observation period (hemodynamic instability) or there may be a concern about potentially reversible metabolic conditions. Hence, irreversibility of brain damage can be confirmed and the observation period reduced by the appropriate and timely use of confirmatory tests. In view of the multitude of tests available, it is generally preferred that a single method is adopted by the medical team involved as the study of choice. This will provide consistency and improved accuracy as expertise is developed using that particular study. CEREBRAL BLOOD FLOW STUDIES Contrast angiography of the cerebral vessels has long been considered the gold standard to determine the absence of cerebral blood flow.3,4 Failure to opacify the intracranial vessels during conventional or digital subtraction angiography is accepted as confirmatory evidence for brain death. Some have expressed concerns that radio-opaque contrast can be artifactually introduced into the intracranial circulation if injected too vigorously during angiography. This worry is remedied with venous digital subtraction imaging or aortic arch injections rather than selective (carotid or innominate artery) injections. Patient transportation to the an-

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giography suite, however, remains a potential hazard in unstable and critically ill patients. In addition, this study frequently presents technical challenges in small children, eliminating its role in that setting. Hence, many have favored the use of radionuclide angiography as the first choice study for cerebral blood flow imaging. Radionuclide angiography has been found to be a reliable, sensitive and safe method in the evaluation of cerebral blood flow in both adults and children.18,23 The test can also be performed at the bedside, making it very practical. For many years, blood pool agents, including Tc-99m pertechnetate, DTPA or glucoheptonate, have been used for this study. These agents do not cross the bloodbrain barrier. They are injected intravenously as a bolus while imaging of the brain is performed over the head with a portable gamma camera for about 15 minutes. Blood pool agents are not reliable indicators of posterior fossa and brainstem perfusion, though in the appropriate clinical setting this information is not typically needed. In the event of poor bolus injection, gamma camera malfunction or imaging interruption, the study cannot be interpreted and repeat imaging is not possible. Cerebral perfusion agents that cross the blood brain barrier, Tc-99m hexamthylpropylene-amine oxime (HMPAO) or I-123 iodoamphetamine (IMP), have been recommended instead of blood pool agents for the confirmation of brain death.3,4 These agents are taken up by perfused and viable gray matter cells after the initial flow phase and held for several hours. An initial image is taken during the flow phase (Fig. 1.1) showing absence of flow. This is followed by delayed images that can be performed in more than one plane (Fig. 1.2). Radionuclide cerebral perfusion can be coupled with single photon emission computed tomography (SPECT) to provide more precise regional information including blood flow to the posterior fossa. If initial flow imaging is interrupted, delayed images can be obtained without repeat bolus administration. Transcranial doppler and real time cranial ultrasound have been used to confirm brain death, especially in the newborn and young infant.20,3 Characteristic findings in brain death include oscillating movement of the blood column within cerebral arteries, short systolic spikes and absence of a signal when previously found. This technique has the advantage of being noninvasive, portable, quick and relatively inexpensive. However, it requires considerable practice and skill. Specificity and sensitivity have been reported to be as high as 100% and 91% respectively.20 Stable xenon computerized tomography (XeCT) is another noninvasive method capable of measuring cerebral blood flow (mL/min/100g) in multiple brain regions. XeCT is more sensitive than radionuclide angiography, particularly in children,18 because it yields anatomic and regional quantitative flow information. Minimal (less than 1-5 mL/min/100g) or absent cerebral blood flow is indicative of brain death.20 ELECTROENCEPHALOGRAPHY AND THE CONFIRMATION OF BRAIN DEATH Electroencephalography has long been used to evaluate coma and brain death.1,2 Electrocerebral silence, defined as no electrocerebral activity over 2 FV, has been used for confirmation of brain death. The President’s Commission criteria for

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Fig. 1.1. Early flow phase of a Technetium 99m-HMPAO radionuclide brain scan supporting the diagnosis of brain death.

brain death did not include EEG as a requirement. However, EEG has been used as a confirmatory study and diagnostic adjunct for brain death diagnosis in young children.17 Due to multiple technical problems that may be encountered during the test, strict guidelines have been developed by the American Electroencephalographic Society.3 A 16- or 18-channel instrument is used with a minimum of eight scalp electrodes. Electrodes are set at least 10 cm apart and the recording is continued for at least 30 minutes. Many artifacts are possible and may be related to electrical interference, faulty equipment or neuromuscular activity. Hence the test should be performed only by a qualified technician, adhering strictly to the methodology formulated by the American EEG Society. In adults, if the EEG is not indicated and brain death has been declared on clinical grounds, it may be prudent not to perform this examination. Most patients fulfilling the criteria for brain death will have an isoelectric EEG. However, as many as 20% will have residual activity that can last for many hours,12 frequently delaying brain death declaration and allowing for cardiorespiratory failure.

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Fig. 1.2. Delayed images showing no tracer uptake within the brain confirming the clinical diagnosis of brain death. Peripheral shadows are attributed to scalp circulation.

In infants and children, the EEG is the most widely used laboratory study for determining brain death. Many unique aspects must be considered in this population.18 Most importantly, the test should be performed and interpreted by personnel experienced with pediatric EEGs. In patients with a clinical diagnosis of brain death, electrocerebral silence is confirmatory of brain death. However, the EEG may still demonstrate some activity in some patients with established brain death by clinical examination and cerebral blood flow study.11,18 Some of these patients may progress to have an isoelectric EEG although many will succumb to cardiorespiratory failure with persistent EEG activity. Hence, in children as well as in adults, the EEG may not correlate with the clinical diagnosis of brain death or cerebral blood flow studies. Brainstem auditory evoked potentials (BAERs) evaluate the function of the auditory pathway from the cochlea to the thalamus. In the usual clinical setting, this study has very limited practical applications. In children, published reports suggest that BAERs should not be used as confirmatory evidence for brain death.18,3

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Organ Procurement and Preservation CONCLUSION

1 The concept of brain death has evolved significantly over the past decades. Much of the controversy revolved around its significance in relation to survival and potential reversibility. In addition, studies that fueled some of the controversy (EEG as an example) attempted to establish the survival of few intracranial neurons but without much clinical relevance. In adhering to the methodology outlined above, one should rely mostly on clinical criteria to establish death of the “brain as a whole”. Confirmatory studies have a role in select situations where clinical criteria are not entirely applicable. With the knowledge we currently have about brain death diagnosis, timely diagnosis and clinical disposition reduces the futile supportive efforts in the intensive care unit and spares the family much prolonged agony over this terminal event. In addition, at a time when organ transplantation has become such a widely applied modality, the need for potentially transplantable organs continues to rise. It is our responsibility to promote the awareness about brain death and support sound clinical practices to assure timely diagnosis and organ donation as a benefit to society. REFERENCES 1. 2.

3. 4. 5. 6. 7.

8. 9. 10. 11.

12. 13. 14.

Mollaret P, Goulon F. Le Coma Depasse (Memoire Preliminaire). Rev Neurol 1959; 101:3-15. Jouvet M. Diagnostic electro-sous-corticographique de la mort du systeme nerveux central au cours de certains comas. Electroenceph Clin Neurophysiol 1959; 11:805-808. Ad Hoc Committee of the Harvard Medical School. A definition of irreversible coma. JAMA 1968; 205:85-88. Mouhandas A, Chou SN. Brain death: A clinical and pathological study. J Neurosurg 1971; 35:211-218. Conference of the Royal Colleges and Faculties of the United Kingdom. Diagnosis of brain death. Lancet 1976; 2:1069-1070. Pallis C. ABC of brain stem death. Br Med J 1982; 285:1409-1490. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Guidelines for the determination of death. JAMA 1981; 246:2184-2186. Kaste M, Hillbom M, Palo J. Diagnosis and management of brain death. Br Med J 1979; 1:525-527. Curran WJ. Legal and medical death: Kansas takes the first step. New Engl J Med 1971; 5:260-261. Cappron MA. The development of law on human death. NYAS 1978; 315:45-49. Pallis C. Brainstem death: The evolution of a concept. In: Morris PJ ed, Kidney Transplantation: Principles and Practice 4th edition, Philadelphia: WB Saunders 1994; 71-85. Wijdicks EFM. Determining brain death in adults. Neurology 1995; 45:1003-1011. Ivan LP. Spinal reflexes in cerebral death. Neurology 1973;23:650-652. Frumin JM, Epstein RM, Cohen G. Apneic oxygenation in man. Anesthesiology 1959; 20:789-798.

Principles of Brain Death Diagnosis 15. 16. 17. 18. 19. 20. 21. 22.

23. 24. 25. 26.

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Schaffer JA, Caronna JJ. Duration of apnea needed to confirm brain death. Neurology 1978; 28:661-666. Benzel EC, Mashburn JP, Conrad C et al. Apnea testing for the determination of brain death: a modified protocol. J Neurosurg 1992:1029-1031. Task Force for the Determination of Brain death in Children. Guidelines for the determination of brain death in children. Pediatrics 1984; 80:298-300. Ashwal S, Schneider S. Pediatric brain death: Current perspectives. Adv Pediatr 1991; 38:181-202. Kricheff II, Pinto RS, George AE et al. Angiographic findings in brain death. NYAS 1978; 315:168-183. Monsein. Imaging of the brain. Anaesth Intens Care 1995; 23:44-50. Ashwal S, Schneider S. Brain death in children. Part I. Pediatr Neurol 1987; 3:5-11. Riva A, Gonzalez FM, Llama-Elvira JM et al. Diagnosis of brain death: Superiority of perfusion studies with 99Tcm-HMPAO over conventional radionuclide cerebral angiography. Br J Radiol 1992; 65:289-294. Spieth ME, Ansari AN, Kawada TK et al. Direct comparison of Tc-99m DTPA and Tc-99m HMPAO for evaluating brain death. Clin Nucl Med 1994; 19:867-872. McMenamin JB, Volpe JJ. Doppler ultrasonography in the determination of neonatal brain death. Ann Neurol 1983; 14:302-307. American Electroencephalographic Society: Guidelines in EEG 1-7 (revised 1985). J Clin Neurophysiol 1986; 38:227-30. Steinhart CM, Weiss IP. Use of brainstem auditory evoked potentials in pediatric brain death. Crit Care Med 1985; 13:560-562.

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Approaching the Family 2

Jerome Menendez, Tammie S. Peterson, Alison B. Smith Approaching the Family ....................................................................................... Phase 1–Identification and Referral of the Potential Donor ................................ Phase 2–Pre-donation Family Evaluation ............................................................ Phase 3–Understanding Brain Death ................................................................... Phase 4–The Grieving Process .............................................................................. Phase 5–Presenting the Option ............................................................................. Phase 6–Aftercare of the Family ...........................................................................

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APPROACHING THE FAMILY Life eventually becomes death. We first learn of this inevitability during childhood and observe it again and again throughout our lifetimes. And although we may be exposed to death many times, the loss of our own loved one brings a uniquely emotional pain and grief. It is with this empathy, and often sympathy, that the organ procurement representative (OPR) approaches families about organ and tissue donation, helping death become life. When family members experience the medical course of a traumatic injury or illness of a loved one, their primary focus is often on the patient’s recovery and how he or she will be affected by this life-altering event. Family members all too often focus only on the positive information that the primary physician shares, choosing not to hear the life threatening or grim prognosis. It is with these positive thoughts that loved ones stand at the bedside, believing that the patient has defeated death because of the twitch of an eye or the slight movement of a finger—“everything will be all right”. It is not until the family members actually hear the words “brain death” that they are forced to accept the reality that their loved one is dead. Approaching a family about organ donation is a matter requiring expertise, sensitivity and the cooperation of a variety of individuals. Its success is contingent on hospital staff working in conjunction with the OPR. For optimal results, the process can be separated into six phases: 1) identification and referral of the potential donor, 2) predonation family evaluation, 3) understanding brain death, 4) grieving process for the family, 5) presenting the option of donation, and 6) aftercare of the family.

Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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PHASE 1–IDENTIFICATION AND REFERRAL OF THE POTENTIAL DONOR Successful referrals are largely dependent on how well a hospital has been educated or “developed” by the organ procurement organization (OPO) prior to the actual referral. This “development” is a service provided to hospitals by the OPO, with the overall goal of implementing educational programs and strategies that maximize the hospital’s ability to identify potential organ and tissue donors. Specific strategies should include the development of a hospital profile, detailing the flow of decision making within the institution as it affects donor activity. This profile ensures that key hospital personnel involved are aware of their individual role in the process. Other services provided by the OPO include: assisting hospital personnel in the development and implementation of organ recovery policies and procedures; providing donor education and awareness programs to hospital personnel; conducting donor and referral follow-up conferences and meetings; and assessment of the hospital’s compliance with federal and state laws regarding organ and tissue donation. THE HOSPITAL/OPO RELATIONSHIP One vital way for OPOs to increase donor referrals is by providing quality service. This is done, in part, by acknowledging that the hospital is the vital link to organ donors. The challenge for the OPO lies in helping hospitals to organize their practices so that: 1) all eligible families are offered donation, and 2) the elements associated with higher rates of consent (privacy, decoupling, and OPO participation) are incorporated into each donation request.1 Generally, hospitals are committed to donation and appreciate assistance in identifying potential areas for improvement. When weaknesses in donor identification are noted, hospitals are eager to improve their performance. By providing hospital-specific feedback on identification and referral rates, along with guidelines on when to call the OPO, this critical first phase of the process can be dramatically improved. During a two-year period following Southwest Transplant Alliance’s implementation of development plans targeted to meet specific hospital needs, eight of nine hospitals studied experienced a decrease in the number of “not identified” donors. Essential to these hospital-specific development plans was cultivating and educating key personnel involved in the donor process. Active collaboration between the hospital and OPO is essential to increasing donor referrals. When a hospital feels the working relationship with the OPO is a true partnership, the hospital develops a sense of “ownership” for the success of the donation process and an increased responsibility for identifying and referring potential donors. A strong working relationship between the OPR and the potential donor’s nurse is essential because the nurse serves as an invaluable member in the donation process. Initially, the nurse updates the OPR on the potential donor’s medical status and hemodynamic stability. Of equal importance, the nurse may be able to

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give the OPR insight into the dynamics of the potential donor family. This includes identifying the next of kin, discussing how the family is dealing with the death, and identifying any difficult family dynamics. The nurse can also provide invaluable information on the family’s religious, cultural and socioeconomic background. Other staff members, including pastoral care and social work can also be very helpful in this area. THE REFERRAL CALL Typically, potential organ donors have suffered a devastating neurological injury, considered nonsurvivable in nature. Calls referring potential organ donors usually originate from critical care areas and emergency departments. The patient being considered as a potential donor requires mechanical ventilation and often requires hemodynamic support. The OPR gathers essential information during the referral phone call, e.g., the patient’s name, age, sex, race and cause of impending death. A brief hemodynamic summary may also be requested. THE ON-SITE EVALUATION Depending on the OPO’s policy, the OPR usually goes to the hospital to further evaluate the patient as a potential donor. An on site assessment is important for: 1) building the partnership between hospital and OPO, 2) interacting with the family, and 3) making an accurate assessment of the potential donor. It is also important to get a complete picture of both the medical and family situations through conversations with physicians, nurses, chaplains, or social workers involved. Speaking with the primary physician and/or the neuroscientist helps the OPR in obtaining the potential donor’s medical history and hospital course, and also aid in planning the family approach. The potential donor’s physician is encouraged not to bring up organ donation at the same time he/she is explaining that the patient is brain dead. Families need to experience their initial grief before making decisions about what to do next. We recommend that the physician inform the family of the patient’s brain dead status and close the conversation by letting them know that there are important options to consider and that someone will be speaking with them about these options shortly. Once the OPR has become acquainted with the hospital staff, the next phase is developing a pre-donation plan for approaching the family.

PHASE 2–PRE-DONATION FAMILY EVALUATION Effective communication between the potential donor family and the medical staff is essential. Families often do not fully understand explanations about diagnosis or treatment when the healthcare provider relies on medical jargon and fails to clearly and simply explain details. If family members are intimidated by the medical staff, they may reluctantly agree to treatment options that they do not

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fully understand. Families must not only receive a thorough explanation, but also verbalize their understanding of what is happening to the patient. This may mean sitting with a family, answering questions, and addressing their concerns. Only when family members feel they know exactly what is happening, do they develop a trust in the medical personnel involved in the patient’s care. Physicians and other medical staff may feel they cannot afford the time to sit and speak in depth with families. When this happens, trust is not established and it becomes very difficult for family members to believe that treatments are being performed in the best interest of their loved one. Among the factors that bear consideration during the pre-donation family evaluation are specific relationships to the patient, religious and cultural beliefs, the family’s stage of grief, and any emotional responses and language barriers. Families are often uncertain whether their religious beliefs support the decision to donate. The OPR can assure the family that almost all religions in the United States either support or encourage organ and tissue donation. If the family has a clergy member available, he or she is frequently consulted for guidance and counsel. For families practicing a religion that does not support organ donation, a decision consistent with those beliefs should be supported by the OPR and hospital staff. RELIGIOUS CONSIDERATIONS The following list explains religious considerations in tissue and organ donation and transplantation:16 Amish: Organ donation and transplantation are acceptable, but the Amish are reluctant to donate their organs if the transplant outcome is questionable. Assemblies of God: There is no position. Baptist: Organ donation is encouraged. Buddhist: Organ donation is an individual decision. Those who donate their bodies and organs for the advancement of medical science are honored. Catholic: Organ donation and transplantation are acceptable. Disciples of Christ: Organ donation is an individual decision. Christian Reformed: Members are urged to support the Anatomical Gift Act. Church of the Brethren: Organ donation is encouraged. Church of Christ: Organ donation is an individual decision. Christian Scientists: Normally rely on spiritual, rather than medical means for healing. However, organ donation is an individual decision. Church of Jesus Christ of Latter Day Saints: Organ donation is an individual decision. Episcopal Church: The Church does not object to donation as long as it is done reverently. Greek Orthodox Church: Donation is not consistent with traditional Orthodox practice and belief. Gypsies: Gypsies are opposed to organ donation. Although they have no formal resolution, their opposition is associated with their belief about the afterlife. Gypsies believe that for one year after a person dies, the soul retraces

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its steps. All of the body parts must be intact because the soul maintains a physical shape. Hindu: Organ donation is an individual decision. Islam: In 1983, the Moslem religious council initially rejected organ donation by followers of Islam, but it has reversed its position, provided donors consent in writing prior to their death. The organs of Moslem donors must be transplanted immediately and should not be stored in organ banks. Jehovah’s Witnesses: Organ donation is an individual decision. All organs and tissue must be completely drained of blood before transplantation. Jewish: Judaism teaches that saving a human life through donation is a mitzvah (good deed) and that if you are in a position to save a human life, you must do so. Lutheran Church: Organ donation is an individual decision. Mennonite Church: Organ donation and transplantation are acceptable. Methodist Church: Organ donation is encouraged. Presbyterian Church: There is no position. Protestant: Protestants encourage and endorse organ donation. The Protestant faith respects an individual’s conscience and a person’s right to make decisions regarding his or her own body. Quaker Religious Society: Organ donation is an individual decision. Seventh-Day Adventists: Organ donation and transplantation are acceptable. The United States is a very culturally diverse country, and as a result, many potential organ and tissue donors are of varying nationalities and cultural backgrounds. The basic tenets of life, death, and grieving vary widely among cultures. There is no “normal” or “right” way to grieve. It is possible to approach one family that is “celebrating” the death of a loved one, while approaching another family could mean trying to speak with a next of kin that is thrashing about in grief. Families must not be judged by the way they grieve, but instead be given the opportunity to do so in the way most comforting to them.

PHASE 3–UNDERSTANDING BRAIN DEATH One of the greatest challenges for any physician or OPR is explaining death to a family. The definition of death with which most people are familiar is the permanent cessation of respiration and circulation. The concept of brain death is extremely challenging to explain not only to family members, but also to hospital personnel. In fact, it was not until 1968 that the major step was taken toward redefining death to include brain death. The Harvard criteria, developed at the Harvard Medical School, allowed for certain criteria to deem a patient brain dead, brain death being consistent with death. The criteria focused on (1) unreceptivity and unresponsiveness, (2) lack of spontaneous movements or breathing, and (3) lack of reflexes.3 These criteria, although modified and revised due to advancements in medical practice, continue to serve as the medical criteria for diagnosing brain death.

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When explaining brain death to a family, it is essential that the family clearly understand the finality of the diagnosis. Many times, this involves sharing the results of tests that have been performed in order to diagnose brain death (cerebral blood flow, EEG, MRI results). Families have explained that watching the final test performed or viewing the x-ray or EEG is helpful in understanding the finality of brain death. If a family feels the patient needs “more time to turn around”, then more explanation and education are clearly required. It is crucial that the family understands that their loved one is dead. The OPR’s role is to explain to the family that although the patient is brain dead, the patient’s organs are still being supported artificially, and that unless the organs have been damaged by injury or disease, they may be used by other individuals through organ transplantation. The family must be reassured that removing the respiratory support equipment is not the same as causing the death of the patient. Once the patient is brain dead, the ventilator serves only to supply oxygen to the heart and other organs and tissues. Often it is helpful to inform the family that there are no clinically documented cases where a patient was declared brain dead and later restored to a normal life. MINORITIES AND DONATION Research has shown that minorities, African-Americans, Hispanics, Asians, and Native Americans, typically receive less education and information regarding organ donation and tend not to discuss the subject with significant others.2 Minorities are also more likely to distrust the medical community and fear premature death, both affecting the donation decision. In the Hispanic community, potential language barriers and the extended family are important considerations. In this community, the whole family is involved in the decision to donate.11 “Collective hysteria”, a grieving process marked by shouting, crying, fainting and sometimes convulsions has been noted by researchers studying the Hispanic population. In the Asian population, the cultural belief is that the body should go to the grave intact; this will allow the body to reunite with the spirit. In the Filipino culture, cremation has not gained acceptance because of the destruction of the corpse. Organ donation is perceived also to destroy the corpse.20 These cultural beliefs should be respected and, in some instances, organ donation should not be pursued. The issues of distrust and fear do have possible solutions. However, a trusting relationship between the healthcare team and the potential donor family cannot be built without a strong foundation. Education programs focused on improving caregivers’ understanding of organ donation and the specific considerations around the consent process are essential in building that foundation. Each issue that may cause minority families to decline donation should be addressed individually. Minority healthcare workers and community professionals should be utilized to implement educational programs.

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Since religious beliefs are frequently verbalized by minority families when considering organ and tissue donation, the support of religious leaders can be extremely helpful. Information on organ donation and how it relates to a particular religious belief will often be well received when coming from a religious or spiritual leader. Regardless of race or ethnicity, a family discussion on donation is the optimal method for determining individual beliefs and preferences. Donor cards may assist in initiating such a family discussion. Providing information on organ donation through the school systems is paramount. Students should be taught about the natural cycles of life that eventually will lead to death. When students learn about the option of organ donation at a young age, they can discuss this option with their family. HOSPITAL-BASED PROFESSIONALS AND ORGAN DONATION The effectiveness of medical personnel in identifying potential organ donors and notifying the OPO of these donors is crucial to the success of organ donation. Historically, the responsibility for approaching the family about organ donation has fallen to the ICU nurse, attending physician, or chaplain. Hospital-based professionals from all disciplines may hesitate or feel uncomfortable speaking to potential donor families because of reluctance to add to the next of kin’s grief or because they feel they are not prepared for the many questions that donor families may have.14 For these reasons, it is strongly advised that hospital personnel team up with OPO personnel to approach families regarding donation.

PHASE 4–THE GRIEVING PROCESS Death is an inevitable part of the human experience yet we all have some level of emotional discomfort with death. It is only natural that we experience fears and concerns when we come in contact with the dead or dying and their loved ones. Even though we cannot do anything medically for those already dead, we can do a great deal to influence the way a family will begin coping with its loss. However, we must understand the grieving process so we can be optimally effective in our interactions.12 There are some basic family needs that, if met, will have a positive effect on our relationship. The first is to listen. FAMILY NEEDS Listening is the first step to assess, understand and empathize. Asking an openended question allows family members to talk freely about their feelings with someone who is willing to listen. Listening offers direct comfort and support and is helpful in planning an individualized approach.12

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NONVERBAL Nonverbal communication may be one of the most reliable indicators of an individual’s emotional state. Some of these indicators may include a lowered head, hunched shoulders and weeping. Holding, rocking, or gently patting are common nonverbal ways to express sympathy. In some instances, offering a quiet and continuing presence that indicates a willingness to stay until the shock of the loss is absorbed is helpful. Often after the initial shock is resolved, family members and significant others can support and comfort each other. No two families or individuals are alike and there are no templates to grief. Understanding a family means needing to gather as much information as possible to know them as a unit and as individuals. This can take time but is invaluable in establishing trust and rapport. Often the smallest acts of kindness can win the trust and confidence of a family.12 Families often have not been prepared about what to expect, which may result in unnecessary anxiety and stress, and the family may become overwhelmed. It is crucial to explain even the smallest of things and to address emotional needs. PHYSICAL AND EMOTIONAL NEEDS When family members are notified of the death, they need a quiet and private place to express their grief and collect their thoughts. Sometimes, a family’s intensity of emotion may be unexpected. It is crucial to avoid making judgments, as this is sure to come through in nonverbal communication. Disapproval of their expression of grief is in no way helpful or constructive. Spending time with families, offering to get them water or a soft drink, offering to make phone calls and expressing emotion can make a big difference in how they begin coping with their loss.12 STAGES OF GRIEVING An important part of assisting families in coping is recognizing the stages of grief. While people do go through stages, they are often not well defined. Some writers list as few as three and others, as many as ten. People tend to vacillate between stages and can be in different stages in one day or at the same time. Overall, it is important to remember that grief is expressed in a variety of ways: anger, depression, irritability, confusion, guilt, anxiety, relief, numbness, preoccupation, ambivalence and fear. What we learn most often from people in grief is that it is a state of transition. What is felt today may not be felt tomorrow. Grief is the natural response to any loss. There is a process humans go through in dealing with grief. The natural process lasts approximately two years, with peaks and valleys during this time. The intense peaks are anniversaries, birthdays, holidays and most Sundays. There is also usually a peak just before the two-year anniversary of the loss. Above all, individuals must be allowed to grieve in a manner suited to them.

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Denial/shock/numbness/isolation This is a documented period of vague unreality in which the body goes into an unconscious function of preventing emotional overload. The person is sad but there is an unreal quality about it. There is a sense that as soon as the movie is over, all will be over. The tears, the wailing, and the stoicism demonstrated by different cultures all indicate both the shock of the loss and the realization that the survivor will also one day die. A common symptom during this period is sleep disturbance. There may be constant sleep or no sleep at all. Feelings of weariness and numbness are pervasive. Time is needed to process what has occurred, which may be demonstrated by staring at the ceiling, remembering and feeling. There may be a feeling of “falling apart” or “going crazy”. There may be dreams, flashbacks to the scene of the death, the funeral and concerns about the future as well as the reality of the loved one not being in the house or in the bed. This can last for approximately three weeks but varies according to the suddenness of the loss. Sudden death creates more shock than a lingering illness.29,16,17 Bargaining/searching This is a time of intense yearning for the dead person that can last for four to six weeks. There will be a disbelief that the death has occurred and there may be an act as if the person were still alive. Symptoms include wanting to tell the person something, calling the person on the phone, writing a note and then looking forward to speaking with the person when driving home from work. There may be a search for the person that has died; driving around town looking for them, frequenting the old places for shopping, entertainment, study, religion or relaxation. It is not uncommon to hear reports from the loved one of being able to hear, see or smell the scent of the deceased. At this time, the survivor will return to the hospital or speak with nurses involved to thank them and then also to visit where the person died. Bargaining may also take place, asking God if the family member can do something in particular, to take away the loss.29,16,17 Reality/mitigation/experiencing the pain This period comes around the third or fourth month when reality becomes apparent. This is a time of depression and deep despair. The survivors may wake up in the middle of the night facing the reality they will never see their loved one again. They may experience chest pain, inability to breathe, they may call friends in the middle of the night, and cry uncontrollably. There may also be tightness in the throat, sighing, emptiness in the stomach, weakness, headaches and their appetite may diminish or disappear. This is a time of great emotional swings with restlessness, tension, fears, panic, fear of dying or of others dying. Dreaming has been reported of seeing the loved one in a casket, seeing the body dead, but talking, and the feeling of the loved one entering a room. Composing a letter of feelings and words left unsaid can be helpful, as well as going to talk to the deceased at the grave. Friends are important and need to listen, support and hold the survivors.29,16,17

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Depression/reaction/anger This is generally around the fifth to sixth month following the time filled with emotional turmoil. This is where survivors hit “rock bottom” and get angry. They may exhibit irritability, bitterness, hostility, and aggression. They may feel hurt, frustration, fear or rejection. There is always anger in grief and it must be focused somewhere. The feeling of guilt causes the “what ifs” to begin. There is a strong feeling of what could have been done differently. Feelings of anger surface and can be aimed at caregivers, family, friends, God and the survivors themselves. The survivors may remember all the quarrels in the past with the deceased and then think about the future of being alone, and then become angry at the deceased. Symptoms that may be exhibited during this time include: sleeping all the time to avoid pain, becoming very busy to avoid thinking, becoming hyper-religious to seek out every emotional and religious experience possible, drinking to mask the hurt, and being promiscuous to fill the need of being loved so deeply. Knowing that these feelings may occur can help, but talking with others who have experienced similar things can be helpful at this time. Again, listening and understanding are of utmost importance.29,16,17 Recovery/acceptance Towards the end of the first year to up to two years, the survivors begin to recover and reconstruct their lives. This may be marked by being able to deal with something that has been avoided until this time. The survivors may begin to participate in social events, religious and community activities, work and more of a routine. They may begin to form new relationships and begin to form new identities for themselves. This is a very vulnerable time and individuals may seek out entirely different types of persons or jump too quickly into relationships. There is also a feeling during this time of survivors wanting everyone to remember their loved one, and to know the significance of that person’s life. The truth is that people handle grief like they handle other major difficulties in their lives. There is no designated time frame when grief must be resolved and most importantly, people need to do what works best for them in their own time frame.13 People in grief need someone to listen while they tell their story. Grief recovery requires telling and retelling the experience. In a sense people talk their grief away. The ability to simply listen is the greatest help possible in every stage of grief.29,16,17

PHASE 5–PRESENTING THE OPTION As very simply stated in the Bill of rights for donor families, Donor Families have the right to make organ and/or tissue donation decisions for themselves and on behalf of their loved one who has died. This opportunity should be part of the normal continuum of care provided to families after the death of a loved one has been determined and they have had sufficient time to acknowledge that death. In addition to the rights of families, federal law requires that all families of brain

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dead patients be offered the option of organ and tissue donation under the Federal Uniform Anatomical Gift Act of 1968. As early as 1985, in response to public pressure, Required Request legislation began passing in states across the country. Their purpose was to assure that all families were presented the option to donate. Hospitals were required by the federal government to present the option of organ donation in order to receive Medicare and Medicaid reimbursement. Shortly thereafter, the Joint Commission for the Accreditation of Healthcare Organizations (JCAHO) instituted similar requirements for hospitals. Although several years have passed since the implementation of these laws, the anticipated increase in donors has not been realized. Part of the problem may have been that physicians and nurses were initially responsible for making the family approach, when they did not feel comfortable doing so. A lack of education in the general public has also played a role. Anecdotal reports have clearly shown that if families have discussed organ donation ahead of time, then when faced with the sudden loss of a loved one, the donation decision is an easier one to make. While “family initiated” discussions are reportedly on the rise, in most instances, if the offer is not made to the families, then consent will not be obtained. It is imperative to the success of any donor program that the hospital and OPO work as a team. Together they can more effectively fulfill the rights and meet the needs of families suffering loss, as well as potentially increase the number of organs available for transplant.17 THE REQUESTOR There is ongoing debate regarding the ideal requestor who can affect a positive response to the organ/tissue donation option. Several studies have shown that when a specialized OPO requestor presents the option and separates it from the discussion of death, the rate of donation significantly increases. One of the major factors that influences outcome is time spent with the potential donor family. The role of the organ recovery coordinator (ORC) has historically included the consent discussion. However, the ever-expanding role of the ORC has meant less time available to devote to the care of the family. When a dedicated requestor is involved, more time is spent with the family and a relationship develops. This affords ample opportunity to explain brain death, ask and answer questions and, in general, results in a more effective consent process. Consent has risen in every case where this has occurred.6,15 Despite concerted efforts by OPOs, there is still a lack of knowledge about organ donation and transplantation among medical professionals. Physicians and nurses traditionally have little or no training in obtaining consent for organ/tissue donation. Even though there is a general consensus among healthcare professionals that organ donation and the family consent process are important, very little time, if any, is spent learning how to most effectively be involved. Many healthcare professionals continue to be hesitant about approaching families or mentioning the subject of donation for a variety of reasons. Often cited reasons include an unwillingness to “intrude” on a family’s grief, lack of knowledge of specific procedures, lack of time, concerns regarding legal issues, and questions regarding donor suitability. It also can be very difficult for physicians and

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nurses to deal with the death of a patient whose life they have worked diligently to preserve.17,19 Some OPOs have compiled data that support the use of “same race” requesters. Theoretically the practice of using a requestor who is the same race as the next of kin helps build rapport with the family. However, emerging data indicate the most important factor affecting a family’s donation decision is how well their needs have been met throughout their hospital experience. Consequently, hospital and OPO personnel must assist families in grief, help them get the answers to their questions regarding brain death, assure them that everything possible was done for their loved one, help them to make arrangements and, above all else, listen. Early findings from a study conducted by Southwest Transplant Alliance suggest that when adequate time, care and concern were not provided to families from the outset of their hospital experience, not only were they less inclined to donate, but they also were more inclined to voice dissatisfaction, frustration, and anger toward the hospital, physicians, and nurses involved. While these findings are not unexpected, it is confounding that despite strong logic dictating that better cared-for patients and families will be more favorably disposed toward a hospital and its practitioners in the event of a negative outcome, more and more hospitals are cutting back on the positions that traditionally have provided that care, i.e., clergy, social workers, etc. One factor vital in the consent process is well within the control of the caregiver in consulting with and including OPO personnel in the approach of a potential donor family. The combined involvement of OPO personnel and the primary caregiver creates an effective team approach in offering the option of donation to the family.6,15 VERBAL TECHNIQUES AND NONVERBAL COMMUNICATION Communication is key in providing the most accurate and sensitive information regarding donation to the family. Those experiencing grief report that the senses are dulled. The most effective way to speak to families experiencing grief is to give good news and bad news, avoid medical/technical jargon, and speak softly and slowly. People in grief need time to process information. It is critical to be clear, consistent, to the point, and to repeat information as frequently as needed. When talking to families in grief, nonverbal communication is as important as what is being said. It is important to be relaxed, to avoid quick, jerky movements, and to maintain eye contact that is respectful of the situation. This usually means that the eyes are lowered and eye contact is less direct than normal.18 TIMING When determining the appropriate time to discuss organ donation with a family, it is important to know the status of brain death pronouncement, whether the patient has been declared dead or the brain death determination is in progress. Before approaching a family about organ donation, it is imperative to know whether the physician has talked with them about the death or expected outcome. If not, it is important to know when that conversation will take place. Time must be spent

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obtaining important information about the next of kin and any other family members present. For example, is the next of kin the decision-maker or is another family member in that role? How are they coping with the loss? What is their level of understanding about brain death? Who is present to provide support? As previously discussed, the time needed to process the events that have resulted in their loved one’s death is different for every family depending on religious, cultural and personal beliefs, individual personalities and ways of handling grief. The best time to present the donation option will be different for every family. No matter where in the process, if the family has questions regarding organ/ tissue donation, the procurement agency(s) should be contacted. Supporting data indicates that when the family has been told that their loved one is dead and been given sufficient time to question and understand this, then consent is more likely to occur. This is known as a decoupled request. Time is a crucial component in the consent process. Its importance cannot be overstated. Families need time to deal with their loss, time to spend with their loved one, and time to make an informed decision.18 LOCATION Hospitals are usually busy, crowded institutions. However, it is important to allow the family time alone, away from others and all the activities that normally occur in a critical care waiting room. The request for organ donation is best done in a private room where there is a place to sit with a table. Some hospitals have private rooms where family members may have been waiting since the results of the brain death examination. These can be used; however, it is crucial to ascertain from the next of kin who should be present for the discussion. They may or may not want to have extended family involved in the decision. If there is no ideal place, locations that would suffice include a small area of the cafeteria, in a stairwell or perhaps outside the hospital. Chapels are comforting to some families but can be viewed as a coercive situation if the family is not comfortable in this environment. The general waiting room and the bedside should never be used.18 THE CONVERSATION The conversation or the approach must include the next of kin but may also include grown children, powerful support people and relatives. The smaller the number of people involved, the more effective the approach. However, it is important to take the cue from the family regarding whom to include in the discussion. The conversation should include several steps: establishing a climate, introducing the subject of donation, providing information, asking questions regarding concerns, addressing any fears, responding to the decision and closing the conversation. It is critical that the family’s understanding of the specifics are frequently checked, and that sympathy and support are offered.18 THE INFORMATION Every family facing a decision about donation should be given as much information as possible in order to insure they make the best decision for them, both

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immediately and on a long-term basis. The role of the requestor is to ensure that families make informed decisions, based on fact, not rumor or tabloid headlines. The family should be provided with a description of all transplantable organs and tissues along with an overview of the benefits of transplantation and the number of waiting candidates. They should be assured that the donor will be treated with the utmost respect throughout the donation process. The family may have questions regarding the effect donation will have on funeral arrangements. While the donation process can frequently delay funeral arrangements up to 24 hours, the type of funeral the family desires (e.g., open casket viewing) is usually not affected. There are no additional costs to the family for the donation. All costs related to the recovery of organs and tissues are paid by the procuring agency. The family considering donation also should be informed that even though they may choose to donate, there are many variables that determine whether organs or tissues are ultimately transplanted (i.e., organ function, medical/social history, current hemodynamic condition).18

PHASE 6–AFTERCARE OF THE FAMILY

FAMILIES THAT DECLINE Several OPOs are currently obtaining follow-up information from families who choose not to donate. The intent of the follow-up is to identify those situations or circumstances that may have influenced the family’s decision to decline. The importance of making a decision about donation and sharing that decision with family members is clear from this follow-up. Many families report that they did not know the wishes of their next of kin regarding donation. They chose not to donate because they were unsure of what their loved one would have wanted. Again, the most telling reason families chose not to donate was their perception that the hospital failed to show adequate care and concern for their wellbeing during their loss. FAMILIES THAT ACCEPT If the family chooses donation, a detailed consent form outlining the specific organs and tissues they wish to donate is signed. The final requirement is the completion of a detailed medical and social history questionnaire on the donor. Once complete, the family is free to leave. However, some families prefer to stay and say their good-byes closer to the time of the actual recovery. CARE OF DONOR FAMILIES In 1994, the National donor family council was developed to help those that are in the unique role of being donor families. At that time the charter members developed goals which include: • To serve as an advocate for families and provide support;

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To facilitate research necessary to ascertain needs and expectations of families and how best to service those needs; • To act as a body to develop standards and guidelines for the care of families; • To develop programs that support families and professionals throughout the entire donation experience from hospital admittance through bereavement aftercare; • To identify ways to improve and enhance communication and understanding with potential donors and their families; and • To increase the potential for organ and tissue donation through collaboration as an integral component of the transplantation process. The council has also developed a newsletter and book named For Those Who Give and Grieve. In addition, they have developed the Bill of rights for donor families. This document was created to represent the rights and expectations of families of loved ones who die and who may be considered potential organ and/or tissue donors. In summary, these rights include: • To have a full, careful explanation about what happened to their loved one, his or her current status, and his or her prognosis; • To be full partners with the healthcare team in making decisions; • To have a full and careful explanation about death; • To have the opportunity to be with their loved one during and after his or her death; • To be cared for in a sensitive manner; • To have an opportunity to make organ and/or tissue donation decisions; • To have this information presented in a manner suited to the family and time to make a decision; • To have this decision be accepted; • To have assurance that their loved one will be treated with respect; to receive timely information about the organs and/or tissues utilized; • To be given the opportunity to exchange communication with recipients; • To be assured they will not be burdened with expenses; and • To receive ongoing bereavement follow-up support for a reasonable period of time.5 Other contributions this council has brought to donor families are the Understanding Brain death Fact Sheet, the National Donor Family Survey, The Donor Family Quilt and “Making the Critical Difference Workshop”, a critical care nurse education program.4 Many OPOs have expanded the function of donor families far beyond the traditional volunteer speaker role. Donor family members are becoming more active in advising and directing the activities of the OPOs. They are strong and vested advocates of donation and are uniquely qualified to impart the benefits of donation. As a way to honor donors and their families, most OPOs host an annual donor family/recipient celebration. Booklets, medals and grave markers are just a few of the items that are presented to donor families in honor of their loved one.7

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Contact with recipients is a valuable form of support available to donor families. While many donor families and recipients choose to remain anonymous, many others choose to communicate. Studies have shown that direct interaction enables donor families to see the benefit of their donation and it also provides recipients an opportunity to express their gratitude.8 Overall, involving donor families in the OPO is very valuable. By sharing their thoughts, feelings, and experiences related to donation, the donor families help the OPO staff to see direct benefit from their activities and they revitalize the OPO’s dedication to improve the quality of life for many and save the lives of others. REFERENCES 1.

2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

16. 17.

Beasley C, Capossela C, Brigham L et al. The impact of a comprehensive, hospital-focused intervention to increase organ donation. Journal of Transplant Coordination. 1997; 7:6-13. Blagg CR, Helgerson SD, Warren CW et al. Awareness and attitudes of Northwest Native Americans regarding organ donation and transplantation. Clinical Transplantation. 1992; 46:436-442. Blank RH. Life, Death, and Public Policy. Springfield, IL: Northern Illinois University Press: 1988:129. Coolican M, Politoski G. Donor Family Programs. Dying, Death, Donation and Bereavement Care. 1994; 6:3:613-623. Corr C, Nile L. Bill of rights for donor families. National Donor Family Council of the National Kidney Foundation. (Item #06-13) Dunn D. Motivation for giving: Consent for the donation of organs and tissues. Journal of Transplant Coordination. 1995:5:2-8. Holtcamp S. Something More For Donor Families, 1990:1-6. Lewino D, Stocks L, Cole G. Interaction of organ donor families and recipients. Journal of Transplant Coordination. 1996:6:191-195. Manning D. Comforting Those Who Grieve. A Guide For Helping Others. San Francisco, CA: Harper Collins Publishers:1985:16-22, 56-69, 69-71. Meyer C. Surviving Death A Practical Guide To Caring For The Dying and Bereaved. Mystic, CT: Twenty-third Publications: 1991:103. Perez MS, Trevino L, Swasey L. Hispanic experience of organ donation in New York City. Transplant Proceedings 1993; 25:2492-2493. Raphael B. The Anatomy of Bereavement. Northvale, NJ: Jason Aronson Inc: 1983; 5,29,53,59-61,352,389. Reese CD. Please cry with me. Nursing 96. 1996:August:56. Robbins RA, McLaughlin N, Nathan HM. Using self-efficacy theory to predict organ donor card signing. Journal of Transplant Coordination 1991:1:130-136. Shafer T, Kappel D, Heinrichs D. Strategies for success among OPOs: A study of three organ procurement organizations. Journal of Transplant Coordination 1997:7:22-31. Smith SL, Hawke D, Draft J et al. Tissue and Organ Transplantation. St. Louis, MO: Mosby: 1990:84. Verble M, Worth J. Biases among hospital personnel concerning donation of specific organs and tissues: Implications for the donation discussion and education. Journal of Transplant Coordination 1997:7:72-77.

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2

20. 21.

Verble M, Worth J. Handout given at The Donation Conversation and Presentation Skill for Procurement Professionals Seminar in Lexington, KY; Feb. 1998. Von Pohle WR. Obtaining organ donation: Who should ask? Heart and Lung 1996:25:304-309. Wheeler D, Swasey L. Cultural beliefs in organ donation. Journal of Transplant Coordination. 1996; 4:41-46. Zunin LM, Zunin HS. The Art of Condolence. New York, NY: Harper Perennial 1991; 11:153-232.

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Physiologic Consequences of Brain Death Dimitri Novitzky Introduction .......................................................................................................... Histological Changes ............................................................................................. Endocrine Changes ............................................................................................... The Impact of Brain Death on the Hemodynamic and Metabolic Functions, the Role of Hormonal Replacement .................... Hormonal Therapy in the Brain Dead Organ Donors ......................................... Discussion .............................................................................................................

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INTRODUCTION Observations done in well managed brain-dead organ donors on ventilatory support, and the fine tuning of the acid-base balance in whom irreversible loss of the brain has occurred, will inevitably lead to a progressive dysfunction of all organs. Ventricular fibrillation will be the terminal event. Once brain death was established, 62% suffered cardiac arrest within 24 hours and 87% by the end of 72 hours.1 Continuous improvement of solid organ transplantation procured from braindead beating heart organ donors resulted in an increasing demand of this commodity. The current organ donor pool no longer can meet the continuously expanding demand and approximately 30% of cardiac, liver, lung, heart/lung and 7% of renal patients, will die or deteriorate further. They will be deemed unsuitable for transplantation before a donor organ becomes available.2 The outcome of a transplanted marginal donor organ in a marginal recipient has the worst survival provided the quality of the donor organ is improved before harvesting from the brain-dead organ donor. This is of great relevance for organs from which immediate function is required, such as the heart or liver. The complexity of brain death induced organ injury is multifactorial. Patients who will become brain-dead and eventual organ donors will undergo a variety of traumatic events such as direct tissue/organ injury, hemorrhagic shock, excessive inotropic support, hypoxia, variety of blood products and crystalloid transfusions, infections, nutritional starvation. etc. These events, and the primary brain injury, may contribute or precipitate the death of the brain. The major source of donor organs will be from patients dying of head injury or spontaneous intracranial Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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hemorrhage.2 The multiple noxious events may vary in severity and duration. Whatever the precipitating event that leads to brain death, two sets of injury will impact the body as a whole: a) an autonomic storm3 (parasympathetic and sympathetic) lasting from minutes to hours4 and b) a rapid disintegration of the hypothalamic-hypophyseal axis, endocrine collapse3 (cortisol, thyroid hormones, insulin, anti-diuretic hormone and others), which will result in progressive inhibition of cellular metabolic aerobic pathways and diabetes insipidus lasting from hours to days. Organs such as the heart, procured from unstable brain dead organ donors dependent on dopamine in excess of 20-30 mcg/kg/min, may have poor functional outcome in the recipient. This is due to further cellular injury that will occur during the cold preservation time followed by reperfusion tissue injury in the recipient. The described additive detrimental events may result in an organ requiring further inotropic or mechanical support, or result in primary graft failure thus compromising further a successful outcome of the transplanted organ in the recipient. Understanding the mechanisms of organ injury in the brain dead organ donor and in the recipient will allow timely pharmacological and endocrine intervention, reversal of correctable conditions and prevention of metabolic abnormalities in the potential brain dead organ donor. This will result in a wellfunctioning organ in the recipient, not only enlarging the donor organ pool but improving the survival following transplantation. THE AUTONOMIC STORM In experimental animal models of brain death, a sudden increase of the endocranial pressure3 or acute brain ischemia4 are associated with an Autonomic storm involving the parasympathetic and sympathetic systems (Fig. 3.1). The well recognized Cushing’s reflex is part of the initial response as endocranial pressure increases.5 The continuous hemodynamic and electrocardiographic monitoring done in baboons over 24 hours has shown initial significant changes, during which the sympathetic activity impacts the entire body. There is a significant release of endogenous and circulating plasma catecholamines.3 The adrenergic activity is manifested on the cardiovascular system at the level of beta and alpha receptors. The cardiac activity clearly expresses these initial effects of the Autonomic storm,6 and the consequences of calcium-induced injury are observed on light and electron microscopy. ELECTROCARDIOGRAPHIC CHANGES The continuous electrocardiographic (EKG) monitoring done in baboons before, during and following the induction of brain death, clearly shows the various stages of the autonomic activity.3 Initially, there is a marked parasympathetic activity (Stage I). This is characterized by sinus bradycardia, sinus stand still, asystole, junctional escape beats and a combination of A node, bundle of His and fascicular bundle conduction blocks. As this initial period progresses into the next stages, the sympathetic activity pre-

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3

Fig. 3.1. Plasma catecholamines in the experimental animal measured prior to induction of brain death (BD). There is a significant increment following induction of endocranial hypertension, by 2 h neoepinephrine plasma levels fell below control values.

dominates resulting initially in sinus tachycardia without ischemic changes (stage II). Stage III is characterized by the development of unifocal and multifocal ventricular ectopic activity and runs of ventricular tachycardia. During stage IV, sinus rhythm resumes again manifesting now marked acute ischemic changes (Fig. 3.2), ST segment abnormalities and development of Q waves. Stage V starts at the time of recovery of the ST segments and the phase out of the sympathetic overactivity. The heart is in sinus rhythm. Nonspecific ST changes, QRS abnormalities, and flattening or biphasic T waves are noted.7 The autonomic overactivity is initially vagus-mediated, followed by endogenous catecholamine release from sympathetic nerve endings. In baboons, bilateral surgical vagotomy performed before induction of brain death prevents all EKG changes observed in stage I. The bilateral surgical ablation of the sympathetic ganglia abolishes the tachycardia, the EKG ischemic changes observed during stages II-IV, as well as the final QRS and ST-T changes previously described in stage V.8 Animal pretreatment with beta blockers and calcium blockers prior to the induction of brain death9 also resulted in complete prevention of the EKG stages II-V. This obviously will have relevance in the pharmacological management of potential organ donors. HEMODYNAMIC CHANGES Systemic and pulmonary hemodynamic monitoring correlate well with the autonomic overactivity.3 At the systemic level, the initial parasympathetic activity

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Fig. 3.2. Transient electrocardiographic acute ischemic changes during the induction of brain death in the baboon observed at the peak of the systemic vascular resistance (SVR), resembling an acute myocardial infarction. As the SVR normalizes the Q waves and ST changes recover.

is short lived. This is mainly manifested by hypotension. As the massive catecholamine release occurs, the muscular arterioles constrict, the arterial blood pressure (BP) significantly rises as well as the systemic vascular resistance (SVR), and the observed acute increment of the heart rate results in a marked increment of the heart work. The left ventricle (LV) is unable to overcome the acute work load and global LV failure occurs which is manifested by a drop of the cardiac output (CO), elevation of the end-diastolic pressure (LVEDP), pulmonary wedge pressure (PCWP) and dilatation of the LV cavity10 (Fig. 3.3). In the pulmonary circulation, the consequences of acute LV failure are manifested by rapid elevation of the pulmonary artery (PAP) pressure. However, this does not exceed the left atrial pressure. The large compliance of the pulmonary circulation rapidly accommodates and pools the systemic blood returning to the right atrium. Thus, there is a temporary increase of the PA flows while the systemic CO is transiently reduced. These systemic and pulmonary changes are observed at the peak of the SVR. Furthermore, the rapid work increment induced by the excessive sympathetic activity induces inadequate subendocardial oxygen delivery to match the demand. This is clearly evident during EKG stages III-IV. Furthermore, the acute subendocardial ischemia and LV dilatation may induce acute mitral valve regurgitation, which may explain the significant elevation of the LA pressure. Recovery of this abnormal hemodynamic status is rapid and may well explain one of the possible mechanisms of neurogenic pulmonary edema observed in head injury, in which the PCWP is normal at the time of the patient examination.10

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3

Fig. 3.3. Systemic and pulmonary hemodynamic response to induction of experimental BD. There is a significant increment of the systemic vascular resistance (SVR) and of the arterial pressure (MAP), resulting in the left ventricular failure. The aortic (AO) flow falls markedly while the pulmonary artery blood flow recovers rapidly and exceeds the AO flows. This results in blood pooling in the lungs. At the peak of the SVR, the left atrial pressure exceeds the pulmonary artery pressure, possibly as a result of LV failure and mitral valve regurgitation inducing pulmonary capillary disruption.

HISTOLOGICAL CHANGES As result of the adrenergic storm, tissue injury has been observed in the experimental animal and in organs procured from brain-dead organ donors. The injury pattern is widely distributed through the examined organs and follows the pattern observed in conditions in which ischemia and reperfusion play an important role. Thus, the role of calcium overload and oxygen free radicals are interrelated to the Autonomic storm.3 In the heart, under light microscopy, approximately 75% of the experimental animals exhibited various degrees of focal myocyte necrosis (Fig. 3.4). This has

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Fig. 3.4. Light microscopy of the heart following induction of brain death in the baboon. The subendocardium (Left) has the histological appearance of an acute myocardial infarct. There is myocyte necrosis, edema and interstitial hemorrhages. H & E X 100.

been observed mainly in the sub-endocardial area but does occur in both the atria and ventricles.7,8 The myocyte necrosis assumes the form of contraction bands, coagulative and myocytolysis. There is also mononuclear cell infiltrate and edema surrounding the necrotic myocyte, on occasion, resembling the appearance of acute rejection.11,12 Contraction band necrosis has also been observed in the conduction tissues such as in the AV node and the bundle of His. Histological examination of the lamina media of the coronary arteries has shown the presence of smooth muscle contraction bands and intracellular calcium deposits. Examination by electron microscopy of the donor heart has shown sarcomeres in a hypercontractile state as well as disrupted organelles (Fig. 3.5). The mitochondrial injury consists of various degrees of integrity disruption affecting the membranes, matrix, cristae and deposition of electron dense material evolving towards a secondary lysosome.13 In the lungs, approximately 30% of examined animals subjected to experimental brain death had pulmonary edema rich in protein (Fig. 3.6). Hemorrhages were also present in the alveolar wall and in the alveolar spaces. Endothelial capillary disruption was also observed.10 Possibly the most striking findings were detected by electron microscopy in the kidney (Fig. 3.7). The glomerular structure remained preserved. However, examination of the glomerulus from kidneys procured from brain-dead animals had significant engorgement and the capillary spaces were filled with red blood

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Fig. 3.5. Electron microscopy of a rabbit heart following induction of brain death. The sarcomeres are in a hyper-contractile state. Some are stretched and disrupted. There is scalloping of the sarcolemma and electron dense deposits in the mitochondria. Uranyl acetate and lead citrate x 11.000.

Fig. 3.6. Light microscopy of a baboon lung following induction of brain death. There is disruption and thickening of the alveolar septa as well as interstitial hemorrhages. Protein rich deposits within the alveolar spaces are observed. H & E x 100.

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Fig. 3.7. Electron microscopy of the renal cortex from (A) alive and following brain death (BD) induction (B) in the rabbit. Significant glomerular abnormalities are observed: Following BD, there is significant red blood cells entrapment in the glomerular capillaries and marked reduction of the capillary diameter. This may result from a hyper-contractile response of the afferent and efferent glomerular arterioles to the catecholamine storm. Uranyl acetate X 5.500.

cells. These changes are possibly directly related to arteriolar capillary spasms which occurred during the sympathetic storm. Other changes were observed at the mitochondrial level, but in lesser degree than in the heart.14 The liver under light microscopy shows frequent fatty deposits and loss of glycogen. Electron microscopy again shows preserved nuclear and membrane structure. However, scattered mitochondrial injury was noted, similar to that observed in the kidneys.

ENDOCRINE CHANGES In the baboon, following induction of brain death, a rapid disintegration of the endocrine system has been observed. The loss of the hypothalamic-hypophyseal function results in reduction or cessation of antidiuretic hormone (ADH) production, which is followed by diabetes insipidus.3 Following the adrenergic storm, plasma levels of various hormones become reduced. There is a rapid reduction of ACTH, growth hormone, cortisol and insulin.3 The thyroid profile falls within the typical plasma level profile of the Euthyroid sick syndrome (ESS).15 The thyroid stimulating hormone remains unchanged or slightly reduced (Fig. 3.8). The total thyroxine (T4) and free triiodothyronine

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3

Fig. 3.8. Plasma free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) following induction of brain death in the baboon. The mean values and the standard error of the mean are shown.

(FT3) are markedly reduced. There is a marked increment of reverse T3 (rT3). In a healthy state, 90% of the thyroid gland hormone production is released as T4, a prohormone. In peripheral tissues, T4 is converted into T3 as the active hormone.16 The ESS is the result of catecholamine activation of a tissue monodeiodinase converting the thyroid produced T4 into rT3 rather than T3. This is considered to be an adaptive beneficial response to stress. The current thought is that in acute states, thyroid hormone replacement should not be administered. However, our experience in the laboratory and in clinical studies clearly has shown beneficial results of T3 replacement.

THE IMPACT OF BRAIN DEATH ON THE HEMODYNAMIC AND METABOLIC FUNCTIONS, THE ROLE OF HORMONAL REPLACEMENT Following induction of brain death in the experimental animal, a rapid reduction of plasma free T3, cortisol and insulin was described. This clearly indicated the need to assess the impact of hormonal replacement in organs used for transplantation and on the body as a whole. In a study done in pigs T3 (2 mcg), cortisol

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(100 mg) and insulin (10 IU) were administered at hourly intervals for two hours.4 The heart and kidneys were procured from living anesthetized animals (Group A), from brain-dead animals supported for four hours on a ventilator where the blood volume was replaced and inotropic support administered (Group B) and from brain-dead animals as in Group B to which hormonal therapy was administered for an additional two hours (Group C). The excised hearts underwent hemodynamic testing in an ex vivo modified Langendorff model under similar loading conditions (Fig. 3.9). Hearts procured from brain-dead animals (Group B) had a significant hemodynamic impairment. There was reduction of the dp/dt, peak LV pressure, cardiac output and elevation of the LVEDP. The ex vivo testing of hearts procured from Group C animals, which received hormonal replacement, showed a significant hemodynamic recovery no different from hearts procured from living animals (Group A)4 (Table 3.1). At the completion of the hemodynamic testing, myocardial biopsies were procured and analyzed. Hearts from Group B animals had a significant reduction of glycogen, high energy phosphates (ATP and CP), and significant increment of myocardial lactate. The biochemical testing of Group C was no different from hearts procured from living animals (Table 3.1) (Fig. 3.10). Further studies examined the impact of brain death on the metabolic pathways by injecting intravenous 14C-R (glucose, pyruvate and palmitate) to living, brain-dead and brain-dead T3 treated animals (Fig. 3.11). Brain-dead animals were unable to metabolize aerobically the injected metabolites. Following injection of 14C-R, brain-dead animals exhibited a significant reduction of the exhaled 14CO 2.

Fig. 3.9. Ex vivo hemodynamic testing of hearts procured from: (A) alive animals, (B) brain-dead, (C) braindead, T3 treated animals, (D) brain-dead and stored, and (E) brain-dead, T3 treated and stored. A vs. B p < 0.01 vs. A p < 0.001. Groups C and E were no different from Group A.

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Table 3.1. Hemodynamic and metabolic study of hearts procured from live, brain-dead, and brain-dead hormonally treated pigs tested in a modified ex vivo Langendorf model Groups

CO (mL/min)

Nonstored Alive 2320 (220) BD1850 (329) 4.30 (0.59) p < 0.02 BD and HT 2357 (406) ns Stored Alive 2500 (90) BD742 (65) 16.0 (1.98) p < 0.0001 BD and HT 2074 (276) ns

LVEDP (mm Hg)

ATP (µmol/g)

CP (µmol/g)

Lactate (µmol/g)

Glycogen (µmol/g)

5.30 (1.03) 3.29 (0.22) ns 3.80 (1.68) ns

3.73 (0.25) 3.69 (0.85) ns 3.75 (0.38) ns

6.61 (0.72) 12.9 (3.39) 0 < 0.02 6.80 (1.14) ns

5.0 (0.7) 29.6 (3.14) 12.7 (2.95) p < 0.01 p < 0.005 7.07 (1.56) 30.5 (4.21) ns ns

4.8 (1.05) 2.49 (0.37) p < 0.0001 4.6 (1.80) ns

3.5 (0.20) 4.07 (0.17) p < 0.02 3.10 (0.18) ns

5.30 (0.52) 2.80 (1.19) ns 9.66 (0.38) p < 0.0001

5.1 (0.8) 26.1 (2.42) 25.4 (4.57) ns ns 9.65 (1.66) 21.2 (3.92) p < 0.05 ns

Fig. 3.10. Creatine phosphate (CP) measured in hearts procured from: (A) alive animals, (B) brain-dead, (C) brain-dead T3 treated, (D) brain-dead stored, and (E) brain-dead, T3 treated and stored. A vs. B p < 0.02, D vs. A p < 0.05. The CP in T3 treated animals remained unchanged or improved: C vs. A ns and E vs. A p < 0.05.

The half life was prolonged and the plasma clearance reduced. The studied metabolic pathways were normalized in brain dead animals receiving T3 alone at 2 mcg/h.17 These findings clearly indicate mitochondrial failure to incorporate two carbon compounds in the TCA cycle. The pyruvate is converted into lactate and, as a result of the aerobic pathways, inhibition of CO2 production and high energy phosphate synthesis are reduced. The reduction of substrate availability for the

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Organ Procurement and Preservation

3

Fig. 3.11. Best fit curves obtained from exhaled 14CO2 following single bolus administration of 14C-palmitate. In brain-dead animals (BD), the inability to metabolize aerobically fatty acids is evident. Following T3 administration to BD animals, the CO2 production is no different from living animals.

cellular ATPases will eventually lead to an inability to regulate ionic gradient across cellular compartments, eventually resulting in cell death and functional organ impairment. The impact of hormonal therapy was further examined at the renal level.18 The Na/K ratio was measured in renal slices. This measurement is a good indicator of cellular viability and depends on the Na-K ATPase activity. The Na/K ratio was significantly increased in renal slices obtained from brain-dead animals. This ratio difference was not observed between renal slices obtained from living animals and brain-dead animals subjected to hormonal therapy. Further beneficial effects of the hormonal therapy were explored in experimental kidney transplantation.19 Kidneys were procured from living animals, braindead, brain-dead dopamine supported animals and from brain-dead dopamine supported animals subjected to hormonal therapy. The harvested kidneys were transplanted into nephrectomized pigs. Animals receiving renal grafts from braindead dopamine supported animals had a significant creatinine elevation and functional loss of the graft. However, the brain-dead dopamine supported and hormonally treated animals had normal creatinine levels in the recipient animals. The renal function was no different from kidneys procured from living animals.

Physiologic Consequences of Brain Death

43

HORMONAL THERAPY IN THE BRAIN-DEAD ORGAN DONORS Based on the animal experimental work and evidence obtained from human brain-dead organ donors, the brain-dead undergo metabolic abnormalities such as reduction of plasma FT3, elevation of rT3, development of metabolic lactic acidosis, and elevation of plasma free fatty acids (FFA) necessitating progressive increases of the inotropic demand and bicarbonate replacement. Hormonal replacement was initially carried out in 21 circulatory unstable patients who were on high inotropic support, exhibiting high plasma lactic acidosis and FFA and compared with 26 donors managed in a standard fashion.20 Once the brain-dead organ donor was referred to the transplant program and hormonal therapy was initiated, triiodothyronine 2 mcg/h, cortisol 100 mg/h and insulin 10-20 IU/h was administered for four hours. The hemodynamic parameters rapidly normalized, inotropic requirements were significantly reduced as was the need of bicarbonate replacement. In six patients, the cardiac output improved over 100% within minutes after T3 replacement. All organs, including the heart, were successfully harvested and transplanted with excellent function in the recipient. However, in the control group during the same time interval, the hemodynamics continued deteriorating despite further inotropic increment and bicarbonate replacement. Four donors developed ventricular fibrillation and were excluded from the donor pool (p < 0.04). The advantages of hormonal therapy was further explored by other transplant groups confirming again the value of the hormonal therapy in stabilizing the hemodynamic parameters. This was clearly shown in a prospective randomized study done in potential brain-dead humans.21 Vasopressin was added and sequential cardiac catheterization was done for hemodynamic assessment. In the control group, hemodynamic deterioration progressively took place and half of the braindead patients suffered a cardiac arrest. The hormonally treated group during the entire time maintained excellent hemodynamics. The need of larger and more frequent T3 doses became evident in the hemodynamically unstable organ donors, allowing the use of hearts from donors dependent up to 40 mcg/kg/min of dopamine.22 In these particular patients, T3 therapy increased to 4-6 mcg bolus at 15 min intervals until the desired hemodynamic effect could be obtained and the dopamine requirements were reduced. The need for K+ replacement is markedly increased, as well as intravascular volume expansion as T3 is a potent vasodilator. The use of DDAVP or vasopressin will control the excessive diuresis and the need for crystalloid replacement.23,24

DISCUSSION Organs procured from brain-dead organ donors undergo a series of noxious events which are initiated in the potential organ donor such as shock, hypoxiaischemia, multiple transfusions etc. During the death of the brain, two types of injury occur: the first, as a result of the catecholamine storm and the second, as a

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result of the endocrine derangement and inhibition of the aerobic pathways. Further manipulation, such as prolonged cold preservation and reperfusion injury in the recipient, enhances potential endothelial-cellular damage of the transplanted organ. In the donor, the initial tissue injury related to the catecholamine storm is associated with cellular ischemia and reperfusion.25 Catecholamines induce changes of the cytosolic calcium homeostasis, which is ATP dependent,26 affecting the voltage-gauged calcium entry into the cells,27 and have a key role in the excitationcoupling process in the heart, smooth muscle vascular tissue and neuropeptide release.28 The cytosolic Ca2+ increment precipitates activation of lipases, proteases and endonucleases. Activation of nitric oxide synthase leads to further cellular membrane injury induced by oxygen free radicals, the increment of adenosine (a byproduct of ATP catabolism) and activation of adenosine deaminase. Xanthine oxidase potentiates further the generation of cytotoxic oxygen free radicals inducing peroxidation of unsaturated fatty acids and lipids. The combination of Ca2+ and superoxide mediated tissue injury, which occurs simultaneously, is followed by the endocrine disintegration in the donor. As a result of this, there is inhibition of aerobic pathways,17,29 the cell can no longer metabolize mitochondrial fuels and the cellular energy charge is progressively reduced, eventually resulting in cellular death and possible to primary organ failure. The aggressive management of the potential organ donor and the institution of hormonal therapy to brain-dead donors has been shown to reverse some of the brain death induced organ injuries, particularly to the heart and kidneys. Triiodothyronine plays a major role in restoring mitochondrial function, producting high energy phosphates and activating of various ATPases.30 Triiodothyronine mobilizes cytosolic Ca2+ in the sarcoplasmic reticulum31 and restores the Na+/K+ gradients. Thus, organs are in a more optimal condition for transplantation. REFERENCES 1. 2. 3.

4.

5.

6.

7.

Joergensen EO. Spinal man after brain death. Acta Neurochir (Wien) 1973; 28:259. Fragomeni LS and Kaye MP. The Registry of the International Society for Heart Transplantation: Fifth official report. J Heart Transplant 1988; 7:249-53. Novitzky D, Wicomb WN, Cooper DKC, Frazer R, Barnard CN. Electrocardiographic hemodynamic and endocrine changes occurring during experimental brain death in the Chacma baboon. Heart Transplant 1984; 4:63-9. Novitzky D, Wicomb WN, Cooper DKC, Tjaagard MA. Improved cardiac function following hormonal therapy in brain-dead pigs: Relevance to organ donation. Cryobiology 1987; 24:1-10. Cushing H. Concerning a definite regulatory mechanism of the vasomotor center which controls blood pressure during cerebral compression. Bull Johns Hopkins Hospital 1901; 12:290. Shanlin R, Sole MJ, Rahimifar M, Tator CH, Factor SM. Increased intra-cranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damage in rats. J Am Call Cardiol 1988; 12:727-736. Novitzky D, Horak A, Cooper DKC, Rose AG. Electrocardiographic and histolopathological changes developing during experimental brain death in the baboon. Transplant Proc 1989; 21:2567-9.

Physiologic Consequences of Brain Death 8.

9.

10.

11.

12. 13.

14. 15. 16. 17.

18.

19.

20.

21.

22.

23.

24.

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Novitzky D, Cooper DKC, Wicomb WN, Rose AG, Fraser RC, Reichart B. Prevention of myocardial injury during brain death by total cardiac sympathectomy in the Chacma baboon. Ann Thorac Surg 1986; 41:520-524. Novitzky D, Cooper DKC, Reichart B. Prevention of myocardial injury by pretreatment with verapamil hydrochloride following experimental brain death in the baboon. Am J Emerg Med 1987; 15:11-18. Novitzky D, Wicomb WN, Rose AG, Cooper DKC, Reichart B. Pathophysiology of pulmonary edema following experimental brain death in the Chacma baboon. Ann Thorac Surg 1987; 43:288-94. Shivalkar B, Van Loon J, Wieland W, Tjandra-Maga TB, Borgers M, Plets C, Flameng W. Variable effects of explosive or gradual increase of intra-cranial pressure on myocardial structure and function. Circulation 1993; 87:230-239. Novitzky D, Rose AG, Cooper DKC, Reichardt B. Interpretation of endomyocardial biopsy: a potentially confusing factor. SAMJ, 1986; 70: 789-792. Novitzky D, Rhodin J, Cooper DKC, Ye Y, Min K-W, DeBault L. Ultrastructural changes associated with brain death in the human donor heart. Transplant International 1997; 19(1):24-32. Novitzky D, Rhodin J, Saba M. Experimental ultrastructural changes associated with brain death in the rabbit. (In press). Wartofsky L, Burman K. Alterations in thyroid function in patients with systemic illness: The “euthoid sick syndrome.” Endocr Rev 1982; 3(2):164-217. Madsen M. The low T3 state, an experimental study. Medical dissertations No. 229, 1986; Sweden: Linkoping University. Novitzky D, Cooper DKC, Morrell D, Isaacs S. Change from aerobic metabolism after brain death, and reversal following triiodothyronine (T3) therapy. Transplantation 1998; 45:32-6. Wicomb WN, Cooper DKC, Novitzky D. Impairment of renal slice function following brain death, with reversibility of injury by hormonal therapy. Transplantation 1986; 41:29-33. Pienaar H, Schwartz I, Roncone A, Lotz A, Hickman R. Function of kidney grafts from brain-dead donor pigs. The influence of dopamine and triiodothyronine. Transplantation 1990; 50:580-2. Novitzky D, Cooper DKC, Reichart B. Haemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987; 43:852-4. Taniguchi S, Kitamura S, Kawachi K, Doi Y, Aoyama N. Effects of hormonal supplements on the maintenance of cardiac function in potential donor patients after cerebral death. Eur J Cardiothorac Surg 1992; 6:96-101. Novitzky D, Cooper DKC, Chaffin JS, Greer AE, Debault LE, Zuhdi N. Improved cardiac allograft function following triiodothyronine (T3) therapy to both donor and recipient. Transplantation 1990; 49:311-6. Jeevanandam V, Barbara T, Regillo T, Hellman S, Elridge C, McClurken J. Reversal of donor myocardial dysfunction by triiodothyronine replacement therapy. J Heart Lung Transplant 1994; 13:681-687. Wheeldon D, MIBiol, Potter C, Oduro A, Wallwork J, Large S. Donor management and organ distribution: transforming the “unacceptable” donor. Outcomes from the adoption of a standardize donor. Management technique. J Heart Lung Transplant 1995; 14:734-742.

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Organ Procurement and Preservation 25. 26. 27. 28.

3

29.

30.

31. 32.

Hearse DJ. Stunning: A radical review. Cardiovasc Drugs Ther 1991; 5:853-76. Sterling K. Direct thyroid hormone activation of mitochondria: The role of adenine nucleotide translocase. Endocrinology 1986; 119:292-295. Bean BP, Coccivc ARP. Classes of calcium channels in vertebrate cells. Ann Rev Physiol 1989; 51:367-84. Tsien RW, Lipscombe D, Madison DV, Bley KR, Fox AP. Multiple types of neuronal calcium channels and their selective modulation. TINS 1988; 11:431-7. Montero JA, Mallol J, Alvarez F, Benito P, Concha M, Blanco A. Biochemical hypothyroidism and myocardial damage in organ donors, are they related? Transplant Proc 1988; 20:746-748. Warnick PR, Davis FB, Cody V, Davis PG, Blas SD (1988). Stimulation in vitro of rabbit skeletal muscle sarcoplasmic reticulum Ca2+ ATPase activity by thyroid hormone and by pyridines (abstract). Proceedings of the Annual Meeting of the Endocrine Society New Orleans; 356. Limas CJ. Enhance phosphorylation of myocardial sarcoplasmic reticulum in experimental hyperthyroidism. Am J Physiol 1978; 234:H426-H431. Philinson KD, Edelman IS. Thyroid hormone control of Na+/K+ ATPase and K+dependent phosphatase in rat heart. Am J Physiol 1977; 232: C196-C202.

Assessing Suitability of the Cadaver Donor

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Assessing Suitability of the Cadaver Donor Giuliano Testa, Goran B. Klintmalm Introduction .......................................................................................................... Defining the Donor ............................................................................................... Living Donors ....................................................................................................... The Cadaveric Donor ........................................................................................... The Marginal Donor ............................................................................................ Non-Heart-Beating Donors ..................................................................................

47 48 48 50 58 59

INTRODUCTION The excellent results in terms of patient survival and quality of life after solid organ transplantation reflect the improvements made in donor and recipient selection and management and in surgical technique in the past 30 years. Losing the graft or the patient for a poor selection of the recipient or for a technical mistake has become less and less frequent due to the thorough candidate preoperative evaluation and the established surgical technique. The attention has shifted to the selection of the donor as one of the most important variables in the outcome of the transplanted patient and as the most immediate way of filling the gap between the number of available organs and the number of patients waiting for transplantation. The “ideal donor” is a fluid concept especially nowadays with the transplant community struggling with the organ shortage and stretching the acceptance criteria. Even when applying the concept of the “suitable donor”, aside from few absolute contraindications, it is a challenge to define strict guidelines. As a result, experience and wisdom come to play a very important role in the selection of the donor. The present trend of accepting donor candidates, who at the beginning of this decade were refused at the screening phone call, reflects some of the lessons learned with the use of the so-called “marginal donors” and the persistent paucity of donors. In the future, if the number of donations increases, and if xenotransplantation becomes a viable option, it probably will be feasible to draw strict guidelines to better characterize the “ideal donor”.

Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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Organ Procurement and Preservation DEFINING THE DONOR

In a broad sense we can identify three types of donors: the living donors, the brain-dead donors and the non-heart-beating donors. Each type has to fulfill specific criteria in order to be eligible for the donation and can be used for providing one or more organs and tissues according to its clinical conditions and anatomical characteristics.

4

LIVING DONORS About 27% of the kidney transplants in the United States are performed using living-related and unrelated donors.1 Experience with the living-related lung transplant has been growing, and in selected centers, living-related pancreatic and intestinal transplants have been performed. Since 1990 living-related pediatric liver transplants have been performed worldwide, and in Japan the experience obtained with the pediatric population has been extended to the living-related adult liver transplantation. The living donor represents the closest example of the “ideal donor.” Screening and work-up are the most complete and can be conducted without the time limiting factor dictated by the impending cardiac arrest of the brain-dead cadaveric donor. The donor operation is performed in a truly elective way and the ischemia time is minimized. Age, function of the organ to be donated, absence of serious pathology, absence of transmissible infectious diseases and absence of cancer are among the requirements that the living donor must fulfill. Moreover, anatomical variations that could preclude the donor operation or the use of the organ must be found in advance of surgery. For living-related and unrelated transplants the legal age is the lowest accepted age while the upper age limit is not set and depends mostly on the general health conditions of the donor and function of the specific organ. Most transplant surgeons feel comfortable with donors up to the age of 65. The compatibility of the donor and the recipient is assessed by ABO blood group and HLA typing. The living donor must have a comprehensive history and physical evaluation, normal hematological, hepatic and renal function tests, normal electrocardiogram and chest radiogram and negative serology for hepatitis B and C and for immunodeficiency virus. The presence of any pathology that could put his/her life at risk or could increase the chances of poor organ functioning, in both the donor and the recipient, for example diabetes or hypertension, will rule him/her out for donation. Positive serology for hepatitis B and C and HIV are also contraindications for donation. The presence of malignancy in past medical history is not necessarily considered an absolute contraindication. Living donors with more than 10 years history of malignancy and who are proven free of disease may be accepted as candidates.

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KIDNEY In living-related and unrelated kidney transplantation the renal function is assessed by glomerular filtration rate which is the most precise method to assess renal function in relation to the age of the person.2 Table 4.1 shows the corrected and uncorrected glomerular filtration rates. An angiogram which defines the anatomy of the vasculature is obtained. Vascular anomalies permitting, the left kidney is chosen over the right because of its longer renal vein which makes the transplant procedure technically easier. If one of the donor kidneys has some imperfection, i.e., related to anatomy or dimension, that kidney is taken for donation, leaving the perfect kidney with the donor. LIVER For living-related liver transplantation the donor and the recipient must be blood group ABO compatible and HLA typing does not play a crucial role. The organ specific assessment is done by computed tomography that demonstrates the absence of any liver mass and also defines adequate liver volume. An angiogram is also performed to assess the anatomy of the vessels and to guide the surgeon during the dissection. The portion of the liver removed corresponds to segments 2 and 3.3 OTHER ORGANS While the above general guidelines can be applied to any potential living-related organ donor, special tests and criteria are necessary for pancreatic, small bowel and lung transplants, due to their still limited use or experimental status.

Table 4.1. Corrected and uncorrected glomerular filtration rates GFR/1.73 m2

GFR* Age Male (n)

Female (n)

Male (n)

Female (n)

< 20

126 ± 19 (10)

115 ± 12 (9)

103 ± 6 (2)

109 ± 12 (7)

21-30

121 ± 18 (50)

111 ± 18 (43)

102 ± 15 (25)

114 ± 17 (17)

31-40

122 ± 21 (65)

105 ± 18 (74)

97 ± 15 (39)

102 ± 14 (42)

41-50

117 ± 18 (32)

98 ± 22 (46)

95 ± 13 (17)

95 ± 21 (35)

51-60

96 ± 14 (14)

83 ± 21 (27)

84 ± 13 (12)

79 ± 15 (18)

> 60

100 ± 15 (6)

80 ± 12 (9)

78 ± 12 (5)

79 ± 8 (7)

* ml/min, mean ± SD. Reprinted with permission from: Gonwa TA, Atkins C, Zhang YA et al. Transplantation 1993; 55(5):983-985.

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Organ Procurement and Preservation THE CADAVERIC DONOR

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The cadaveric or brain-dead donor is the source of the majority of organs and tissues for transplantation. The use of the brain-dead person as a donor is supported by the scientific evidence that complete cessation of cortical and brain stem function is followed by the organism death. This scientific concept is acknowledged by the American Medical Association and the American Bar Association. Clinical criteria, outlined in Table 4.2, are usually sufficient to diagnose brain death. The clinical diagnosis can be supported by confirmatory tests like an electroencephalogram and/or radionuclide cerebral blood-flow studies, especially when coma coexists with hypothermia or the donors have received neurotropic medication, like opioids or barbiturates. When diagnosing brain death in pediatric donors less than 1 year of age, two neurological examinations in conjunction with electroencephalography, separated by 24 hours, are recommended. Even longer evaluation time, 48 hours, is recommended for infants of less than 2 months of age.4 More details on the definition of brain death and the management of the donor can be found in chapters 1, 3, 5, and 7. Once the potential organ donor has been identified, his/her suitability needs to be assessed with the critical knowledge that some of the parameters taken into account may be distant from the definition of the “ideal donor” but still be acceptable considering the status of the recipient, the organ to be transplanted and the necessity of using all the organs that offer a “reasonable likelihood” of good posttransplant functioning. The initial assessment of the potential organ donor follows the same steps no matter what organ is to be donated. The primary goal is to attempt to retrieve as many organs as possible from every donor. After obtaining a very detailed past medical and social history, a thorough physical examination is performed in order to detect any sign of infectious or tumor pathology, and not the least, needle

Table 4.2. Brain death criteria Clinical Coma with an established cause: no CNS depressants or hypothermia Absent spontaneous movements except spinal reflexes Positive apnea test Absent cranial reflexes Confirmatory Tests EEG Cerebral blood flow scan CNS = Central nervous system; EEG = electroencephalogram Reprinted with permission from Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Chapter 38, p 387. ©1996 WB Saunders Publishing Co.

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track marks, tattoos and body piercing jewelry that may indicate social habits that could result in a contraindication to the donation. Also the presence of skin incision may raise questions about his/her past medical history and help the family members in recollecting previous medical events. The presence of an extracerebral malignancy or less than a 5-year history of a treated malignancy is an absolute contraindication. Also, when a donor affected by brain tumor has undergone a ventriculo-peritoneal or a ventriculo-atrial shunt, he/she should not be considered for donation due to the increased risk of neoplastic dissemination. Relative contraindications are represented by low-grade skin cancers or by low-grade solid organ tumors when a sufficient, more than 2-5 years, tumor-free interval is present and documented.5,6 The acceptance of organs from these donors that harbor the risk of transferring a malignancy to the recipients must be weighed against the clinical urgency of the recipients under such circumstances and the recipient’s family must be fully informed of the potential risks. It is our policy to reserve these organs only for patients that would otherwise die in hours or days unless transplanted. In the unfortunate event that a cancer is discovered during the autopsy of the donor the transplanted organ should be removed because there is at least a 45% chance that it harbors cancer cells.5 An alternative approach would be to reduce the immunosuppressive regimen and follow the patient closely. This is the only option for a cardiac or a liver transplant recipient short of retransplanting the patient, but this has also been suggested for kidney recipients instead of performing a transplant nephrectomy. History of AIDS or documented HIV infection is an absolute contraindication to donation. The guidelines for preventing transmission of HIV through organ and tissue transplantation were published in 1994.6,7 Donors who have social history of homosexual practices, intravenous drug abuse, prostitution, incarceration or past medical history of hemophilia are considered high risk for being viral carriers. Specific exclusion criteria are also set for pediatric donors born to mothers belonging to one of the above categories or HIV-positive mothers. They may be accepted if older than 18 months, HIV-negative, with negative physical examination and negative past medical history of infection, and no record of breastfeeding within the last 12 months. Nonetheless, in donors who belong to any of these categories but test negative for HIV, the FDA encourages the donation and transplantation of life-saving organs. Obviously in this situation the circumstances must be fully discussed with the recipient and the family. A bill from the Center for Disease Control dated October 1996 states “In the context of the current organ shortage transplant teams are encouraged to accept and transplant organs from medically appropriate donors who test HIV-antibody negative but have behavioral risk criteria for HIV infection after the transplant team has discussed the risk and benefit with potential recipients and/or their families.” Hepatitis B antigen positivity represents active infection and infectivity and is an absolute contraindication to organ donation while hepatitis B surface antibody positivity reflects immunity or lack of infectivity, and therefore, allows transplantation of the organs. The case of a donor who has anti-HBc antibody and is hepatitis B surface antigen negative is a situation that could represent a resolved

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acute infection or a chronic carrier status and the organs may be used in recipients who already are infected by the hepatitis B virus using hepatitis B immunoglobulin following transplantation as prophylaxis for the recurrence. The use of such donors in recipients who are not hepatitis B core positive is debated due to the relatively high recurrence rate but can still be considered for kidney recipients where the risk of infection seems to be minimal.8 The use of hepatitis C antibody positive donors has become more frequent in the past 5 years and the guidelines for the utilization of the hepatitis C positive organs are drawn in the paragraph about infections. The second step is the evaluation of all those criteria that do not follow absolute and strict parameters but which overall analysis must give, as a result, a graft with the highest chance of good functioning after the transplant. Some of these criteria are different according to the organ to be transplanted and will be analyzed separately. AGE Many lessons have been learned regarding the age factor. Transplant surgeons recognize an “ideal donor age” and know that at the two extremes from this “ideal age,” infants and very old grafts, do not function as well and that both graft and patient survival decrease. However, it is also clear that without the use of the older or the very young donors the donor pool would shrink even more and more patients would die on the waiting list. Therefore, the use of these grafts is justified by the greater number of patients who will survive once transplanted. Ideally, the best results are achieved when donors younger than 45 years are used. In the past decade three important factors have influenced an increase in the donor pool age limit far beyond 45-years-old used in the 60s and 70s. First, the decrease in traumatic deaths that usually occurs with younger people (from 34.3% in 1988 to 21.9% in 1993),1 second, the increased awareness about HIV and, third the exclusion of donors potentially at risk, (again, more typical of younger people) and the ever increasing demand for organs. These factors and the good results obtained with the older donors reflect the change in the donor pool in the period from 1988 to 1995, with the donor pool 50-64 years old increasing from 2.5% to 17.9%, the donor pool above 65 years of age increasing from 0.1% to 5% and the donor pool 18-34 years old decreasing by 13% in the same period.1 In general the “ideal donor age” can be set between 10-12 years old and 45-50 years old. For kidney transplant the best results have been obtained with donors between 18 and 38 years of age. The 2- and 5-year-graft survival from these donors is 79.3% and 63.9%, respectively, compared to 69.2% and 49.4% for grafts from donors 50-64 years old and 61.3% and 40.3% for grafts from donors 65 years and older.1 A decrease in the graft survival rate at 2 and 5 years can be appreciated also for grafts from donors of age 6 to 10 years and 1 to 5, 69.9% and 56%, and 66.9% and 55.1%, respectively. It is interesting to note that the causes of graft loss from donors of 5 years or younger are more often caused by technical complications and vascular thrombosis that may be related to the size of the graft vessels

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and the difficulties in performing the anastomosis or to an increased responsiveness to vasospastic stimuli.9 The age of the donor plays as an independent factor in the survival of the liver graft, and consequently, in the patient survival. UNOS data show that graft survival decreases from 62.5% to 45% at 5 years when the donor age increases from 11-17 years to 50-64 years. Patient survival at 5 years decreases from 71.1% when the donor age is 11-34 years to 59.9% when donor age is 50-64 years. The more dramatic decrease in graft and patient survival is appreciated when the donors of 11-34 years of age are compared with the ones above 65 years with a drop of 20% in graft survival at 3 years. In pancreas transplantation donor age also plays a critical role in the outcome of the graft. There are very few studies on pediatric pancreas donors but very good results have been obtained with donors as young as 5 years.10 It is instead generally accepted that when donors older than 45 are utilized the graft survival decreases with a drop as high as 20% at 1 year when donors younger than 50 years of age are compared with donors older than 50 years.11,12 GENDER At the present time grafts are not allocated according to gender, and donor/ recipient sex mismatch does not play a role in the scheme. Nevertheless, there have been several reports of poorer results when a graft from a female donor is given to a male. The reason for this decreased graft survival is unknown, but it is speculated that the estrogen/androgen receptor may be a factor.13,14 Gender mismatch seems to have even a stronger impact if the donor is elderly, but becomes less important if there is a complete HLA match or if a retransplant is performed.15 Due to the present shortage of suitable donors and the lack of scientific knowledge to support the above described clinical findings, gender does not influence organ allocation and gender mismatched organ transplants are an accepted practice in any center. SIZE Body size is not one of the criteria in allocating kidney grafts. Technically, it is always possible to place the kidney in the retroperitoneal space and perform the vascular anastomosis in the adult recipient regardless of the size of the graft. As mentioned earlier, the use of kidneys from pediatric donors less than 5 years of age is associated with a higher incidence of surgical complications related to the vascular anastomosis. Of greater importance is the issue regarding the function of a kidney donated by a small size donor, pediatric or not, when transplanted in a patient with a bigger body habitus. There are reports of decreased graft functioning and survival when there is a greater than 20% body weight discrepancy between donor and recipient, probably because of a smaller nephron reserve that would enhance susceptibility to immunologic or nephrotoxic injuries. This factor has been suggested as one of the variables in the poorer results when a kidney from a female donor is given to a male recipient or when a pediatric donor is used

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for an adult.15 In the latter case en bloc renal transplantation, using both kidneys from a pediatric donor on a single aortic and vena cava conduit has been used in order to overcome size mismatch. In liver transplantation chest circumference, height and weight are recorded in the recipient information together with blood group, sex, age and diagnosis. A recipient of about 170 pounds can accommodate a liver from a donor with a weight range of 100 to 300 pounds, especially when ascites is present. The transplant of a liver too big for the recipient can have devastating consequences on its function such as caval compression and venous congestion, parenchymal necrosis, portal vein thrombosis, delayed closure of the abdomen and need for a splenectomy. A small liver in a large recipient can be a problem becasue of rotation of the allograft around the cava-axis creating a kink in the suprahepatic vena cava and venous congestion of the liver. The size factor has always been a problem in pediatric transplantation due to the small number of pediatric donors available. In pediatric liver transplantation, a donor-recipient weight ratio can be used as a guide to determine if the whole organ can be transplanted or a reduced size using the left lobe with the donor vena cava or a split using segments 2 and 3 of the donor without vena cava will be needed. Different values of donor-recipient weight ratio, from 2 to 12, have been reported when the technique of reduced size liver transplantation is used, to be critical nevertheless, a donor recipient weight ratio greater than 6 indicates the need for size reduction of the graft, especially in the absence of splenomegaly or ascites in the recipient.16 The other very important implication of size is the presence of fatty liver in the overweight donors. Obese donors are at high risk for having severe macrovesicular steatosis which is associated with high incidence of primary nonfunction.17 When presented with an obese donor, > 130% ideal body weight, a biopsy of the graft should be performed and a percentage of macrovesicular fat greater than 40% should preclude transplantation. The importance of microvesicular fatty infiltration is not clear but a recent report states that no difference in patient and graft survival is seen if grafts with severe microvesicular steatosis are used.18 When borderline fatty grafts are used, keeping the cold ischemia time short, i.e., less than 6 hours, appears to minimize the problem of poor graft function connected with fatty infiltration. It is essential to visually evaluate the graft both at the time of the first exploration and after the portal flush. A liver with a yellowish appearance, rounded margins and firm consistency after flushing should be discarded or should at least require a biopsy. The increasing use of donor percutaneous liver biopsy has allowed a useful preoperative screening and saved unnecessary surgical explorations. Nevertheless, if the surgeon in charge of the donor operation judges that the liver is not obviously unusable it is our policy to bring the graft back home with a biopsy. It is important to stress that these biopsies have to be obtained with a tru-cut needle, processed as frozen sections, prepared with regular hematoxylineosin stain without using any fat stains, since they stain even a normal liver, and read by a pathologist with expertise in the field and by the transplant surgeon. A tru-cut needle biopsy is favored over a wedge biopsy because the latter is always affected by subcapsular changes.

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CAUSE OF DEATH Although not very often contemplated in the screening of the donor, the cause of death may alert the transplant surgeon to some of the factors that may play a role in the retrieval operation itself and also in the long-term outcome of the graft. For example, in a donor who died in a motor-vehicle accident attention should be directed to the possibility of abdominal and/or thoracic injuries. Donor death by cerebral vascular accident should warn the accepting surgeon of the possibility of vascular disease of the aorta involving the orifices of the celiac axis and the renal arteries, thus making the transplant not feasible or increasing the chances of arterial complications after the transplant. In a liver donor whose death was associated with a prolonged hypoxic event, i.e., suffocation, drowning in warm water, esophageal intubation, it is important to consider the possibility of hypoxic hepatic cellular damage and impending cellular death manifested by nuclear pyknosis. Liver grafts from donors who died of cranial injury have proved to have better survival than in the case of cerebral hemorrhage.19 There have been reports that donor death by head injury plays a role as an independent factor on graft outcome.20 A report from Gruessner points out how the association between donor age and cardio-cerebral cause of death could become a significant detrimental factor in posttransplant pancreas function.21 PAST MEDICAL HISTORY There is little data available regarding criteria of acceptance for donors with previous history of hypertension and/or diabetes. A short history of hypertension, well controlled with only one medication, should not be of major concern to the accepting surgeon. Donors requiring more than one medication to control their hypertension and/or whose medical history is positive for insulin-dependent diabetes mellitus, peripheral vascular disease or myocardial infarction should undergo a biopsy of both kidneys prior to the acceptance of the organs. The biopsy allows the assessment of the degree of glomerulosclerosis, interstitial fibrosis and arterial changes and thus determines the suitability of the kidneys for transplantation. Diabetes per se is not a contraindication to organ donation, with even some evidence that diabetic nephropathy can be reversed after transplant of the kidney in a nondiabetic patient. However, the presence of other comorbidities and a long history of insulin-dependent diabetes mellitus would warrant a biopsy of the graft prior to the transplant. In liver transplantation, diabetes and hypertension do not play a role in ruling out a potential donor but when long lasting, severe and/or associated with other risk factors like old age or obesity, they mandate a biopsy of the graft to assess fatty infiltration. Any history of metabolic disease like alpha1antitrypsin deficiency, hemophilia, glycogen storage disease or sarcoidosis is an absolute contraindication to the use of the liver graft. Oxalosis is also a contraindication for kidney donation, since the patients are usually discovered by renal dysfunction. Regarding pancreas transplantation two absolute contraindications to the use of the allograft are past medical history in the donor and the donor who is positive for pancreatitis or diabetes mellitus.

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INFECTIONS Most surgeons would refuse donors with active systemic bacterial infection because of the risk of transmitting it to the immunosuppressed patient. An infectious process localized to any organ system outside the abdominal cavity does not represent an absolute contraindication to liver, kidney or pancreas transplantation. A donor with history of treated sepsis with recent negative blood culture is suitable for donation. Also, in the case of meningococcal and pneumococcal sepsis, donors who have received 24-48 hours of penicillin should be considered. An interesting issue is raised by the hepatitis C serology positive donor. Most of the reports confirm the risk of transferring the virus from the donor to the recipient and the high probability of the recipient developing active disease. At the same time there seems to be increasing consensus in transplanting kidneys from hepatitis C positive donors in hepatitis C positive recipients.22 The almost universal seroconversion in a recipient of a hepatitis C serology positive donor and the high incidence of histology-proven recurrence make the hepatitis C positive donors suitable only for patients with end-stage liver disease caused by hepatitis virus C. In hepatitis C positive recipients, the use of hepatitis C positive donors have not demonstrated any impact on disease recurrence and graft or patient survival. A biopsy of the donor positive liver is mandatory in order to exclude those organs with histopathological signs of viral damage. However, for hepatitis C positive recipients in an urgent need for a transplant, using informed consent, we have used hepatitis C positive donors with chronic active hepatitis and even bridging fibrosis with good results.23 Positive cytomegalovirus (CMV) serology in the donor does not seem to have any adverse effect on patient and graft survival even when the recipient is seronegative for CMV.24 This is in contrast with earlier experiences that showed a decreased graft and patient survival when a graft from a CMV positive donor was given to a CMV negative recipient and reflected the excellent results obtained from prophylaxis with the anti-viral medication ganciclovir. Nevertheless, documented severe CMV infection may affect the allocation of the organ since it can have a negative impact on patient and graft survival when the recipient is CMV negative.19,25 ORGAN FUNCTION The stability or deterioration of the function of each organ since the event leading to brain death must be evaluated, taking into consideration the cause of death, any cardiac arrest, cardiovascular stability and the donor age. Organs from young donors, less than 25 years old, withstand even a significant injury and seem to heal quickly with minimal consequences on posttransplant organ function. Often the stabilization of the donor hemodynamics and the normalization of the fluid status are crucial and sufficient actions in stopping a downward trend in the patient condition and the function of the potentially transplantable organs, but no further delay should occur in the organ’s procurement.

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KIDNEY The assessment of renal function is based on creatinine and BUN at the time of the admission of the donor to the hospital and on hourly urine output. Increasing creatinine values or decreasing urine output may reflect acute tubular necrosis (ATN) due to prerenal factors and does recover after the transplant. A study by Busson analyzing donor serum creatinine levels and hourly urine output did not show any significant difference in graft survival even in the presence of creatinine higher than 3mg/mL and urine output less than 30 mL/h.19 However, a biopsy should be performed in those donors who, together with increasing creatinine values and decreasing urine output, have other comorbidities that affect renal function. This is particularly important in donors with history of diabetes in order to diagnose Kimmelsteil-Wilson nephropathy. LIVER Presently, the only method of assessing liver function is the evaluation of liver function tests, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamine transferase (GGT), alkaline phosphatase and of the coagulation parameters. Although they are not perfect predictors of posttransplant graft function they do give a fair indication of the liver status. It is ideal to have liver function tests within normal limits; although, this is rarely seen in most of the donors, but a slight or moderate increase in values usually does not constitute a serious problem.26 It is normal to accept a graft from a donor who first presented with moderately elevated liver biochemistries that decline to normal or near-normal after the resuscitation phase. Donor age and cause of death are crucial factors to take into account when assessing such organs. Initial transaminases as high as 800 U/liter in a young donor following traumatic death, that subsequently improved declining toward normal values, reflect the function of a graft that is usually perfectly usable. On the other hand, rising levels should warn the surgeon of a suffering liver and suggest a biopsy of the graft. In these cases it is also very important to diagnose the cause of poor functioning of the liver and act promptly on the donor in order to save the organs. In summary, the transplant surgeon must always evaluate the organ function and its development in relation to the cause of death, the donor age and past medical history. Despite the reports of good assessment of liver function with the MEGX test and its use as a predictive tool of posttransplant organ functioning, this test has not achieved widespread use in the United States.27 The measurement of amylase level and glycemia are the only indirect methods of determining good pancreatic function. It is clear that the isolated amylase level per se is not an indicator of poor function, and most of the transplant surgeons do not consider an elevated amylasemia as a criterion to reject the donor. The presence of hyperglycemia in a donor without history of diabetes is no longer a contraindication to the use of the pancreas. Earlier reports of decreased graft survival in pancreata obtained from hyperglycemic donors28,29 have not been confirmed by more recent studies.11,30

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HOSPITAL COURSE A short hospital stay is always preferable and in some reports is associated with better outcome,20 but as long as the donor has had a stable course and no signs of sepsis, there is not a set length of stay that should preclude the use of the organs. The main problems caused by a long hospital stay are the deterioration of organ function secondary to complications and use of potentially toxic drugs, and the increased risk for nosocomial infections (staphylococcus, klebsiella, fungi). The use of vasopressors and cardiopressors in the form of dopamine and/or epinephrine to maintain normal/acceptable cardiovascular hemodynamics is common. These medications are often required to maintain a mean blood pressure above 60 mm Hg that allows good perfusion of the transplantable organs.14,26 We strive to maintain the systolic blood pressure above 100 mm Hg and start vasopressors only if absolutely necessary. The use of vasopressors instead of fluid resuscitation is routine in patients with head injury. Once brain death has been established, appropriate fluid therapy should be favored over vasopressors to maintain hemodynamic stability and the vasopressors should be stopped or at least decreased. To rule out a potential donor only on the basis of high doses of vasoand cardiopressors is not always appropriate. Past medical history, length of time that the pressor medication has been infused and change in the dosage of pressor medications over time in order to maintain adequate perfusion pressure are all factors that must be considered prior to accepting or refusing the potential donor. A single center study, looking at pancreatic graft function, outlined duration of brain death prior to the procurement, 15 hours or longer, and length of hospital stay from admission to brain death, 48 hours or longer, as predictors of graft failure.31 The factors above must be critically analyzed by the transplant surgeon and taken into consideration at the time of the surgery when the organs are visually evaluated, the anatomy defined and the vasculature examined. The final decision in transplanting the organ comes from the summation of all the information acquired during the work-up and actual status of the organ at the time of the retrieval.

THE MARGINAL DONOR A plethora of articles has been written on the issue of the “marginal donor,” i.e., any donor who for age, body habitus, past medical history, unstable hemodynamics and length of stay in the hospital represents a potential risk of posttransplant organ dysfunction and would not assure the same consistency of patient and graft survival as the ideal donor.26,32-35 The use of these donors is somewhat justified by the ever-increasing gap between the number of patients on the waiting list for organ transplantation and the number of available donors. It must be also stated that with a positive assessment of the organ and excellent technique in the retrieval by the accepting transplant surgeon, the risk of transplanting an organ that will not function can be minimized and patient and graft survival can match the ones of the patients who received organs from ideal donors. The almost

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general consensus is that, although it is clear that there is a decreased graft survival rate of an average of 10% at 5 years when marginal donors are used, this is counterbalanced by a greater number of patients who undergo transplantation with nonideal organs, do well and return to a normal life. With the increasing number of patients dying while on the transplant waiting list we cannot limit donations to only “ideal donors.” The use of marginal donors is now the norm in any large transplant institution. At times, when relying solely on the information collected by the organ procurement coordinator, it is very difficult to decide whether a potential donor is acceptable. In these cases of uncertainty the personal, visual and tactile assessment of the donor surgeon correlates with graft survival better than any other objective test, and it has been shown to be the only variable significantly correlating to the quality of the retrieved liver.35,36 As a rule of thumb: the surgeon should retrieve all organs which are not clearly unusable and obtain biopsies that should be read at the home institution together with a senior pathologist with expertise in that particular organ system. The use of routine biopsies in kidneys from nonideal donors has not increased the number of available organs but has greatly helped in discarding the ones that for unacceptable degree of glomerulosclerosis, > 10-20%, presence of interstitial fibrosis and arteriolar changes would have been at great risk of poor function. Interesting reports of good results (actuarial 1 year graft survival of 100%) with the transplant of the two kidneys from a marginal donor in the same recipient may increase the acceptance criteria to include older donors with up to 30% of glomerulosclerosis or frozen section.37 SMALL BOWEL Intestinal transplantation is still in its early era and so no recognized guidelines in the selection of the donors exist. Overall, the same criteria outlined above for the liver are utilized for the small bowel donor, also considering that at the present time most intestinal transplants are performed in combination with the liver. At our institution we consider a potential donor for bowel transplant a person less than 45 years of age, nonobese, CMV negative and of the same blood group of the recipient. With increasing experience in this field some of these criteria, like the blood group barrier, may prove not to be such a determinant in the outcome of the intestinal transplant recipients.38-40

NON-HEART-BEATING DONORS The use of non-heart-beating donors is not a new concept; in fact, it constituted the only method of organ procurement at the beginning of the era of transplantation. In the past few years the use of non-heart-beating donors has witnessed a comeback. In Japan, for social reasons, non-heart-beating donors represent, together with living-related donation, the main source of transplantable organs. In the United States its use represents an adjunctive way of increasing the number of available organs. This method has been mainly reserved for the

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procurement of kidneys and pancreata although an extension to the utilization of liver and lung grafts has been attempted in some centers.41 The criteria utilized in the selection of these donors are the same described above for the cadaveric donors, the difference being represented by the method of procurement and the longer warm ischemia time.42 The results in a recent report by a center with a large experience with nonheart-beating donors show kidney graft survival at 1 and 2 years of 84% and 76%, respectively and are comparable with the one obtained from heart-beating cadaveric donors 90% and 85%, respectively.43 Also, in the case of pancreas transplantation, good results were obtained with 8 out of 11 patients reaching posttransplant insulin independence, when non-heart-beating donors were younger than 55 years, had only 10 minutes of warm ischemia time, and in situ perfusion with cold UW solution.44 The experience with liver procurement from a non-heart-beating donor appears to be promising. The University of Wisconsin was able to increase the number of organs transplanted by 8.6% over a 17-month period. The practice of using such donors should possibly be pursued more aggressively in view of the fact that the survival of these grafts is comparable to the ones from the marginal donors. REFERENCES 1.

2.

3.

4. 5. 6. 7.

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1996 Annual Report of the U.S. Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation Network—Transplant Data: 19881995. UNOS, Richmond, VA, and the Division of Transplantation, Bureau of Health Resources Development, Health Resources and Services Administration, U.S. Department of Health and Human Services, Rockville, MD, page 65. Gonwa TA, Atkins C, Zhang YA et al. Glomerular filtration rates in persons evaluated as living-related donors: Are our standards too high? Transplantation 1993; 55(5):983-985. Heffron TG, Emond JC. Living related liver transplantation. In: Busuttil RW and Klintmalm GB, eds. Transplantation of the Liver. Philadelphia: WS Saunders Publishing Co 1996:518-528. Trinkle JK, Banowsky LHW. Identification and management of organ donors. Texas Medicine 1988; 84:38-43. Penn I. Donor transmitted disease: Cancer. Transplant Proc 1991; 23(5): 2629-2631. Hauptman PJ, OíConner KJ. Procurement and allocation of solid organs for transplantation. N Engl J Med 1997; 336(6):422-431. CDC. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. MMWR 1994; 43(RR-8): 1-17. Wachs ME, Amend WJ, Ascher NL et al. Risk of transmission of hepatitis b from HbsAg(-), HbcAb(+), HBIgM(-) organ donors. Transplantation 1995; 59(2):230-234. Harmon WE, Alexander SR, Tejani A et al. The effect of donor age on graft survival in pediatric cadaver renal transplant recipients—A report of the North American pediatric renal transplant cooperative study. Transplantation 1992; 54(2):232-237.

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Abouna GM, Kumar MSA, Miller LI et al. Combined kidney and pancreas transplantation from pediatric donors into adult diabetic recipients. Transplant Proc 1994; 26(2):441-442. Gruessner RWG, Troppmann C, Barrou B et al. Assessment of donor and recipient risk factors on pancreas transplant outcome. Transplant Proc 1994; 26(2):437-438. Gruessner A, Gruessner R, Moudry-Munns K et al. Influence of multiple factors (age, transplant number, recipient category, donor source) on outcome of pancreas transplantation at one institution. Transplant Proc 1993; 25(1):1303-1305. Brooks BK, Levy MF, Jennings LW et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation 1996; 62(12):1784-1787. Marino IR, Doyle HR, Aldrighetti L et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995; 22(6):1754-1762. Neugarten J, Silbiger SR. The impact of gender on renal transplantation. Transplantation 1994; 58(11):1145-1152. de Ville de Goyet J and Otte JB. Cut-down and split liver transplantation. In: Busuttil RW and Klintmalm GB, eds. Transplantation of the Liver. Philadelphia: WS Saunders Publishing Co., 1996:481-496. DíAlessandro AM, Kalayoglu M, Sollinger HW et al. The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. Transplantation 1991; 51(1):157-163. Fishbein TM, Fiel MI, Emre S et al. Use of livers with microvesicular fat safely expands the donor pool. Transplantation 1997; 64(2):248-251. Busson M, NíDoye P, Benoit G et al. Donor factors influencing organ transplant programs. Transplant Proc 1995; 27(2):1662-1664. Greig PD, Forster J, Superina RA et al. Donor-specific factors predict graft function following liver transplantation. Transplant Proc 1990; 22(4):2072-2073. Gruessner AC, Barrou B, Jones J et al. Donor impact on outcome of bladderdrained pancreas transplants. Transplant Proc 1993; 25(6):3114-3115. Alexander JW, Zola JC. Expanding the donor pool: Use of marginal donors for solid organ transplantation. Clin Transplantation 1996; 10:1-19. Testa G, Goldstein RM, Netto G et al. Long-term outcome of patients transplanted with liver from hepatitis C-positive donors. Transplantation 1998; 65(7):925-929. Krishnan G, Vaughn WK, Capelli JP et al. Positive donor/recipient CMV status is not a detrimental factor for renal allograft/patient survival. Transplant Proc 1993; 25(1):1485-1486. Schnitzler MA, Woodward RS, Brennan DC et al. The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: Implications for organ allocation. Am J Kidney Dis 1997; 29(3):428-434. Mor E, Klintmalm GB, Gonwa TA et al. The use of marginal donors for liver transplantation. A retrospective study of 365 liver donors. Transplantation 1992; 53(2):383-386. Oellerich M, Burdelski M, Ringe B et al. Functional state of the donor liver and early outcome of transplantation. Transplant Proc 1991; 23(1):1575-1578. Hesse UJ, Gores PF, Sutherland DER. Serum amylase and plasma glucose levels in pancreas cadaver donors: correlation with functional status of the pancreatic graft. Transplant Proc 1989; 21:2765-2766.

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Gores PF, Gillingham KJ, Dunn DL et al. Donor hyperglycemia as a minor risk factor and immunologic variables as major risk factors for pancreas allograft loss in a multivariate analysis of a single institutionís experience. Ann Surg 1992; 215(3):217-230. Shaffer D, Madras PN, Sahyoun AI et al. Cadaver donor hyperglycemia does not impair long-term pancreas allograft survival or function. Transplant Proc 1994; 26(2):439-440. Douzdjian V, Gugliuzza KG, Fish JC. Multivariate analysis of donor risk factors for pancreas allograft failure after simultaneous pancreas-kidney transplantation. Surgery 1995; 118(1):73-81. Leikin JB, Heyn-Lamb R, Aks S et al. The toxic patient as a potential organ donor. AM J Emerg Med 1994; 12(2):151-154. Alexander JW, Vaughn WK. The use of ìmarginalî donors for organ transplantation. The influence of donor age on outcome. Transplantation 1991; 51(1):135-141. Alexander JW, Vaughn WK, Carey MA. The use of marginal donors for organ transplantation: The older and younger donors. Transplant Proc 1991; 23(1):905-909. Makowka L, Gordon RD, Todo S et al. Analysis of donor criteria for the prediction of outcome in clinical liver transplantation. Transplant Proc 1987; 19(1):2378-2382. Hoofnagle JH, Lombardero M, Zetterman RK et al. Donor age and outcome of liver transplantation. Hepatology 1996; 24(1):89-96. Johnson LB, Kuo PC, Schweitzer EJ et al. Double renal allografts successfully increase utilization of kidneys from older donors within a single organ procurement organization. Transplantation 1996; 62(11):1581-1583. Webb MG, Tzakis AG, Olson L. Donor small bowel procurement. In: Phillips MG, ed. UNOS Organ Procurement, Preservation and Distribution in Transplantation. 2nd ed. Richmond: UNOS, 1996:139-143. Sindhi R, Fox IJ, Heffron T et al. Procurement and preparation of human isolated small intestinal grafts for transplantation. Transplantation 1995; 60(8):771-773. Langnas AN, Shaw BW Jr., Antonson DL et al. Preliminary experience with intestinal transplantation in infants and children. Pediatrics 1996; 97(4):443-448. D’Alessandro AM, Hoffmann RM, Knechtle SJ et al. Controlled non-heart-beating donors: A potential source of extrarenal organs. Transplant Proc 1995; 27(1):707-709. Eckhoff DE, D’Alessandro AM. The non-heartbeating donor. In: Phillips MG, ed. UNOS Organ Procurement, Preservation and Distribution in Transplantation. 2nd ed. Richmond: UNOS, 1996:183-189. Hattori R, Kinukawa T, Ohshima S et al. Outcome of kidney transplantation from non-heart-beating donors: Comparison with heart-beating donors. Transplant Proc 1992; 24(4):1455-1456. Teraoka S, Babazono T, Tomonaga O et al. Donor criteria and technical aspects of procurement in combined pancreas and kidney transplantation from nonheart-beating cadavers. Transplant Proc 1995; 27(6):3097-3100.

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Organ Preservation James H. Southard Introduction .......................................................................................................... Brief Historical Perspective on Organ Preservation .............................................. Principles of Organ Preservation .......................................................................... Delayed Graft Function and Chronic Rejection ................................................... Future of Organ Preservation ...............................................................................

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5 INTRODUCTION The development of methods to safely preserve organs retrieved from victims of life-ending accidents greatly improved the versatility of human organ transplantation. In fact, the development of organ preservation is one of the cornerstones on which organ transplantation is built. Safe methods for organ preservation meant that organs thousands of miles from the recipient could be used for transplantation. Preservation also provided the time needed to identify the right recipient based on immunological tissue matching, size of organ and urgency of need for the transplant. Thousands of organs have been successfully transplanted, transforming the prospects of patients with end-stage organ diseases from one of potential death or serious morbidity to practically normal, useful and fulfilling lives. This great medical revolution is due not only to the availability of safe organ preservation methods, but also to the development of innovative surgical techniques and immunosuppression methods. All of this enormous success is directly attributed to the concerted efforts of research scientists exploring and solving problems related to human medicine with animal experimentation. Clearly, the role of organ preservation in clinical organ transplantation is and continues to be of great importance.

BRIEF HISTORICAL PERSPECTIVE ON ORGAN PRESERVATION It was apparent from the experiments of Medawar in the 1940s that allografted tissues and organs would be vigorously attacked by the recipient’s immune system and destroyed in a short time. Early attempts at kidney transplantation failed in animals due to rejection of the allograft. There was little concern about preserving organs at this time because of the immunological hurdles that needed to be overcome. In the 1950s and 1960s, studies to understand the nature of allograft rejection as well as the discovery of agents (beta-mercaptopurine) to block rejection Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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were critical components in making organ preservation a clinical reality. Clinicians and basic scientists recognized that the availability of drugs to constrain rejection made it possible to use immunologically mismatched tissues obtained from cadaveric organ donors. Using cadaveric organs as the major source of organs for transplantation would be the only way to make transplantation therapy widespread. In the 1960s, after Murray demonstrated successful kidney transplantation in a set of twins, several laboratories became active in pursuing organ preservation. Many laboratories made contributions, especially those of Pegg and Calne in Cambridge, UK, Belzer at the University of California (San Francisco), Collins at UCLA, Starzl in Denver and Pittsburgh, Marshall in Melbourne, and Halasz in San Diego. At this time, these labs’ primary interest was in kidney preservation. The concept of metabolic inhibition by hypothermia as a cornerstone of organ preservation was quickly accepted. Pegg and his colleagues1 attempted to preserve kidneys by simple cooling in cold saline or blood. They achieved successful results, viable as tested by transplantation, with preservation times of about 12 hours. Belzer et al2 reasoned that continuous hypothermic perfusion with a biologically based fluid (plasma) would be superior to simple cold storage of the kidney because the organ would be continuously supplied with metabolic-stimulating substrates, removing end products of metabolism. This would not only stimulate and support hypothermic metabolism but also allow tissues injured during the agonal period and harvest to be repaired. This was demonstrated successfully by transplanting dog kidneys after preservation for three days using low perfusion pressure (50-60 mm Hg), low flow (about 0.6-1.0 mL/min/g) and oxygenated cryoprecipitated plasma (CPP). CPP was prepared by freezing and thawing autologous dog plasma to remove cold-sensitive lipoproteins (by millipore filtration). These lipoproteins, which were found to aggregate in the kidney glomerular vessels,3 cause an increase in renal vascular resistance, endothelial cell injury, and possibly occlusion and ischemia in portions of the kidney. This method of machine perfusion using CPP as the perfusate became the standard method of human kidney preservation in the early 1970s4 and helped to increase dramatically the number of renal transplants performed nationally. At this time there was no clear definition or acceptance of brain death as a criterion for organ removal. Therefore, most organs were obtained from donors that were allowed to undergo death as judged by cessation of heart function. This resulted in kidneys that were not well-perfused for varying lengths of time, while death by cessation of heart function was awaited. Machine perfusion allowed successful preservation of these ‘less than ideal’ kidneys damaged by hypotension or ischemia. It has since been shown5-6 that machine perfusion for “less than ideal” kidneys is superior to other methods such as simple cold storage. In the late 1970s Collins et al7 showed that dog kidneys could be safely preserved for 30 hours by simple cold storage. This method relied on refrigerated storage after flushout with a solution composed primarily of glucose, potassium, and phosphate. The Collins solution contained a high concentration of K+, used to suppress the loss of intracellular K+ that occurred in metabolically depressed

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cells in exchange for extracellular cations, principally Na+.8 This so-called “extracellular-type solution” became the standard method for human kidney preservation over the next 8 to 10 years, primarily because of its simplicity. At this time, brain death also had become a criterion for organ donation; thus, organs could be retrieved from heart-beating cadavers. No machine was required, the solution was simple to prepare and shelf-stable, and the time of safe preservation (about 24 hours) was sufficient for use of most cadaveric kidneys. Since these two landmark developments in organ preservation, many modified preservation solutions have been tested, but only a few have been found to be significantly better. Table 5.1 lists the various preservation solutions used either experimentally or clinically and the reference that describes the composition and method of use. Two solutions developed in the late 1980s at the University of Wisconsin have had much success in advancing organ preservation. The composition of these solutions is given in Table 5.2 and Table 5.3. The UW solution (ViaSpan, DuPont) is a cold-storage solution that extended preservation times for the liver9 and pancreas10 from about 4 hours (with Collins solution) to between 30 and 72 hours. The UW solution appears to give better and longer-term preservation of kidneys11 than the Collins-type solutions, and is safe for 6 to 12 hours’ preservation of the heart and lung.12,13 Also, the UW gluconate solution (Belzer machine perfusion solutions, MPS) has found widespread use in the few centers that continue to use machine perfusion of kidneys.14 This solution is similar to the UW cold-storage solution, except that lactobionate has been replaced with gluconate, and the Na+/K+ ratio is higher. The UW gluconate solution has been used to obtain successful dog kidney preservation for 5 and 7 days.15,16 A modification of this solution is also capable of preserving the dog liver by machine perfusion for 3 days.17 Table 5.1. Some preservation solutions used clinically Solution Name

Active Components

Reference

Collins (1967)

PO4 buffered glucose solution

#7

Euro-Collins (1980)

Same as Collins (no Mg2+)

Euro Surg Res 12 (Suppl 1):22, 1980

Hypertonic Citrate (1976)

Citrate, mannitol

Transplantation 21:498, 1976

PBS (1989)

PO4 buffered sucrose

Clinical use = Transplantation 48:1067, 1989 Discovery = Transplantation 35:136, 1983

HTK (Date 1970s)

Histidine

Trans Proc 22:2212, 1990

Silica-gel Plasma (1974)

Perfusion solution Plasma defatted with silica gel

Surg Gyn Obstet 138:901 (1974)

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Table 5.2. UW cold storage solutiona Substance +

5

K -lactobionate (mM) KH2PO4 (mM) MgSO4 (mM) Raffinose (mM) Adenosine (mM) Glutathione (mM) Insulin (U/L) Bactrin Dexamethasone (mg/L) Allopurinol (mM) Hydroxyethyl starch (g/L)

Amount 100 25 5 30 5 3 100 0.5 ml/L 8 1 50

a

This solution is brought to pH 7.4 at room temperature with NaOH. The final concentrations are: Na+ = 30 ± 5 mM; K+ = 120 ± 5 mM; mOsm/L = 320 ± 5. Bactrim = trimethoprim (16 mg/ml) and sulfamethoxazole (80 mg/ml).

Table 5.3. Composition of the UW Hydroxyethyl starch/K-Gluconate Solution* Substance K-gluconate Raffinose Ribose NaH2PO4 Mg-gluconate Adenine Adenosine Hydroxyethyl starch Gutathione Glucose HEPES Insulin Dexamethasone Cotrimoxazole CaCl2+

Concentration 100 mmol/L 35 mmol/L 1 mmol/L 25 mmol/L 5 mmol/L 1 mmol/L 5 mmol/L 50 g/L 3 mmol/L 5 mmol/L 10 mmol/L 100 U/L 16 mg/L 2 ml/L 1.5 mmol/L

*

The pH is adjusted by the addition of NaOH/KOH (1:3) to pH = 7.7 (at room temperature). ± CaCl2 was omitted when the solution was used for the initial flush.

PRINCIPLES OF ORGAN PRESERVATION

SIMPLE COLD STORAGE This method involves flushout of the organ with a suitable solution to remove blood elements and to cool the organ. The organ is then stored in the preservative solution at a temperature of 0° to 4°C.

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The success of this method is dependent upon the use of hypothermia. Cooling the organ from 37°C to 0° to 4°C slows enzymatic reactions by 10-fold or more.18 The low temperature is one of the most critical components of successful preservation. This is evident by considering the differences in organ viability when exposed to cold ischemia versus warm ischemia. In warm ischemia, organs lose viability in a couple of hours or less, depending upon the organ. Under the condition of cold ischemia, organ viability is extended many fold. The kidney tolerates up to about 12 hours of cold ischemia when flushed out and stored in cold blood,1 but will tolerate only about 60-90 minutes when stored warm.19 Why hypothermia is effective is deduced from mechanisms of ischemic injury proposed to cause organ death at normothermia.20,21 In warm ischemia the lack of oxygen and perfusion leads to a very rapid decrease in the availability of energy (ATP) derived from mitochondrial and glycolytic catalyzed reactions. Without ATP, the tissue loses control of its intracellular environment, resulting in changes in cytosolic ionic composition (protons, Ca2+, K+, Na+), activation of hydrolytic enzymes (phospholipases, proteases, endonucleases), and destruction in the stability of the intracellular structural components (microtubules, cytoskeleton membranes). It is readily apparent that the loss of ATP is the critical factor in induction of ischemic injury. For instance, the tolerance of the liver to an ischemic or hypoxic insult is extended significantly by stimulating anaerobic energy production through glycolysis.22,23 Similarly, inhibition of anaerobic energy production in the heart24 leads to a more rapid onset of irreversible ischemic injury. Preservation of the cold stored kidney can be extended by persufflation of oxygen into the organ,25 which appears to affect viability only by stimulating the rate of ATP turnover. The preservation of the pancreas has also been extended by exposing the organ to high concentrations of oxygen without continuous perfusion.26 This method also appears to improve preservation by a mechanism related to ATP generation.27 Although hypothermia slows down the rate of ATP loss in tissues and organs, this does not explain the beneficial effect of hypothermia. Most organs that are cold stored lose 90% or more of their ATP within 2 to 4 hours, yet when stored appropriately remain viable for one or more days. Hypothermia may be effective, therefore, by blocking the activities of various hydrolytic enzymes. This has been shown to increase the tolerance of organs, tissues and cells to ischemia.28 Various phospholipase and protease inhibitors have been shown to improve the viability of cells and tissues exposed to warm and cold ischemia.29 Hypothermia is the simplest method to block the activity of these enzymes. Clearly, enzymatic reactions continue at 0°-4°C, as is evident by the accumulation of end products of metabolism (lactate, glucose, purine nucleotides, etc.) in cold-stored tissues. It is likely that continued enzymatic activity leads to the ultimate destruction of the organ by altering its capability to re-establish metabolic control when rewarmed and reperfused, i.e., transplanted. The combination of hypothermia and chemical inhibition of enzymes is an attractive approach to suppressing cold ischemic injury. However, it is unclear which of the many intracellular enzyme systems is responsible for ischemic injury. Most likely a wide range of inhibitors would be needed to suppress the activity of multiple enzyme activities.

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Even with metabolic suppression by hypothermia, the longer an organ is subjected to ischemia, the greater the extent of reperfusion injury. At some point in time, the reperfusion injury becomes irreversible. Although hypothermia is the single most important factor in successful storage of organs for transplantation, there are other important considerations as well; lack of attention to them can negate the beneficial effect of hypothermia. One important factor appears to be the presence of impermeant molecules that remain outside the cells of the organ, helping them resist the tendency to swell during cold storage. Cell swelling is caused by the metabolic inhibition associated with hypothermia and lack of energy production due to hypoxia. The intracellular milieu, which contains a large number of impermeants (proteins, phosphorylated compounds, etc.), exerts osmotic and oncotic forces that tend to draw water into the cell. To resist this, the cell under normal conditions uses membrane-bound ion pumps (such as the Na+-K+ ATPase) to maintain a high concentration of K+ inside the cell and a high concentration of Na+ outside the cell. In this way, the large concentrations of Na+ act as an impermeant and energy is needed to maintain an equilibrium between intra- and extracellular water activities. This equilibrium helps the cell resist the tendency to gain water and swell, preventing the concomitant disruption of the cellular concentrations of reactants, activities of enzymes, and cell ultrastructure. In cold storage of organs, impermeants, such as saccharides (glucose, mannitol, sucrose, raffinose), colloids (hydroxyethyl starch, dextran, polyethylene glycols), and anions (phosphate, sulfate, lactobionate, gluconate) counteract the tendency for hypothermia-induced cell swelling and appear to provide stability to the ultrastructure of the cell during cold storage. The presence of the appropriate impermeant appears to be essential for successful long-term preservation of organs.30,31 Many of the earlier cold storage solutions, such as Collins, EuroCollins, Marshall’s hypertonic citrate, and others used saccharides as agents to counteract hypothermia-induced cell swelling. However, many of these agents were not completely impermeable and would enter the cell with time, thus losing their efficacy. Lactobionate and gluconate, the two impermeants in the UW solutions, have so far been the most successful in suppressing hypothermia-induced cell swelling for long periods of time and in every organ tested. These agents appear to be the most important ones in the UW solutions for successful preservation of organs for 24 to 30 hours. Other agents in preservation solutions may be less important than the impermeants, but were chosen for their potential usefulness in suppressing preservation or reperfusion injury.31 There is evidence that some of these agents do, in fact, assist recovery of function in cold stored organs; however, controversy exists about these issues. The use of antioxidants in organ preservation is a common approach to improving results. There are numerous studies32-34 showing that warm and cold ischemia/reperfusion leads to the rapid formation of oxygen free radicals (OFR). Furthermore, the generation of OFR during reperfusion of numerous organs leads to tissue injury. Numerous types of antioxidants have been shown to ameliorate reperfusion injury in many model systems.35-37 Also, during cold ischemia, there is

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a loss of the naturally occurring antioxidants vitamin E and glutathione.38,39 Thus, cold-stored organs are sensitive to OFR-induced injury because of the lower concentration of endogenous antioxidants. In the development of the UW solutions we used glutathione to enhance the antioxidant capacity of the solution and allopurinol to block the activity of xanthine oxidase. Xanthine oxidase has been proposed to be a major source of superoxide anions during reperfusion of ischemic organs.40 Studies have now shown that glutathione is an important component of the UW solution and can increase the viability of preserved dog livers,41 rat livers,42 kidney tubules,43 isolated hepatocytes,44 and hearts.45 The mode of action of glutathione is not clear but may be related to inhibition of proteases46 or reduction in lipid peroxidation stimulated by OFR generation.47 Furthermore, mitochondria are highly dependent upon glutathione for suppression of oxidative injury; preserving the liver in UW solution maintains the mitochondrial GSH level.48 GSH, however, is unstable in solution and is oxidized during storage.49 For this reason, our center adds fresh GSH (3 mmole per liter) to the UW solution prior to use for organ preservation. A controversy also exists over the need for a colloid (hydroxyethyl starch) in cold-storage solutions.50 The presence of a colloid in a preservation solution was based upon the need for an agent to counteract the hydrostatic pressure in continuous machine perfusion of organs. In cold storage, however, the organ is not exposed to an hydrostatic perfusion pressure except during the initial flushout of blood. Therefore, theoretically, there should be no need for a colloid in cold storage solutions. This is in fact the case and many preservation solutions, such as Collins or Marshall’s hypertonic citrate, have been used successfully for short periods of time without the presence of a colloid. Also, over the past few years, many investigators have attempted to develop their own preservation solution by using the basic components of the UW solution and subtracting various agents, such as the colloid, hydroxyethyl starch.51,52 Some studies suggest that there may be a role for the colloid, even in cold storage of organs. For instance, better preservation of the dog pancreas was obtained in the UW solution with starch versus that without.53 Preservation of the rat heart also seems improved when hydroxyethyl starch remained in the UW solution.54 Finally, hydroxyethyl starch has recently been shown to suppress proteolysis in cold-stored rat livers. Proteolysis is thought to be a contributing factor to liver injury during cold storage55 and its suppression may be a key factor in prolonging the viability and quality of preserved livers. For kidney preservation, however, the presence of a colloid has never been shown to be essential. Because the UW solution is used for the preservation of all transplantable organs, and because some organs are preserved better with the colloid, it would appear prudent to use the UW solution that contains hydroxyethyl starch for all cold stored organs. Another controversy in cold-storage solution composition is related to the solutions’ content of sodium and potassium. The clinically most popular and successful cold storage solutions were the so-called ‘intracellular-type’ solutions. These contained high concentrations of K+ relative to Na+, making them similar

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to the intracellular environment of most cells. Solutions such as Collins, EuroCollins, Marshall’s hypertonic citrate, and the UW solution all contain high concentrations of K+. The benefit of a high K+ concentration was thought to relate to the suppression of hypothermic-induced efflux of K+ during cold ischemia. Thus, the cell would retain a near-normal K+ concentration and would not need to expend a great deal of energy during reperfusion to re-establish a normal intracellular K+ concentration had the K+ been replaced with another cation, such as Na+. This has not been proven, but the concept may be valid. Conserving energy during the first minutes of reperfusion may be essential to providing the necessary energy for cellular repair and other critically important cellular functions. Many investigators,57 as well as our own studies,58 have shown that the electrolyte content of preservation solutions may not be critical and can be reversed to contain a high Na+ content relative to K+. Some investigators have attempted to show that a high K+ concentration is detrimental to organ storage,59 but others have found no such effect.60 Therefore, it appears clear that a preservative containing a high concentration of Na+ or K+ is probably equally effective for shortterm (24-30 hours) organ preservation. A key factor in successful organ preservation may be the rate of regeneration of ATP upon reperfusion. This requires leaving the energy-generating machinery (mitochondria) intact during preservation and reperfusion, as well as supplying the cell with the appropriate precursors for ATP regeneration. During cold storage there is a loss of the precursors for ATP synthesis. ATP is degraded to phosphate and its purine constituents. The purines are permeable across the cell membrane and rapidly flushed out of the tissue upon reperfusion.61 Thus, in developing the UW solution, adenosine was added to elevate the concentrations of this ATP precursor and provide substrate of ATP regeneration.62 Although there is not an apparent critical dependency of successful short-term organ preservation on adenosine, some studies have attested to its value in stimulating regeneration of ATP62 in the kidney, liver, heart and pancreas. The suitability of the UW solution for liver preservation has been recently questioned by some investigators63 because of the presence of microcrystalline materials. These investigators showed that in some bags of the UW solution there were crystals made up of salts of naturally occurring fatty acids (palmitate and sterate). Palmitate and sterate are components of the packing material and necessary as plasticizers for the manufacture of the containers. The fatty acid crystals form because of the relatively high pH of the UW solutions (pH 7.4) compared to other parenteral solution. The higher pH causes the fatty acids to slowly leach out of the container and form salts of Ca2+ or Mg2+. The study that showed that these crystals could be injurious in liver preservation came from measuring microcirculation of rat livers after about 16 hours cold storage.63 In livers stored in the presence of crystals, there was poorer blood reperfusion after cold storage than in livers stored in UW solution without crystals. Because of the presence of crystals in UW solution, the manufacturer has contacted the United States Food and Drug Administration, and with their guidance advised users of the UW solution to 1) discard bags if visible crystals are present, and 2) to use a blood filter (Pall) in

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the administrations of the UW solutions. It was shown in studies submitted to the FDA that the Pall filter effectively removed crystals from bags of UW solutions containing known loads of crystals. This demonstrates that there are certainly reasonable solutions to this problem. Our center has had little concern for the presence of these crystals in the UW solution for a number of reasons. First, on a macroscopic level, we have never observed crystalline materials in commercially produced bags of UW solution. Second, studies have shown a problem in rat livers but not yet in larger animals. Third, if the crystals are injurious, their effect should be seen in short-term preserved livers (1 to 2 hours) as well as in longer-term preserved livers, and this has not been shown. In fact, the incidence of liver problems, including primary nonfunction and initial poor function, increases slightly, but significantly, with preservation times above 24 hours,64,65 not including the early stages of preservation. Fourth, we have used commercially prepared UW solution for the past 10 years in clinical preservation of kidneys, livers, pancreases, hearts, and lungs, and have reported outstanding results. In fact, the results have been superior to those obtained with other solutions, presumably not containing crystalline materials. Fifth, other centers in the USA and Europe have also used commercially prepared UW solution for over 10 years and have also reported excellent results in organ preservation. Although it is clear that the presence of crystals of any type is not desirable in preservative solutions, it is also clear that they have caused no apparent problems in organ storage in the UW solution. Work is underway to find a suitable method to prepare the UW solution without crystalline materials without decreasing its efficacy and importance in organ preservation. In conclusion, simple cold storage is the most popular method for organ preservation because of its simplicity. The primary reasons cold storage is successful are because of the hypothermic-induced inhibition of metabolism, use of impermeants to suppress cell swelling, the presence of agents to stimulate metabolism on reperfusion, and the short periods of preservation used. This method is very suitable for preservation times of 24-30 hours, and most organs can be transplanted within this period of time. However, the simplicity of cold storage is also one of its drawbacks. First, this method is not well suited for preservation of nonideal donor organs, such as those exposed to hypoxia or ischemia during or prior to the harvest. This fact may become more important in the future because there is an increasing need for organs and great interest in procuring organs from non-heart-beating cadavers. These organs are exposed to varying periods of low flow and ischemia (20 to 60 minutes) and will require better methods of preservation (such as machine perfusion) than ideally harvested organs. Furthermore, many organs come from donors that are not ideal due to age, weight, cause of death, nutritional factors. Preservation of these organs may require more sophisticated means than simple cold storage to assure that good organ function is restored immediately after transplantation. Preservation/reperfusion injury may be a factor in acute and chronic rejection and may complicate immunosuppressive therapy after transplantation.66,67

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Finally, improving organ preservation by cold storage may be very difficult and we may have reached the clinically practical limits of successful cold storage (24 to 48 hours). In the laboratory, cold storage allows successful 48- to 72-hour preservation of the liver, kidney, and pancreas, but this is under relatively ideal conditions. The donor (a dog, pig, or rat) is usually ideal, healthy, well fed, and not traumatized by accidental death. Furthermore, the recipient is not ill with serious complications due to organ failure. Thus, clinically safe preservation by cold storage is probably more likely to be shorter than shown in the laboratory. Also, during cold storage there is a nearly complete loss of metabolic control due to the lack of a continuous input of energy and removal of metabolic end products. This leads slowly even at hypothermia to disruption of the functional and structural components of the cell, which are only able to remain stable with a constant supply of energy. It is sometimes argued that if we knew precisely the mechanisms of cold storage injury, we could use appropriate drugs to block the injurious reactions, either during cold storage or during reperfusion. There have been numerous attempts to accomplish this, but there has been very limited laboratory success. Most of the results have not found serious clinical utility. The reasons for this may be that the mechanism of cold ischemic injury is multifactorial, and blocking one or two reactions that lead to organ injury is not sufficient to prevent organ failure or injury. The agents that are effective may be those that improve the reperfusion of the organ, allowing a better opportunity for repair of damaged tissues and cells. Thus, agents such as nitric oxide donors, calcium channel blockers, antioxidants, and phospholipase or protease inhibitors all may function by increasing reperfusion of the microvascular of the organ. The future of organ preservation, therefore, may lie in developing or utilizing new methods, such as continuous machine perfusion. CONTINUOUS MACHINE PERFUSION Continuous machine perfusion, developed by Belzer et al,2 is used in about 6 to 8 centers in the US. Kidneys are perfused by a pulsatile perfusion pump (about 60 beats per minute) at a pressure of about 40-50 mm Hg, resulting in a flow rate of 0.5-1.0 mL/min/g per kidney. The perfusate is a UW-gluconate-based solution (Trans Med, Belzers MPS) as described above. The temperature is maintained at about 4°-6°C. A retrospective analysis of kidneys preserved by machine perfusion shows a one-year graft survival rate similar to those cold stored.67 However, there is significantly less delayed graft function (DGF) (need for dialysis) in machineperfused kidneys versus cold-stored kidneys. Centers that machine perfuse kidneys have reported DGF rates of less than 5 to 10%, compared to DGF rates for cold stored kidneys of, on average, greater than 20%.68-70 The cost of DGF nearly doubles the cost of a renal transplant71 and therefore, the possibility of reducing DGF should be an important consideration in choosing a method of preservation. Furthermore, the possibility of late graft failure due to chronic rejection (progressive injury to the renal vascular system) may be greater in kidneys showing initial poor function than in those with good initial function,72 as discussed below.

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These results suggest that machine perfusion is a better method for preserving organs than simple cold storage. This appears true for the kidney, liver, heart, lung, and pancreas. The lung and pancreas can be successfully preserved without continuous perfusion, but the continuous delivery of oxygen to the organ (one of the important functions of perfusion) maintains the ATP content and provides better protection than in the ischemic state. Machine perfusion not only maintains a high ATP content, but also removes end products of metabolism that could accumulate to toxic concentrations in the tissue. Machine perfusion also allows control of cellular pH and can continuously deliver substrates and other cytoprotective agents to the tissue. For instance, antioxidants, enzyme inhibitors, and precursors for cytoprotective agents could be delivered to the preserved organs. Thus, upon reperfusion (transplantation) the organ will be better suited to resist injury and regenerate more normal cellular concentrations of metabolites.

DELAYED GRAFT FUNCTION AND CHRONIC REJECTION Delayed graft function(DGF) occurs in every organ preserved and transplanted. The magnitude and consequences of DGF, however, is different for each organ. In the kidney DGF is characterized as the need for dialysis because of insufficient renal function to regulate the composition of the blood. Most kidney transplant patients with DGF recover near-normal function within a few weeks or so after transplantation. In the liver, delayed graft function (initial poor function) leads to longer ICU stays and can progress to primary nonfunction (PNF), requiring immediate retransplantation. In kidney transplantation there are now very few incidences of primary nonfunction. In heart and lung transplantation, delayed graft function inevitably leads to death because of the immediate need for these two organs to sustain life. However, in transplant of these organs there is often poor functional return immediately after transplantation and various methods of intraoperative assist are required to save the organ. Delayed graft function as related to preservation has been more comprehensively studied in renal transplantation than in other organs. The incidence of DGF increases with increasing preservation times. The percent of recipients requiring dialysis with kidneys preserved for 0 to 12 hours (n=7264) was 21%, at 13 to 24 hours (n=18682) 24%, at 25 to 36 hours (n=13585) 30%, and greater than 36 hours (n=5246) 35%.72 The incidence of delayed graft function is also a function of the type of cold storage solution;73 there is an approximate 10% reduction of DGF in kidneys preserved in UW versus EuroCollins solution. The method of preservation also affects the rate of DGF: machine perfused kidneys had on average an 18% rate of DGF versus 29% for those cold stored. The incidence of initial poor function (INF) or PNF in liver transplantation is also dependent upon the type of preservation solution used74 and length of preservation.64,65 In general, INF occurs in 10 to 12% of the patients and PNF in 2 to 6% of the recipients. Although these statistics suggest that DGF is related to preservation injury, it is also clear that DGF and PNF have many other correlates, including donor and

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recipient health. In fact, the donor and recipient may be greater determinants of the outcome of preservation/reperfusion injury than the conditions of preservation. For instance, kidneys preserved for only 0 to 12 hours showed a significant degree of DGF (21%). From laboratory studies, one would assume that this short period of time should have caused minimal to practically no injury to the kidney. The differences between the clinical and laboratory results could be the status of the donor and recipient; in the laboratory, both are healthy animals. In livingunrelated kidney transplantation, the incidence of DGF is very low since the kidneys are not subjected to lengthy preservation. However, the kidney is also harvested from a relatively healthy individual and this fact, combined with short to no preservation time, may contribute to the lack of DGF. Chronic rejection as a cause of loss of kidney grafts remains a major problem and there may be a relationship between initial renal injury and chronic injury. Studies from the Minnesota group suggest that both acute and chronic rejection are more prevalent in patients with kidneys that do not regain initial function rapidly.75 This is also supported by information obtained from the kidney transplant registry. The relationship between liver injury due to preservation and longterm complications is not clear. One study suggested greater rejection in livers that showed preservation/reperfusion injury than in those that functioned immediately.76 However, other studies did not show this relationship.77 Although the relationship between preservation/reperfusion injury and longterm graft survival may not be entirely clear, due to the many compounding factors involved in the process of transplantation and drug use, there should be little doubt that the most optimal methods of preservation should be advocated. Furthermore, it is also apparent that shorter preservation periods may give a more favorable outcome and since this is one of the few variables that can be controlled in organ transplantation, strong consideration should be given to the use of short preservation periods combined with the most ideal preservation method.

FUTURE OF ORGAN PRESERVATION Improving organ preservation by developing a new cold storage solution is a goal of many investigators. Currently, a common approach is to make minor changes in the UW solution and make a claim for an improved and different preservation. It may be difficult to dramatically improve organ preservation by simple cold storage and we may have reached the limits of safe storage (about 24 to 48 hours). The reason for this conclusion is based upon the organ’s need for a source of energy to prevent tissue destruction. Energy must be constantly brought into the thermodynamically unstable tissues and cells; otherwise, membranes, cytoskeletal networks, cell-cell interactions, and various complex molecular structures break down. In cold ischemic storage there is no currently known method to maintain a satisfactory energetic state without continuous perfusion with perfusate or oxygen. The use of machine perfusion may be the method that could improve organ preservation. Improving the quality and longevity of heart preserva-

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tion certainly may require continuous perfusion. In the heart, the lack of ATP leads to ischemic contracture due to the high concentration of contractile proteins. This ischemic contracture destroys the viability of the tissue. The liver can tolerate machine perfusion for 3 days and the kidney for 5 to 7 days. However, the arguments against using machine perfusion in a clinical setting are formidable. First, one-year graft survival in kidneys machine perfused or cold stored are about equal (about 90%). Second, machine perfusion is more expensive and requires a trained perfusionist. Third, most kidneys are now shared between centers that require some form of simple cold storage for shipment. Thus, without a clearly convincing rationale for machine perfusion, cold storage with short preservation times will probably continue to be used for most organs. REFERENCES 1.

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Jamieson NV. A new solution for liver preservation. Br J Surg 1989; 76:107-108. Ploeg RJ, Boudjema K, Marsh D et al. Importance of a colloid in canine pancreas preservation. Transplantation 1992; 53:735-741. Wicomb WN, Collins GM. 24-hour rabbit heart storage with UW solution: Effects of low-flow perfusion, colloid, and shelf storage. Transplantation 1989; 48:6-9. Charrueau C, Blonde-Cynober F, Coudray-Lucas C et al. Aminoacids in a cold preservation solution inhibits proteolysis of rat livers and improves portal flow rate and bile production at reperfusion. Clin Nutr 1994; 13:35-43. Ko W, Zelano JA, Lazenby WD, Isom OW, Krieger KH. Compositional analysis of a modified University of Wisconsin solution for extended myocardial preservation. A study of the left ventricular pressure-volume relation. Circulation 1991; 86:II-326-II-332. Howden BO, Jablonski P, Self G, Rosenfeldt F, Marshall VC. Effective organ preservation with modified HES-free UW solution with lowered potassium content. Transplant Proc 1992; 24:2274-2275. Moen J, Claesson K, Pienaar BH et al. Preservation of dog liver, kidney, and pancreas using the Belzer-UW solution with a high-sodium and low-potassium content. Transplantation 1989; 47:940-945. Cartier R, Dagenais F, Hollmann C, Carrier M, Pelletier LC. The role of preservation solutions in coronary endothelial damage during cold storage. Transplantation 1993; 56:997-1000. Reitz B, Brady W, Hickey P. Protection of the heart for 24 hours with intracellular (high K) solution and hypothermia. Surg Forum 1974; 25:149. Osswald H, Schmitz HJ, Kemper R. Tissue content of adenosine, inosine and hypoxanthine in the rat kidney after ischemia and postischemic recirculation. Pflugers Arch 1977; 371:45-49. Southard JH, Belzer FO. The University of Wisconsin Organ Preservation Solution: Components, Comparisons, and Modifications. Transplantation Reviews 1993; 7:176-190. Marzi I, Walcher F, Menger M, Buhren V, Harbauer G, Trentz O. Microcirculatory disturbances and leukocyte adherence in transplanted livers after cold storage in Euro-Collins, UW and HTK solutions. Transplant Int 1991; 4:45-50. Ploeg RJ, D’Alessandro AM, Knechtle SJ et al. Risk factors for primary dysfunction after liver transplantation: A multivariate analysis. Transplantation 1993; 55:123-129. Furukawa H, Todo S, Imventarza O et al. Effect of cold ischemia time on early outcome of human hepatic allografts preserved with UW solution. Transplantation 1991; 51:1000-1004. Najarian JS, Gillingham KJ, Sutherland DER, Reinsmoen NL, Payne WD, Matas AJ. The impact of the quality of initial graft function on cadaver kidney transplants. Transplantation 1994; 57:812-816. Opelz G, Wujciak T. Comparative analysis of kidney preservation methods. Transplant Proc 1996; 28:87-90. Mozes MF, Finch WT, Reckard CR, Merkel FK, Cohen C. Comparison of cold storage and machine perfusion in the preservation of cadaver kidneys: A prospective, randomized study. Transplant Proc 1985; 17:1474-1477. Jaffers GJ, Banowsky LH. The absence of a deleterious effect of mechanical kidney preservation in the era of cyclosporine. Transplantation 1989; 47:734-736.

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Henry ML, Sommer BG, Ferguson RM. Improved immediate function of renal allografts with Belzer perfusate. Transplantation 1988; 45(1):73-75. Rosenthal JT, Danovitch GM, Wilkinson A, Ettenger RB. The high cost of delayed graft function in cadaveric renal transplantation. Transplantation 1991; 51:1115-1117. Koyama H, Cecka JM, Terasaki PI. A comparison of cadaver donor kidney storage methods: Pump perfusion and cold storage solutions. Clin Transplant 1993; 7:199-205. Ploeg RJ, Hajo van Bockel J, Langendijk PTH et al. Effect of preservation solution on results of cadaveric kidney transplantation. Lancet 1992; 340:129-137. Todo S, Podesta L, Ueda Y et al. Comparison of UW with other solutions for liver preservation in dogs. Clin Transplant 1989; 3:253-259. Najarian JS, Gillingham KJ, Sutherland DER, Reinsmoen NL, Payne WD, Matas AJ. The impact of the quality of initial graft function on cadaver kidney transplants. Transplantation 1994; 57:812-816. Howard TK, Klintmalm GB, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA. The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 1990; 49:103-107. Shackleton CR, Martin R, Melinek J et al. Lack of correlation between the magnitude of preservation injury and the incidence of acute rejection, need for OKT3, and conversion to FK506 in cyclosporine-treated primary liver allograft recipients. Transplantation 1995; 60:554-557.

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Optimal Management for Abdominal Organ Donation Allan M. Roza, Christopher P. Johnson, Mark B. Adams

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Introduction .......................................................................................................... Hemodynamic Monitoring ................................................................................... Management of Hypertension .............................................................................. Management of Hypotension ............................................................................... Management of Electrolyte Disorders ................................................................... Management of Coagulopathy ............................................................................. Management of Hypothermia .............................................................................. Management of Hypoxemia ................................................................................. Management of Arrhythmias ............................................................................... Management of Hyperglycemia ............................................................................ Nutritional Support of the Abdominal Organ Donor .......................................... Modulation of the Inflammatory Response in the Abdominal Organ Donor ...... Organ Specific Issues ............................................................................................. Conclusion ............................................................................................................

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INTRODUCTION Outcome following transplantation is directly related to the quality of organs procured. Poor graft function following abdominal organ transplantation results in increased patient morbidity and mortality. Following renal transplantation, poor graft function is known as transplant acute tubular necrosis or ATN. This term is borrowed from the syndrome of acute renal failure occurring as a result of a number of different causes, such as hypovolemic shock and crush injuries, where classic renal morphologic changes are seen on microscopy. Posttransplant ATN is remarkable for the paucity of histological changes. Fortunately for most patients, posttransplant ATN resolves and unlike the nontransplant variety rarely leads to renal failure. Following liver transplantation, poor hepatic graft function may range from primary nonfunction to persistent enzyme abnormalities. Histological analysis of the transplanted liver may show areas of extensive hepatocyte necrosis and bile duct damage. For both primary nonfunction and livers with significant microscopic abnormalities and poor function, retransplantation is required with

Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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significant risk for increased morbidity and mortality. Following pancreatic transplantation, poor function may be manifest as posttransplant allograft pancreatitis or failure to achieve insulin independence. In our current era of cost containment and managed care, transplant professionals are acutely aware that poor graft function, in addition to increasing morbidity and mortality, substantially increases the costs of transplantation by leading to longer hospital stays, increasing medication costs, necessitating dialysis and in some cases leading to retransplantation. As transplant programs are coming under increasing public and governmental scrutiny and oversight, every effort must be made to minimize morbidity and mortality and to contain costs. Poor graft function results from any number of insults sustained by the organ from the moment of injury leading to brain death, during organ donor management, during the procurement process and finally during the transplant procedure itself. This chapter will focus on the optimal management of the abdominal organ donor. Optimal donor management and avoidance of organ injury will significantly minimize posttransplant graft dysfunction.

HEMODYNAMIC MONITORING Brain death leads to loss of vasomotor control. Therefore, hemodynamic instability is characteristic of the majority of organ donors. Monitoring catheters are necessary for correct and rational fluid resuscitation. The central venous pressure (CVP) line reflects right heart preload and function and usually provides adequate cardiovascular monitoring. All donors require a central venous line. The internal jugular approach is recommended to avoid the higher incidence of pneumothorax seen with subclavian lines. A Swan-Ganz pulmonary artery catheter is only necessary in donors whose CVP exceeds 15 mm Hg or who have suspected valvular heart disease, cardiomyopathy, persistent hypotension or pulmonary edema. Indwelling arterial catheters provide continuous and accurate measurement of blood pressure as well as access to arterial blood for blood gas measurements and may be required in the potential lung donor. Routine use of pulse oximetry however, minimizes the need for continuous arterial blood sampling by providing rapid, on-line determination of arterial oxygen saturation.

MANAGEMENT OF HYPERTENSION Hypertension results from an intense sympathetic “storm”. Increased circulating catecholamines associated with rises in intracranial pressure produce marked hypertension as well as tachycardia and pronounced vasoconstriction. Electrocardiographic and enzyme changes indicative of myocardial ischemia have been documented during this phase. Acute left ventricular failure and pulmonary edema may result. Fortunately this period is usually self-limiting and requires no treatment.

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If treatment is considered necessary, use of sodium nitroprusside, an agent with rapid onset and offset of action is recommended. In experimental studies, beta-blockers have also been used to abolish the hypertension seen during brain herniation. In the clinical setting, the short acting beta-blocker esmolol (Brevibloc) can be considered. The negative inotropic effects of esmolol are short-lived due to its short half-life and rapid disappearance from the circulation when the infusion is discontinued. A loading dose of 500 mg/kg over 1 minute is followed by an infusion of 50 mg/kg to the desired endpoint or 350 mg/kg. Perfusion of the abdominal organs may suffer as a result of myocardial damage and low cardiac output during this phase. Poor cardiovascular function despite supportive therapy may preclude liver and pancreas recovery leading to wastage of abdominal organs. In this situation, rapid and timely transfer of the organ donor to the operating room, oftentimes without complete serological information allows procurement of the kidneys. Ultimately, cardiovascular collapse transforms a previous “heart-beating” donor into a potential “non-heart beating donor”. To maximize organ retrieval all programs should have in place a protocol for the non-heart beating donor.

MANAGEMENT OF HYPOTENSION

ETIOLOGY Hypotension is common in the organ donor and its etiology is multifactorial. Hypotension may result from iatrogenic causes such as inadequate fluid resuscitation or fluid replacement, causes related to brain death such as neurogenic diabetes insipidus and loss of central vasomotor control or ventricular dysfunction secondary to myocardial ischemia or traumatic injury. Endocrine failure as a cause of hypotension has received much attention recently. The mechanism and rationale for hormone replacement as treatment will be discussed elsewhere. Numerous studies have reported a significant increase in ATN and primary nonfunction in kidneys from donors with systolic pressure below 80-90 mm Hg. Blood pressure should therefore be maintained at systolic pressures of 100-120 mm Hg. Attempts to maintain pressures above this range with excess fluids or vasopressors will have deleterious effects on the donor. HYPOVOLEMIA Hypovolemia is the most common cause of hypotension in the abdominal organ donor and there are two principal iatrogenic causes. First, in an attempt to avoid CNS edema, deliberate maintenance of volume depletion is pursued in the brain-injured patient. Second, following declaration of brain death, volume depletion may facilitate lung recovery by avoiding pulmonary edema but also contributes to hypotension and hypoperfusion of abdominal organs. Ischemia related to poor perfusion in the organ donor may not itself result in significant injury but rather “primes” the tissue for damage resulting from reperfusion of oxygenated

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blood. Organ reperfusion injury may occur during subsequent successful resuscitation of the donor or following revascularization in the recipients. Strategies proposed to ameliorate ischemia-reperfusion injury are discussed below. VENTRICULAR DYSFUNCTION Ventricular dysfunction following brain death falls along a spectrum from mild to severe. Failure to achieve hemodynamic stability in the donor despite fluid resuscitation and inotrope support (see below) may well be a marker of the severity of myocardial damage. Timely placement of the organs and rapid transport to the operating room may then be necessary prior to cardiac collapse. NEUROGENIC DIABETES INSIPIDUS Neurogenic diabetes insipidus is characterized by polyuria, hyperosmolality with a serum osmolarity greater than 295, a urine osmolarity less than 300 mOsm/L and a urine specific gravity less than 1.005. Treatment requires aggressive replacement of urinary output for the previous hour together with hourly maintenance infusions. If urine output exceeds 400 mL/h and is not related to diuretic administration, fluid loading, inotropes or hyperglycemia, pharmacologic treatment is required with antidiuretic hormone. If not treated or treated inadequately, diabetes insipidus will result in further metabolic derangements of hypernatremia, hypokalemia, hypomagnesemia and hypocalcemia. DDAVP (desmopressin acetate) is a synthetic analog of the natural pituitary hormone 8-arginine vasopressin (ADH). DDAVP given IV (0.5-1.0 µg q 2-4 h) has a rapid onset (within minutes) and its duration of action is prolonged (6-20 hours). It has almost no pressor effects and the dose may be repeated if necessary. Administration by other routes is not recommended due to variation in absorption. Pitressin is bovine or porcine derived arginine vasopressin (AVP) and is an alternative if DDAVP is unavailable. AVP may result in decreased renal and splanchnic blood flow further impairing renal, pancreatic and hepatic perfusion. Recommended starting dose of Pitressin is 50 units in 500 mL D5W at 5 units/h titrated to maintain urine output equal to or greater than 100 mL/h. Exacerbation of hyponatremia may occur if vasopressin is administered together with hypotonic fluids. During treatment of neurogenic diabetes insipidus close monitoring of central venous pressures is required to guide therapy and help avoid volume overload. GOALS OF FLUID RESUSCITATION The goals of fluid resuscitation should be a CVP of 6-12 cm H2O, urine output greater than 100 mL/h and a systolic BP greater than 100 mm Hg on minimal vasopressors (see below). Despite fluid resuscitation and achievement of targeted blood pressure, if urine output is inadequate, mannitol or furosemide should be given. The choice of fluids is based on two important criteria. The first is coexisting electrolyte and glucose abnormalities and the second is the need to avoid edema. Pulmonary edema precludes lung procurement, but if the lungs have been excluded volume expansion is limited insofar as it affects systemic oxygenation.

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However, edematous organs, especially the liver, may not flush as well and, therefore, cool less efficiently during the final stages of procurement. Whether edematous organs tolerate prolonged periods of cold storage poorly is not known.

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CHOICE OF FLUIDS Fluids should be warmed both to prevent the exacerbation of pre-existing hypothermia or the induction of hypothermia. Administration of excess salt solutions during rapid diuresis (induced by diuretics or diabetes insipidus) may aggravate pre-existing hypernatremia. Frequent monitoring of serum sodium is required. Ringer’s lactate is a good choice for volume expansion, as it has a lower sodium content (130 mEq/L) as compared to normal saline (154 mEq/L). Inadequate fluid resuscitation may transform a planned multiorgan retrieval into a kidney only retrieval as the organ donor becomes further unstable during transport to the operating room. Boluses of colloids such as albumin may also be required to correct hypotension and maintain tissue perfusion. Blood should be transfused if the hematocrit is less than 30% especially if a multiorgan recovery is anticipated with a longer operative time and the greater potential for intraoperative blood loss. It is important to ensure that pretransfusion serology has been drawn before giving blood. VASOPRESSORS If hypotension persists despite adequate fluid resuscitation inotropic agents are required to maintain adequate blood pressure. Dopamine (Intropin) is the preferred first-line drug. Its effects on blood pressure result from its positive inotropic effect on the myocardium and resultant increase in cardiac output. At low doses (0.5-2.0 mg/kg/min), it also acts to vasodilate renal and splanchnic blood vessels thereby increasing perfusion to the abdominal organs. Its onset of action is rapid (5 min) and it must be given as a continuous infusion titrated to the patient’s response. At doses greater than 10 mg/kg any advantages of this drug are lost as vasoconstriction occurs (alpha-adrenergic effect). Dopamine often is available from the hospital pharmacy premixed as 400 mg/250 mL which is equivalent to 1600 mg/mL. If a greater concentration is required due to fluid restriction, this needs to be communicated to the pharmacy. With dopamine, peripheral vasodilation and the resulting decrease in peripheral resistance may counteract the increases in systolic blood pressure and pulse pressure. In practice, low dose dopamine is infrequently sufficient to adequately treat hypotension in the organ donor. Alpha agonists are commonly required such as Levophed or Neosynephrine. Norepinephrine (Levophed) is identical to the endogenous catecholamine which is synthesized in the adrenal medulla and in sympathetic nervous tissue. It acts predominately by a direct effect on alpha-adrenergic receptors increasing total peripheral resistance with increases in systolic and diastolic blood pressure. However, constriction of renal blood vessels will reduce renal blood flow. Norepinephrine can increase glycogenolysis and inhibit insulin release from the pancreas, resulting in hyperglycemia. This drug must be administered cautiously in

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patients chronically receiving tricyclic antidepressants. Administration of Lasix may decrease responsiveness to norepinephrine. Norepinephrine should be administered in the lowest effective dose for the shortest period of time. Generally 2-4 mg/min titrated to blood pressure is recommended. Phenylephrine (Neosynephrine) also acts predominately by a direct effect on alpha-adrenergic receptors. Like Levophed, Neosynephrine should be administered in the lowest effective dose for the shortest period of time and only after volume resuscitation is complete. The recommended infusion rate is, 10-50 mg/min titrated to blood pressure. Not infrequently, despite adequate volume resuscitation and combination therapy with Dopamine and other vasopressors as well as correction of other conditions contributing to donor deterioration e.g., pneumothorax, hypotension persists. This is most often due to significant myocardial dysfunction. When inotrope requirements continue to rise or the expected response does not occur, pulmonary artery catheterization (Swan-Ganz) is recommended if not already in place. To minimize the contribution of catecholamines to posttransplant ATN, some centers routinely administer alpha blockade to donors in the operating room (Regitine, 10 mg). In the situation where the potential organ donor is responding poorly to massive doses of inotropes, some authors have suggested cardiac support in the form of intra-aortic balloon counterpulsation (IABP) or cardiopulmonary bypass. The ability to institute these measures in a timely fashion is limited in most centers. The outcome in the recipients of these organs would likely be poor with a high incidence of primary nonfunction or persistent graft dysfunction. Sample Calculation A 70 kg donor has a serum Na of 170 mEq/1 Elevated Na reflects hypertonicity in all fluid compartments. All compartments need water, so space involved is TBW (total body water) = 0.6 x Body Wt (kg) Present Na x Present TBW = Desired Na x Desired TBW OR: 170 mEq/L x 42 L = 150 mEq/L x ? ? = 47.6 L So, TBW needs to be expanded from 42 to 47.6 Liters 5.6 liters of WATER are needed A quicker way to the same answer: ? = 0.6 x Body Wt (kg) x {Present Na–Desired Na} { Desired Na }

MANAGEMENT OF ELECTROLYTE DISORDERS

HYPERNATREMIA The impact of donor hypernatremia upon posttransplant organ function is controversial. Recent studies in liver recipients are conflicting suggesting either no effects or harmful effects in terms of graft outcome. The true significance of hypernatremia may well be masked by many other variables and changes which

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occur in organ donors. The presence of hypernatremia is however significant in that it indicates excessive water loss or excess sodium intake and should therefore serve as a guide to volume requirements or type of fluids used. Inadequate treatment of diabetes insipidus (see above) is the commonest cause of hypernatremia in the organ donor. An approach to the correction of hypernatremia is shown below.

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HYPONATREMIA Hyponatremia is uncommon in the organ donor and when it occurs it may be an artifact secondary to hyperglycemia. The following formula will allow calculation of the corrected sodium: Corrected Na = Observed Na + .015 (Observed Glucose–100) If the donor glucose is normal then the causes of hyponatremia may be inappropriate administration of hypotonic solutions (excess water) alone or in combination with administration of antidiuretic hormone. The presence of hyponatremia should serve as an indication that the donor may in fact be over hydrated. HYPERKALEMIA Hyperkalemia will initially cause delayed AV conduction with prolonged PR interval and a widening QRS complex. If severe it will induce sinus bradycardia and sinus arrest or ventricular standstill. Correction of hyperkalemia with the cation exchange resin, sodium polystyrene sulfonate (Kayexalate) either PO or per rectum is impractical. Furthermore with Kayexalate, for every 1 mEq of potassium removed, 3 mEq of sodium is provided which is undesirable if hypernatremia is also present. Hypertonic glucose and insulin is recommended for rapid correction of hyperkalemia. In 300 mL of 25% glucose mix 1 unit of short acting insulin per gram of glucose and infuse over 30 minutes. NaHCO3 (45 mEq) IV may need to be combined with glucose-insulin therapy. HYPOKALEMIA Hypokalemia is associated with ventricular irritability and atrial tachycardia. The frequency of arrhythmias is particularly increased in the patient receiving digoxin. Potassium replacement should never be via a central venous route to avoid hyperkalemic sinus arrest. HYPOPHOSPHATEMIA Hypophosphatemia although common after brain death has no significant cardiovascular consequences and therefore requires no specific treatment.

MANAGEMENT OF COAGULOPATHY Coagulopathy is common in the brain injured potential organ donor. Disseminated intravascular coagulation (DIC) or fibrinolysis may occur after penetrating

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or severe closed head injury. This results from the release into the circulation of tissue thromboplastin and plasminogen. Hypothermia and catecholamines both affect platelet function further contributing to coagulopathy. Resuscitation may also result in a dilutional coagulopathy resulting from decreased numbers of platelets. In the massively transfused patients a number of considerations are important which will exacerbate coagulopathy. Packed red cells contain no active platelets. The platelet count should be measured. Banked blood greater than 3 weeks old contains only 10-15% of normal levels of clotting factors V and VIII. Obviously in a brain dead organ donor, spontaneous CNS hemorrhage is significant only insofar as it may further contribute to donor instability. The severely coagulopathic organ donor may, however, become unstable during multiorgan procurement due to excessive blood loss. To avoid intraoperative blood loss that might adversely affect multiorgan recovery in the severely coagulopathic patient, replacement of clotting factors should be considered. This can be accomplished with either fresh frozen plasma or cryoprecipitate. Platelets should be transfused if the count is less than 50,000/mm3. Red cell replacement should be considered to keep the hemoglobin greater than 10 g/dl. If the potential organ donor has been massively transfused, citrate, an anticoagulant in banked blood can produce hypocalcemia and cardiac arrest. Calcium chloride, 1 mg/kg IV every 15-20 minutes during periods of rapid transfusion will obviate hemodynamic compromise. Ionized calcium and the Q-T interval of the ECG can be monitored if there are concerns.

MANAGEMENT OF HYPOTHERMIA Hypothermia is a complex issue in the management of the potential abdominal organ donor. Failure to correct hypothermia can delay certification of brain death with further deterioration of the patient. Following establishment of brain death, hypothermia may result from the inability of the patient to shiver and thereby compensate for heat losses as well as failure of vasoconstriction. Iatrogenic causes of hypothermia include resuscitation with large volumes of unwarmed fluids and blood products and conductive and convective heat loss to the environment. A liter of crystalloid at a room temperature of 20°C will lower a 70 kg patient’s temperature by 0.25°C, a unit of blood (250 ml) at 4°C will lower body temperature by 0.125°C. Hypothermia has a number of adverse consequences in the organ donor. Chief among them is resultant myocardial depression. This can progress to cardiac arrest. Decreased oxygen delivery can also occur due to shifting of the oxyhemoglobin dissociation curve to the left. At temperatures less than 32°C coagulopathy can occur. Fluid losses may also be exacerbated as hypothermia decreases renal tubular cell reabsorptive function with a resultant “cold diuresis”. Prevention of hypothermia is therefore extremely important. Convective heat losses result from high turnover of cool air in air-conditioned intensive care areas.

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The relative humidity can also exacerbate heat losses. Conductive losses occur through exposure to wet drapes and cool surfaces. Heat loss may also result from evaporation of surgical prep solutions applied for line placement or cardiac catheterization. Core temperature must be monitored. Because of the loss of thermoregulation, skin temperature is the least reliable measure of core temperature. Esophageal, rectal or bladder probes or tip of a pulmonary artery catheter are much more reliable measures of core temperature. Treatment of hypothermia involves covering exposed surfaces, use of a warming blanket, adding heated humidifiers to the anesthetic circuit, warming of administered fluids and raising room temperature and humidity.

MANAGEMENT OF HYPOXEMIA

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Monitoring of arterial oxygen saturation with pulse oximetry or by arterial blood gases is essential. Blood gas determination will allow monitoring of acidbase balance. Goals of management should be maintenance of PaO2 between 70-100 torr and O2 saturation of 95% with appropriate FiO2. Hypoxemia may be due to cardiac causes, neurogenic pulmonary edema or pulmonary problems such as pneumonia, atelectasis or fluid overload. Careful review of the chest X-ray to exclude pneumothorax is important. Diagnosis of pneumothorax in a supine chest film is difficult. Consultation with a radiologist is therefore required if there is a suspicion of pneumothorax. Treatment of hypoxemia requires careful attention to fluid status and correction of contributing factors such as atelectasis and pneumothorax. Pulmonary edema should respond to diuresis. Atelectasis may be secondary to poor pulmonary toilet. Bronchoscopy may be required to diagnose and treat bronchial mucus plugs. Finally, positive end expiratory pressure (PEEP) should be instituted. PEEP should be instituted carefully and should not exceed 5-10 cm H2O because of potential adverse hemodynamic causes. These include reduced venous return from increased intrathoracic pressure and/or a direct effect on cardiac output with resultant decreased poor perfusion. PEEP should be increased in 2.0-2.5 cm H2O increments. Minute ventilation and tidal volume need to be adjusted to maintain an arterial pH of 7.4. Hyperoxia may predispose to atelectasis. If the lungs have been excluded however, maintenance of arterial saturation by increasing FiO2 is preferred to increasing levels of PEEP.

MANAGEMENT OF ARRHYTHMIAS Arrhythmias may occur in the potential organ donor at the time of brain herniation. Use of high dose inotropes, acid base derangements, electrolyte abnormalities, hypothermia and myocardial injury will further increase the incidence of arrhythmias. Timely correction of these problems is important as arrhythmias

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in an organ donor may be difficult to treat. The heart is denervated after brain death and is atropine-resistant. Chronotropic agents (isoproterenol hydrochloride or epinephrine) or a pacemaker may be necessary to treat bradycardia.

MANAGEMENT OF HYPERGLYCEMIA Hyperglycemia is common in the organ donor and results from a combination of factors. These include the stress response to injury and the effects of catecholamines (insulin resistance) or results from the rapid infusion of glucose containing fluids. Hyperglycemia increases osmolality and leads to an osmotic diuresis with further loss of water and electrolyte imbalances. Intravenous infusions of short-acting insulins are required for serum glucose in excess of 200 mg%.

6 NUTRITIONAL SUPPORT OF THE ABDOMINAL ORGAN DONOR Extended hospitalization is associated with varying degrees of malnutrition. Since the observation that length of ICU stay correlated with transplant liver function, i.e., a longer stay adversely affects function, attention has focused on nutritional support of the donor. In the catabolic, brain-dead patient receiving inadequate nutritional support hepatic glycogen stores are rapidly depleted. Glycogen represents the only fuel available for ATP generation during anoxic cold storage. ATP depletion renders the liver more susceptible to ischemic damage during anoxic storage and reperfusion injury following revascularization. Numerous animal and some clinical studies support the administration of glucose to replete glycogen stores with improvement in posttransplant hepatocellular function. In practice, repletion of glycogen stores requires 24-48 hours, therefore a major limitation to this approach is time. Donor instability often precludes such an approach.

MODULATION OF THE INFLAMMATORY RESPONSE IN THE ABDOMINAL ORGAN DONOR Optimal donor management may have favorable immunological consequences in addition to improving graft function. Recipients of living unrelated renal allografts (e.g., spousal donors), despite HLA disparity, have 1 and 5 year graft survival that is equivalent to grafts received from haploidentical donors. Thus, when injury associated with brain death, donor management and prolonged cold ischemia time is eliminated as in living unrelated donor transplants, HLA mismatch is considerably less significant in influencing long-term outcome. The impact of HLA match in cadaveric transplantation is also questionable. Recent evidence suggests that nonimmunologic injury sustained by the organ may predispose to a cascade of self-sustaining immunologic events resulting in increased likelihood of rejection and graft loss. Poor donor management with resultant graft injury

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may, therefore, serve to negate any potential benefit that derives from improved HLA matching. Studies in animal models support the use of various agents to blunt nonimmunologic, nonspecific injury which can occur during the recovery process or result from reperfusion injury in the organ recipient. These agents include inhibitors of lipid peroxidation, antioxidants, free radical scavengers, nitric oxide modulation, protease inhibitors, prostaglandins, calcium channel blockers and monoclonal antibodies directed against adhesion molecules. Unfortunately, the limited clinical studies to date examining the use of selected agents in humans is less than encouraging. Faults with study design and inability to control for the great number of donor variables that eventually contribute to outcome may account for conflicting data or apparent lack of efficacy. Failure to standardize organ preservation techniques, i.e., cold storage versus pulsatile perfusion, will further confound interpretation of these studies.

6 ORGAN SPECIFIC ISSUES Multiorgan recovery should be the goal in all potential organ donors. Therapeutic interventions targeted to specific organs are generally unnecessary beyond maintenance of adequate oxygenation and perfusion. However, in the management of the abdominal organ donor certain issues may be significant. PANCREAS Hyperglycemia is common in the organ donor. The etiology is multifactorial and likely due to a combination of catecholamine induced insulin resistance and rapid infusions of large volumes of glucose containing fluids. The goal of treating hyperglycemia is to minimize fluid losses secondary to the resultant obligatory osmotic diuresis. Donor hyperglycemia does not adversely affect posttransplant pancreatic allograft function and unless fluid losses are the issue, requires no treatment. Hyperamylasemia of pancreatic origin has been well described in the severely brain-injured patient. This finding may occur in the absence of known abdominal trauma or history of pancreatitis. The putative mechanism is through a central nervous system regulation of serum amylase. Hyperamylasemia may also result from hypoperfusion of the pancreas or pancreatic ischemia occurring during any stage of the procurement process from initial injury to organ recovery. As noted above, donor hyperglycemia is not a contraindication to pancreatic procurement unless the donor has a previous history of diabetes mellitus. Donor hyperamylasemia also does not preclude consideration of the pancreas. At the time of recovery, the donor surgeon must assess the pancreas for any evidence of trauma or pancreatitis. The pancreas is vulnerable to ischemia. Significant and prolonged hypotension in the donor coupled with the requirement for high dose vasopressor administration is a relative contraindication to pancreatic procurement.

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SMALL INTESTINE As small intestinal transplantation becomes increasingly widespread, a number of organ specific issues may arise. Some centers use a bowel prep consisting of antibiotics and mechanical irrigation, but these protocols have not yet become standardized. Based on original early experimental work on graft manipulation to remove “passenger leukocytes”, donor treatment with antilymphocyte monoclonal antibodies or lymphoid irradiation may improve intestinal allograft survival. Analogous to nutritional support to improve cadaveric liver function posttransplant, these other two approaches are time consuming. Unless the donors are stable, application of these protocols is impractical and may contribute to donor instability and unnecessary organ loss. KIDNEY Radiocontrast agents Protection of renal function from such potentially injurious agents as radiocontrast dyes is a common clinical problem. Donors must often undergo cardiac catheterization before the heart can be considered suitable for transplant. Radiocontrast dye administration may therefore contribute to renal dysfunction posttransplant. Furthermore, as improvements in neurosurgical care result in a decrease in deaths from cranial trauma, greater numbers of our donors sustain a cerebrovascular event. Therefore, we are increasingly selecting donors with preexisting hypertension and atherosclerosis. In these patients, clinically silent but histologically significant renal lesions may be present. Radiocontrast agents are particularly problematic in this situation. Protection of renal function from radiocontrast dyes was recently examined in a series of patients with known serum creatinine abnormalities undergoing cardiac angiography. Hydration with 0.45% saline alone provided better protection against an acute decrease in renal function than hydration with 0.45% saline together with either mannitol or furosemide. These data suggest that addition of a diuretic to the fluid management of the organ donor prior to cardiac catherization is not indicated. Rather, assuring that the donor is volume resuscitated and diuresing adequately are sufficient protection against renal damage. MANDATORY BIOPSY Significant age related changes or glomerulosclerosis resulting from hypertension may be present in the organ donor despite a normal serum creatinine. Mandatory biopsy following recovery of the kidneys is therefore required in the older donor (> 50), in donors with a history of hypertension or diabetes or in donors with an abnormal urinalysis (e.g., unexplained hematuria, proteinuria). Glomerulosclerosis exceeding 20% is used as the cutoff by most surgeons. Sclerotic changes in excess of this normally result in discarding the kidneys although there is interest in using both kidneys from these marginal donors in a single recipient. This innovative approach is controversial and its proponents suggest that it will minimize unnecessary wastage of organs.

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The increasing demand for transplantable organs is a major challenge. As pressures to expand the donor pool continue, we will be faced with donors with additional medical problems that might impact upon donor management. Numerous studies have defined donor age as an independent risk factor in determining outcomes. Are organs from older donors or those donors with comorbid medical conditions less tolerant to hypotension and ischemia, reperfusion injury and prolonged cold storage? Should procedures for organ recovery be altered based upon these variables? The answers to these questions and many more must be forthcoming as we attempt to maximize organ retrieval and maintain and improve our current patient and graft survival. REFERENCES

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1.

2. 3. 4. 5. 6.

7. 8. 9.

10. 11.

12.

13. 14.

Ali MJ. Essentials of organ donor problems and their management. In: Gelb AW and Sharpe MD, eds. Anesthesiology Clinics of North America Philadelphia, PA: W.B. Saunders Company, 1994:655-671. Black PM. Medical progress-brain death. N Eng J Med 1978; 299(Part 1):338-344. Black PM. Medical progress-brain death. N Eng J Med 1978; 299(Part 2):392-401. Darby JM, Stein K, Grenvik A, Stuart SA. Approach to management of the heartbeating “brain dead” organ donor. JAMA 1989; 261(15):2222-2228. Doyle HR, Marino IR, Morelli F et al. Assessing risk in liver transplantation. Ann Surg 1996; 224(2):168-177. Driscoll DF, Palombo JD, Bistrian BR. Nutritional and metabolic considerations of the adult liver transplant candidate and organ donor. Nutrition 1995; 11:255-263. Gonzalez FX, Rimola A, Grande L et al. Predictive factors of early postoperative graft function in human liver transplantation. Hepatology 1994; 20:565-573. Hauptman PJ, O’Connor KJ. Procurement and allocation of solid organs for transplantation. N Eng J Med 1997; 336(6):422-431. Hesse UJ, Sutherland DE. Influence of serum amylase and plasma glucose levels in pancreas cadaver donors on graft function in recipients. Diabetes 1989; 38(Suppl 1):1-3. Justice AD, DiBenedetto RJ, Stanford E. Significance of elevated pancreatic enzymes in intracranial bleeding. Southern Med J 1994; 87(9):889-893. Mor E, Klintmalm GB, Gonwa TA et al. The use of marginal donors for liver transplantation. A retrospective study of 365 liver donors. Transplantation 1992; 53:383-386. Power BM, Van Heerden PV. The physiological changes associated with brain death–current concepts and implications for treatment of the brain dead organ donor. Anaesth Intens Care 1995; 23:26-36. Scheinkestel CD, Tuxen DV, Cooper DJ, Butt W. Medical management of the (potential) organ donor. Anaesth Intens Care 1995; 23:51-59. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol and furosemide on acute decreases in renal function induced by radiocontrast agents. N Eng J Med 1994; 331(21):1416-1420.

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16.

17.

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Terasaki PI, Cecka M, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Eng J Med 1995; 333(6):333-336. Troppmann C, Gruessner AC, Benedetti E et al. Vascular graft thrombosis after pancreatic transplantation: Univariate and multivariate operative and nonoperative risk factor analysis. J Am Coll Surg 1996; 182:285-316. Warshaw AL, O’Hara PJ. Susceptibility of the pancreas to ischemic injury in shock. Ann Surg 1978; 188(2):197-201.

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Optimal Thoracic Organ Donor Management Dan M. Meyer, Michael A. Wait, Michael E. Jessen, W. Steves Ring Donor Selection (General) .................................................................................... 94 Donor Selection (Organ Specific) ....................................................................... 101 Donor Preoperative Management ...................................................................... 105

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The success of heart and lung transplantation begins with the careful selection of suitable donors. This is achieved by developing a database of donor specific factors likely to influence either the short term or long term survival following transplantation. The transplant physician and surgeon must then balance the risk of transplanting a particular organ into a specific recipient against the risk to both the recipient and all other recipients of not using the organ. This judgment is based on the projected natural history of the potential recipient’s underlying disease process (i.e., likelihood of survival on the waiting list), along with that of all others on the waiting list. The ultimate goal should be the best long-term survival and quality of life for the greatest number of recipients. The database of donor characteristics which can influence outcomes includes both general and organ specific donor factors (Table 7.1). General donor factors have been dealt with in previous chapters but will be discussed with regards to both heart and lung transplantation. For medical-legal protection, a careful documentation of brain death is essential and should be reviewed by the organ procurement team and the transplant surgeon prior to proceeding with further evaluation. The on-site organ procurement organization representative collects the information for completion of the donor database, requests additional testing as indicated, assists in donor stabilization and management, facilitates placement of all suitable organs, communicates with the remainder of the procurement teams, and coordinates the entire procurement process. Based on the original experience at Stanford,1 specific guidelines have been adopted to maximize long-term function of cardiac allografts2 (Table 7.2). Similar guidelines have been developed for lung allografts3-6 and are summarized in Table 7.3. As the results of heart and lung transplantation have improved over the past decade, more patients are being considered for transplantation. This has caused a sharp rise in the number of recipients listed for transplant, contributing to prolonged time on the waiting list, a greater need for pretransplant intensive care with inotropic or mechanical support, and an increased waiting list mortality. As the shortage of suitable donors has become apparent, efforts have been made to Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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Table 7.1. Thoracic donor database General Documentation of brain death Demographics: Age, Sex, Race, Size History Current: Cause of death, Resuscitation, Procedures, Monitoring, Hemodynamics, Medications, Infection Past: Medical, Surgical, Social, Medication, Transfusion, Malignancy, Infection, Substance Abuse Laboratory: ABO type, Toxicology, Viral serology, Cultures, Chemistry, Hematology, Coagulation Organ Specific Heart Current history: Trauma, CPR, Arrhythmias Past History: Cardiac disease/symptoms, Risk factors Function: ECG, ECHO, Hemodynamics, Pressors, Angiography Laboratory: CKMB, Troponin I Lung Current history: Trauma, Aspiration, Ventilation Past history: Pulmonary disease/symptoms, Smoking Function: Ventilation mechanics, O2 challenge, Bronchoscopy Laboratory: CXR, ABG, Sputum gram stain, Cultures

Table 7.2 Standard heart donor criteria ABO compatible Age < 50 years ECHO: EF > 50%, no significant wall motion or valve abnl Inotropes: < 15 mcg/kg/min Dopamine D/R Weight Ratio 0.7-1.5 Ischemic Time < 4 hours ECG: normal or minimal ST changes No active infection or malignancy Seronegative for HBV, HCV, and HIV

Table 7.3. Standard lung donor criteria ABO compatibility Age < 55 years CXR clear Bronchoscopy: normal airways and mucosa Mechanics: normal compliance Normal gas exchange: pO2 > 300 on FIO2 = 1.0 No history primary lung disease No active infection or malignancy

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extend these donor guidelines to increase the donor pool.7 Newer strategies have included extending the donor age limits,8-13 accepting longer donor ischemic times,1,8,10 using donors on high inotropic support or with wall motion abnormalities on echocardiogram,10 using cardiac donors with reconstructable coronary artery disease, using living-related lung donors16,17 and using nonbeating heart donors.18-20

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ABO COMPATIBILITY Specific ABO blood type and ABO compatibility versus identity each have a significant impact on graft survival. The use of ABO mismatched incompatible donors results in hyperacute rejection and early graft loss as with other organs.21 Early studies from the group in South Africa suggested a reduction in long-term survival for non-O recipients, particularly those with blood type B.22 This was supported by the Texas Heart Institute who also demonstrated up to a 20-30% reduction in long-term survival with the use of nonidentical donors.23 However, this was not confirmed by the Stanford group.24 Recent studies from the Cardiac Transplant Research Database25 have again shown reduced one-year survival for non-O identical and for all nonidentical donor-recipient matches. The one-year survival for blood group O identical matches was 88%, compared with 81% for ABO compatible matches (O donor into A or B recipient), 85% for blood group A identical matches, and 78% for blood group B identical matches. Based on these data, we have attempted to use only ABO identical donor-recipient matches except for critically ill patients. These results and the prolonged waiting time for blood group O recipients, have recently prompted UNOS to alter their allocation scheme for heart donors within each status category. Blood group O donors may be allocated only to O or B recipients, A donors only to A or AB recipients, and B donors only to B or AB recipients within each clinical status category. AGE A number of centers have advocated the use of older heart donors to expand the donor pool and have reported no significant difference in 1-year graft survival with donors over the age of 40,10,11 over the age of 45,8,12 or over the age of 50.13 However, the number of older donors reported from these centers is small and only univariate analysis has been employed. The major multivariate analyses of the effects of increased donor age on both early and long-term survival after heart transplantation have been reported from UNOS,26 the CTRD,25,27 and the ISHLT Registry.28 Each of these reports has found decreased survival for recipients of hearts from donors over the age of 40. Similar findings have been reported from the ISHLT for recipients of lungs from donors over the age of 50.28 Although the odds ratio for 1-year mortality using heart donors over the age of 50 is approximately 1.5, this only translates into an increase in 1-year mortality from

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10%-15% which contrasts quite favorably with a waiting list mortality of 20% or a predicted mortality of 40-50% with NYHA Class III-IV congestive heart failure. Therefore, we continue to utilize highly selected older donors particularly for older recipients or those who are critically ill (e.g., facing the prospect of death or mechanical assistance within the near future). SEX Recipients of hearts from female donors were initially felt to have worse outcomes than those receiving male donor hearts. In fact, data from both the ISHLT Registry28 and from UNOS26 would initially appear to support this assumption. However, a more thorough analysis by the TCRD27 has noted that this effect disappears when the data are normalized for body surface area, suggesting that small body size rather than gender alone produces the differential outcomes. Although the use of female donors does not effect survival following heart transplantation, data from the TCRD does show a significant increase in acute rejection29 and late recurrent rejection30 with the use of female donors. Based on these findings, we have generally avoided using undersized female hearts for larger male recipients and monitor the recipients of female donors (particularly female recipients) more closely for rejection. RACE The effect of racial mismatches in heart or lung transplantation has not been critically analyzed. Recently released data from UNOS suggest that using nonwhite donors does not significantly impact early (30 day) graft or patient survival, but does have a negative impact on 1-year graft and patient survival for both heart and lung recipients.26 However, donor size was not factored into the analysis. Since the impact of racial mismatch appears to be small, we have chosen not to let racial factors influence donor selection. SIZE Cardiac donors Donor-recipient size matching (D/R wt ratio > 0.8) has long been advocated for cardiac transplantation.31 Attempts to expand the donor pool have prompted many centers to expand their size matching criteria.32-35 Success has been achieved with D/R weight ratios as low as 0.5. However, the undersized donor adapts by utilizing chronotropic and isotropic reserves (increased heart rate and filling pressures) to maintain a normal cardiac output.32 This suggests that the undersized donor heart may have less functional reserve and be less able to tolerate any additional perioperative hemodynamic stress prior to undergoing adaptation. In fact, the group at the University of Virginia has shown that the use of undersized donors in critically ill status I patients may be associated with a worse outcome.37 The role of pulmonary hypertension and elevated pulmonary vascular resistance in donor selection remains controversial. However, most centers will attempt to avoid undersizing in this situation. We have taken the approach favored by most major centers of not undersizing below a D/R weight ratio of 0.7 for older donors,

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for female donors into male recipients, for recipients with elevated pulmonary vascular resistance (above 4 Wood units), or in those cases where a prolonged donor ischemic time is anticipated. Oversizing of donors for adult recipients is rarely ever an issue. Additional space can be created by opening the pericardium into the pleural spaces to accommodate almost any oversized heart. Thus, there is no upper limit on the D/R weight ratio for adults. However, in the pediatric population there are some geometric size constraints. The Loma Linda group have reported successful transplantation with a D/R weight ratio of up to 4.038,39 and we have had similar experience. However, this requires leaving the sternum open for a prolonged period of time which may compromise pulmonary function or increase the risk of infection. We would suggest not exceeding a D/R weight ratio over 3.0 for most recipients.

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PULMONARY DONORS The optimal technique of size-matching for pulmonary transplantation is not entirely clear. Very little data are available regarding the adverse consequences of over-sizing or under-sizing donor lungs. Anecdotal experience suggests that oversizing the donor lung may lead to difficulties with intraoperative exposure, hemodynamic compromise, or wound closure, in addition to difficulty with postoperative clearing of secretions and atelectasis. Similarly, under-sizing of the donor lung may lead to persistent air leaks, pleural space problems, or empyema.6,40,41 Initial attempts to size lung donors according to weight proved inadequate since the usual D/R weight ratio often exceeded 1.5/1 because of the severe cachexia associated with end-stage lung disease. Comparisons of the donor and recipient chest measurements taken either directly (circumference at the xyphoid) or obtained from the chest radiographs (vertical apex to dome of diaphragm; transverse internal thoracic diameter at dome of diaphragm) have also been used for size matching. However, these measurements are affected by position (upright/supine) and level of inspiration or ventilation. Several studies have suggested that matching the estimated vital capacity (VC) or total lung capacity (TLC) based on height, age, sex, and race (not weight) of the donor to the predicted normal values for the recipient is the most appropriate method for size-matching.41-43 Size-matching should also consider both the disease process of the recipient and the type of transplant planned (single versus bilateral sequential). Single lung transplantation is generally recommended for patients with idiopathic pulmonary fibrosis, and older individuals (> 50 years of age) with chronic obstructive pulmonary disease (COPD) or alpha-1-antitrypsin (A1A) deficiency. For recipients with idiopathic pulmonary fibrosis or restrictive lung disease, matching the donor and recipient to within 20% of expected recipient lung volume (based on age, sex, height, and race) is recommended. For those with chronic obstructive lung disease or A1A deficiency, oversizing up to 25% is recommended because of the mediastinal shift caused by hyperinflation of the diseased native lung. In some centers, primary pulmonary hypertension patients receive single lung transplants. In these patients, a single lung that closely matches (± 20%) the size of the native lung is preferable.

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Bilateral sequential single lung transplantation is performed in younger patients with COPD or alpha-1-antitrypsin deficiency (< 50 years of age), septic lung disease (cystic fibrosis, end-stage bronchiectasis), and for many patients with primary pulmonary hypertension. In most situations, size matching to within 20% of the recipient’s estimated lung volume is recommended. Again, in patients with obstructive pulmonary disease, oversizing of up to 25% is well tolerated. CURRENT HISTORY Critical to the selection process is a detailed history of the events leading to the death of the donor, the measures used to resuscitate the donor, a complete hemodynamic history, a summary of all medications used in the management of the donor, and any additional procedures performed on the donor since first being observed (e.g., special testing, surgery, transfusions, invasive monitoring, etc.). CAUSE OF DEATH Considerations include the cause of death and mechanism of injury as it may relate to the proposed organ of interest. In cases of blunt chest trauma, for example, the potential for an unsuspected cardiac or pulmonary contusion could be important. RESUSCITATION The need and duration of cardiopulmonary resuscitation (CPR) is often discussed, but not always a factor if echocardiography at the time of donor assessment demonstrates preserved cardiac function. ACTIVE INFECTION While the presence of donor transmissible infectious disease that will adversely affect the recipient remains an absolute contraindication to transplantation, not all infectious diseases have a significant impact on recipient outcomes. Transmissible infectious diseases that predate the donor’s terminal illness such as HIV, HTLV, hepatitis B, malaria, Jakob-Creutzfeldt’s disease, and disseminated tuberculosis are absolute contraindications to organ donation.44 The presence of other infectious diseases such as hepatitis C, EBV, CMV, bacterial or fungal infections, are only relative contraindications to organ donation depending on whether the organism is treatable, its location (localized or disseminated), or the medical urgency for transplantation of the recipient.7 The presence of active sepsis has traditionally been viewed as an exclusion criteria for organ donation. The donor organ in these cases is thought to harbor the blood-borne pathogen, or be affected functionally by the myocardial depressant effect of endotoxins or exotoxins. While active bacterial sepsis continues to be viewed as a relative contraindication for organ donation, its risks to the recipient may not be as high as initially suspected.45 A report of 19 donors with positive blood cultures showed that bacterial transmission from donor heart to recipient occurs more frequently with gram negative organisms than with gram positive species.46 Additionally, no serious infectious sequelae occurred in recipients from

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donors with gram positive bacteremia, although significant morbidity and mortality was found in organ recipients from donors with gram negative bacteremia. Any history of encephalitis of unknown cause is an absolute contraindication for organ donation. However, pneumococcal meningitis is an occasional cause of brain death that does not preclude the use of donor organs for transplantation if the donor has received appropriate antibiotic therapy (usually high dose penicillin) for at least 24 hours prior to organ procurement. We have adhered to a policy of treating the recipient for 7-10 days with appropriate antibiotics to cover any documented bacteremia or infection noted in the donor.

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MALIGNANCY Potential donors with active or hematologic malignancies should not be considered for organ donation, due to the risk of a malignancy being transmitted from the donor to a recipient.44,47 While most surgeons would consider a five year disease-free interval from a prior malignancy as a “cure”, some cancers (e.g., breast, colon, or malignant melanoma) have been reported to develop late metastases (beyond five years). Therefore, Penn48 has strongly advocated obtaining a complete autopsy on any donor with a history of a prior malignancy. Donors with low grade cutaneous malignancies such as basal cell carcinoma, low grade squamous carcinoma, or carcinoma-in-situ of the cervix have been utilized for transplantation, as they are not considered to be at high risk for occult metastatic disease to the transplanted organ.48,49 Donors with primary CNS tumors are also considered to be suitable for transplantation if it is unequivocally documented that the brain tumor is not a metastatic lesion. SOCIAL HISTORY Any social history which could increase the risk of transmissible infectious disease such as a multi-partner homosexual or heterosexual life style, prostitution, recent prison confinement, or history of recent IV drug abuse is a relative contraindication for organ donation, even in the face of negative serologic testing. These donors should be considered high risk, and should be used only in high risk recipients and only after obtaining the informed consent of the recipient. TOXICOLOGY Exposure of the donor to known cardiac toxins should alert the procurement team to obtain a more careful history of drug abuse or toxin exposure, and to more carefully evaluate their effects on the performance of the donor heart. Alcohol Acute and chronic alcoholism are known to impair myocardial function. Experience from several centers suggests that the results of heart transplantation from chronic alcoholic donors, even with normal function at the time of donor evaluation, is associated with a significantly worse outcome.50,51 A history of chronic alcoholism can be obtained in up to 20% of donors, and is associated with a reduction in 1-year survival from 95%-61%.51 A careful history regarding the level of alcohol consumption and any laboratory tests documenting the acute alcohol

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level should be obtained. We would avoid using donors with a history of heavy and prolonged alcohol abuse except in very extenuating circumstances for a critically ill recipient, and then only if the donor had normal function on echo. Carbon monoxide Carbon monoxide poisoning causes approximately 1500 accidental deaths and about 2000 suicidal deaths in the United States each year, certainly a potential source of donors. However, in addition to causing cerebral ischemia and brain death, carbon monoxide also causes myocardial ischemia and possible necrosis by inhibiting oxygen transport and oxidative metabolism. Both hearts and lungs have been successfully transplanted using donors who died from carbon monoxide poisoning.52-55 However, severe myocardial ischemia and necrosis with early graft failure has also been reported.56 We would recommend not using the heart from donors with carbon monoxide poisoning unless the echocardiographic function is normal, the ECG shows no evidence of ischemia, and there is no biochemical evidence for myocardial necrosis. We would also avoid using the lungs from a smoke inhalation victim unless the chest xray is clear and the oxygen challenge is exceptional (pO2 > 400 on FIO2=1.0). Cocaine Cocaine can cause coronary vasospasm, myocardial ischemia, myocardial infarction, malignant arrhythmias, and sudden death. While intravenous cocaine usage remains a strong contraindication to use of a donor, 57 recreational nonintravenous cocaine usage does not preclude organ donation. In a series of 112 heart transplants, 16% of donors were found to have either a history of recreational cocaine usage or a positive toxicology screen without adverse effects on graft function, length of hospital stay, rejection, or survival.58

DONOR SELECTION (ORGAN SPECIFIC)

HEART History Current history Careful and complete documentation of the circumstances surrounding the death of the donor is essential. A history of blunt chest trauma raises the question of myocardial contusion, which can be ruled out with a combination of myocardial specific enzymes, ECG, and direct inspection of the chest wall and heart. A history of sudden death without known cause raises the question of a primary cardiac event such as an arrhythmia or myocardial infarction. Even with a clear history of a closed head injury due to a fall or motor vehicle accident, it is important to determine if a sudden cardiac event could have precipitated the accident. The role of any toxin exposure contributing to the cause of death (e.g., cocaine, alcohol, or carbon monoxide) may increase the risk of myocardial damage. Documentation of the duration or estimated duration of any “down time” prior to resuscitation is important to determine the possibility of ischemic injury to the

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heart. The need for prolonged CPR or DC cardioversion should be documented, although it does not preclude transplantation of the heart if the functional assessment is satisfactory. Past history Any prior medical or surgical history of cardiac disease, or other disease with systemic manifestations likely to affect the heart, will likely preclude cardiac donation. These may include malignancy, connective tissue diseases, blood dyscrasias, or peripheral vascular disease. Potential cardiac donors with a recent or distant myocardial infarction, valvular heart disease, or a documented history of arrhythmias should be excluded. Coronary artery disease is the most common form of cardiac disease in the United States, affecting up to 40% of those over the age of 40. Therefore, any risk factors for coronary artery disease including male sex, a family history of premature coronary disease, smoking, diabetes mellitus, hypertension, hyperlipidemia, and obesity should be carefully documented. The presence of any of these risk factors in a patient over 40 years of age may prompt the request for a coronary angiogram prior to accepting the organ. Additionally, the transplant surgeon should take special care in assessing the coronary arteries at the time of organ procurement. Robiscek59 has suggested performing bench coronary angiography at the time of organ procurement to rule out significant coronary disease in the older or high risk donor. On occasion, coronary revascularization has even been performed on donor hearts at the time of transplantation into high risk recipients.14,15,60 Cardiac function Primary graft failure remains the leading cause of early death after heart transplantation.25 Early graft failure may occur as the result of (1) preexisting cardiac disease, (2) inadequate cardiopulmonary resuscitation after brain death, (3) myocardial injury resulting from brain death, (4) organ preservation injury, or (5) technical complications during implantation (e.g., air embolism). A careful history and functional evaluation of the donor heart can reduce the risk of early graft failure due to the first three factors. The techniques for functional assessment of the heart are outlined below. Preventing graft failure from preservation injury or technical complications is addressed in other chapters. Electrocardiography (ECG) An electrocardiogram is obtained from all donors looking for evidence of active ischemia, prior infarction, rhythm or conduction disturbances. Other abnormalities such as fluctuation in the ST segment are often seen in patients with increased intracranial pressure or subarachnoid hemorrhage.61-64 These ECG changes may not always indicate irreversible myocardial injury. However, when associated with wall motion abnormalities on echocardiogram, they are frequently associated with histopathologic evidence for injury (contraction band necrosis, coagulation necrosis, and myocytolysis) and the risk of early graft failure is substantial.65-69 These findings have been attributed to the “catecholamine storm” which occurs following brain death. The very high levels of norepinephrine, epinephrine, and dopamine noted after brain death are felt to cause a rapid influx of cal-

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cium into the myocyte with overload of the contractile apparatus similar to that observed with ischemia.65,70 Echocardiography (ECHO) ECHO evaluation is the key study used in assessing the potential cardiac donor. Information regarding cardiac anatomy, valvular structure and function, ventricular chamber size and function, wall thickness and motion abnormalities is readily obtained by this modality. Interpretation of such crude quantitative measures of global ventricular function as ejection fraction or shortening fraction must always take into account the heart rate, volume status, and evidence for septal dysfunction caused by pulmonary hypertension and right ventricular afterload. ECHO may be particularly helpful in assessing cardiac function and structure after trauma, where it can exclude valvular abnormalities or cardiac contusions. Moreover, rare congenital defects and cardiac tumors can be identified. More subtle abnormalities such as septal hypokinesis, mitral valve prolapse without regurgitation, or small pericardial effusions can be detected by this modality. In general, such findings would not preclude transplantation. Hemodynamic status and pressors Basic hemodynamic data such as systemic blood pressure, heart rate, and central venous pressure (when available) are reviewed. The current level of pressor and/or inotropic support is of significant importance. The use of dopamine at a dose of < 10 mcg/kg/min is usually preferred. More than low or moderate doses of these agents should alert the evaluating physician to potential problems with the heart. Etiologies of cardiac dysfunction may include preexisting disease, myocardial contusion, prolonged pressor support, systemic sepsis, hypoxemia, or cardiac depression secondary to brain death. The use of a pulmonary artery catheter is of occasional utility in assessing these patients. Coronary angiography As the age range of donors has expanded, the requests by transplant programs for coronary angiography has also increased. Potential donors with risk factors for coronary artery disease can now be assessed and many may remain acceptable based on results of angiography. Laboratory Cardiac enzymes are often obtained in potential donors but rarely impact the decision to use the organ. They become useful when there is a question about myocardial injury prior to organ donation, such as with prolonged CPR or resuscitation, multiple DC cardioversions, or concerns about possible myocardial infarction or contusion. The level of total CK alone is virtually useless since it is too nonspecific, being elevated with any brain, muscle, or heart injury. The combination of total CK with the CKMB isoenzyme determination is more helpful, but timing is quite critical since the CKMB usually peaks within 6-12 hours after injury and often falls to near normal within 24-48 hours. We have found that a measurement of troponin-I is often much more useful since it is quite cardiac specific and usually remains elevated for up to a week following myocardial injury.

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LUNG History Current history Only about 25% of cardiac donors (15-20% of all cadaver solid organ donors) have lungs suitable for lung transplantation using standard lung donor criteria.71 Multiple factors account for this discrepancy including 1) early colonization of the airway caused by loss of upper airway clearance mechanisms with mechanical intubation, 2) aspiration during resuscitation, 3) neurogenic pulmonary edema caused by brain injury, 4) excessive volume resuscitation to compensate for the loss of peripheral vasomotor tone associated with brain death, 5) acute respiratory distress syndrome (ARDS) due to release of cytokines with the systemic bacterial infection (SIRS), 6) traumatic pulmonary contusion, and 7) fat embolization following long bone fractures. A careful history of the events surrounding the death of the donor is important. Any blunt or penetrating chest trauma which could lead to direct lung injury should be noted, in addition to any long bone or pelvic fractures which might cause injury secondary to fat emboli. Closed head injury alone has been associated with up to a 40% incidence of pneumonia within the first week after intubation, most occurring within the first three days.72 Thus, the duration of intubation is a critical historical factor, but would not independently exclude the use of an otherwise acceptable organ. Any history of aspiration noted at the time of intubation and resuscitation must be considered in the context of the chest xray, sputum gram stain, bronchoscopy, and functional assessment. Past history A history of significant pulmonary disease likely to effect function and long term organ durability or any prior thoracic (not cardiac) surgery should preclude lung donation. While lungs with a history of prior granulomatous disease have been successfully transplanted, we feel that the risk of reactivation of the disease with immunosuppressive therapy is too risky. However, a history of asthma or mild reactive airway disease easily controlled on low doses of bronchodilators is not a contraindication to lung transplantation. Patients requiring steroids for control of asthma should be excluded. Similarly, tobacco smoking with a normal chest x-ray, bronchoscopy, lung function and mechanics, does not preclude lung transplantation. Function Chest X-ray Obtaining serial chest radiographs every 6-8 hours during the period of onsite donor management and within 2 hours of organ procurement is recommended.73-75 Serial chest radiographs are reviewed initially by a radiologist or pulmonologist on site at the donor hospital and then by the donor surgeon looking for signs of atelectasis, pulmonary infiltrates (suggesting pneumonia or aspiration), pulmonary edema, contusion, or other pulmonary abnormalities. The presence or de-

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velopment of an infiltrate would strongly influence the decision against the use of the specific lung. In situations where the infiltrate is thought to be secondary to aspiration, use of both lungs would be in question. In some circumstances, such as a pulmonary contusion, the affected lung may still be used. Similarly, if the infiltrate is thought to be related to pulmonary edema, diuresis can be attempted to aid in salvaging the donor organs. Some of these earlier guidelines have been recently expanded, and less than optimal donors have been utilized to combat the severe shortage of available organs.9 The chest radiograph is also useful for sizematching the recipient and donor as previously discussed. Ventilation mechanics An assessment of the static compliance of the donor lungs should made to assure normal lung mechanics. This usually means a peak airway pressure (PAP) of less than 25 cm H2O using a tidal volume (TV) of 10-15 mL/kg and 5 cm of PEEP. Evidence for reduced static compliance (evidenced by higher PAP with adequate TV) may indicate atelectasis or airway obstruction caused by secretions which can usually be corrected. If it cannot be corrected this suggests either acute (aspiration, pneumonia, pulmonary edema, etc.) or chronic intrinsic lung disease, a strong contraindication for transplantation. Gas exchange The key element in the assessment of the potential lung donor is the adequacy of gas exchange. Oxygenation as defined as the partial pressure of oxygen (paO2) of the donor should be greater than 300 mm Hg immediately prior to procurement on ventilator settings which include a FIO2 of 1.0, a tidal volume of 10-15 mL/kg, and a PEEP of 5 cm H2O. Serial determinations are important during the donor assessment period to assist in recognizing unfavorable trends in pulmonary function. The partial pressure of CO2 is given less emphasis but should reflect adequate ventilation parameters. Bronchoscopy Bronchoscopy is performed in all donors to detect the presence of occult aspiration as well as anatomical or pathological abnormalities that would preclude organ utilization. This may be performed by a pulmonologist, intensivist, or thoracic surgeon during the preliminary evaluation phase, but should always be repeated by the donor surgeon at the time of organ procurement. The finding of either endobronchial secretions that cannot be cleared by suctioning or diffuse erythema of the bronchial mucosa indicates aspiration, which usually precludes lung procurement.

DONOR PREOPERATIVE MANAGEMENT

INVASIVE HEMODYNAMIC MONITORING/INITIAL MANAGEMENT Invasive hemodynamic monitoring is used selectively in donors to assist in optimizing cardiovascular management prior to organ procurement. In the unstable donor it is essential to determine the relative need for volume expansion

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versus inotropes versus vasopressors, since appropriate therapy will maximize the number of suitable organs. An arterial line is used for close monitoring of all donors. Central venous pressure monitoring is also useful in most cases for monitoring of volume status and for reliable delivery of drugs. A pulmonary artery catheter is used selectively in situations of hemodynamic instability or questionable cardiac function. The ability to distinguish hemodynamic instability caused by inadequate preload (relative hypovolemia) versus inappropriate afterload (peripheral vasomotor collapse) versus depressed inotropic state (cardiac contractile dysfunction) is essential to guide effective donor management.76 The use of a pulmonary artery catheter can be most useful under these circumstances. A urinary drainage catheter is placed in all potential donors to monitor urinary output, assess renal function, and keep pace with the large urine output seen with diabetes insipidus which occurs in 50-70% of all organ donors. Although not always considered from the outset of the patient’s hospital course, placement of a nasogastric tube is critical to help prevent aspiration in all potential lung donors. Early placement of a nasogastric tube should be stressed to all hospitals and organ procurement organizations caring for multi-organ donors. INTRAVENOUS FLUID MANAGEMENT Following most forms of brain injury but prior to declaration of brain death, intravenous fluid is usually restricted in an attempt to limit cerebral edema and salvage any existing CNS function. This management, along with the nearly universal occurrence of diabetes insipidus due to pituitary nonfunction, may result in profound hypovolemia. Moreover, as part of the pathophysiology of brain death, there is usually a secondary loss of vasomotor tone. Therefore, when a potential donor is first identified, they are frequently intravascularly volume depleted, vasodilated, and hypotensive. Once a potential donor is declared brain dead, the first maneuver in donor management is to accurately assess the intravascular volume status and the peripheral vasomotor tone and then appropriately pursue aggressive volume repletion, with an intravenous fluid infusion ratio equal to the hourly urine output plus 100 mL/hr, maintaining the CVP in the 4-12 cm H2O range. Vasopressin or DDAVP (water soluble form of shorter acting vasopressin) is often required to sustain euvolemia. Close observation and correction of electrolyte abnormalities is required to avoid hypo- or hyperosmolar states which can have deleterious consequences such as tissue damage and dysrhythmias. While aggressive volume resuscitation may benefit most solid organs, it will often have a detrimental effect on donor lung function. One report has demonstrated that merely raising the CVP from 4-6 cm H2O up to 8-10 cm H2O with crystalloid solution causes a significant increase in the alveolar arterial oxygen gradient.77 The careful use of colloid solutions is recommended whenever possible in an attempt to maintain intravascular volume. Hemodynamic problems related to peripheral vasomotor tone are best managed with pressor agents with the goal of maintaining a normal systemic vascular resistance. With careful attention to volume management, the need for inotropic or pressor support is less common. Sustained or excessive inotropic requirements in the presence of ad-

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equate filling pressures and peripheral resistance should raise questions about the suitability of the heart for organ procurement. BLOOD PRODUCTS Blood products are used very judiciously in organ donors due to the risks of transmissible infectious diseases and of sensitizing the recipient to multiple additional other donor antigens. The role of donor specific transfusion and nonspecific transfusion is not completely understood. We prefer to avoid transfusion of all blood products in both the donor and the recipient unless absolutely necessary. We would prefer to transfuse only leuko-reduced blood products when the oxygen carrying capacity of the blood falls too low (Hemoglobin < 8.0 gm% or SVO2 < 60). MEDICATIONS In the donor population, low dose inotropes or pressor agents are often utilized in order to limit the volume of fluid infused (Table 7.4). Additionally, inotropic agents can be used as a test to observe the hemodynamic response in a questionable donor. Antiarrhythmic agents are infrequently used, as the more common dysrhythmia would be sinus tachycardia, typically due to hypovolemia. DDAVP (vasopressin), as described above, is commonly used to manage diabetes insipidus. Thyroxine has been used in situations where conventional pressor support is not effective. Support for this practice is controversial in the literature but has been effective in selected clinical settings.78,79

Table 7.4. Frequently utilized medications for donor management 1. Hormonal Agents Desmopressin (DDAVP) 0.3 mcg/kg IV over 30 min repeat if urine output not controlled maximum total dose–4 mcg Vasopressin (Pitressin) 5-10 U q8h IV, or continuous infusion 0.5 to 1 U/hour titrate to maintain urine output between 100 and 300 ml/hour Thyroxine (T4) 20 mcg IV followed by a thyroxine infusion of 200 mcg in 500 mL normal saline at 25 mL/hour titrate to maintain adequate blood pressure 2. Inotropic Agents Dopamine Dobutamine Epinephrine

3-10 mcg/kg/min 5-10 mcg/kg/min 0.01-0.03 mcg/kg/min

3. Pressor Agents Phenylephrine

0.06-0.18 mg/min

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VENTILATOR MANAGEMENT After establishing donor status, ventilator management should be directed at limiting barotrauma. A CMV mode is usually appropriate, with a weight proportional tidal volume (10-15 mL/kg). Fraction of inspired oxygen should be maintained at less than or equal to 40%, or sufficient to keep the arterial saturation above 90%. Airway pressures should be in normal range (less than 25 cm H2O), and low levels of PEEP (5 cm H2O) are used to help limit atelectasis. Any changes in lung compliance should be reported to the transplant teams.

7

TEMPERATURE Abnormalities in thermoregulation are relatively common after brain death, reflecting hypothalamic dysfunction. Treatment of both hypo- and hyperthermia are important to avoid complications such as dysrhythmias and tissue damage. Management of these temperature fluctuations are relatively basic. For hypothermia, application of warming blankets, heating lights, warmed intravenous fluids and ventilator circuit gases are means to maintain body temperature between 36.5°C-37.5°C. Conversely, treatment of hyperthermia includes the use of cooling blankets, ice packs, and alcohol compresses after searching for systemic infection by obtaining blood, urine, and sputum cultures. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

12.

Griepp RB, Stinson EB, Clark DA et al. The cardiac donor. Surg Gynecol Obstet 1971; 133:792-798. Copeland JG. Only optimal donors should be accepted for heart transplantation: Protagonist J Heart Lung Transplant 1995; 14:1038-1042. Todd TR, Goldberg M, Koshal A et al. Separate extraction of cardiac and pulmonary grafts from a single organ donor. Ann Thorac Surg 1988; 46:356-359. Zenati M, Dowling RD, Armitage JM et al. Organ procurement for pulmonary transplantation. Ann Thorac Surg 1989; 48:882-6. Sundaresan S, Trachiotis GD, Aoe M et al. Donor lung procurement: Assessment and operative technique. Ann Thorac Surg 1993; 56:1409-13. Egan TM. Selection and management of the lung donor. In: Patterson GA and Couraud L, ed, Lung Transplantation. Elsevier Science B.V. 1995:103-115. Kauffman HM, Bennett LF, McBride MA et al. The expanded donor. Transplant Rev 1997; 11:165-190. Pflugfelder PW, Singh NR, McKenzie FN et al. Extending cardiac donor ischemic time and donor age: Effects on survival and long-term cardiac function. J Heart Lung Transpl 1991; 10:394-400. Shumway SJ, Hertz MI, Petty MG et al. Liberalization of donor criteria in lung and heart-lung transplantation. Ann Thorac Surg 1994; 57:92-95. Ott GY, Herschberger RE, Ratkovec RR et al. Cardiac allografts from high-risk donors: Excellent clinical results. Ann Thorac Surg 1994; 57:76-82. Livi U, Bortolotti U, Luciani GB et al. Donor shortage in heart transplantation. Is extension of donor age limits justified? J Thorac Cardiovasc Surg 1994; 107:1346-1355. Drinkwater DC, Laks H, Blitz A et al. Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant 1996; 15:684-91.

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Livi U, Caforio ALP, Tursi V et al. Donor age greater than 50 years does not influence midterm results of heart transplantation. Transplant Proc 1996; 28:91-2. Burnett CM, Radovancevic B, Birovljev S et al. Concomitant donor heart coronary artery bypass grafting during orthotopic heart transplantation. Texas Heart Inst J 1990; 17:126-8. Laks H, Gates RN, Ardehali A et al. Orthotopic heart transplantation and concurrent coronary bypass. J Heart Lung Transplant 1993; 12:810-15. Starnes VA, Barr ML, Cohen RG et al. Living-donor lobar lung transplantation experience: Intermediate results. J Thorac Cardiovasc Surg 1996; 112:1284-91. Couetil JPA, Tolan MJ, Loulmet DF et al. Pulmonary bipartitionaing and lobar transplantation: A new approach to donor organ shortage. J Thorac Cardiovasc Surg 1997; 113:529-37. Gundry SR, Alonso de Begona J, Kawauchi M et al. Transplantation and reanimation of hearts removed from donors 30 minutes after warm, asystolic ëdeathí. Arch Surg 1993; 128:989-93. D’Alessandro AM, Hoffman RM, Knechtle SJ et al. Successful extrarenal transplantation from non-heart-beating donors. Transplant 1995; 59:977-82. Buchanan SA, DeLima NF, Binns OA et al. Pulmonary function after non-heartbeating lung donation in a survival model. Ann Thorac Surg 1995; 60:36-48. Cooper DKC. Clinical survey of heart transplantation between ABO blood groupincompatible recipients and donors. J Heart Transplant 1990; 9:376-81. Lanza RP. Effect of ABO blood-group antigens on long-term survival after cardiac transplantation. N Engl J Med 1982; 307:1275-6. Nakatani T, Aida H, Frazier OH et al. Effect of ABO blood type on survival of heart transplant patients treated with cyclosporine. J Heart Lung Transplant 1989; 8:27-33. Shumway SJ, Baumgartner WA, Soule LM et al. Lack of effect of ABO bloodgroup antigens on survival after cardiac transplantation. N Engl J Med 1987; 317:772-3. Bourge RC, Naftel DC, Costanzo-Nordin MR et al. Pretransplantation risk factors for death after heart transplantation: A multiinstitutional study. J Heart Lung Transplant 1993; 12:549-62. UNOS 1997 Report of Center Specific Graft and Patient Survival Rates. UNOS, Richmond, VA 1997; 88-139. Young JB, Naftel DC, Bourge RC et al. Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: A multivariable, multiinstitutional study. J Heart Lung Transplant 1994; 13:353-65. Hosenpud JD, Bennett LF, Keck BM et al. The registry of the International Society for Heart and Lung Transplantation: Fourteenth official report, 1997. J Heart Lung Transplant 1997; 16:691-712. Kobashigawa JA, Kirklin JK, Naftel DC et al. Pretransplantation risk factors for acute rejection after heart transplantation: A Multiinstitutional study. J Heart Lung Transplant 1993; 12:355-66. Kubo SH, Naftel DC, Mills RM et al. Risk factors for late recurrent rejection after heart transplantation: A multiinstitutional, multivariable analysis. J Heart Lung Transplant 1995; 14:409-18. Baumgartner WA. Evaluation and management of the heart donor. In: Baumgartner WA, Reitz BA, and Achuff SC, ed, Heart and Heart-Lung Transplantation. WB Saunders Co. 1990:86-102.

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Hosenpud JD, Pantely GA, Morton MJ et al. Relation between recipient:donor body size match and hemodynamics three months after heart transplantation. J Heart Transplant 1989; 8:241-3. Sweeney MS, Lammermeier DE, Frazier OH et al. Extension of donor criteria in cardiac transplantation: Surgical risk versus supply-side economics. Ann Thorac Surg 1990; 50:7-11. Sethi GK, Lanauze P, Rosado LJ et al. Clinical significance of weight difference between donor and recipient in heart transplantation. J Thorac Cardiovasc Surg 1993; 106:444-8. Morley D, Boigon M, Fesniak H et al. Posttransplantation hemodynamics and exercise function are not affected by body-size matching of donor and recipient. J Heart Lung Transplant 1993; 12:770-8. Mather PJ, Jeevanandam V, Eisen HJ et al. Functional and morphologic adaptation of undersized donor hearts after transplantation. J Am Coll Cardiol 1995; 26:737-42. Blackbourne LH, Tribble CG, Langenburg SE et al. Successful use of undersized donors for orthotopic heart transplantation—with a caveat. Ann Thorac Surg 1994; 57:1472-6. Fullerton DA, Gundry SR, Alonso de Begona J et al. The effects of donor-recipient size disparity in infant and pediatric heart transplantation. J Thorac Cardiovasc Surg 1992; 104:1314-9. Bailey LL, Gundry SR, Razzouk AJ et al. Bless the babies: One hundred fifteen late survivors of heart transplantation during the first year of life. J Thorac Cardiovasc Surg 1993. Noirclerc M, Shennib H, Giudicelli R et al. Size matching in lung transplantation. J Heart Lung Transplant 1992; 11:S203-8. Egan TM, Thompson JT, Detterbeck FC et al. Effect of size (mis)matching in clinical double-lung transplantation. Transplantation 1995; 59:707-13. Otulana BA, Mist BA, Scott JP, er al. The effect of recipient lung size on lung physiology after heart-lung transplantation. Transplantation 1989; 48:625-9. Miyoshi S, Schaefers HJ, Trulock EP et al. Donor selection for single and double lung transplantation: Chest size matching and other factors influencing posttransplantation vital capacity. Chest 1990; 98:308-13. UNOS Ad Hoc Donations Committee: Expanded donor criteria: Background and suggestions for kidney donation. Richmond, VA, UNOS, 1992. Lammermeier DE, Sweeney MS, Haupt HE et al. Use of potentially infected donor hearts for cardiac transplantation. Ann Thorac Surg 1990; 50:222-5. Bull DA, Stahl RD, McMahan DL et al. The high risk heart donor: Potential pitfalls. J Heart Lung Transplant 1995; 14:424-8. Sack FU, Lange R, Mehmanesh H et al. Transferral of extrathoracic donor neoplasm by the cardiac allograft. J Heart Lung Transplant 1997; 16:298-301. Penn I. The problem of cancer in organ transplant recipients: An overview. Transplant Sci 1994; 4:23-. Weiss L. An analysis of the incidence of myocardial metastases from solid cancers. Br Heart J 1992; 68:501-4. Houyel L, Petit J, Nottin R et al. Adult heart transplantation: Adverse role of chronic alcoholism in donors on early graft function. J Heart Lung Transplant 1992; 11:1184-7.

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Freimark D, Aleksic I, Trento A et al. Hearts from donors with chronic alcohol use: A possible risk factor for death after heart transplantation. J Heart Lung Transplant 1996; 15:150-9. Smith JA, Bergin PJ, Williams TJ et al. Successful heart transplantation with cardiac allografts exposed to carbon monoxide poisoning. J Heart Lung Transplant 1992; 11:698-700. Shennib H, Adoumie R, and Fraser R. Successful transplantation of a lung allograft from a carbon monoxide-poisoning victim. J Heart Lung Transplant 1992; 11:68-71. Iberer F, Konigsrainer A, Wasler A et al. Cardiac allograft harvesting after carbon monoxide poisoning. Report of a successful orthotopic heart transplantation. J Heart Lung Transplant 1993; 12:499-500. Koerner MM, Tenderich G, Minami K et al. Extended donor criteria. Use of cardiac allografts after carbon monoxide poisoning. Transplantation 1997; 63:1358-60. Karwande SV, Hopfenbeck JA, Renlund DG et al. An avoidable pitfall in donor selection for heart transplantation. J Heart Lung Transplant 1989; 8:422-4. Baldwin JC, Anderson JL, Boucek MM et al. Twenty-fourth Bethesda Conference: Cardiac Transplantation. Task force 2: Donors guidelines. J Am Coll Cardiol 1993; 22:15-22. Freimark D, Czer LSC, Admon D et al. Donors with a history of cocaine use: Effect on survival and rejection frequency after heart transplantation. J Heart Lung Transplant 1994; 13:1138-44. Robiscek F, Masters TN, Thomley AM et al. Bench coronary cineangiography. A possible way to increase the number of hearts available for transplantation. J Thorac Cardiovasc Surg 1992; 103:490-5. Thomson DJ, Kostuk W, Pflugfelder P et al. De novo coronary artery grafting in a heart transplant recipient. J Heart Transplant 1988; 7:468-70. Doshi R, Neil-Dwyer G. A clinicopathologic study of patients following a subarachnoid hemorrhage. J Neurosurg 1980; 52:295-301. Shanlin RJ, Sole MJ, Rahimifar M et al. Increased intracranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damage in rats. J AM Coll Cardiol 1988; 12:727-36. Pollick C, Cujec B, Parker S et al. Left ventricular wall motion abnormalities in subarachnoid hemorrhage: An echocardiographic study. J AM Coll Cardiol 1988; 12:600-5. Kono T, Morita H, Kuroiwa T et al. Left ventricular wall motion abnormalities in patients with subarachnoid hemorrhage: Neurogenic stunned myocardium. J Am Coll Cardiol 1994; 24:636-40. Novitsky D, Wicomb WN, Cooper DKC et al. Electrocardiographic, hemodynamic and endocrine changes occurring during experimental brain death in the Chacma baboon. J Heart Transplant 1984; 4:63-9. Novitsky D, Wicomb WN, Cooper DKC et al. Prevention of myocardial injury during brain death by total cardiac sympathectomy in the Chacma baboon. Ann Thorac Surg 1986; 41:520-4. Novitsky D, Cooper DKC, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987; 43:852-4.

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69.

70. 71. 72. 73. 74. 75. 76.

7 77.

78.

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Novitsky D, Cooper DKC, Rose AG et al. Early donor heart failure following transplantation from myocardial injury sustained during brain death. Clin Transplantation 1987; 1:108-13. Novitsky D, Horak A, Cooper DKC et al. Electrocardiographic and histopathologic changes developing during experimental brain death in the baboon. Transplant Proc 1989; 21:2567-9. Bittner HB, Kendall SWH, Campbell KA et al. A valid experimental brain death organ donor model. J Heart Lung Transplant 1995; 14:308-17. Egan TM, Boychuk JE, Rosato K et al. Whence the lungs? A study to assess suitability of donor lungs for transplantation. Transplantation 1992; 53:420-2. Hsieh AH, Bishop MJ, Kublis PS, et al Pneumonia following closed head injury. Am Rev Respir Dis 1992; 146:290-4. Cooper JD. The lung donor: Special considerations. Transplant Proc 1988; 20:17-18. Egan TM, Kaiser LR, Cooper JD. Lung transplantation. Curr Probl Surg 1989; 26:673-752. Griffith Clin Chest Med 1989. Potter CDO, Wheeldon DR, Biol MI et al. Functional assessment and management of heart donors: A rationale for characterization and a guide to therapy. J Heart Lung Transplant 1995; 14:59-65. Pennefather SH, Bullock RE, Dark JH. The effect of fluid therapy on alveolar arterial oxygen gradient in brain-dead organ donors. Transplantation 1993; 56:1418-22. Novitsky D, Cooper DKC, Chaffin JS et al. Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation 1990; 49:311-16. Goarin JP, Cohen S, Riou B et al. The effects of triiodothyronine on hemodynamic status and cardiac function in potential heart donors. Anesth Analg 1996; 83:41-7.

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Surgical Technique for Multiple Organ Recovery Osman Abbasoglu, Marlon F. Levy The Role of the Anesthesiologist in Organ Procurement ..................................... Liver Procurement .............................................................................................. Kidney Procurement ........................................................................................... Pancreas Procurement ........................................................................................ Small Bowel Procurement ................................................................................... Summary ............................................................................................................

114 114 120 122 124 126

The dramatic improvement in the quality of life after successful transplantation has increased demands for solid organ transplantation. In general only braindead donors are accepted for cadaveric transplantation. Despite all efforts to increase the organ procurement rate, the number of organs retrieved is still short of the needs. Because of organ shortage and the growth of transplantation of many solid organs including kidney, liver, pancreas, heart, lung and intestines, the number of donor organs should be maximized through multi-organ procurement.1,2 Currently, all donors are considered for multi-organ procurement unless specific contraindications exist. Differences in the techniques for organ procurement among transplantation centers necessitate close cooperation and good communication between operative teams for optimal procurement without organ ischemia or injury. Technical principles of abdominal procurement procedures are the same regardless of the organs removed.3 These are wide exposure, placement of cannulas for in situ perfusion, isolation of organs to be removed in continuity with their central vascular structures and orderly removal of the organs under cold perfusion protection. Organs are removed according to their susceptibility to ischemia, the need for their immediate function and their anatomic location. In multiple organ procurement the order of organ removal is: 1. Heart 2. Lungs 3. Liver 4. Pancreas (or small intestine) 5. Kidney

Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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Organ Procurement and Preservation THE ROLE OF THE ANESTHESIOLOGIST IN ORGAN PROCUREMENT

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The anesthesiologist has an important role in organ procurement mainly regarding hemodynamic instability.4 Spinal reflexes can be present after brain death and muscle relaxants are reserved for the operation. During organ retrieval, maintenance of cardiac output and adequate oxygenation are of great importance. Careful fluid and electrolyte replacement and monitoring of cardiovascular status is critical. Donors may be dehydrated because of fluid restriction and diuretics that were given in an effort to control brain edema before declaring brain death. Hypotension and oliguria should be treated by fluid replacement, often monitored by a central venous pressure line. Packed red blood cells may be used if the hematocrit is less than 21% or hypotension does not respond to intravenous fluids. A urine output of 1 mL/kg/h should be maintained. For hypotension that is not responding to volume challenge, dopamine can be used. Norepinephrine and epinephrine should be avoided as much as possible, and considered only when adequate volume resuscitation and dopamine fail to maintain blood pressure. Maintenance of body temperature is important. Because of impaired hypothalamic thermoregulation, donors may become hypothermic. Warming of all intravenous fluids and blood products and the use of a warming blanket may help in preventing hypothermia.

LIVER PROCUREMENT According to the degree of preliminary dissection, liver procurement can be classified into standard and rapid perfusion techniques.5 In the standard technique, preliminary dissections of the hepatic artery, celiac axis and portal vein are carried out before aortic and portal flushing with preservation solutions. Standard technique allows the dissection of vascular structures to an extent that anatomy is clarified.6 The rest of the dissection is then completed easily and safely after reperfusion of the liver. This technique tends to be time consuming and sometimes is associated with excessive blood loss during dissection. The rapid perfusion technique minimizes dissection before flushing with preservation solutions.7 The preparatory steps include cannulation of the aorta and portal vein. The entire hilar dissection is performed after aortic cross-clamping. In this way donor hepatectomy can be completed in a nearly bloodless field. This technique requires dissection of asanguinous blood vessels, making them more difficult to identify, and may be associated with vascular injury. The rapid perfusion technique is mainly suitable for the hemodynamically unstable donor. The method of procurement procedure principally depends on the preference and experience of the surgeon. Either of these techniques can be used for retrieval of organs without functional or anatomical damage.

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STANDARD TECHNIQUE We currently use this technique for liver procurement. The procedure begins with a midline incision with electrocautery from the suprasternal notch to symphysis pubis. A midline sternal splitting is performed with a bone cutting saw or a Lebsche knife. This allows maximum exposure, intrapericardial division of suprahepatic vena cava, and provides immediate access to the heart in case of instability. Hemostasis of the cut surface of the sternum is achieved with electrocautery and bone wax. A self-retaining sternal retractor is placed and spread laterally. A large Balfour retractor is used for the abdomen. Upon entering the abdomen rapid intra-abdominal exploration is made for suitability of organs to be harvested. Intra-abdominal malignancy, peritonitis and ischemic bowel are the main intraoperative findings that preclude organ procurement. The liver is inspected and palpated to assess color, size, consistency and any injury. Usually small lacerations or hematomas do not preclude the use of the liver. A normal liver is red-brown in color with sharp edges. A large, brown-yellow soft liver with round edges is consistent with steatosis. Yellow color during blanching following the release of fingertip pressure on the liver surface is also a sign of steatosis. If gross appearance of the liver suggests steatosis a frozen section biopsy should be performed. The degree of steatosis is best determined by an experienced pathologist. For this reason we recommend frozen section biopsies to be examined by the hepatopathologist at the transplantation center. Livers that contain more than 40-50% macrovesicular fat on frozen section should be used very cautiously as we believe that they carry a higher risk of primary nonfunction. A swollen liver with round edges may be seen in the presence of high central venous pressure. This appearance improves with intraoperative administration of diuretics. A swollen liver in the presence of low or normal central venous pressure is usually a sign of ischemic injury. Capillary perfusion can be assessed by pressing on the liver with fingertips and observing reperfusion after release. Any lesion of the liver which is suspicious for malignancy should be biopsied. Livers from hepatitis-C antibody positive donors should undergo histopathologic examination regardless of their macroscopic appearance. Their use in transplantation is acceptable under special circumstance. Mobilization of the liver begins with division of the round ligament between ligatures. Left triangular and falciform ligaments are divided with electrocautery. Then attention is turned to the distal aorta. We prefer to carry out aortic dissection early in the operation so that in the event of cardiovascular collapse, the aorta can be cannulated immediately and the rest of the dissection completed after aortic and portal flush as in the rapid flush technique. The entire right colon and small bowel mesentery are mobilized by dividing retroperitoneal attachments and the intestines are swept up. An extended Kocher maneuver is then performed exposing the vena cava. The distal aorta is identified and dissected free. The inferior mesenteric artery is divided between ligatures. The aorta at the level of inferior mesenteric artery is encircled with two umbilical tapes. Care should be taken in encircling the aorta as lumbar arteries may be injured.

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Table 8.1. Incidence of variations of the hepatic artery (%) Variation Common hepatic artery originating from left gastric artery Left hepatic artery originating from left gastric artery Right hepatic artery originating from superior mesenteric artery Entire hepatic artery trunk originating from superior mesenteric artery Combination of left hepatic artery originating from left gastric artery and right hepatic artery from superior mesenteric artery Others

8

Suzuki et al (200 cases)20

Emre et al 496 cases4

70

67

12.5

14

7.5

10

3

4.5 2.5

2

<1 6

Next attention is directed to the supraceliac aorta. The gastrohepatic ligament is divided with electrocautery. If a left hepatic artery arising from the left gastric artery is palpated and/or visualized in the gastrohepatic ligament, it should be preserved by dissecting the artery back to its origin from the main left gastric artery (Table 8.1).8 The gastric branches of the left gastric artery are divided between ligatures and the continuity of the left hepatic artery with the left gastric artery is preserved. The diaphragmatic muscle fibers overlying the supraceliac aorta are separated longitudinally and divided with electrocautery. During this dissection the stomach is retracted laterally and the left lateral segment of the liver is retracted medially. After exposing the aorta, the preaortic fascia is incised and the aorta is encircled with an umbilical tape. Intercostal or lumbar aortic branches are usually not encountered in this location. Next attention is directed to hepatoduodenal ligament. First, the hepatic artery is dissected out. The peritoneum overlying the superior border of the pancreas is incised. The common hepatic artery usually lies in the groove between the pancreas and the common hepatic lymph node. Following identification of the common hepatic artery, gastroduodenal and right gastric arteries are divided between ligatures. By retracting the pancreas caudally, the left gastric and splenic branches of the celiac axis are identified, ligated and then divided. If there is a left hepatic artery coming from the left gastric artery, it is preserved as described previously. Further dissection of the celiac axis is not required at this point. The ligation of all branches is always performed away from the main artery to prevent intimal dissection. An adequate length of splenic artery cuff should be provided for possible anastomosis of right hepatic artery originating from superior mesenteric artery. The peritoneum overlying the distal part of hepatoduodenal ligament is incised. The common bile duct is identified and mobilized to a level as low as possible to have adequate length for later reconstruction of the biliary tract. The bile

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duct is then transected after distal ligation. To preserve the blood supply of the common bile duct, dissection is kept to a minimum. The gallbladder fundus is opened with the electrocautery and bile is washed out with saline by a cathetertipped syringe to prevent autolysis of the biliary mucosa. After the division of common bile duct, the presence of an anomalous replaced right hepatic artery arising from superior mesenteric artery is assessed.9 A finger is inserted into the foramen of Winslow to identify the replaced right hepatic artery. It can be located by its pulsation lateral to the portal vein and posterior to the common duct. Its origin from the superior mesenteric artery is usually found beneath the splenic vein near its junction with the portal vein. If a replaced right hepatic artery is present its further dissection all the way to its origin from superior mesenteric artery is usually performed after cold perfusion. The portal vein which typically lies under the gastroduodenal artery is identified by dividing the areolar tissue. Then it is isolated by dividing the connective tissue and lymph nodes surrounding the vein. Dividing the lymph nodes between ligatures may facilitate a bloodless dissection. The coronary vein is ligated and divided. The portal vein is cleaned inferiorly to the junction of splenic and superior mesenteric veins. The next step is the identification of superior mesenteric artery. The intestines are elevated from the retroperitoneum and areolar tissue over the aorta and vena cava cleaned until the left renal vein is exposed. The superior mesenteric artery is located at the base of the small bowel mesentery just above the renal vein. The connective tissue surrounding the superior mesenteric artery is divided and it is encircled with a heavy tie. The superior mesenteric artery is not tied at this point to prevent intestinal ischemia. Following this preliminary dissection, the next step is cannulation of the aorta and portal vein for cold perfusion. Either the splenic or inferior mesenteric vein can be cannulated for portal perfusion. Inferior mesenteric vein cannulation is easier and less time consuming. After isolating proximally in the mesentery of the left colon, the inferior mesenteric vein is ligated and cannulated. The cannula is advanced until the tip is felt just entering the portal vein. If the splenic vein is chosen for cannulation, it is dissected free at least 1 cm and encircled. If necessary for exposure, the neck of the pancreas can be divided between ligatures. Then the splenic vein is ligated and through its central side a cannula is placed. The splenic vein is divided behind the cannula. The superior mesenteric vein is also encircled with a ligature to be tied off later. Some surgeons infuse a total of 1-2 liters of chilled lactated Ringer’s solution through the portal vein for liver precooling before aortic cross-clamping. This step probably is not necessary. If precooling is used, close monitoring of temperature and blood pressure is crucial not to compromise the heart. After all teams have completed their dissections, the donor is heparinized with 20,000-30,000 U (300 U/kg). The previously encircled aorta is ligated distally with umbilical tape and cannulated with a cardiovascular cannula. The cannula is secured to the aorta with the second umbilical tape. If there is a thoracic team, both teams coordinate the cardiopulmonary arrest and the supraceliac aorta is clamped.

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Then vena caval decompression is performed by incising the inferior vena cava at its junction with the right atrium. We favor right chest venting of the vena cava as optimal. Sufficient length of supradiaphragmatic inferior vena cava should be obtained for adequate recipient anastomosis. The length of inferior vena cava staying on the liver graft is decided between heart and liver teams. The effluent is drained by a Poole suction tip through the transected vena cava. If lungs are not to be retrieved, the right pleura can be opened to keep the warm effluent away from the heart. If the heart and/or lung team favors intra-abdominal caval decompression to keep the warm blood and effluent away from the thorax, the inferior vena cava can be cannulated just above the iliac bifurcation. This allows distal drainage of blood with perfusion fluids. In this case effluent is collected into a drainage bag. Intra-abdominal vena caval decompression needs extra dissection and may not be as effective in keeping the liver decompressed as supradiaphragmatic caval decompression. During donor exsanguination, aorta and portal vein flushing with cold University of Wisconsin (UW) solution, the abdominal and thoracic cavities are filled with slushed-ice saline for topical cooling. With aortic and portal perfusion the liver and kidneys become cold and bloodless. We prefer to use 2 liters of infusate through each of the cannulas (aortic and portal). Perfusion volumes for children are 50 mL/kg for aorta and 30-50 mL/kg for portal vein. After starting cold perfusion the previously encircled superior mesenteric artery and superior mesenteric vein are ligated. The heart and/or lungs are removed first. This allows time for perfusion and topical cooling. Liver recovery begins with an incision of the pericardium surrounding the intrapericardiac inferior vena cava. The suprahepatic vena cava is freed completely. This requires an incision of the diaphragm over the esophageal hiatus. Care should be taken not to enter the esophagus. The right diaphragm is incised with a wide margin away from the liver. During this dissection, pulling the liver or the right kidney forcefully can cause tears in the liver capsule. The peritoneum overlying the infrahepatic vena cava and right kidney is incised. The right kidney is retracted laterally and caudally to allow the surgeon to encircle the inferior vena cava with index finger. The left renal vein is identified and the inferior vena cava is transected above the left renal vein. The right adrenal gland is divided leaving half of the gland with the liver and the other half with the right kidney. Using the right adrenal gland as a point of division allows both the liver and kidney teams reassurance that neither organ is “shortchanged.” The liver is lifted anteriorly and superiorly and the right diaphragm with retroperitoneal attachments is divided sharply. The splenic and superior mesenteric veins are divided (if the inferior mesenteric vein was cannulated for portal flush and the splenic vein was not previously divided). The portal vein is reflected superiorly and freed up to the level of the transected bile duct. The portal vein cannula is kept in for subsequent back table flush. Next, the celiac axis is dissected free. This requires division of the left diaphragmatic crus and the nerve fibers of the celiac trunk around the celiac axis.

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The previously ligated superior mesenteric artery in the root of the small bowel mesentery is identified at its confluence with the aorta. The aorta is then divided between the celiac and superior mesenteric arteries. At this point care should be taken not to injure the left renal artery. The supraceliac aorta is divided distal to the previously placed aortic clamp. In this way a cylinder of aorta which includes the celiac axis can be obtained. This provides an aortic Carrel patch with the celiac axis for the recipient arterial anastomosis. Next the liver is lifted anteriorly. The remaining right diaphragmatic and retroperitoneal attachments are divided and the liver is removed. In the presence of an anomalous right hepatic artery branching from superior mesenteric artery, the superior mesenteric artery is dissected clean from its beginning at the aorta to beyond the origin of the anomalous right hepatic artery branch. This requires retraction of the pancreas inferiorly and division of the connective tissue with nerve bundles around the superior mesenteric artery. Then a segment of the superior mesenteric artery including the origin of the right hepatic artery is excised. The anomalous right hepatic artery usually originates within the first 3 cm of the superior mesenteric artery. After procurement of all organs, the iliac arteries and veins are recovered for possible vascular reconstruction in the recipient. In case of atherosclerotic iliac arteries which renders them unusable, the carotid arteries may be recovered. A part of the spleen and mesenteric lymph nodes in the terminal ileum mesentery are removed for tissue typing. Usually 10-12 lymph nodes are sufficient. If there are not enough lymph nodes in the mesentery, as can be seen in the elderly donor, mediastinal lymph nodes are taken. RAPID PERFUSION TECHNIQUE In this technique minimal dissection is needed before cold perfusion. A midline incision from the suprasternal notch to the symphysis pubis is made. The left triangular ligament is incised. The diaphragmatic crura overlying the supraceliac aorta are separated and divided with electrocautery. The supraceliac aorta is encircled with an umbilical tape. Next, the distal aorta is dissected free and the inferior mesenteric artery is divided between ligatures. The distal aorta is encircled with two umbilical tapes at this level. The inferior mesenteric vein is isolated, ligated and cannulated. The tip of the cannula is advanced to the level of the portal vein entrance. The gall bladder fundus is opened and bile is washed out with saline irrigation. The distal aorta is cannulated after systemic heparinization. The supraceliac aorta is cross-clamped. The inferior vena cava is transected close to its junction with the right atrium. Cold perfusion and topical cooling are performed as described previously. Hepatectomy is completed in the bloodless field. The suprahepatic inferior vena cava is freed from diaphragm and pericardium. The hepatic hilum is carefully dissected. The gastroduodenal, right gastric, splenic and left gastric arteries are ligated and divided. In the presence of a left hepatic artery originating from the left gastric artery, this artery is preserved by dividing gastric branches. The portal vein is encircled and splenic and superior mesenteric veins are divided

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between ligatures. If present, the anomalous right hepatic artery originating from the superior mesenteric artery is preserved. Liver procurement is completed as described in the standard technique. BACK TABLE PREPARATION The liver is placed in a plastic bag (typically a “bowel bag”) and taken to an ice basin on the back table. The portal vein is perfused with 500 mL of cold UW solution through the previously placed cannula. The effluent is kept in the plastic bag. Next the hepatic artery is perfused with an additional 300-500 mL of UW solution. Less fluid is used for the perfusion of pediatric grafts. The common bile duct is flushed with 20-40 mL of UW solution through a baby feeding tube to clear bile ducts of bile. The liver is completely immersed in UW solution and packed in two sterile plastic bags. One liter of cold lactated Ringer’s solution is placed between two bags for protection from trauma. The packaged liver is placed in a cooler and covered with ice for transportation.

KIDNEY PROCUREMENT

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The main principle of donor kidney procurement is en bloc removal of both kidneys with an intact segment of aorta and inferior vena cava.10-12 This allows safe and rapid excision of kidneys with maximal vessel length available for anastomosis. Operative trauma to renal vessels and vascular supply of the ureter is kept minimal with this technique. Organ donors can be expected to have a renal vascular or ureteric anomaly in up to 49% of cases (Table 8.2).13 KIDNEY PROCUREMENT AS A PART OF MULTIPLE ORGAN RECOVERY If the kidneys are to be procured as a part of multiple organ recovery, they are removed after hepatectomy and/or pancreatectomy. The technique described previously for liver procurement is compatible for simultaneous kidney removal. Cold perfusion of the liver for in situ cooling also allows cooling of the pancreas and kidneys. All of the dissection is made in a cold and bloodless field.

Table 8.2. Renal vascular and ureteric anomalies. Findings in a series of 400 cadaver kidney donors.13 Renal artery Double Triple Renal vein Double Triple Double ureter

Right (%)

Left (%)

25 4

22 3

13 1 1

2 <1 1

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First, ureters are identified in the pelvis. They are dissected free and divided distally close to the urinary bladder. Periuretral fatty areolar tissue containing the vascular supply to the ureter should be preserved as much as possible to avoid devascularization. Both ureters are freed to the level of the lower kidney pole. Hemostats are applied to the periureteral fat at the distal ends of the ureters for traction. Next kidneys are dissected out. They are dissected beyond the plane of Gerota’s fascia. The right kidney usually has already been exposed as the right colon and duodenum are mobilized as a part of liver procurement. For the exposure of the left kidney, the line of Toldt is incised and the left colon is retracted medially. Splenic and diaphragmatic attachments are divided. Then the left mesocolon is divided for complete dissection of the left kidney. While retracting anteriorly both kidneys are mobilized in the superior and lateral aspects staying away from the capsule. Hilar dissection is avoided. The inferior vena cava is transected just above the bifurcation. The aorta is divided distal to the cannula and the cannula is kept in place for traction. Kidneys, ureters, aorta and vena cava are lifted upward and are not allowed to fall posteriorly. All tissue lying posteriorly is cut, staying on the prevertebral fascia until the previously transected suprarenal aorta and inferior vena cava are reached. After completing the posterior dissection, the residual attachments between the kidneys and gastrointestinal tract are divided. With this technique kidneys are removed en bloc. The kidneys are taken to the back table and placed in a basin of ice saline. If the organs appear to have been uniformly flushed, no additional back table flush is needed. The block is placed in the anatomic position and properly oriented. The left renal vein passing anterior to the aorta is divided with a cuff of vena cava. The entire vena cava stays with the right kidney. This technique allows the recipient surgeon to increase the length of the right renal vein with the cuff of vena cava in case of a short renal vein. Next the block is turned posteriorly. The aorta is opened in the midline between the lumbar arteries in the posterior aspect. The renal arteries are identified from the inside and the anterior wall of the aorta is then divided. With the internal view, the risk of injury to renal arteries is minimized. Frequent vascular anomalies (venous and arterial) to the kidneys require the meticulous attention of an experienced surgeon. Obvious perinephric fat can be removed but the rest of the dissection is left for the recipient surgeon. The kidneys are separately packaged in plastic bags with UW solution. Then plastic bags are placed in a cooler and kept in ice for transportation. KIDNEY PROCUREMENT ALONE If only kidneys are to be removed we still make an incision from the sternal notch to the symphysis pubis. Wide exposure reduces the risk of operative injury to kidneys and their vascular supply. After placement of sternal and abdominal retractors the peritoneum in the right paracolic gutter is incised. The right colon is mobilized and retracted superiorly and medially. The small bowel mesentery is incised and swept up. The duodenum is Kocherized and retracted upward with

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the pancreas. After this preliminary dissection, the right kidney, aorta, vena cava and superior mesenteric artery are exposed. The inferior mesenteric artery is ligated and divided. The distal aorta is dissected free and encircled with two umbilical tapes. With the retraction of intestines upward, the superior mesenteric artery is identified above the left renal vein. It is encircled with heavy ligature to be tied off later. The supraceliac aorta is isolated and encircled with an umbilical tape. At this point, although it is not necessary, the celiac axis can be ligated or clamped. After systemic heparinization with 20,000 U, the distal aorta is cannulated and the supraceliac aorta is cross-clamped. The vena cava is vented by incising it in the pericardium. The aorta is infused with 2 liters of UW solution. Previously encircled superior mesenteric artery is ligated. The abdominal cavity is filled with slushed-ice saline for topical cooling. The rest of the dissection is carried out in a bloodless field as described previously.

PANCREAS PROCUREMENT

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Pancreas retrieval is usually a part of a multiple intra-abdominal organ procurement. Combined liver and pancreas procurement requires meticulous surgical technique.14 The main technical consideration in combined liver and pancreas procurement is preservation of arterial blood supply and adequate length of portal vein for both organs.15 As the liver and pancreas share the same arterial supply and arterial anomalies are common, careful dissection and good communication between pancreas and liver procurement teams are necessary. The tail and most of the body of the pancreas are supplied by the splenic artery which is a branch of the celiac axis. The head of the pancreas and duodenum have a dual arterial supply: the superior pancreaticoduodenal arcade off the gastroduodenal artery and inferior pancreaticoduodenal arcade off the superior mesenteric artery. Hence, preservation of both the splenic and superior mesenteric arteries is critical for this organ. In combined liver and pancreas procurement the gastroduodenal artery is ligated and divided to keep the entire celiac axis with an aortic patch on the liver graft. In this case, the superior pancreaticoduodenal arcade is fed by the inferior pancreaticoduodenal arcade. The venous drainage of the pancreas is by the splenic vein and superior mesenteric vein that come together as the portal vein. COMBINED LIVER AND PANCREAS PROCUREMENT A midline incision with electrocautery from the suprasternal notch to the symphysis pubis is made. The right colon and small bowel mesentery are mobilized. The inferior mesenteric artery is divided between ligatures and the distal aorta is encircled. The supraceliac aorta is encircled after division of diaphragmatic muscle fibers. The bile duct is divided close to the duodenum. The hepatic artery is identified and isolated as described previously. The gastroduodenal, right gastric and left gastric arteries are divided between ligatures. The splenic artery is preserved. The portal vein is dissected free.

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The inferior mesenteric vein is dissected and cannulated for portal perfusion. The cannula is advanced into the portal vein. The splenic vein is preserved and should not be used for cannulation. The greater omentum is divided between ligatures along its entire length. The short gastric vessels between the stomach and spleen are ligated and divided. The spleen is mobilized by dividing the splenocolic and splenorenal ligaments and diaphragmatic attachments. The spleen is used as a handle to minimize trauma to the pancreas. The stomach is retracted upward and to the right exposing the lesser sac and anterior surface of the pancreas. The peritoneum at the superior and inferior borders of the pancreas is incised. Ligation of identifiable blood vessels prevents pancreatic injury that may happen during the control of bleeding from these vessels. This also avoids bleeding after implantation. The spleen is retracted medially and the tail of the pancreas is dissected free off the retroperitoneum. Care should be taken to carry out the dissection away from the surface of the pancreas. An extended Kocherization is performed for mobilization of the pancreatic head with duodenum. The ligament of Treitz is divided. The duodenum and pancreas are retracted to the left until the aorta is exposed. The stomach and duodenum are irrigated with an antibiotic or povidone-iodine solution through a nasogastric tube. The duodenum is transected just distal to pylorus with a GIA stapler. The proximal jejunum just distal to the ligament of Treitz is cleared circumferentially and divided in the same way. Spillage of intestinal content should be prevented. Next, the root of small bowel mesentery is divided after ligation of mesenteric vessels. We favor individual ligation of the major branches of the superior meseteric veins and arteries. We are concerned that mass ligature (or stapling) of their vessels could lead to the development of large arterio-venous fistulas in the implanted pancreas. This dissection is carried out away from the pancreas to avoid injury to the proximal superior mesenteric artery that supplies the pancreas. After this preliminary dissection the pancreas is ready for cold perfusion. The rest of the dissection is completed in the bloodless field. The donor is heparinized systemically and the distal aorta is cannulated. The supraceliac aorta is crossclamped. The inferior vena cava is divided in the pericardium. Cold perfusion with UW solution is initiated through aortic and portal cannulas. The portal vein is ligated over the previously placed cannula leaving 2 cm of portal vein on the pancreas side. The portal vein is incised just below the ligature for venous decompression of the pancreas. Topical cooling is performed with slushed-ice saline. After completion of cold perfusion, the liver is retrieved. During liver procurement, the splenic artery is ligated close to the celiac axis and divided leaving as much length of splenic artery with the pancreas as possible. The free end of the splenic artery is marked with a fine polypropylene suture for its later identification. The portal vein is divided between the liver and pancreas. Nerve bundles and lymphatic tissue around the superior mesenteric artery are divided and the superior mesenteric artery is dissected free down to the aorta. The superior mesenteric artery with a narrow cuff of aorta is excised. Care should be taken to avoid injury to renal arteries.

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Table 8.3. Suggested compositions of luminal flush at the back table a) Pancreaticoduodenal graft 1. Povidone-iodine 10% 250 mL 2. Amphotericin B 50 mg in 50 mL 5% dextrose solution b) Small bowel graft 1. Lactated ringers 1000 mL 2. Amphotericin B 50 mg 3. Gentamicin 80 mg 4. Polymyxin E 100 000 U 5. Povidone-iodine 10% 40 mL

8

If an anomalous right hepatic artery originating from the superior mesenteric artery is encountered, this does not necessarily preclude simultaneous liver and pancreas procurement. Often, careful dissection with good cooperation between liver and pancreas procurement teams can salvage both the liver and pancreas vasculature particularly when the anomalous right hepatic artery takes off close to the SMA take-off. In this case the replaced right hepatic artery is dissected free down to the superior mesenteric artery and the SMA is divided to the take-off of the right hepatic. After removal, the pancreaticoduodenal graft is taken to the back table and placed in a basin of cold saline.16 The duodenum lumen is irrigated with a cold povidone-iodine and amphotericin solution (Table 8.3). The effluent is drained outside of the basin. The rest of the dissection is left to the recipient surgeon. The organ is packed in a plastic bag filled with UW solution. It is then packed in a second plastic bag and placed in a cooler and covered with ice for transportation. PANCREAS PROCUREMENT WITHOUT LIVER PROCUREMENT This procedure is easier than combined pancreas and liver procurement. The gastroduodenal artery is preserved. The proper hepatic artery distal to the gastroduodenal artery and left gastric artery are ligated and divided. A cuff of aorta, including the celiac axis and superior mesenteric artery in continuity, is excised with the pancreaticoduodenal graft. The portal vein can be transected high in the hilum of the liver leaving a long portal vein on the graft. The rest of the procedure is completed as described above.

SMALL BOWEL PROCUREMENT Small bowel retrieval can be a part of multivisceral procurement.17 The principles of multivisceral procurement were described by Starzl.18 In brief, a complete multivisceral specimen is removed as a grape cluster with a double central stem consisting of the celiac axis and superior mesenteric artery. If only the small bowel is to be procured then only the superior mesenteric artery is preserved. Venous outflow of the grafts that include the liver is with a segment of the

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retrohepatic inferior vena cava which is used either to replace the recipient vena cava at the resected segment or anastomosed piggyback to the anterior wall of preserved recipient vena cava with ligation of its lower end. If the intestines are to be procured without the liver, the venous drainage of the graft is by the portal vein. Before intestinal procurement, selective bacterial and fungal decontamination is performed. The intestines are flushed with a hyperosmolar cathartic solution (polyethylene glycol), amphotericin B, tobramycin and polymixin E through a nasogastric tube. Additionally, the donor may also be treated prior to procurement with antilymphocyte antibody to the CD-3 receptor (OKT3). COMBINED HEPATIC AND INTESTINAL PROCUREMENT The abdomen and chest are opened with midline laparotomy and median sternotomy.19,20 The right colon and small bowel mesentery are mobilized. The duodenum is Kocherized. The distal and supraceliac aorta are encircled in the usual manner. The portal vein is cannulated through the inferior mesenteric vein. The hepatoduodenal ligament is dissected out. The gastroduodenal, splenic and left gastric arteries are ligated and divided to isolate the celiac axis. If a left hepatic artery arising from left gastric artery is found, it is preserved. The common bile duct is encircled and transected distally. The gall bladder fundus is incised and the bile is washed out with saline irrigation. The gastrocolic omentum is divided between ligatures. The right and middle colic vessels are divided sparing ileal branches of the ileocolic artery. The right and transverse colons are mobilized completely. The jejunum is divided with a GIA stapler just distal to ligament of Treitz. The peritoneum at the inferior border of the pancreas is incised. The neck of the pancreas is encircled with blunt dissection and divided between heavy ligatures. The pancreas and duodenum are dissected from the intestinal graft with ligation of potentially numerous small branches of the superior mesenteric artery and vein at this location. The distal small bowel is transected with a GIA stapler at the ileocecal valve. The distal aorta is cannulated after systemic heparinization. The supraceliac aorta is cross-clamped. The vena cava is incised in the pericardium close to its junction with the right atrium. One liter of UW solution flushed through each cannula serves as cold perfusion. Overperfusion should be avoided. After cold perfusion, the inferior vena cava is divided above the renal veins. An aortic patch including the celiac axis and the superior mesenteric artery is removed with the composite liver-small bowel graft. The rest of the procurement is completed as described previously. The intestinal lumen is flushed at the back table (Table 8.3). An alternative method is en bloc removal of liver-small bowel graft with pancreas and duodenum. In this technique the small bowel is separated from the pancreas and duodenum ex vivo. This involves dissection of the portal vein from the posterior surface of the pancreas and division of the splenic and pancreatic tributaries between ligatures. Then the superior mesenteric artery is dissected free of

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the posterior surface of the pancreas. This technique minimizes the in vivo surgical dissection and is particularly useful in unstable donors. SMALL BOWEL PROCUREMENT ALONE If the intestine is to be transplanted alone, the liver can be separated from the small bowel during procurement or on the back table.21,22 The celiac axis remains on the liver graft and the superior mesenteric artery is retained with the small bowel. The portal vein is shared between liver and small bowel grafts and divided 2 cm above the upper border of the pancreas.

SUMMARY With meticulous surgical technique the experienced transplant surgeon should be able to retrieve any and all of the intra-abdominal organs currently considered for transplantation (liver, kidney, pancreas, intestine). Thorough communication between (potentially many) abdominal organ teams and between the liver and chest teams is critical to ensure optimal organ quality for all teams. Anatomical anomalies forcing sacrifice of one organ in favor of another are rare.

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REFERENCES 1. 2. 3. 4. 5. 6.

7. 8. 9.

10. 11. 12.

Rosenthal JT, Shaw BW, Hardesty RL et al. Principles of multiple organ procurement. Ann Surg 1983; 198:617-621. Starzl TE, Hakala TR, Shaw BW et al. A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet 1984; 158:223-230. Flye MW, Pasque MK, Kaiser LR et al. Multiple organ recovery. In Flye MW, ed. Atlas of organ transplantation. Philadelphia: WB Saunders Company, 1995:47-71. Jordan CA, Snyder. Intensive care and intraoperative management of the braindead organ donor. Transplant Proc 1987; 19:21-25,. Van Buren CT, Barakat O. Organ donation and retrieval. Surg Clin North Am 1994; 74:1055-1081. Emre S, Schwartz ME, Miller CM. The donor operation. In Busuttil RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: WB Saunders Company, 1996:392-404. Starzl TE, Miller C, Broznick B et al. An improved technique for multiple organ harvesting. Surg Gynecol Obstet 1987; 165:343-348. Suzuki T, Nakayasu A, Kawabe K et al. Surgical significance of anatomic variations of the hepatic artery. Am J Surg 1971; 122:505-512. Gordon RD, Shaw BW, Iwatsuki S et al. A simplified technique for revascularization of homografts of the liver with a variant right hepatic artery from the superior mesenteric artery. Surg Gynecol Obstet 1985; 160:474-476. Ackermann JR, Snell ME. Cadaveric renal transplantation: A technique for donor kidney removal. Br J Urol 1968; 40:515-521. Linke CA, Linke CL, Davis RS et al. Cadaver donor nephrectomy. Urology 1975; 6:133-138. Taylor RJ, Rosenthal JT, Hakala TR. Combined cedaveric hepatic and renal organ procurement in infants. Arch Surg 1985; 120:1084-1085.

Surgical Technique for Multiple Organ Recovery 13. 14. 15.

16. 17. 18. 19. 20. 21. 22. 23.

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Pollak R, Prusak B, Mozes M. Anatomic abnormalities of cadaver kidneys procured for purposes of transplantation. Am Surg 1986; 233-235. Marsh CL, Perkins JD, Sutherland DER et al. Combined hepatic and pancreaticoduodenal procurement for transplantation. 1989; 168:254-258. Sutherland DER, Moudry KC, Najarian JS. Pancreas transplantation. In: Cerilli GJ, ed. Organ transplantation and replacement. Philadelphia: JB Lippincott Company, 1988:535-574. Bandlien KO, Mittal VK, Toledo-Pereyra LH. Procurement and workbench procedures in preparation of pancreatic allografts. Am Surg 1988; 54:578-58. Margreiter R, Konigsrainer A, Schmid T et al. Multiple organ procurement. Transplant Proc 1991; 23:2307-2308. Starzl TE, Todo S, Tzakis A et al. The many faces of multivisceral transplantation. Surg Gynecol Obstet 1991; 172:335-344. Casavilla A, Selby R, Abu-Elmagd K et al. Logistics and technique for combined hepatic-intestinal retrieval. Ann Surg 1992; 216:605-609. Grant D, Wall W, Mimeault R et al. Successful small-bowel/liver transplantation. Lancet 1990; 335:181-184. Sindhi R, Fox IJ, Heffron T et al. Procurement and preparation of human isolated small intestinal grafts for transplantation. Transplantation 1995; 60:771-773. Todo S, Tzakis AG, Abu-Elmagd et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992; 216:223-233. Van Buren CT, Barakat O. Organ donation and retrieval. Surg Clin North Am 1994; 74:1055-1081.

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Surgical Technique for the Thoracic Organ Recovery Michael A. Wait, Dan M. Meyer, Michael E. Jessen, W. Steves Ring

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Thoracic Organ Procurement Technique ............................................................ Isolated Donor Cardiectomy ............................................................................... Combined Donor Cardiectomy and Pneumonectomy ........................................ Principles of Lung Preservation .......................................................................... Perfusate Composition ........................................................................................ Prostaglandins .................................................................................................... Preservation Temperature, Ventilation Volume and Composition ........................................................................................ Bronchial Arterial Perfusion ............................................................................... Retrograde vs. Antegrade Flush Administration ................................................. Principles of Myocardial Preservation ................................................................ Cardiopulmonary Bypass and Procurement ...................................................... Adenosine ........................................................................................................... Impact of Brain Death on the Heart ................................................................... Reimplantation-Reperfusion .............................................................................. Summary ............................................................................................................

128 129 131 134 134 136 136 137 137 138 139 140 141 141 142

THORACIC ORGAN PROCUREMENT TECHNIQUE The potential thoracic organ donor should have the minimum invasive hemodynamic monitoring that would allow safe preoperative and intraoperative management. Usually this requires a central venous line and upper extremity arterial catheter. Pulmonary artery balloon flotation catheters are avoided unless absolutely needed for evaluation and management of the unstable or marginal donor. Femoral arterial catheters will suffice up until the infrarenal aorta is cannulated. An arterial catheter can also be placed directly into the innominate artery intraoperatively, if required. The donor is positioned on the operating table supine with both arms tucked at the sides to allow ample access for multiple surgical teams on both sides of the operating table. The anesthesiologist plays a critical role in maintaining donor stability by maintaining proper ventilation, titrating inotropic infusions, assessing intravascular volume status, and maintaining normothermia. Supranormal tidal volumes are required to eliminate areas of dependent atelectasis, which are ubiquitous in the posterior segments of the lower lobes in supine ICU patients. Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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Intravenous hormone administration (thyroxine, vasopressin, and corticosteroids) is useful in maintaining donor stability. Approximately 25% of donor patients are CMV negative. Therefore, blood products are administered only through leukopore filters to limit the risk of transmitting CMV to donors (and thus to recipients). All cardiac donors undergo routine transthoracic and/or transesophageal multiplane echocardiography. When possible, cardiac donors with risk factors for coronary artery disease (age > 50 years, smoking history, a strong family history for coronary artery disease, hyperlipidemia, hypertension, diabetes, or ECHOcardiographic wall motion abnormalities) are evaluated with coronary arteriography. Ventriculography is avoided to reduce the contrast load on the donor kidneys. Ex vivo coronary arteriography by occlusive aortic injection on the dissecting table has also been reported.1

ISOLATED DONOR CARDIECTOMY The heart and great vessels are exposed through an extended sternotomy incision, which is connected to the midline celiotomy incision (Fig 9.1). The central tendon of the diaphragm initially is left intact, and a pericardial cradle is created after dissection of the superior vena cava (SVC) to the level of the innominate vein. A visual assessment of right atrial and ventricular volume loading and contractility is made. Topographical anatomic evaluation of the heart is performed Fig. 9.1. Contiguous midline celiotomy and median sternotomy for ample exposure during multiple organ procurement. (From Baumgartner WA, Reitz BA, Achuff SC. Heart and Heart-Lung Transplantation. Copyright 1990 Philadelphia W.B. Saunders Co. Harcourt Brace Jovanovich, Inc. p.114, with modifications)

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and the presence or absence of visible or palpable epicardial atherosclerotic coronary plaque is noted. Coronary artery occlusive disease in the donor usually is a strong contraindication for transplantation. Although donor hearts with coronary disease have been revascularized at the time of transplant, the long-term outcome of this approach is uncertain.2 Following the administration of heparin (3 mg/kg) and SoluMedrol (10 mg/kg), the superior vena cava is ligated (or clamped) after retraction of any central venous or pulmonary artery catheters. The superior vena cava is divided above the azygous confluence if a bicaval anastomosis is anticipated (Fig 9.2). A vented needle or cannula is inserted into the ascending aorta for administration of the cardioplegic preservation solution. The inferior vena cava (IVC) is partially transected in coordination with the liver-harvesting surgeon. The cavotomy effluent is allowed to exsanguinate into the open right pleural space and a suction catheter is placed directly into the IVC. The distal ascending aorta is cross-clamped at the root of the innominate artery. The aortic root is infused with 20 ml/kg of cold asanguinous crystalloid preservation solution. Our preference is to use U W solution. The left atrium is vented by transection of the right superior pulmonary vein at its entry point into the pericardium. Topical hypothermia is also induced with iced saline slush applied directly to the epicardial surface. Following complete diastolic depolarized arrest, the apex of the heart is retracted cephalad and the transection of the IVC is completed. The inferior and superior pulmonary veins are amputated flush with the pericardial sac, as are the right and left pulmonary artery branches (Fig 9.3). The ascending aorta is transected at the level of the innominate artery. Additional segments of superior vena cava, branch pulmonary artery, or aortic arch may be required for some recipients with end stage congenital heart disease. Fig. 9.2. Antegrade cardioplegic arrest with topical hypothermia, following division of the inferior and superior vena cava. (From Baumgartner WA, Reitz BA, Achuff SC. Heart and Heart-Lung Transplantation. Copyright 1990 Philadelphia W.B. Saunders co. Harcourt Brace Jovanovich, Inc. p.116, with modifications)

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Fig. 9.3. Completion of isolated donor cardiectomy, by division of pulmonary veins. (From Baumgartner WA, Reitz BA, Achuff SC. Heart and Heart-Lung Transplantation. Copyright 1990 Philadelphia W.B. Saunders co. Harcourt Brace Jovanovich, Inc. p.117, with modifications)

The excised heart is then examined for evidence of a patent foramen ovale, which is suture closed when encountered. The superior vena cava snare is reinforced with a suture ligature if a biatrial modified Lower-Shumway transplantation technique will be used. The superior vena cava is left open when a bi-caval anastomotic technique will be used. The heart is placed in a rigid sterile container which is filled with preservation solution and insulated with an iced slush bath. Both the container and iced slush are then placed inside two sterile plastic bags for transport in an iced cooler.

COMBINED DONOR CARDIECTOMY AND PNEUMONECTOMY Prior to operative extraction of the lung block, a flexible fiberoptic bronchoscopic examinaton of the trachea, lobar, and segmental bronchi is performed. The airways are inspected for evidence of gastroesophageal aspiration including gross purulence, mucosal erythema, blood, foreign bodies, or gastric contents. Minor purulent endobronchial secretions that clear easily with bronchial lavage and are not associated with mucosal inflammation are not considered a contraindication to transplantation. Careful inspection of the endobronchial tree is performed looking for tumors and extrinsic compression of the airways. The initial operative procedure for combined heart and lung retrieval is similar to that for isolated donor cardiectomy. The use of bone wax is discouraged to avoid embolization to the pulmonary microvasculature. The pleurae are opened widely to allow visual inspection and palpation of both lungs, lysis of minor pleural

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Organ Procurement and Preservation Fig. 9.4. Placement of pulmonary artery catheter proximal to the confluence of the branch pulmonary arteries for combined heart and lung procurement. The pulmonary artery will be divided at the level of cannulation. (From Baumgartner WA, Reitz BA, Achuff SC. Heart and Heart-Lung Transplantation. Copyright 1990 Philadelphia W.B. Saunders co. Harcourt Brace Jovanovich, Inc. p.114, with modifications)

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adhesions, and release of the inferior pulmonary ligaments bilaterally. Careful systematic inspection of the visceral pleura is made for evidence of significant pulmonary contusion, consolidation, laceration, or hemorrhage. Atelectatic portions of the lung can be reexpanded by having the anesthesiologist hyperinflate the lungs. The main pulmonary artery and lesser curvature of the aorta are dissected from each other. The main pulmonary artery is cannulated near its bifurcation (Fig 9.4). A competent pulmonic valve will allow equal pressurization of both branch pulmonary arteries, avoiding the need for clamping of the pulmonary artery. The right pulmonary artery is dissected free from the superior vena cava. The interatrial groove (Watterston’s groove) is dissected to allow an adequate atrial cuff to be distributed between the donor heart and lung organ blocks. Thymectomy and division of the innominate vein (only if the CVP line enters from the right side) greatly improves exposure of the great vessels for later division. After the other organ procurement teams have completed their preparations and systemic heparinization is achieved (3 mg/kg), 500 micrograms of prostaglandin E1 (Prostin VR) diluted in 30-50 ml of D5W is administered centrally over 60 seconds. This will cause acute pulmonary and systemic vasodilatation and hypotension and should not be given until all organs are ready for immediate perfusion and extraction. Donor cardiectomy is initiated by ligating or clamping the superior vena cava and dividing the inferior vena cava. In contrast with the standard donor cardiectomy, the warm effluent from the inferior vena cava is not vented into the pleural

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space to prevent uneven cooling of the lungs. A suction catheter is placed directly into the inferior vena cava to evacuate any blood or abdominal organ perfusate. The ascending aorta is cross clamped and 20 mL/kg of cold cardiac perfusate is delivered antegrade into the aortic root. The pulmonary perfusate (4-6 liters) is delivered simultaneously into the main pulmonary artery from an infusion bag which is elevated not more than 30 inches above the level of the chest. The tip of the left atrial appendage is amputated immediately to prevent pulmonary venous hypertension and left heart distension. The interatrial groove may also be incised to further vent the left heart and lungs. Topical cooling with an iced slush bath is performed and the lungs are visually inspected to ensure adequate blanching and uniform distribution of the perfusate. Ventilation is continued with 50%-100% oxygen delivered at a peak airway pressure of 20-25 cm H2O. The lungs are removed while inflated to prevent atelectasis, while avoiding hyperinflation. The donor cardiectomy is performed prior to removal of the lung block. The superior vena cava is divided above the azygous followed by division of the distal ascending aorta. The main pulmonary artery is transected through the pulmonary cannulation site at the level of the bifurcation. The cuff of left atrial tissue is left attached to the left pulmonary veins by incising the left atrium at a point midway between the left pulmonary veins and the coronary sinus while leaving the left atrial appendage with the heart. Similarly, a cuff of left atrial tissue is left attached to the right pulmonary veins by incising a portion of the dissected interatrial groove. The heart is then able to be removed from the mediastinum and prepared for transport. The donor pneumonectomy is completed by exposing the trachea through the posterior pericardium behind the ascending aorta and above the right pulmonary artery. The trachea is dissected from the esophagus lying posteriorly taking care to avoid injury to the membranous trachea and bronchi. The endotracheal tube is partially withdrawn while maintaining gentle insufflation of the lungs. The distal trachea is occluded proximally with a TA-30 stapling device to prevent contamination of the mediastinum, and distally at a point 2-3 cm above the carina with the lungs inflated. The trachea is then divided between the staple lines. The nasogastric tube is removed and the upper thoracic esophagus is divided with a GIA stapler. Suprahilar attachments are divided followed by the inferior pericardium and inferior pulmonary ligaments. The lower thoracic esophagus is divided with a GIA stapler along with the distal thoracic aorta which are left attached to the lung block. After removal of the remaining posterior vertebral attachments, the combined lung block is removed to a back table and immersed into an iced saline bath. If both lungs are being procured for the same patient, they may simply be stored together for transport in nonrigid plastic bags filled with chilled lung perfusate, and placed on ice. If each lung is destined to separate recipients, the lung block is divided on the back table by division of the juxtacarinal left main bronchus, using a double application of a stapling device.

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Organ Procurement and Preservation PRINCIPLES OF LUNG PRESERVATION

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Optimal lung preservation requires limiting lung injury. It is dependent not only upon the procurement, perfusion, and ventilation techniques, but also upon the initial management of reperfusion and ventilation following implant. Lung injury that occurs following restoration of blood flow during transplantation is called the ischemia-reperfusion injury, or reimplantation response. Organ dysfunction from reperfusion injury is characterized by impaired gas exchange, decreased compliance, interstitial and alveolar edema (due in part to increased vascular permeability), and death. Ischemia-reperfusion injury may also predispose grafts to early rejection via upregulation of class II major histocompatibility complex antigens or through local production of cytokines.3 Lung preservation is unique from other organ preservation techniques due to the following factors: 1) the lung has a large alveolar-capillary surface area created from approximately 300 million delicate alveolar units; 2) the lung has a blood gas interface; 3) the lung has a dual blood supply (pulmonary arterial and bronchial arterial); and 4) the inflated lung has a ready oxygen source during the ischemic transport phase (alveolar gas). Preservation techniques have focused on modifications of antegrade and retrograde vascular perfusion as well as ventilation. Given the high incidence of acute rejection observed following lung transplantation (compared to cardiac transplantation) and the role ischemia-reperfusion injury plays in acute organ rejection, adequate preservation is paramount to successful immediate and long term graft function. Single flush perfusion followed by static hypothermic storage has emerged as the standard procurement technique. Cardiopulmonary bypass with profound hypothermia (donor-core cooling) is a labor-intensive technique, which found great success by Yacoub et al at Harefield and Reitz and Baumgartner at the Johns Hopkins Baltimore Transplant Center.4,5 Topical cooling after absorption atelectasis, which was the method used for the first long-term successful lung transplant in 1981, is no longer used today. Hardesty and Griffith at Pittsburgh utilized normothermic autoperfusion of the heart-lung block and achieved early successful results; this is rarely used and of historical interest only.

PERFUSATE COMPOSITION A diverse number of perfusates have been utilized both clinically and experimentally to extend the ischemic procurement time and decrease the incidence of ischemia-reperfusion injury and acute lung rejection. Lung preservation solutions are variably referred to as pulmonoplegia or pneumoplegia. The Euro-Collins (EC) solution contains a high concentration of K+ and is typical of the “intracellular”type solution, which became the benchmark for human kidney preservation and has had widespread use in lung transplantation. The high potassium content ex-

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erts its effect by suppression of K+ efflux across the cell membrane during hypothermic ischemic storage; thus near normal intracellular K+ concentrations, and consequently Na+ concentrations, would be available to the cell during reperfusion. The high potassium concentration has been perceived by some to contribute to endovascular injury during the flush and storage phases of preservation, deemed an important step in the ischemia-reperfusion phenomenon. High K+ causes vasoconstriction, inhomogeneous flushing of the graft, and elevated pulmonary vascular resistance during reperfusion. Some centers have reported that prostaglandin administration and/or hyperinflation ameliorates this effect and offers results indistinguishable from low K+, extracellular type solutions.6 Another prototypical intracellular-type solution is the University of Wisconsin (UW, Viaspan, Belzer) solution. It differs from EC solution due to many additives, and has been demonstrated to enhance and extend the preservation of hepatic, pancreatic and renal allografts relative to the EC solution. High molecular weight impermeants (lactobionate), colloid (hydroxyethylstarch, HES) and trisaccharide (raffinose) are osmotically active agents which help prevent edema formation. Glutathione is added for the antioxidant effect of its sulfhydryl group, adenosine is added as an ATP precursor and pulmonary vasodilator, and hydroxyethyl starch as a stable nontoxic colloid. Allopurinol is added as a xanthine oxidase inhibitor and free radical scavenger. Two canine lung allotransplantation studies comparing EC to UW demonstrated improved gas exchange, lung compliance, lower pulmonary vascular resistance, and improved histologic indices of pulmonary edema in the UW treated group.7,8 One clinical trial comparing EC to UW solution in a nonrandomized fashion showed that UW solution conferred equivalent gas exchange and chest radiograph exams despite a longer preservation period than in the EC solution group.9 Which of the numerous components of the UW solution confer the additive benefit over the EC solution is a matter of debate. A rat model using paracorporeal perfusion of preserved lungs and sequentially depleted UW components indicates that it is the impermeant trisaccharide raffinose which appears to be the major factor responsible for its efficacy.10 “Extracellular-type” solutions, such as LPD (low potassium dextran) have been found both clinically and experimentally to avoid this observed high K+-induced pulmonary vascular injury.11,12 In a primate bilateral allotransplantation model, antegrade LPD pulmonary artery perfusion conferred excellent acute graft function after 12 hours of ischemic time.13 Attempts to modify the standard UW solution to avoid high K+-induced pulmonary vascular injury have found no significant change in organ storage efficacy, raising questions about the mechanism of intracellular solution preservative effect. Rabbit lung preservation studies looking at low-potassium UW solution demonstrated that a lower concentration of K+ (from 120 mmol/L to 3 mmol/L) was associated with improved gas exchange and organ wet/dry weight ratios than standard UW solution.14,6 A more complete discussion of the components of organ preservation solutions and their effect can be found in Chapter 5.

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Unique to the pre-crossclamp approach among procured organs is the pretreatment of the pulmonic vasculature with prostaglandin E1 (Prostin VR). Prostaglandins and prostanoids are potent eicosanoid pulmonary microvascular dilator agents; they are administered to counteract the vasoconstrictive effects of high K+ “intracellular”-type solutions (i.e., EC and UW). Additional effects include inhibition of pulmonary intravascular leukocyte sequestration, stabilization of lysosomal membranes, bronchodilation, suppression of vascular endothelial permeability, and inhibition of platelet aggregation. Immunologic effects of this class of compounds include inhibition of T-lymphocyte cytotoxicity and mitogenesis and diminished production of interleukin-2 (IL-2).7 Prostaglandin E is metabolized in the lungs.

PRESERVATION TEMPERATURE, VENTILATION VOLUME AND COMPOSITION

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Lungs maintained in the atelectatic state, hyperinflated state or with 100% FIO2 have increased capillary permeability and alveolar edema, with worsened gas exchange when compared to normally inflated lungs with 50% FIO2.15,16 Even segmental atelectasis should be assiduously avoided as it causes significant maldistribution of lung preservation solutions regardless of the route of delivery. The presence of a higher than ambient FIO2 in the alveoli during the ischemic phase of procurement and transport allows the lung to uniquely have an O2 source for continued aerobic metabolism despite the fact that the blood supply has been Table 9.1. Preservative composition Component (mmol/L)

Modified Euro-Collins (EC)

Na+ 9.3-10 K+ 108-115 Cl– 14-15 3– PO4 59-93 HCO3– 9.3 Mg2+ 8 SO43– 8 Glucose (gm/L) 35 Dextran-40 (g/L) Raffinose Lactobionate Glutathione Adenosine (g/L) Allopurinol (g/L) Pentafraction (Hydroxyethyl starch, HES)

Low Potassium Dextran (LPD)

University of Wisconsin (UW)

168 4 103 37

27-28 120-125 0 25

2 2

5 5

20 30 100 0.9-3 1.3-5 0.1-1 50 g/L

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halted.17 Indeed, data reported three decades ago demonstrated that canine lungs can tolerate 3-4 hours of warm ischemia in situ as long as ventilation was maintained.18 Preservation temperature at 10°C induced by core perfusion was found to be superior to 4°C and to topical cooling methods in an ex vivo rabbit lung model. Nevertheless, topical cooling as an adjunct to core cooling is felt to be essential to lung preservation during the transport period in the ischemic phase.19 Excessive hypothermia may be injurious due to cold injury, cryodessication, or by eliminating the low level of metabolic activity required for membrane homeostasis. Topical cooling of the inflated lung during transport in the ischemic, postharvest phase has been hampered by inhomogenous cooling of the graft due to buoyancy of the lung. A non-slush, non-immersion technique of graft cooling was investigated using cold air storage, and compared to slush immersion storage.20 After 8 hours, lung grafts from cold air storage at 4°C, 8°C, and 12°C demonstrated improved gas exchange and less lung edema than those grafts immersed in iced slush.

BRONCHIAL ARTERIAL PERFUSION Inadequate perfusion of the bronchial vascular bed during standard antegrade pulmonary artery flush might be a possible mechanism of inadequate pulmonary preservation. Perfusion of the isolated descending thoracic aorta allows delivery of preservative solution through the bronchial arteries, in addition to the usual mechanism of direct pulmonary artery perfusate delivery. A canine study demonstrated superiority in terms of intrapulmonary shunt fraction, improved static compliance, intrapulmonary leukosequestration, and elastic work when lungs were preserved with dual circulation extracellular-type preservative perfusion than with either isolated bronchial or pulmonary arterial perfusion.21 This dual blood supply was exploited by some transplant centers by revascularizing the segment of thoracic aorta, which contains the bronchial arteries with internal thoracic artery or saphenous vein grafts, thereby preserving the dual circulation and theoretically improving bronchial anastomotic outcomes (in terms of healing and stenosis).

RETROGRADE VS. ANTEGRADE FLUSH ADMINISTRATION Standard antegrade pulmonary artery flush with intracellular type solutions is felt by many to cause pulmonary arterial microcirculatory vasoconstriction and fails to offer perfusion through the bronchial circulation. Borrowing from the concept of retrograde cardioplegia and coronary sinus retroperfusion experiments of Claude Beck, retrograde perfusion of preservation fluid given through the left atrium was reported in clinical use in 1993,22 with good lung transplant results in three patients. Pulmonoplegic solution was vented through the opened pulmonary artery, and left atrial pressures were kept < 20 mm Hg during infusion. Retrograde perfusion of the bronchial arteries was confirmed by observing flush

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solution flowing from the bronchial artery ostia through the opened descending aorta. Pulmonary artery vasoconstriction consequent to high K+ intracellular type solutions (EC) is unlikely to affect retrograde preservative distribution, and may even enhance it. It offers a simpler technique of dual lung circulation perfusion (than separate antegrade pulmonary artery and descending aorta) and may allow for better distribution of preservative solution while sparing the use of prostaglandins. Conspicuously absent from this clinical report, however, is the outcome of the hearts from the same three donors. A porcine model comparing antegrade with retrograde perfusion of an intracellular type solution (EC) using dye-labeled microspheres demonstrated improved preservative flow to the airways, despite the absence of prostacyclin in the retrograde group.23 A canine study comparing ante- and retrograde EC flush demonstrated less lung edema, improved gas exchange, and lower peak airway pressures in the retrograde flush group; the antegrade flush group showed evidence of occluded capillaries, damaged epithelial basement membranes and thicker air-blood barrier on electron microscopy.24

PRINCIPLES OF MYOCARDIAL PRESERVATION

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The heart, similar to every other transplanted solid organ, undergoes a series of nonphysiologic steps during the arrest-procurement-preservation, ischemicstorage-transport, and reimplantation-reperfusion phases of transplantation. The functional recovery of grafted hearts, therefore, depends upon critical attention and manipulation of all of the above three phases of transplantation. The functional assessment of the transplanted heart has been reported in terms of myocardial adenine nucleotide content (adenylate charge, or high energy phosphate content), myocardial functional measures (ejection fraction, inotrope dependence, compliance, elastance, preload recruitable stroke work, cardiac output, rate-pressure product, oxygen consumption), and histological evidence of cellular and subcellular injury (especially mitochondrial ultrastructure). A curious observation by Belzer et al25 is that the ATP supply of the hypothermic UW preserved liver, pancreas and kidney is completely exhausted by only 4 hours of hypothermic storage, whereas, the heart retains 80% of its ATP level at 18 hours. However, the time limits to human transplantation with UW hypothermic flushstorage techniques are 18-24 hours for kidneys and livers, and only 4-6 hours for hearts. The heart must regain nearly 90% of its function almost immediately upon reperfusion to be life-sustaining, but other organs have several hours or days to regain life-sustaining function. Adenine nucleotide content measured by myocardial biopsy of hypothermic preserved hearts does not reliably predict postoperative graft function at clinically relevant cold ischemic times,26 but does reliably predict the onset of ischemic contracture after prolonged (12-24 hour) hypothermic storage.25

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The heart, unlike the liver or kidney, has a much greater energy demand immediately upon establishment of reperfusion. This energy demand may be damaging to an already energy-depleted myocardium. ATP levels may be depleted sufficiently to cause dysfunctional actin and myosin interaction and ischemic contracture of the myocardium, and yet the level is insufficient to result in cell-membrane dysfunction and death. Ischemic contracture onset coincides with the loss of myocardial ATP stores, such that as ATP drops to less than 80% (between 12-18 hours in hypothermic UW stored rabbit hearts) the onset of contracture occurs. SINGLE FLUSH, INTERMITTENT OR CONTINUOUS CORONARY PERFUSION As in pulmonary preservation, a single asanguinous perfusate flush followed by static hypothermic storage is an effective, unencumbered method of procuring and preserving the heart in an ischemic, anaerobic, metabolically arrested state. This technique of hypothermic nonperfused storage allows for a maximum safe limit of 4-6 hours of preservation under current clinical practice. Aerobic preservation by continuous perfusion of oxygenated preservative solution27 or blood (autoperfusion)28 easily meets the low, residual oxygen demands of the hypothermic heart. This can increase the preservation period up to 48 hours but increases the complexity of procurement and risk of infection by many orders of magnitude. Continuous coronary perfusion (or “microperfusion”) has been advocated as a method of extending the preservation and storage phases of transplantation from the current limitations of 4-6 hours. The detrimental effects of cellular swelling and interstitial edema from a disturbance in Starling’s forces consequent to a continuous perfusion technique tend to offset its beneficial effects.29,30 Intracellular edema occurs from a failure of the ATP-dependent Na+-K+ pump in the sarcolemmal membrane during the anoxic-ischemic interval. The addition of the trisaccharide impermeant raffinose and lactobionate, and the oncotic agent pentafraction to the University of Wisconsin solution add the ability to suppress cellular and interstitial edema during preservation. Unfortunately, hypothermia induces capillary permeability even to high molecular weight colloids. To counteract this, a low perfusion pressure strategy (10-20 mm Hg) low flow strategy of continuous perfusion has been employed.31-33

CARDIOPULMONARY BYPASS AND PROCUREMENT Finally, as mentioned in the section on “Lung Preservation”, distant organ procurement for heart and lung transplantation can be accomplished by the induction of profound hypothermic circulatory arrest afforded by cardiopulmonary bypass. In the Harefield experience, blood cardioplegia is administered prior to harvesting the heart-lung block which has been cooled to 8°C. The heart-lung block is stored in hypothermic donor blood for transport. Although much more cumbersome than preservative flush-storage, this technique was simplified by the advent of portable cardiopulmonary bypass.34

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PERFUSATE-STORAGE VEHICLE During organ procurement and storage, ATP depletion and subsequent decreased activity of Na+-K+ ATPase allows an influx of extracellular Na+, Ca2+ and water, an efflux of intracellular K+ and Mg2+, with myocyte edema formation. Adenosine derived from the catabolism of ATP is further metabolized to xanthine and hypoxanthine, prerequisites to the formation of oxygen free radicals during the oxidative respiratory burst following reperfusion. Additionally, the intracellular adenylate pool decreases as nonphosphorylated nucleotide precursors freely cross the cell membrane and escape into the extracellular mileu. A goal of all preservation solutions currently in clinical use is the prevention of this untoward ionic redistribution.35 The ideal perfusate for the induction of cardioplegic arrest and subsequent preservation is uncertain. The optimal ionic composition is partially temperature dependent, as well, in order to avoid the paradoxical effects of totally acalcemic solutions.36 Blood contains physiologic concentrations of calcium as well as an extracellular type ionic composition. Blood based cardioplegia strategies support the notion that blood is an excellent physiologic vehicle with favorable oncotic, buffering, antioxidant, substrate delivery, and oxygen transport capabilities, is readily available and is superior to crystalloid asanguinous cardioplegia.37 An attempt to modify intracellular preservation solutions (e.g., St. Thomas, EuroCollins) by the addition of impermeants, oncotic agents, metabolic substrates, ATP precursors and antioxidants was the goal of the development of the UW solution, in an effort to mimic the favorable effects of blood. Although there continues to be regional variation worldwide over the preferred perfusate for simple flush-storage, the balance of clinical series and experimental reports favors intracellular solutions, specifically the University of Wisconsin solution, over other extracellular solutions.38 Nonetheless, a number of studies have used UW solution bases with single compound deletions, substitutions, or additions in an attempt to identify the importance of the different components to clinical heart transplantation.39-42

ADENOSINE During hypothermic anoxic storage, low level metabolism continues and ATP levels are depleted. Soluble ATP precursors diffuse across the sarcolemma and are unavailable for high energy phosphate reformation during the reperfusion phase. The purine nucleoside adenosine serves as a nucleotide donor to replenish the adenylate charge of the myocyte during reperfusion via the purine salvage pathway. However, laboratory evidence to support this theory is lacking.43 Exogenously administered adenosine may be cleared rapidly by adenosine deaminase, converting it to inosine. Adenosine and inosine diffuse across the sarcolemma and are washed out of the interstitium upon reperfusion.

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PERFUSATE TEMPERATURE Controversy still remains regarding the optimal degree of hypothermia in terms of ischemic protection. Van Hoff and Arrhenius demonstrated that for every 10°C drop in temperature, the rate of an enzyme-catalyzed reaction was decreased from 1.5- to 4-fold.44 Therefore, cooling from 37°C to 4°C (the most commonly used practice today), decreases the metabolic rate 12- to 13-fold.45 Intracellular low molecular weight solutes depress the freezing point to -0.6°C. However, most cells do not freeze internally until less than -10°C. Rat hearts preserved in an extracellular type perfusate at 4°C had less ATP depletion, intracellular acidosis, and improved post ischemic recovery than at 15°C. Equivalent hypothermic storage in moist air versus cardioplegic solution showed no difference in functional outcomes in a rat heart transplant study47 at 10°C. Hypothermia seems to have a protective influence on the endothelium with regards to high potassium concentration mediated endothelial injury.48

IMPACT OF BRAIN DEATH ON THE HEART Brain death has damaging effects on the cellular and subcellular level of the myocardium.49 Myocardial preservation, therefore, begins with proper donor management and manipulation of the deranged neurohormonal milieu consequent to brain death. As early as 1954 it was noted that subendocardial hemorrhage occurs subsequent to brain death,50 and that EKG changes simulating myocardial ischemia occur in patients dying from intracranial hemorrhage, status epilepticus, meningoencephalitis, or traumatic brain herniation.51 Neuroendocrine changes consequent to anoxic brain death are marked by an initial hypertensive response due to catecholamine release, followed by progressive vasomotor tone collapse. Free triiodothyronine (T3), thyroxine (T4), cortisol, and insulin, TSH, and ADH decrease significantly within a few hours of the onset of brain death. Myocardial ATP, creatine phosphate, glycogen stores subsequently decrease and myocardial lactate increases. The rates of glucose, pyruvate, and palmitate metabolism as energy substrates are markedly reduced following brain death. Diabetes insipidus, thyroid dysfunction, and an altered HPA (hypothalamic-pituitaryadrenal) axis are factors which are felt to contribute to myofilament ATP unresponsiveness.52-54 Hormonal supplementation with triiodothyronine (T3), cortisol, and insulin has been found to augment the hemodynamic status of donor hearts and improve postop graft function.53 However, it should be noted that T3 supplementation may need to be given to both the donor and the recipient in order to have optimal effect.

REIMPLANTATION-REPERFUSION Many of the deleterious aspects of reperfusion, such as calcium overload, myocyte edema, and free radical production, occur very rapidly during the first few

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minutes of reperfusion, as demonstrated by electron spin resonance studies.55 Just as they were investigated in the setting of preservation perfusate, modifications of the reperfusate vehicle base (blood vs. asanguinous) and chemical composition (acalcemic, leukocyte depleted, additives) have been investigated both experimentally and clinically in an attempt to abrogate the entire spectrum of the ischemicreperfusion syndrome. The “oxygen paradox” and “calcium paradox” of reperfusion (that is, the paradoxically deleterious effects of reperfusion with oxygen and without calcium) have been demonstrated in cardiac transplantation, as in other organ transplants. RESUSCITATIVE EFFECTS OF CONTROLLED REPERFUSION Convincing evidence exists regarding the reanimation and engraftment of asystolic heart donors in the laboratory setting, in primate, rat and rabbit heart models.56-58 The prototypical animal model preparation uses a period of prolonged, sublethal normothermic ischemia followed by preservative perfusion and prolonged storage. This is followed by engraftment with controlled reperfusion (with substrate enriched blood cardioplegic solutions typically) immediately preceding uncontrolled reperfusion with normothermic unmodified blood.

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SECONDARY BLOOD CARDIOPLEGIA The administration of oxygenated blood cardioplegia during reimplantation of the transplanted heart functionally decreases the ischemic interval without changing the time to conventional reperfusion.59, 60 The largest series (n = 99 patients) reporting on secondary blood cardioplegia, given in an antegrade route, demonstrated benefit in terms of catecholamine requirements, endomyocardial biopsy evidence of ischemic injury, and a decrease in operative mortality from 21% to 9%, with graft failure mediated deaths reduced from 13% to 4.9%.61

SUMMARY The ultimate goal of cardiac and pulmonary organ procurement is to facilitate storage of functional organs for transplantation at remote sites, and to ameliorate the obligatory ischemia-reperfusion injury. To this end, modifications of preservation perfusate ionic and macromolecular composition, temperature and delivery vehicles have been met with variable success both clinically and experimentally. The temporal restrictions upon cardiac and pulmonary transplantation, relative to other solid organ transplantation, highlights the ubiquity of this problem and gives direction for avenues of future research. REFERENCES 1.

Robicsek F, Masters T, Thomley A, Rice H, Morales-Reyna J. Bench coronary cineangiography. A possible way to increase the number of hearts available for transplantation. J Thorac Cardiovasc Surg 1992; 103:490-495.

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Laks H, Gates RN, Maehali A, Stevenson LW et al. Orthotopic heart transplantation and concurrent coronary bypass. J Heart and Lung Transplant 1993; 12:810-815. Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg 1996; 62:302-314. Yacoub MH, Khangani A, Banner N, Tajkarimi S, Fitzgerald M. Distant organ procurement for heart lung transplantation. Transplant Proceedings 1989; 21:2548-2550. Baumgartner WA, William GM, Fraser CD. Cardiopulmonary bypass with profound hypothermia: an optimal preservation method for multiorgan procurement. Transplantation 1989; 47:123-127. Oka T, Puskas JD, Mayer E, Patterson GA et al. Low-potassium UW solution for lung preservation. Transplantation 1991; 52:984-988. Lin PJ,Hsieh MJ, Cheng KS, Chang CH et al. University of Wisconsin solution extends lung preservation after prostaglandin E1 infusion. Chest 1994; 105:255-261. Hirt SW, Wahlers T, Haverich A et al. University of Wisconsin versus modified Euro-Collins solution for lung preservation. Ann Thorac Surg 1992; 53:74-79. Hardesty RL, Aeba R, Armitage JM, Kormos RL, Briffith BP. A clinical trial of University of Wisconsin solution for pulmonary preservation. J Thorac Cardiovasc Surg 1993; 105:660-665. Hopkinson DN, Odon NJ, Bridgewater BJ, Hooper TL. University of Wisconsin solution for lung graft preservation: Which components are important? J Heart Lung Transplant 1994; 13:990-997. DeLima NF, Binns OAR, Tribble CG, Kron IL et al. Low-potassium solution for lung preservation in the setting of high-flow reperfusion. Ann Thorac Surg 1996; 61:973-976. Bando T, Liu CJ, Kosaka S, Wada H et al. Twenty-hour canine lung preservation using newly developed solutions containing trehalose. Transplantation Proceedings 1994; 26:871-872. Sundaresan S, Lima O, Cooper JD et al. Lung preservation with low potassium dextran flush in a primate bilateral transplant model. Ann Thorac Surg 1993; 56:1129-1135. Miyoshi S, Shimokawa S, Cooper JD et al. Comparison of the University of Wisconsin preservation solution and other crystalloid perfusates in a 30-hour rabbit lung preservation model. J Thorac Cardiovasc Surg 1992; 103:27-32. Veith FJ, Sinha SBP, Graves JS et al. Ischemic tolerance of the lung, the effect of ventilation and inflation. J Thorac Cardiovasc Surg 1971; 62:176-182. Aoe M, Okabayashi K, Cooper JD, Patterson GA. Hyperinflation of canine lung allografts during storage increases reperfusion pulmonary edema. J Thorac Cardiovasc Surg 1996; 112:94-102. Date H, Matsumura A, Manchester JK, Cooper JD et al. Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation; the maintenance of aerobic metabolism during lung preservation. J Thorac Cardiovasc Surg 1993; 105:492-501. Homatas J, Bryant L, Eiseman B. Time limits of cadaver lung viability. J Thorac Cardiovasc Surg 1968; 56:132-140. Wang LS, Nakamoto K, Hsieh CM, Cooper JD et al. Influence of temperature of flushing solution on lung preservation. Ann Thorac Surg 1993; 55:711-715.

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Kon ND, Hines MH, Harr CD et al. Improved lung preservation with cold air storage. Ann Thorac surg 1991; 51:557-562. LoCicero J, Massad M, Matano J, Michaelis LL et al. Contribution of the bronchial circulation to lung preservation. J Thorac Cardiovasc Surg 1991; 101:807-815. Sarsam MAI, Yonan NA, Rahman AN et al. Retrograde pulmonaryplegia for lung preservation in clinical transplantation: A new technique. J heart Lung transplant 1993; 12:494-498. Baretti R, Moreno JB, Kreitmayr B et al. Distribution of lung preservation solutions in parenchyma and airways: Influence of atelectasis and route of delivery. J Heart Lung Transplant 1995; 14:80-91. Chen CZ, Gallagher RC, Arderty, Dyckman W, Low HBC. Retrograde versus antegrade flush in canine left lung preservation for six hours. J Heart Lung Transplant 1996; 15:395-403. Stringham J, Southard J, Hegge J, Triemstra L, Fields B, Belzer F. Limitations of heart preservation by cold storage. Transplantation 1992; 53:287-294. Starling R, Hammer D, Binkley P, Galbraith T, Howanitz E, Myerowitz P et al. Adenine nucleotide content in cold preserved human donor hearts and subsequent cardiac performance after orthotopic heart transplantation. J Heart Lung Transplant 1991; 10:508-517. Warner M, Guerraty A, Alivazatios P, Lower R, Hess M et al. Assessment of myocardial subcellular function after 24 hours of invitro presevation and transplantation. J Thorac Cardiovasc Surg 1982; 83:290-297. Solis E, Tago M, Kaye M. Cardiac function following prolonged preservation and orthotoic transplantation. heart Transplantation 1985; IV:357-361. Takami H, Matsuda H, Hirose H, Kaneko M, Kawashima Y et al. Myocardial energy metabolism in preserved heart: Comparison of simple storage and hypothermic perfusion. J Heart Transplant 1988; 7:205-212. Karck M, Frantzen V, Schwalb H, Haverich A, Uretzky G. Prolonged myocardial protection with St. Thomas’ Hospital solution and University of Wisconsin solution. Eur J Cardio-Thor Surg 1992; 6:261-266. Okada K, Yamashita C, Okada M, Okada M. Successful 24-hour rabbit heart preservation by hypothermic continuous coronary microperfusion with oxygenated University of Wisconsin solution. Ann Thorac Surg 1995; 60:1723-1728. Ohtaki A, Ogiwara H, Sakata K, Takahashi T, Morishita Y. Long-term heart preservation by the combined method of simple immersion and coronary perfusion. J Heart Lung Transplant 1996; 15:269-274. Ferrera R, Marcsek P, Dureau G et al. Comparison of continuous microperfusion and cold storage for pig heart preservation. J Heart Lung Transplant 1993; 12:463-469. Yacoub M, Khaghani A, Banner N, Tajkarimi, Fitzgerald M. Distant organ procurement for heart and lung transplantation. Transplantation Proc 1989; 21:2548-2550. Collins G, Halasz N. Composition of intracellular flush solutions for hypothermic kidney storage. Lancet 1975; 25:220-222. Baker J, Bullock G, Hearse D. The temperature dependence of the calcium paradox. Enzymatic, functional and morphological correlates of cellular injury. J Mol Cell Cardiol 1983; 15:393-411.

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Fremes S, Christakis G, Weisel R. A clinical trial of blood and crystalloid cardioplegia. J Thorac Cardiovasc Surg 1984; 88:726-741. Ko W, Zelano J, Lazzaro R, Lazenby D, Hamilton T, Isom O, Krieger K. Superiority of the Univeristy of Wisconsin solution over simple crystalloid for extended heart preservation. J Thorac Cardiovasc Surg 1992; 103:980-992. Ko W, Zelano J, Lazenby D, Isom O, Krieger K. Compositional analysis of a modified University of Wisconsin solution for extended myocardial preservation: A study of the left ventricular pressure-volume relation. Circ 1992; 86[suppl II]:II-326-II-332. Wicomb W, Hill D, Collins G. Twenty-four-hour ice storage of rabbit heart. J Heart Lung Transplant 1994; 13:891-894. Wokowicz P, Caulfield J. Cardioplegia with aged UW solution induces loss of cardiac collagen. Transplantation 1991; 51:898-901. Fremes S, Guo L, Furukawa R, Mickle D, Weisel R. Cardiac storage with UW solution and glucose. Ann Thorac Surg 1994; 58:1368-1373. Mollhoff T, Sukehiro S, Van Aken H, Flameng W. Long-term preservation of baboon hearts: effects of hypothermic ischemic and cardioplegic arrest on highenergy phosphate content. Circ 1990; 82(suppleIV): IV 264-IV 268. Krogh A. The quantitative relation between temperature and standard metabolism in animals. Int Z Phys Chem Biol 1914; 1:491-508. Pegg D. The biology of cell survival in vitro. In: Organ Preservation for Transplantation. New York: Marcel Dekker, 1981:21-52 . Karck M, Vivi A, Tassini M, Uretzky G et al. Optimal level of hypothermia for prolonged myocardial protection assessed by 32P nuclear magnetic resonance. Ann Thorac Surg 1992; 54:348-351. Takahashi A, Braimbridege M, Hearse D, Chambers D. Long term preservation of the mammalian myocardium: Effect of storage medium and temperature on the vulnerability to tissue injury. J Thorac Cardiovasc Surg 1991; 102:235-245. Mankad p, Slavik Z, Yacoub M. Endothelial dysfunction caused by University of Wisconsin preservation solution in the rat heart; the importance of temperature. J Thorac Cardiovasc Surg 1992; 104:1618-1624. Bittner H, Kendall S, Chen E, Davis R, Van Trigt III P. Myocardial performance after graft preservation and subsequent cardiac transplantation from brain-dead donors. Ann Thorac Surg 1995; 60:47-54. Smith R, Tomlinson B. Subendocardial hemorrhages associated with intracranial lesions. J Path Bact 1954; 68:327-333. Burch G, Meyer R, Abildskov J. A new electrocardiographic pattern observed in cerebrovascular accidents. Circ 1954; 9:719-721. Darracott-Cankovic S, Stovin P, Wheeldon D, Wallwork J, Wells F, English T. Effect of donor heart damage on survival after transplantation. Eur J Cardiothorac Surg 1989; 3:525-532. Benito P, Montero J, Avila L, Concha M et al. Thyroid function in potential organ donors. Influence on myocardial damage. Clin Transplantation 1989; 3:355-358. Novitzky D, Cooper D, Human P, Reichart B, Zuhdi N. Triiodothyronine therapy for heart donor and recipient. J Heart Transplant 1988; 7:370-376. Bolli R, Patel BS, Jeroudi MO, Lai E, McCAy P. Demonstration of free radical generation in the “stunned” myocardium in the intact dog with the use of spin trap alpha-phenyl-N-tert-butyl nitrone. Fed Proc 1988; 2352:A701.

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57.

58. 59.

60. 61.

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Gundry SR, Fukushima N, Eke CC, Bailey LL et al. Successful survival of primates receiving transplantation with “dead”, nonbeating donor hearts. J.Thorac Cardiovasc Surg 1995; 109:1097-1102. Bolling SF, Olzanski DA, Childs KF, Gallagher KP, Ning X. Stunning, preconditioning and functional recovery after global myocardial ischemia. Ann Thorac Surg 1994; 58:822-827. Przybylski R, Olivson A, Chandra M et al. Resuscitation of the ischemic heart by warm blood cardioplegia. J Mol Cell Cardiol 1993; 25(Suppl I):VI p4 Carrier M, Leung T, Pelletier C et al. Clinical trial of retrograde warm blood reperfusion versus standard cold topical irrigation of transplanted hearts. Ann Thorac Surg 1996; 61:1310-1315. Pradas G, Cuenca J, Juffe A. Continuous warm reperfusion during heart transplantation. J Thorac Cardiovasc Surg 1996; 111:784-790. Soots G, Crepin F, Gosselin B, Pol A, Moreau D, Devulder J. Cold blood cardioplegia and warm cardioplegic reperfusion in heart transplantation. Eur J Cardiothorac Surg 1991; 5:400-405.

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The Role of the Recovery Services Coordinator Cindy Morphew-Magie, Alison B. Smith Interviewing/Hiring ............................................................................................ Training .............................................................................................................. Referral Process ................................................................................................... Evaluation Process .............................................................................................. Consent ............................................................................................................... Medical/Social History ....................................................................................... Medical Examiner Release .................................................................................. Saying Good-Bye ................................................................................................ Donor Management ........................................................................................... UNOS ................................................................................................................. Organ Placement ................................................................................................ Organ Allocation ................................................................................................ Operating Room ................................................................................................. Arranging Transportation ................................................................................... Marketing Department ....................................................................................... Donor Family Follow-Up .................................................................................... Other Job Duties ................................................................................................. Conclusion ..........................................................................................................

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Searching for employees to fulfill the role of Recovery services coordinator (RSC) is a challenge. The recovery services staff maintains specialized knowledge and abilities through intense training, enhanced clinical and technical expertise, and continued education. The RSC is available 24 hours a day for telephone consultation, donor screening, on-site evaluation, medical assessment, and family approach. During this evaluation/consent phase, the RSC determines whether organ and tissue donation is an option that the family can consider. If so, the RSC compassionately provides the family with the information necessary to make a fully informed decision. Once consent is obtained from the next-of- kin, the RSC obtains pertinent information regarding the donor’s past medical and social history. The RSC then initiates a complex process of optimizing the number and viability of organs and tissues available for transplantation. During this donor management phase, specialized protocols are instituted to achieve optimal organ function. This process involves laboratory studies, physician consults, and other diagnostic services available at the donor hospital. The information obtained is used Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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by transplant physicians/surgeons to determine if the available organs are suitable for their patients. The organ placement phase begins as a computerized printout is generated, ranking potential recipients based on medical urgency and waiting time. Organs are placed through detailed communication with each potential recipient’s physician. Once all available organs are placed, the RSC’s focus turns to coordinating the surgical recovery. This involves arranging transportation, gathering medical supplies, and preparing the operating room and the OR staff, while constantly updating all parties involved. The surgical procedure involves preservation of organs using protocols specific to each transplanting center. Often with multi-organ donors, two or more RSCs are required to provide the highest level of service to both the donor hospital and the transplant teams. The RSC is committed to educating each individual involved about how the donor process works and the positive results of organ donation. Explaining the rationale behind each step creates a higher level of participation, cooperation and support. Follow up to each donor referral is also essential in providing service to hospitals; the RSC facilitates that follow up and identifies further educational needs.

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One of the most important questions an interviewee may be asked is, “This job may create a lot of stress and our employees need ways to decrease stress. What is your major interest outside of work?” This question is one of many included in a two-day United Network of Organ Sharing (UNOS) workshop, “Successful Interviewing and Hiring of Procurement Coordinators.” Margeret Verble, Ed.D., and Judy Worth, M.A., in collaboration with UNOS, developed a specialized interviewing methodology known as SCARSO. This approach is a standardized method of finding individuals who are most likely to develop into “happy, dedicated and long-lasting procurement coordinators.” The SCARSO method identifies eleven character and personality traits that are common in long-term procurement coordinators and crucial to quality performance. This interview method also provides a set of questions that predict future performance from past experiences rather than hypothetical answers. It includes a system of ranking candidates based on their interviews. This system allows for multiple interviews conducted by varying members of the OPO. Many OPOs require RSCs to have specific training in nursing or another allied health field certification. Prior experience should be complimentary of the RSC’s job duties. For example, emergency room, operating room, or intensive care unit nursing experiences seem to be the most beneficial during the RSC training. While each OPO sets its own standards and hires accordingly, hiring the right person is a critical piece of the attrition puzzle, and is no small feat.1 Improved hiring standards may increase the average length of employment for recovery services coordinators, leading to a more experienced, better prepared staff.

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TRAINING Training programs vary from one OPO to another, however, many require detailed and highly structured training which may last for months because specific goals must be met. Structured training programs often require dedicated preceptors. Some methodology, such as a check list, should be used to ensure the trainee accomplishes each job responsibility at an acceptable level, and exhibits a full understanding of the RSC job requirements. Separating every responsibility into phases provides training data in an orderly, systematic manner. Southwest Transplant Alliance (STA) has segmented its training program into ten phases. STA’s training manuals explain every detail of the organ donation process in a sequential, logical order. STA also has dedicated preceptors that oversee the development and weekly progress of every trainee. Criteria for the preceptor position include years of experience as an independent RSC, outstanding performance, and demonstrated leadership characteristics. As part of the training process, weekly meetings are held between the preceptor and trainee, in conjunction with the training supervisor, to discuss every detail of each case in which they are involved. The check-list and case evaluation are reviewed and goals are set for the trainee. A monthly report is developed by the preceptor and training supervisor and forwarded to the manager of recovery services. RSC training at STA lasts an average of six months depending on the available experiences during each individual’s training period. Trainees need experiences in a variety of hospitals with different patient acuity levels. Although each trainee may experience many things under the direction of his/her preceptor, prior to practicing independently, the preceptor must be certain that the trainee will be confident and assertive when faced with the challenges of the recovery process. RSCs at OPOs that cover a logistically diverse territory may work in entirely different hospital settings daily. An OPO’s territory may cover a population of up to 10.3 million.7 Once a trainee has completed 12 months of work as an RSC, he or she is eligible to take a national examination for certification, which credentials the RSC as a certified procurement transplant coordinator (CPTC). This signifies a level of competency measured by national standards.2 Upon completion of the training program, the RSC functions independently on the call schedule. The RSC may be required to cover any number of call days during a given month, and call days may involve an entire 24 hour period or be broken down into 12 hour increments.

REFERRAL PROCESS Following the referral call, the RSC talks with the potential donor’s bedside nurse and physician to get an overview of the patient’s status. Information gathered consists of the donor’s name, reason for current hospitalization, demographic

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information, medical and social history, and any other information offered by the medical and nursing staff. At the time of referral many OPOs send staff on site to assess the condition of the patient, review the hospital chart, and answer questions presented by the staff and family members. Common referrals include gunshot wounds to the head, cerebral vascular accidents, intracranial bleeds, head trauma, and anoxic injuries from such events as prolonged cardiopulmonary resuscitation. The RSC first identifies the referral as an organ or tissue donation referral. For organ donation to be an option, the patient must be maintained heart beating on a ventilator. If the patient has become non-heart beating or has been removed from the ventilator, the referral is for tissue and/or eye donation. If the referral is determined as a potential for organ donation, the referring staff may ask for on-site presence of an organ bank representative. When a referring hospital is in the metropolitan area of the OPO, on-site presence is obtainable in a timely manner. However, if outside the immediate area of the OPO office, the on-site visit may require a lengthy drive or even an airplane trip. While daytime referrals may allow for the use of commercial airlines, if commercial flights are not available, the only option for the RSC to perform an on-site evaluation may be the use of chartered aircraft. For rural areas where a regional coordinator is not available, OPOs may have specially trained local nurses to facilitate early assessments of potential donors.3 The local nurse is contacted, informed about the situation and instructed to go on-site for review of the patient’s status and chart. The RSC keeps in close contact with the local nurse to answer any questions or concerns that may arise from the donor’s medical and social history. This local nurse also provides a knowledgeable person to help answer staff and family member questions.

EVALUATION PROCESS A referral call may be made prior to brain death being declared, before family has been found, or to see if the patient is viable before approaching the next-ofkin for consent. As information is gathered, questions may arise regarding suitability. OPOs utilize their administrators, medical directors, and transplant surgeons for consults when such concerns surface. For example, if the donor’s lab results that assess liver viability are elevated, a liver transplant surgeon is consulted. If the transplant surgeon voices no concern, that may be the only call the RSC makes at that time. However, if the transplant surgeon declines the patient as a potential donor, then several calls may be made to receive more opinions. The OPO procedure may require calls to all of its local transplant centers before officially declining a potential donor, which can result in multiple calls if several surgeons are called for each organ. After the surgeons are called, the OPO administrator and medical director of the OPO are called for the final determination regarding suitability of the potential donor. Because evaluation of similar potential

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donor situations may result differently due to the recipient needs of that particular day, this type of situation can result in confusion among hospital staff members.

CONSENT While the consent process may include a variety of hospital staff members, it should always involve the RSC. Some healthcare professionals believe that bringing up the topic of donation with a grieving family is an imposition, and may try to protect the family from being approached. Yet recent Gallup polls indicate that nearly nine in ten Americans support donation, and more than two-thirds are willing to donate their organs upon death. Hence, healthcare professionals should always be sure to provide the potential donor’s family with the opportunity to donate.4 The consent process is discussed thoroughly in a previous chapter. The RSC follows each hospital’s individual policy regarding forms to be signed or the process required for telephone consent. Whether consent is obtained by an RSC or a hospital staff member, the process should also include asking the nextof-kin a set of thorough medical/social history questions.

MEDICAL/SOCIAL HISTORY The U.S. Public Health Service (USPHS) set the standard for current clinical practice in Draft Guidelines for Prevention of Transmission of HIV Through Transplantation of Human Tissue and Organs, March 1993.5 In 1994, the Center for Disease Control (CDC), a division of USPHS, announced regulations regarding behaviors that constitute a high-risk donor.8 OPOs then determined how best to screen potential donors for high-risk behaviors and prepared detailed questionnaires for use in obtaining the donor’s medical and social history. The RSC would conduct the interview, which would be the vital link to assuring the highest level of quality control for the intended recipients. Formalized training for the interviewer is arranged by OPOs.5 The medical/social history interview is conducted with the next-of-kin and significant life partners in a confidential, sensitive and professional manner. All questions are asked exactly as written to provide objectivity and all answers must be recorded. In addition to the interview, medical records must be reviewed and discussions conducted with physicians, friends and other healthcare agencies that may be able to provide pertinent information. In pediatric patients under the age of 18 months, the mother and, if possible, the father are interviewed about their behaviors that might place the patient at high-risk. If the potential donor is determined to be high-risk, each OPO has policies regarding which organs will be offered for transplantation and whether to proceed with the donation at all. Beside its use as a screen for high-risk behaviors, the medical/social history provides extensive information that allows the physician to make a better decision for organ acceptance or refusal.

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When high-risk behavior is identified, transplant surgeon(s) are called regarding interest. The number of calls may be determined by the behavior identified, by time constraints, and by current urgent needs. A potential recipient identified as an urgent need may nullify the high-risk behavior due to the patient’s shortened life span without a transplant. If an OPO does not have any urgent needs when the high-risk potential donor is identified, the RSC may be advised by the administrator or medical director to continue making calls on a regional and national level. However, it must be remembered that in light of the current donor crisis, when lifesaving organs are involved, the CDC’s recommendation is to use any potential donor who tests negative for HIV (see chapter 5, Testa). Identified high-risk behaviors can produce confusion for hospital staff members because criteria for the exclusion of high-risk behaviors change daily as recipient conditions change.

MEDICAL EXAMINER RELEASE

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After the next-of-kin has given consent, the medical examiner (ME) may need to be contacted regarding release of the body for donation. Homicides, suspicious deaths, suicides, accidents, and deaths occurring from unexpected or unexplained natural circumstances are investigated by the ME’s office. The goal of the ME investigation is to determine the cause and manner of death. Evidence is collected and documented for the support of such conclusions.7 Organ donation is not contraindicated when an autopsy is required. For example, if the donor suffered a gunshot wound to the head, the autopsy may just involve physical evidence such as hand scrapings and a thorough examination of the patient’s head. Working collaboratively with the ME for the preservation of evidence, the RSC may have the hospital staff place paper bags on the donor’s hands, allowing the patient to become an organ and tissue donor. In conjunction with transplant surgeons, the OPO provides the ME thorough documentation and interpretation of injuries, documentation of the integrity of the organs removed for transplantation, and the preservation of trace evidence. In addition, the medical examiner’s office may allow the retrieval of the eyes or corneas, as well as other tissues after the autopsy is completed.

SAYING GOOD-BYE After consenting to donation, the family and friends may request to say their good-byes at the bedside. Some individuals opt to leave the hospital to take care of details such as funeral arrangements or just to “take care of themselves.” Others choose to stay and with pediatric parents, most opt to stay at the bedside until their child is taken to the operating room. Parents may even want to hold their child, a request that can be facilitated by the RSC. Hospital staff may verbalize

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uneasiness regarding family at the bedside due to their own emotional stress regarding the death of one of their patients. However, the RSC needs to resolve such concerns by explaining to hospital staff members that these are the last hours that family members can hold, touch, and even talk to their loved ones. If family and friends choose to stay at the hospital, they are supported and asked if they would like to step out of the room during such procedures as obtaining blood, echocardiogram, physical examination, etc. Reassurance that they may return after the procedure eases concerns. If family and friends decide to stay, the RSC must communicate this request so they are not asked to leave, which could contradict what they have been told.

DONOR MANAGEMENT Once brain death pronouncement, consent and the ME release have been completed, multiple orders are given to begin the organ donor process. At this time, the OPO begins incurring medical expenses on behalf of the donor. Specific orders for the evaluation of each individual organ are mandated by policy by the United Network for Organ Sharing (UNOS). Donor management techniques have been explained in previous chapters.

UNOS On October 1, 1987, UNOS became fully operational as the nation’s Organ Procurement and Transplantation Network (OPTN). Shortly thereafter, the country’s first organ allocation policies were established. This new national system maintained priority for local use of organs. For the first time OPOs were accountable for allocating organs according to the UNOS computer printout. Since its inception, UNOS has established a national waiting list for individuals in need of organ transplants, a national system for computerized matching of potential recipients with available organs, a 24 hour central office to ensure access to the recipient list, methods to assist OPOs in distribution of organs to transplant centers, and standards for organ recovery and transplantation.7 UNOS policies mandate evaluations that the RSC should perform prior to offering organs for transplant. The policies include: verifying that death has been pronounced according to applicable laws, identifying conditions which may influence donor acceptance, obtaining the donor’s history, reviewing the donor’s medical chart, performing a physical examination of the donor, obtaining the donor’s vital signs, and performing pertinent tests. The pertinent tests include lab tests for each organ and serology testing on all donors. The serology tests required include a hepatitis screen including HepBSAg and anti-HCV, RPR or VDRL, FDA licensed anti-HIV 1 and HIV 2, anti-HTLV 1, and anti-CMV.7 Local transplant centers may also request additional tests.

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The UNOS policy for equitable organ allocation attempts to strike a balance among the following principles: to enhance the overall availability of transplantable organs, to allocate organs based upon medical criteria, to give equal consideration to medical utility and justice, to provide transplant candidates reasonable opportunities to be considered for organ offers within comparable time periods, taking into consideration similarities and dissimilarities in medical circumstances as well as technical and logistical factors in organ distribution, and to respect autonomy of persons. Relevant to the principle of medical utility: number of people receiving successful transplants, patient survival, graft survival, quality of life, cost/ benefit ratio, availability of short term treatments, transplant center performance, and OPO performance. The principle of justice: medical urgency, time waiting, medical disadvantage, reasonable access and information, and equitable access.7 The rationale for achieving objectives of equitable organ allocation is in obtaining balance between each objective. Therefore, the balance is among maximizing the availability of transplantable organs, maximizing patient and graft survival, minimizing disparities in consistently measured waiting times until an offer of an organ for transplantation is made among patients with similar or comparable medical/demographic characteristics, minimizing deaths while waiting for a transplant, maximizing opportunities for patients with biological or medical disadvantages to receive a transplant, minimizing effects related to geography, allowing convenient access to transplantation, minimizing overall transplantation-related costs, providing for flexibility in policy making, and providing for accountability and public trust.7

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ORGAN PLACEMENT The RSC may access UNOS by computer or phone. Hospital staff members often wonder why the RSC makes and receives multiple phone calls to organize an organ recovery. This is because every transplant center is notified when their patients print-up on the computer list for the potential donor’s organs. In some cases the RSC may place every organ with the first transplant center called. Other cases may take multiple calls to find accepting centers or to find no acceptance at all. Organ placement begins after the required lab results and specific consults are completed. The current organ allocation system is complex and takes multiple factors into account. The transplant community constantly investigates ways to improve the organ allocation system. The UNOS policy for organ sharing allows the OPO to place organs from local donors first with local transplant centers. However, UNOS does allow OPOs to formulate special sharing arrangements with their transplant centers to improve overall effectiveness of organ allocation within particular areas. Organ placement may be very time-consuming depending on the donor’s age, size, blood group, test/consult results, etc. In addition, if local transplant centers

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are conservative regarding donor age, medical/social history, etc., the RSC may take additional time to locate potential recipients at distant transplant centers. Organ placement may also be delayed due to current methods of aggressive donor management. Lungs are sometimes improved with the use of bronchodilators, increase in the tidal volume to 10-15 mL/kg (ideal body weight) and the addition of positive end-expiratory pressure (PEEP). These treatments delay the process approximately 2-3 hours, however, the recovery and transplantation of the lungs is a positive trade-off. A 1992 study reported that 25% of all cardiac donors were likely to have lungs suitable for transplantation.4 If the donor is on excessive or numerous vasopressors, the cardiac consult may be affected. Current medical management suggestions include initiating a thyroid replacement therapy (TRT) to improve oxygenation and hemodynamic stability.6 The administration of TRT may allow lower dosages or even the discontinuance of vasopressors that may improve cardiac function resulting in recovery of the heart as well as other organs for transplant.

ORGAN ALLOCATION The organ allocation system will be only partially explained due to its complexity. At any time, a potential recipient may be placed into an inactive status on the waiting list after initially being added. However, policies are in place regarding the amount of time a patient can continue to accrue while inactive. At a specified time interval, inactive patients remain on the list but discontinue accruing additional waiting time. The current lung allocation system is based on waiting time, blood group identity and compatibility, and the patient’s height. Lung recipients have a single status code. Hearts are allocated based on two status codes and waiting time. The status codes are dependent on specific criteria regarding the patient’s critical condition. Heart/lung recipients are combined systematically within the heart list, however, they are not entered by status codes. The current liver allocation system has recipients entered by a tiered status code system. The list is based on waiting time and urgency of need. Blood group and recipient size are also included in the allocation algorithm. Intestinal organ allocation is based on two status codes and waiting time. Blood group identity and body size are more important than for livers. Pancreas and kidney allocation is based on waiting time and HLA matching. Recently the matching system was upgraded by introduction of genetic matching which is more exact than the previously used serologic matching. Kidneys are allocated based on a point system generated from waiting time and HLA matching. A national computer list generated when the donor’s antigens are identified, is checked for a “perfect” genetic match. Genetic matching occurs at approved histocompatibility labs and takes approximately six hours from the time the lab receives the donor sample. When “perfect” genetic matches are identified, the OPOs

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are required to offer kidneys to those recipients nationwide. This is because a perfect match has a better chance for long term success.

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The RSC begins preparing the operating room (OR) staff as soon as the donor process begins in the intensive care unit (ICU). Informing the OR charge nurse that a potential donor is in hospital is critical because this allows time to prepare the staff that will be working in the donor OR. The RSC can also facilitate the OR staff ’s preparation by educating them regarding the process. The most critical information is the timing of the OR procedure which initially can only be estimated at six to eight hours after the ICU process begins. The staff needs to understand that this time estimate may change due to donor stability, number of organs recovered, and location of the recovery teams. The next most important information involves staffing needs for the OR. A circulating nurse, scrub tech or nurse and anesthesia are needed.9 Some OPOs have RSC staff members with OR backgrounds that may assist if an emergency should occur that would not allow for the donor hospital to staff the OR. However, if the OPO has no one with a background in the OR, the recovery teams will wait until a team can be provided. This happens often when the donor recovery extends into weekday OR schedules. A case card can also be provided to the OR staff that lists all of the supplies and equipment required for the organ recovery. Hospital-specific supplies that need to be pulled for the case may include basic laporatomy vascular instruments, light handles and bovie pads. The case card may also include a scenario of the sequence of events during the recovery process in the OR. The RSC brings specialized supplies for the recovery. Some OPOs use premade OR packs, which shorten preparation time by having most of the required supplies opened onto the sterile field quickly. The RSC may also bring abdominal and chest retractors made specifically for organ recoveries. Preservation solutions are brought by the RSC for flushing the organs and they are kept cold until the surgeon(s) inserts the cannulas for flushing. The RSC can help the staff prepare by going to the OR about one hour prior to case start time. The RSC should inform the staff regarding how long the case may last, what organs are to be recovered and the names of the surgeons coming to recover the organs. The RSC may also help obtain supplies such as extra back tables and IV poles. If time allows once the OR case is complete, the RSC may assist with morgue care. If the donor’s body is going to the medical examiner’s office for an autopsy, all the IV lines and Foley must remain in place and tied off. The RSC may not be able to fully assist with morgue care if he or she needs to fly back with the recovery team.

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ARRANGING TRANSPORTATION The RSC for the donor OPO is responsible for arranging the recovery teams’ transportation. Transportation may include charter aircraft, ambulances, or private cars. Arranging simultaneous arrival times for several teams can be complicated. Issues of concern when preparing for the recovery include the amount of time the liver surgeon takes for dissection and whether the pancreas is going to be recovered. The heart and/or lung team may choose to be at the donor hospital closer to cross-clamp time. They may also choose to arrive prior to the recovery time and perform a bronchoscopy in the ICU.

MARKETING DEPARTMENT In an effort to improve relationships with donor hospitals, many OPOs choose to develop a separate department that focuses on providing hospital-specific services, with marketing coordinators assigned to specific donor hospital “accounts.” These services start with educating physicians, nurses, and ancillary staff about their roles in the donor process. Donor manuals may be developed to explain the process and answer common questions. The main goal of such a department is donor identification and referral. The marketing coordinator is also involved with postcase follow-up. A few days following a case, the RSC debriefs the donor hospital’s marketing coordinator. During debriefing, both positive and negative issues are discussed regarding every aspect of the donor process. This discussion may include physicians consulting on the case, nursing staff interactions, trouble with scheduling the OR case, etc. Within a few weeks of a case, the marketing representative may set up a meeting with the ICU and OR staff. This is called a post donor referral conference (PDRC). This is time spent talking over each aspect of the case and answering any questions the staff may have regarding the donor process. Recipient information is shared, which helps the ICU and OR staff understand the importance of their participation in the process.

DONOR FAMILY FOLLOW-UP Follow-up with the donor family includes a letter sharing some information regarding each of the recipients. This letter excludes confidential information such as name and geographic location of the recipient. OPOs may also choose to include a booklet regarding organ donation and/or grieving after the death of a loved one. Some OPOs may have donor family support groups and conduct meetings for new donor families. Similar letters are also sent to all hospital staff involved in the donation, physicians, transportation teams and funeral home directors.

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In addition to call duties, the RSC may have any of the multiple job responsibilities an organ donor produces. Responsibilities may include reviewing and revising performance standards, policy and procedures, serving as a transplant center liaison, updating and enforcing OSHA policy and procedure and quality assurance monitors.

CONCLUSION The role of the recovery services coordinator varies widely from OPO to OPO. The common theme, regardless of locale, is a need to be flexible, adaptable, sensitive, persistent, and enduring. REFERENCES 1. 2. 3. 4. 5.

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6. 7. 8.

9.

Benenson E, ed. Picking Winners: How to Hire Extraordinary People. UNOS Update. 1995; 2:6:18. Dutton SB. Certification of transplant coordinators by the American Board of Transplant Coordinators. Journal of Transplant Coordination 1996; 6:210-214. Holmquist M, Orlowski J, Spees EK. Successful organ procurement in a rural setting: Wyoming experience. Journal of Transplant Coordination 1994; 4:44-47. Johnson D, Joanie B, Travitzky V et al. Utilization of lungs for transplantation. Journal of Transplant Coordination 1994; 4:53-56. Leslie H, Stem M. Training procurement professionals in obtaining effective donor medical/social history. Journal of Transplant Coordination. 1995; 5;84-86. McAdams D, Cearden C, Headrick TR. Use of thyroid replacement therapy in donor management. Journal of Transplant Coordination 1995; 5:117-120. Phillips M. UNOS Organ Procurement, Preservation and Distribution in Transplantation. United Network of Organ Sharing, Richmond, VA: 1996. Public Health Service, Centers for Disease Control. Guidelines for preventing transmission of human immunodeficiency virus through transplantation of human tissue and organs. Morbidity and Mortality Weekly Report. Washington, D.C.: U.S. Government Printing Office 1994; vol. 43, no. RR-8. Van Da Walker S. The attitudes of operation room nurses about organ donation. Journal of Transplant Coordination 1994; 4:75-78.

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Ethical Issues in Organ Donation L.S. Rothenberg Introduction ........................................................................................................ Methods of Obtaining Natural Organs for Transplantation .............................. Special Issues Concerning Living Donors ........................................................... Special Issues Concerning the Determination of Death ...................................... Artificial Organs and Other Body Parts .............................................................

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INTRODUCTION If the transplantation of solid organs is one of the most high-technology procedures in modern medicine, then arguably the current system of procuring natural organs from both living and cadaver donors is a relatively low-tech affair. Indeed, Prottas has described the system’s role, focusing on the usual sources of cadaver organs and the circumstances under which they became available, as providing “a bridge between human tragedy and high technology.”1 Whatever the degree of technology employed, however, there are important ethical issues involved in the retrieval of both organs and tissues, natural or artificial, and the discussion that follows will explore these. To the extent possible, the techniques examined will not be limited to those currently in use, but will also encompass those research approaches that are likely to be clinically validated and employed in the 21st century as a means of resolving the fundamental imbalance between supply and demand. For readers unfamiliar with the language and literature of bioethics (the moral and value problems of the biomedical and life sciences), it may be useful to quote one of that field’s founders, Daniel Callahan, in his endeavor to explain the types of relevant questions one asks: While bioethics as a field may be understood in different ways and be enriched in different perspectives, at its heart lie some basic human questions. Three of them are paramount. What kind of person ought I be in order to live a moral life and to make good ethical decisions? What are my duties and my obligations to other individuals whose life and well-being may be affected by my actions? What do I owe to the common good, or the public interest, in my life as a member of society?2 When these general questions are placed in the context of organ procurement, a series of ethical/moral principles (or values) become relevant. Childress, who Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience

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has written extensively on this topic, would list those principles or values as “respect for persons, including their autonomous choices and actions; beneficence, including the obligation both to benefit others (positive beneficence) and to maximize good consequences–i.e., to do the greatest good for the greatest number (utility); nonmaleficence, the obligation not to inflict harm; and justice, the principle of fair and equitable distribution of benefits and burdens.”3 These principles are often in conflict with each other and must be balanced, in part, by a determination of which principle is the weightiest or most compelling in a given situation. It is also important to note that ethical standards may be far more demanding than the prevailing legal standards, but are never less demanding. These principles must also be applied against a backdrop of an inadequate number of organs to meet the needs of potential transplant recipients, a number that appears to be relatively static in the United States despite growing lists of persons registered for various types of organ transplants. This disparity and resulting scarcity can be seen in the statistics showing the U.S. national patient waiting list in mid-June 1997 with 52,962 registrations for the various types of solid organ transplants, even though only 19,410 transplants of all kinds were performed in the U.S. during the entire year of 1996.4 Finally, there is a need to clarify the term, donor. Childress has pointed out that because this term has been used to refer both to the source of the decision to donate and to the source of the organs, the latter use is inappropriate unless the two are identical.3 Most often, the source of cadaver organs made no such decision, and it is the family or some other person who is in fact the decision-maker. Our enthusiasm for altruism in the retrieval of organs should not cause us to create confusion by our use of terminology.

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METHODS OF OBTAINING NATURAL ORGANS FOR TRANSPLANTATION One analytical method for examining relevant ethical issues in the procurement of organs is to examine the various possible methods for acquiring organs and other human body parts: donation (both express and presumed), routine removal or salvaging, expropriation or conscription, abandonment, and sale.5 DONATION The theory of express donation is that individuals, intellectually and emotionally capable of doing so, have made a specific determination as to the disposition of their organs after their death. Presumed donation, on the other hand, assumes that if individuals fail to make such a determination, pro or con, that failure constitutes permission to take the organs. In the United States, solid organs are usually retrieved under an express donation theory, although, as mentioned above, in the case of cadaver organs it is usually the family making the determination, not the dead person. By contrast, corneas are procured for transplantation in some U.S. states under a theory of presumed donation, specifically by permission of

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medical examiners or coroners who have performed autopsies. The latter approach, of course, has nothing to do with altruism. Several ethical concerns may arise with donation, either express or presumed. First, the wishes of the person who actually makes a determination and signs an organ donor card may be vetoed by the family at the invitation of the organ procurement organization out of public relations concerns.6 Since donors are not informed of this capacity of family members to override their wishes, this raises serious ethical questions regarding truth-telling on the part of the donor card campaigns by the National Kidney Foundation, state motor vehicle departments, and the Coalition on Donation (whose brochure, Share Your Life…Share Your Decision,7 urges speaking to families about a desire to donate organs without ever explaining why it’s crucial to the honoring of one’s wishes). Indeed, many states now legally permit such express donations without the approval of families or the need for witnesses on the donor cards, but this apparently has not changed the insistence of organ procurement organizations in obtaining next-of-kin approval.8 Second, the religious or cultural beliefs and values of the person whose organ is “donated” by others may be violated, thereby not respecting their autonomous choices. Although such viewpoints are not monolithic and universal, negative views regarding organ donation may exist in persons identifying themselves as AfricanAmericans9 and Native Americans,10 as well as members of religious faith traditions including Buddhism, Confucianism, and Shintoism,11 Eastern Orthodox Christianity,12 Roman Catholicism,13 and Orthodox Judaism.14 Of course, the objections of the individual may be secular and personal, and yet raise the same concerns. For official standpoint by various beliefs see chapter 2, “Approaching the Family”, pg. 17. Third, the age, mental health, and intellectual development of the individual whose body parts are being donated may raise concerns both about justice or fairness to that individual as well as not inflicting harm.15 Although philosophers and physicians have debated, for example, as to whether parents have the right to donate an infant’s bone marrow to save a sibling’s life16 or a young child’s kidney to spare a sibling from permanent dialysis,17 controversy often arises when specific cases become publicized in the media. For example, when the parents of Anissa Ayala-Espinosa, then a 17-year-old in Southern California diagnosed with chronic myelogenous leukemia, decided to conceive a child in order to provide her with matching bone marrow for transplantation, there was a national uproar when that fact became known, even though in retrospect the transplant was successful and Ms. Ayala-Espinosa now serves as a healthy volunteer seeking to increase bone marrow donations among Latino-Americans.18 Admiration may be the emotion, however, when acts of generosity to strangers are perceived, such as when the parents of a 7-year-old boy murdered in Italy in 1994 donated his organs to benefit Italian children.19 Obviously, infants and small children cannot ordinarily make an informed decision to donate organs, but Kopelman has argued that the wishes of dying children to donate organs should be respected.20 There is a desire to obtain organs from such young people because “they are frequently the only ones of appropriate size for transplantation into

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small children.”21 Obtaining tissue from fetuses raises yet another set of ethical issues.22,23 Finally, the “donors” whose bodies are not furnishing the organs or tissues— families24 and medical examiners25–increasingly refuse, even when asked, to consent to donation for a wide variety of reasons, some of which may be fears (e.g., a willingness to donate might cause a patient to receive less aggressive care or medical examiners might lose evidence needed for legal cases) that have no basis in fact. These decisions not to donate also have ethical consequences in that they may violate the obligation to benefit others and maximize good consequences, particularly when decisions to donate in these circumstances would not violate other ethical principles, such as the autonomous choices or values of the dead. Merely switching from systems of express donation to those of presumed donation (sometimes called “mandated-choice systems”) doesn’t necessarily resolve the problem. When the state of Texas tried a mandated-choice system tied to drivers’ licenses, 80% of their driving public chose not to be donors.26 Even the European countries, including France, which utilize a presumed donation (“opt-out”) system for obtaining organs, don’t necessarily adhere strictly to that approach. One U.S. ethicist who favored the presumed donation system changed his mind when he discovered that the practice of transplant teams in France is to seek informal family consent before removing organs despite the fact that they are not legally required to do so.27 Spain reportedly has the same practice.1

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ROUTINE REMOVAL OR SALVAGING Although the concepts of “routine removal” (also known as “routine salvaging”) and “presumed donation” would appear to be identical in that in both, action must be taken “to stop the process of donation or removal rather than to initiate it,” there is a moral distinction in that under presumed donation an individual or family has the right to dispose of the organs and their failure to do so constitutes consent; whereas under routine removal the society or state has a right to take organs and tissues because it owns them “or because individuals and families have an enforceable social duty to provide them.”5 Those countries which have used some form of presumed donation or routine removal/salvaging theory as the basis for their organ procurement system (including France, Austria, and Belgium) reportedly have seen little improvement in the supply of organs.28 Thus, whether one favors express donation over presumed donation or routine removal/salvaging because of a belief that altruism and volunteerism are ethically preferable or because of a belief that it is unethical for the society or state to substitute its needs for the interests of the dead person, it remains to be shown that a choice of any of these systems actually makes a difference in the supply of organs or that the public actually is aware of and understands these systems. What is clear is that when the public does understand what the issue regarding organ donation is all about, a majority think it’s a great idea for someone else but not for them or their family.

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CONSCRIPTION OR EXPROPRIATION Conscription or expropriation (taking something away by official action without an owner’s approval) occurs largely in the context of human body parts being removed during autopsies by medical examiners or animal body parts being removed for xenotransplants. For the human dead, the same ethical arguments are involved (the interests and values of the individual vs. the potential benefits to and needs of others in society). For the nonhuman animals, the issues are similar but cast in a slightly different light since most people value the feelings and interests of humans more than they do those of nonhuman animals except for their pets.29 ABANDONMENT Abandonment in this context refers to the failure to claim bodies and their parts. While the circumstances could apply to a simple surgery where body parts, such as a spleen, are removed with permission but without a prior request that the body part be returned to the patient, the more relevant scenario would involve a patient whose body went unclaimed for a legally set period of time, thus giving a medical examiner the right to release organs in it.3 This method, even if ethically acceptable, is hardly likely to produce a significant number of organs or tissue for transplantation, and there are concerns that a less-than-zealous effort to try to identify the body or contact next of kin might occur if the priority shifted to finding body parts for transplantation.5 SALES OR REWARDED GIFTING Although largely forbidden under existing U.S. law (the exceptions being hair, blood, sperm and ova), the sale of, or rewarded gifting for, organs and tissues has been promoted in the U.S. by those who think it would be the most efficient way to resolve the supply deficit. Murray has examined three proposals to introduce an economic incentive (i.e., to create a futures market in organs, to give discounts on health insurance to prospective donors, and to offer money to families of donors to be used for funeral expenses) and has found them both empirically and ethically dubious.30 There are nations which permit or tolerate the offering of financial incentives for organ donation, and in these countries one might assume that the ethical arguments in favor of allowing people to make free choices without pressure or coercion and maximizing the welfare of others are seen as more compelling than those opposing the commodification of organs and favoring volunteerism.28 Singapore rewards those individuals or family members who have indicated a willingness to donate their organs by giving them priority on waiting lists for organ transplants,5 and a similar program was proposed for Canada in 1989 by two physician-ethicists.31

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Ubel and Mahowald have identified four key factors in the ethical assessment of organs or tissues from living donors: 1) risks and benefits to the donor; 2) risks and benefits to the recipient; 3) possibility and validity of consent for donation; and 4) donor privacy and confidentiality.32 RISKS AND BENEFITS TO THE DONOR Two techniques of assessing risk to potential donors involve the consideration of (a) “whether the body can naturally replace the donated material” and (b) the “invasiveness, discomfort, and risks of the procedures used in obtaining tissues or organs.” Similarly, psychological benefits have been found in significant increases in donor self-esteem and confidence.32 RISKS AND BENEFITS TO THE RECIPIENTS The assessment of risks and benefits to the recipients focuses primarily on “the organ, the prospects of success, and the possibility of alternative therapy, including cadaver donation.” Liver donations are seen by Ubel and Mahowald as offering the greatest benefit to recipients because they shorten the time patients wait for organs, whereas they see live-donor kidney transplants being done primarily for a recipient’s better quality of life since dialysis is available, the benefits of pancreas transplants are still unclear, and bone marrow transplants sometimes being used in situations where there is little chance of a recipient’s recovery.32

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POSSIBILITY AND VALIDITY OF CONSENT Here the focus is on both the presence of coercion and the possible absence of informed judgment: “Can a donor, under pressure to save another person, sufficiently understand the risks and benefits described above and arrive at a decision regarding donation without being coerced?” Since most living donors are relatives of recipients, the potential for direct or indirect coercion is great, and aside from needing to find the capacity in the potential donor to make informed decisions, the temptation for donors to make a snap decision to donate without further reflection creates ethical concerns. This may be particularly true with adolescents who may be motivated by “the desire to be recognized as an adult.”32 DONOR PRIVACY AND CONFIDENTIALITY Because transplant teams must evaluate potential donors in a recipient’s family, issues of privacy and confidentiality are raised that may lead to pressure on specific individuals either to donate or not to donate, thus compromising their autonomy. Similarly, issues can arise with unrelated potential donors (e.g., in a bone marrow registry) when potential recipients seek to identify the names of potential donors who may have declined to donate to a nonrelative.32 Other categories of potential living donors in which Ubel and Mahowald find informed consent to be problematic or even impossible include fetuses, anencephalic newborns, prisoners, and women (the last because of their roles often as

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“primary caregivers of those in need of transplants” and their lower incomes when compared to men, thus putting pressure particularly on housewives to make a sacrifice for the employed male spouse).32 There have been numerous proposals for increasing the pool of living organ donors, including those unrelated to the recipient.33 In a most ethically responsible and scientific manner, researchers and clinicians at the University of Chicago have begun a process of what they call “research-ethics consultation for surgical innovations” that includes the publication of a paper in a major clinical journal seeking professional and public criticism. Two of these consultations have involved the use of living donors, one in connection with liver transplantation34 and the other proposing a paired-kidney-exchange between two donor-recipient pairs to resolve the problem of ABO-compatibility.35 Potential living donors should have their autonomy and privacy maximized and an adequate opportunity to reflect on the risks and benefits of their decision regarding donation, according to Ubel and Mahowald. Ideally, their evaluation should be conducted by someone who can be an advocate for the donor and who is not a member of the transplant team, and ethical questions should be considered by an appropriate ethics resource within the institution or community.32

SPECIAL ISSUES CONCERNING THE DETERMINATION OF DEATH Our attitudes about the human cadaver influence profoundly our feelings about organ procurement and transplantation. Hovde has summed up those attitudes in the following way: It is not that the human cadaver is something of inherent value, for it will soon decay unless measures are taken to prevent this. Rather it is that the human cadaver is a symbol of the human person, a reminder to us of our life together as a community of persons. As a symbol, the human cadaver demands respect from the living.36 Bolstered by secular laws and religious beliefs, these attitudes have led to a belief that cadaver organs and tissues should not be removed without appropriate permission and certainly not before the person who occupied that body is “dead.”37 Scholars have suggested that this so-called “dead donor rule” grew out of a desire not only to honor the ethical principle of nonmaleficence (of not doing harm to others), but also as a way of reassuring society that only “severely brain-damaged patients, those with all loss of brain function” would be used as organ sources and that “other severely compromised patients would be protected from [being] killed or used as organ sources prior to their death.”38 The immediate problem, of course, becomes one of definition in deciding what we mean by the phrase, “dead” or “brain-dead,” as can be seen in confusing newspaper headlines such as “Brain-Dead Man Allowed to Die.” This has led not only to public mystification and incredulity at the notion that a breathing person whose heart is beating can be said to be “dead,” but to arcane debates among those who favor the existing “whole-brain-death” formulation, those favoring a less-demand-

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ing “higher-brain-death” criterion, and those who would take organs from people who meet neither of these criteria, all the while failing to morally justify any of these standards by explaining “the concepts of self and human death it presupposed.”39 Aside from pragmatic issues of public acceptance and support of organ procurement and transplantation (or perhaps underlying them), these definitions of death (or suggestions that we take organs and tissues from people not “dead” by conventional standards are arguably related to a sense of personal identity “because brain function is essential to the rational and volitional activities that appear unique to human beings as persons.”40 Thus, serious attention must be given to the social and ethical implications of the criteria used to justify organ and tissue removal from human bodies, both living and dead.

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INFANTS WITH ANENCEPHALY AND PERSONS IN VEGETATIVE STATES The desire to increase the pool of organs available for transplantation has led to suggestions that infants born with anencephaly (i.e., with functioning brain stems but no cerebral hemispheres) and those diagnosed with severe and presumably irreversible brain damage (“vegetative state”)–neither category capable of meeting current “whole-brain-death” legal standards–be added to the list from whom organs could be taken prior to “death” as we currently define it. Numerous ethical, medical and social concerns have been raised regarding such proposals, particularly with regard to infants with anencephaly.41 Nevertheless, the American Medical Association’s Council on Ethical and Judicial Affairs in 1994 endorsed the use of such infants as “live donors” who were not “legally dead” but who could be made an exception to the standard rule “because of the fact that the infant has never experienced, and will never experience, consciousness.”42 Youngner, in critiquing this policy statement as “conceptual gerrymandering,” has noted: “The AMA did not suggest that anencephalic infants were dead, but rather that they were beyond harm and, therefore, could be killed for their organs. Of course, the AMA did not use the word, killed.”43 Two more recent proposals by Emanuel44 and Truog45 would seek to overcome some of the criticism leveled at earlier suggestions by permitting patients and their surrogates to opt for organ donation if they met either the “whole-braindeath” standard or had a diagnosis of anencephaly or persistent vegetative state. Both proposals would return to the traditional “cardiorespiratory” standard of death now used for patients not supported by ventilators, but allow would-be donors an option to choose a “whole-brain-death” or a “higher-brain-death” standard. One of these authors has informally commented that this “would require us to admit that we are killing patients for their organs,” but presumably this would be accompanied by the explanation that the choice was that of the person whose body parts were taken or their surrogates. Such a change would challenge not only the patience and generosity of the public, but of the involved medical and nursing professionals as well.

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NON-HEART-BEATING CADAVER ORGAN RECOVERY Another suggestion to overcome the scarcity of organs was initially made by Shumway in 1971 when he wrote that “[p]rior to the advent of human cardiac transplantation, it was anticipated that the development of techniques for organ resuscitation and preservation would allow the removal of a donor heart after asystole [cardiac arrest] had occurred.”46 Prior to the existence of “brain death” laws, persons whose hearts were no longer beating at the time of organ procurement were the main source of organs for transplantation.47 Following the development of a modern protocol to use such donors at the University of Pittsburgh in 1993, a national ethical debate ensued (over what is still a relatively rare procedure) that was summarized in book form.48 One wellknown ethicist expressed concern that such a policy involved “policy creep” about the definition of an organ donor and was problematic because of such factors as “loss of trust in the transplant community because of confusion over the protocols to be used, blurring the line between life and death, stress on family members, and burdens imposed on health care providers when a long-standing policy regarding who can serve as a cadaver organ donor is unilaterally changed.”49 Others were more supportive of the approach.50 Additional public attention was drawn to the policy standard in 1997 when a similar protocol was proposed at the Cleveland Clinic and criticized by a local ethicist as possibly crossing “the line between permitting and inducing death” which prompted the announced interest of a Cleveland prosecutor.51

ARTIFICIAL ORGANS AND OTHER BODY PARTS The search for artificial organs and tissues has been proceeding for the past four decades as advances in tissue engineering and bioengineering generally have made possible all sorts of off-the-shelf life-sustaining products.52 Research is currently ongoing in the development of artificial lungs, livers, hearts, pancreases, corneas and other organs and tissues; and the expectation is that we will have these available in the 21st century.53 Earlier clinical efforts with implanting mechanical hearts in the 1980s raised ethical concerns about human experimentation, the use of such devices as a temporary bridge to transplantation, and the justice of spending limited research dollars to benefit so few who are often at the later stages of their lives.54 Future use of more artificial organs and tissues will raise similar ethical issues of distributive justice in a U.S. health care system that still denies full access for those seeking primary and preventive medical care, particularly those artificial body parts to be used in high-tech lifesaving that will likely only be available to those with the personal or insurance dollars to pay for it.55

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Prottas J. Organ and tissue procurement: Medical and organizational aspects. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 4:1852-1857. Callahan D. Bioethics. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 1:247-255. Childress JF. Ethical criteria for procuring and distributing organs for transplantation. In: Blumstein JF, Sloan FA, eds. Organ Transplantation Policy: Issues and Prospects. Durham: Duke University Press, 1989:87-113. United Network for Organ Sharing. U.S. waiting list statistics. Richmond: United Network for Organ Sharing, 1997. Childress JF. Organ and tissue procurement: ethical and legal issues regarding cadavers. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 4:1857-1865 Rothenberg LS. Ethical decisions in liver transplantation. In: Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Philadelphia: W.B. Saunders Company, 1996:851-860. Coalition on Donation. Share your life...share your decision: brochure. Richmond, VA: Coalition on Donation, Undated. Rothenberg LS. Ethical and legal issues in kidney transplantation. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 2d ed. Boston: Little, Brown and Company, 1996:310-320. Richardson R. Fearful symmetry: Corpses for anatomy, organs for transplantation? In: Youngner SJ, Fox RC, O’Connell LJ, eds. Organ Transplantation: Meanings and Realities. Madison: The University of Wisconsin Press, 1996:66-100. Lantos JD. Abuse, interpersonal: child abuse. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 1:42-46. Kimura R. History of medical ethics: South and East Asia. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 3:1496-1505. Harakas SS. Eastern Orthodox Christianity. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 2:643-649. Curran CE. Roman Catholicism. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 4:2321-2331. Kliever LD. Death: Western religious thought. In: Reich WT, ed. Encyclopedia of Bioethics. Rev Ed New York: Simon & Schuster Macmillan 1995; 1:505-513. Caplan AL. Am I my bother’s keeper? Suffolk Univ L Rev 1993; 27:1195-1208. Nelson HL, Nelson JL. Family. In: Reich WT, ed. Encyclopedia of Bioethics Rev Ed New York: Simon & Schuster Macmillan, 1995; 2:801-808. Dwyer J, Vig E. Rethinking transplantation between siblings. Hastings Cent Rep 1995; 25(5):7-12. Mozingo J. Bone marrow recipient now eases patients’ ordeals. Los Angeles Times 1997 Jun 25:B1, B3. Prottas J. Lives that depend on the kindness of strangers. Los Angeles Times 1995 Feb 27:B5. Kopelman LM. Children: Health-care and research issues. In: Reich WT, ed. Encyclopedia of Bioethics Rev Ed New York: Simon & Schuster Macmillan, 1995; 1:357-368. Cohen LR. Increasing the supply of transplants: The virtues of an options market. Austin: R.G. Landes Company, 1995.

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48.

49.

50.

51. 52. 53. 54.

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Index

171

C

ABO 48, 49, 95, 96, 165 ABO compatibility 95, 96 ACTH 38 Acute respiratory distress syndrome (ARDS) 104 Acute tubular necrosis (ATN) 57 Adenosine deaminase 44, 140 Age 7, 8, 16, 20, 48-50, 52-59, 71, 91, 92, 95, 96, 98, 99, 102, 103, 129, 151, 154, 155, 161 AIDS 51 Alcoholism 100 Allopurinol 66, 69, 135, 136 Alpha-1-antitrypsin (A1A) deficiency 98, 99 Amylase 57, 90, 92 Anencephaly 166 Antidiuretic hormone (ADH) 38, 83, 141 Antioxidants 68, 69, 72, 73, 90, 140 Apnea testing 6, 13 Arrhythmias 7, 80, 86, 88, 95, 101, 102 Aspiration 95, 104-106, 131 ATP 40, 41, 44, 67, 70, 73, 75, 89, 135, 138-141 Autonomic storm 32, 35

Calcium 32, 33, 35, 36, 44, 72, 87, 90, 102, 140-142 Calcium chloride 87 Carbon monoxide 101 Cardiac enzymes 103 Cardiectomy 128, 129, 131-133 Cardioplegic arrest 130, 140 Cardiopulmonary bypass 85, 128, 134, 139 Catecholamine 32-34, 38, 39, 43, 44, 81, 84, 85, 87, 89, 90, 102, 141, 142 Cause of death 7, 55-57, 71, 95, 99, 101 Central venous pressure (CVP) 81, 83, 106, 132 Chronic obstructive pulmonary disease (COPD) 98, 99 Coagulopathy 80, 86, 87 Cocaine 101 Cold ischemia 54, 67, 68, 70, 89 Cold storage 64, 66, 68-75, 84, 89, 90, 92 Collins solution 64, 65, 73 Combined donor cardiectomy and pneumonectomy 128, 131 Continuous hypothermic perfusion 64 Continuous machine perfusion 69, 72 Contrast angiography 8 Corneal reflexes 5 Coronary angiography 102, 103, 129 Coronary artery disease 96, 102, 103, 129 Cortisol 32, 38, 39, 43, 141 Cough reflex 6 Cryoprecipitated plasma (CPP) 64 Cytomegalovirus (CMV) 56, 59

B Bacteremia 100 Bill of rights for donor families 23, 28 Body size 53, 97, 155 Bone wax 115, 131 Brain death 1-14, 18, 19, 24-26, 28, 31-34, 36-40, 44, 50, 56, 58, 64, 65, 81-83, 86, 87, 89, 94, 95, 100-104, 106, 108, 114, 128, 141, 150, 153, 167 Brainstem auditory evoked potentials (BAERs) 11 Brainstem reflexes 2, 5, 6 Breast-feeding 51 Bronchial arterial perfusion 128, 137 Bronchoscopy 88, 95, 104, 105, 157

D Desmopressin acetate (DDAVP) 43, 83, 106, 107 Delayed graft function (DGF) 72-74 Diabetes 32, 38, 48, 55, 57, 82-84, 86, 90, 91, 102, 106, 107, 129, 141 Diabetes insipidus 32, 38, 82-84, 86, 106, 107, 141 Donor identification 15, 157 Dopamine 32, 42, 43, 58, 84, 85, 95, 102, 103, 107, 114

Index

A

Index

172

E Echocardiography (ECHO) 95, 99, 103, 129 Electrocardiogram 48, 102 Electroencephalogram (EEG) 2, 50 Encephalitis 100 Epinephrine 58, 89, 102, 107, 114 Esmolol 82 EuroCollins 68, 70, 73 Euthyroid sick syndrome (ESS) 38, 39 Express donation 160, 161, 162

Hemostasis and Thrombosis Hyperkalemia 86 Hypernatremia 83-86 Hypertension 33, 48, 55, 81, 82, 91, 97-99, 102, 103, 129, 133 Hypertonic glucose 86 Hypocalcemia 83, 87 Hypokalemia 83, 86 Hyponatremia 5, 83, 86 Hypotension 7, 8, 34, 64, 81, 82, 84, 85, 90, 92, 114, 132 Hypothermia 84, 87, 88, 108, 114 Hypovolemia 82, 106, 107 Hypoxemia 6, 88, 103

F Facial motor response 6 Fat embolization 104

G Gag reflex 6 Ganciclovir 56 Gas exchange 95, 105, 134-138 Gender 53, 97 Genetic matching 155 Gluconate 65, 66, 68, 72 Glutathione 66, 69, 135, 136 Glycogen storage disease 55 Grieving 14, 18-20, 151, 157

H Harvard criteria 18 Hemophilia 51, 55 Hepatic artery 114, 116, 117, 119, 120, 122, 124, 125 Hepatitis B 48, 51, 52, 99 Hepatitis B surface antibody 51 Hepatitis C 52, 56, 99 Hepatitis C antibody 52 HIV infection 51 HLA typing 48, 49, 89, 90, 155 Hormonal therapy 40, 42-44 Hospital stay 58, 81, 101 Hydroxyethyl starch (HES) 66, 68, 69, 135, 136 Hyperamylasemia 90 Hyperglycemia 57, 83, 84, 86, 89, 90

I Idiopathic pulmonary fibrosis 98 Impermeant molecules 68 Insulin 32, 38-40, 43, 55, 60, 66, 81, 84, 86, 89, 90, 141 Intestinal transplantation 59, 91 Intra-aortic balloon counterpulsation (IABP) 85 Intravenous fluid management 106 Intubation 55, 104 Ischemia-reperfusion 142

K Kayexalate 86 Kidney procurement 120, 121 Kimmelsteil-Wilson nephropathy 57

L Lactobionate 65, 66, 68, 135, 136, 139 Lazarus sign 6 Levophed 84, 85 Liver biopsy 54 Liver procurement 60, 114, 115, 120-124 Liver transplantation 48, 49, 54, 55, 73, 80, 165 LPD (low potassium dextran) 135-136 Lung mechanics 105

Index

Malignancy 48, 51, 95, 100, 102, 115 Mannitol 65, 68, 83, 91 Marginal donor 31, 47, 58-60, 91, 128 Marshall’s hypertonic citrate 68-70 Medical examiner (ME) 152, 153 MEGX test 57 Meningitis 100 Myocardial injury 88, 102, 103 Myocyte necrosis 35, 36

Precipitate 31, 44, 87, 101 Preservation solution 65, 68-70, 73, 114, 130, 131, 134-136, 140, 156 Presumed donation 160, 162 Primary nonfunction (PNF) 73 Prostaglandin 90, 132, 135, 136, 138 Prostaglandin E1 (Prostin VR) 132, 136 Pulmonary artery flush 137 Pulmonary contusion 99, 104, 105, 132 Pupillary response to light 5

N Na+-K+ ATPase 68, 140 Nasogastric tube 106, 123, 125, 133 National Donor Family Council 27 Neosynephrine 84, 85 Neurogenic pulmonary edema 34, 88, 104 Nitroprusside 82 Non-heart-beating donor 48, 59, 60 Norepinephrine (Levophed) 84 Nutritional support 89, 91

O Obese donors 54 Oculo-vestibular reflex (caloric response) 5 Oculocephalic reflex (Doll’s Eye Phenomenon) 6 Organ allocation 53, 153-155 Oxalosis 55 Oxygen free radicals 35, 44, 68, 140

P Packed red cells 87 Pall filter 71 Pancreas procurement 122, 124 Pancreas transplantation 53, 55, 56, 60 Pancreatitis 55, 81, 90 Phenylephrine (Neosynephrine) 85 Pitressin 83, 107 Platelets 87 Positive end expiratory pressure (PEEP) 88, 105, 108, 155

R Race 16, 20, 25, 95, 98 Radiocontrast dyes 91 Radionuclide angiography 8, 9 Raffinose 66, 68, 135, 136, 139 Recovery services coordinator (RSC) 147 Regitine 85 Religious considerations 17 Renal vascular anomalies 120 Ringer’s lactate 84 Routine salvaging 162

S Sarcoidosis 55 SCARSO 148 Sepsis 56, 58, 99, 103 Sex 16, 53, 54, 95, 98, 102 Size 5, 52-54, 63, 95, 97-99, 103, 105, 115, 154, 155, 161 Small bowel procurement 113, 124, 126 Smoke inhalation 101 Steatosis 54, 115 Swan-Ganz pulmonary artery catheter 81 Systemic bacterial infection 56, 104

Index

M

173

Index

174

Hemostasis and Thrombosis

T

V

Thyroxine 38, 107, 129, 141 Transaminases 57 Transcranial doppler 9 Triiodothyronine 38, 39, 43, 44, 141

Vasopressors 58, 82, 83, 85, 106, 155 Vegetative state 166 Ventriculo-atrial shunt 51 Ventriculo-peritoneal shunt 51

U

W

Uniform Anatomical Gift Act (UAGA) 3 United Network for Organ Sharing (UNOS) 153 Unrelated kidney transplantation 49, 74 Urine output 57, 83, 106, 107, 114 Ureteric anomalies 120 UW gluconate solution 65 UW solution 60, 65, 68-71, 74, 120-125, 135, 140

Warm ischemia 60, 67, 137 Whole-brain-death 165, 166

X Xanthine oxidase 44, 69, 135 Xenon computerized tomography (XeCT) 9