Modern Surgical Care: Physiologic Foundations and Clinical Applications. Volume 1

medwedi.ru MODERN SURGICAL CARE Third Edition Volume 1 medwedi.ru Associate Editors Barbara L. Bass, M.D. Professo...

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MODERN SURGICAL CARE Third Edition Volume 1

medwedi.ru

Associate Editors

Barbara L. Bass, M.D. Professor of Surgery Department of Surgery Weill Medical College of Cornell University New York, New York, USA Carolyn and John F. Bookout Chair Department of Surgery The Methodist Hospital Houston, Texas, USA

Peter J. Fabri, M.D. Professor of Surgery Associate Dean for Graduate Medical Education University of South Florida College of Medicine Tampa, Florida, USA

Carl E. Haisch, M.D. Professor of Surgery Department of Surgery East Carolina University Brody School of Medicine Director of Surgical Immunology and Transplantation Attending Surgeon Pitt County Memorial Hospital Greenville, North Carolina, USA

David W. Mercer, M.D. Professor and Vice Chairman of Surgery Department of Surgery The University of Texas Health Science Center–Houston Chief of Surgery Lyndon Baines Johnson General Hospital Houston, Texas, USA

Ronald C. Merrell, M.D. Professor of Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Richmond, Virginia, USA

Stuart I. Myers, M.D. Professor of Surgery Division of Vascular Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Attending Surgeon Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

MODERN SURGICAL CARE Physiologic Foundations and Clinical Applications

Third Edition Volume 1

editor-in-chief

Thomas A. Miller, M.D. Ammons Professor of Surgery Division of General Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Chief of Surgery Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

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Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2869-6 (Hardcover) International Standard Book Number-13: 978-0-8247-2869-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Dedication

DEDICATION

To all trainees in surgery, medical students rotating on surgical services, and surgeons in practice who recognize the importance of understanding the physiologic underpinnings of treating surgical disease in order to ensure optimal patient care.

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Preface

When the first edition of this book was published in 1988 under the title Physiologic Basis of Modern Surgical Care, its goal was to bridge the gap that commonly exists between basic science information regarding human disease and the ability to apply this knowledge to everyday clinical care. In teaching medical students rotating on surgery, as well as residents embarking on surgical careers, many of my colleagues and I, serving on medical school faculties across the country, were all too acutely aware that management of surgical disorders by these trainees was frequently based on memorized schemes or protocols rather than a thorough understanding of the pathophysiology underlying a particular disease. To address this issue, we published the initial edition with the intent to approach surgical disease as a derangement in normal physiology and that the best way to diagnose and treat it was to understand thoroughly this deviation from normal. We were very gratified with the acceptance of the book by the surgical community and its adoption by many program directors as essential reading to prepare residents for various examinations, such as the annual in-service training examination in surgery and the board certification examination following completion of surgical training. We also received many positive comments from established surgeons regarding its usefulness in preparing for recertification exams. Because of the wide acceptance of the first edition as an important vehicle to train house officers in the physiologic underpinnings of surgical disease, a second edition was published in 1998 under the title Modern Surgical Care: Physiologic Foundations and Clinical Applications. The title change was made to more adequately reflect the linkage between physiology and clinical care. We have been especially pleased with the continuing acceptance of the second edition as an important educational tool and were extremely grateful when Informa Healthcare (formerly Marcel Dekker, Inc.) asked us to produce a third edition. In addition to being thoroughly updated, the third edition reflects the capable assistance and counsel of a group of associate editors who have contributed greatly in streamlining chapters, minimizing repetitive material, adding new chapters to include cutting-edge material, and selecting a more diverse and mainstream authorship who are the current leaders in their fields. Their recommendations were responsible for the inclusion of 91 new authors

not involved in the previous editions. These associate editors include Drs. Barbara Bass, Jeff Fabri, Carl Haisch, Dave Mercer, Ron Merrell, and Stuart Myers. To each of them, I offer my utmost thanks and gratitude. As reflected in the previous editions, the needs of the general surgeon continue to be emphasized in the present edition. Further, the goal of this third edition remains the same, namely to approach surgical disease as a derangement in normal physiology, which needs to be corrected to as near normal as possible to effectively manage and treat the underlying disorder. This book is divided into nine parts, with the first part devoted to information pertinent to the body as a whole, and the eight remaining sections focused on specific organ systems or themes. Diseases affecting the reproductive organs, disorders of the head and neck (other than the thyroid and parathyroid glands), and disorders of the musculoskeletal system are not specifically dealt with because the current practice of surgery only rarely involves these disciplines. Finally, this book is not meant to replace standard textbooks of surgery and, accordingly, is not a comprehensive discussion of all surgical diseases. For less common types of surgical problems or those not regularly encountered in the practice of general surgery, such books should be consulted. I would personally like to offer my sincere appreciation to the folks at Informa Healthcare who have worked with us during the production of the book. I have found everyone with whom I have collaborated to be extremely professional, cordial, and helpful in making sure that this third edition meets the goals that we have set. I would especially like to recognize two people with whom I have had a very close working relationship. The first is Joe Stubenrauch who has been the project editor. He has more than met my expectations and has demonstrated unusual adaptability when I thought something should be done for which initially he and I had differing viewpoints. The second individual is Joanne Jay who was responsible for the final editing of each chapter and preparing the galley proofs. Her attention to detail has been exemplary. I have been very pleased with the outstanding quality of her editorial review. To both of these individuals I say ‘‘Thank you!’’ They made the process of finalizing this book most pleasurable.

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Thomas A. Miller, M.D.

Contents

6. Surgical Infection: Principles of Management and Antibiotic Usage / 127

Preface / v Contributors / xiii

VOLUME 1 PART ONE: GENERAL CONSIDERATIONS IN THE MANAGEMENT OF SURGICAL PATIENTS

1. Metabolic Response to Starvation, Stress, and Sepsis / 1 Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller Introduction / 1 Body Composition / 1 Normal Metabolism: Intermediary Metabolism and Substrate Interactions / 8 Neuroendocrine Regulatory Mechanisms / 15 Metabolic Response in Starvation, Injury, and Sepsis / 21 Cytokines / 26 Summary / 28 References / 28

2. Pathophysiology of Fluid and Electrolyte Disorders / 33 Peter J. Fabri and Mark Bloomston Introduction / 33 Maintenance of the Internal Milieu / 33 Homeostatic Control Mechanisms / 35 Pathophysiology and Treatment of Specific Electrolyte and Acid/Base Abnormalities / 38 Principles of Fluid Therapy / 45 Summary / 46 References / 46

3. Surgical Nutrition / 49 Rosemary A. Kozar, Margaret M. McQuiggan, and Frederick A. Moore Introduction / 49 Metabolic Response to Stress vs. Starvation / 49 Rationale for Nutritional Support / 50 Initiation of Nutritional Support / 50 Enteral Nutrition / 53 Total Parenteral Nutrition / 56 Disease-Specific Nutrition / 60 Summary / 61 References / 61

Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch Introduction / 65 An Overview of the Immune System / 65 The Immunocompromised Surgical Patient / 76 Summary / 86 References / 87

Yuan Zhai and Rafik M. Ghobrial Introduction / 91 Allograft Rejection / 91 Immunosuppressive Therapy / 112 Clinical Transplant Outcomes / 120 Summary / 124 References / 124

7. Hemostasis and Thrombosis in the Surgical Patient / 157 Stuart I. Myers, Mark R. Jackson, Michael Sobel, and G. Patrick Clagett Introduction / 157 Mechanisms of Hemostasis / 157 Regulation of Hemostasis / 159 Inherited Disorders of Coagulation / 161 Inherited Qualitative Platelet Disorders / 163 Acquired Disorders of Hemostasis / 164 Acquired Disorders of Platelet Function / 164 Bleeding in the Surgical Patient / 165 Congenital Disorders of Hypercoagulability / 167 Acquired Hypercoagulable Disorders / 168 Antithrombotic Therapy / 170 Therapeutic Agents / 171 Summary / 174 References / 174

8. Pathophysiology of Shock / 181

4. The Immune System and the Immunocompromised Patient / 65

5. Physiologic Basis of Transplantation / 91

Christina Paylan and Rodney Durham Introduction / 127 Pathophysiology of Surgical Infections / 127 Systemic Inflammatory Response / 128 Overall Approach to Sepsis / 129 Definitions of Surgical Infections / 130 Evaluation of Suspected Infection in the Surgical Patient / 131 Role of the Laboratory in Infection Diagnosis / 131 Types of Postoperative Infections / 133 Pathogens Responsible for Surgical Infection / 140 Antibiotics in the Management of Infection / 141 Clinical Use of Antibiotics / 148 Summary / 153 References / 153

Ajai K. Malhotra Introduction / 181 Definition of Shock / 181 Cardiovascular Physiology and Types of Shock / 182 Pathophysiologic Response to Shock / 184 Management Considerations / 190 The Future / 193 Summary / 193 References / 194

9. Neoplastic Disease: Pathophysiology and Rationale for Treatment / 197 Gregory Kennedy and John E. Niederhuber Introduction / 197 Basic Concepts of Cancer Biology / 197 Biologic Rationale for Therapy / 202 Summary / 208 References / 208

10. The Physiology of Anesthesia and Pain / 213 Charles Williams and Denise Lester Introduction / 213 The Physiology of Anesthesia / 213 Preoperative Decisions / 213

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Contents Regional Anesthesia / 214 General Anesthesia / 215 Conscious Sedation / 217 Anesthetic Implications of Selected Disease States / 217 Anesthesia Emergencies / 218 The Physiology of Pain and Analgesia / 219 The Physiology of Nociception / 219 Pain Measurement / 221 The Management of Acute Postoperative Pain / 221 Summary / 224 References / 224

15. Gastric Physiology and Acid-Peptic Disorders / 333 Kenneth S. Helmer and David W. Mercer Introduction / 333 Normal Physiology / 333 Gastric Physiology / 338 Abnormal Physiology / 346 Summary / 362 References / 362

& Small and Large Intestine

16. Physiology of Digestion and Absorption / 369 11. Sepsis and the Syndrome of Multiple Organ Failure / 227 Lena M. Napolitano Introduction / 227 Sepsis: Definitions / 227 Incidence and Outcomes of Sepsis / 229 Pathophysiology of Sepsis / 230 Genetic Variability in Sepsis / 232 Treatment Strategies in Sepsis / 234 Multiple Organ Dysfunction and Failure: Definitions / 244 Incidence and Outcome of MODS / 244 Pathophysiology of MODS / 246 Potential Treatment Strategies for Reduction of MODS / 246 Summary / 247 References / 248

12. Application of Cellular and Molecular Biology in Modern Surgical Practice / 253 Huiping Zhou and Jian-Ying Wang Introduction / 253 Basic Genetic Mechanisms / 253 Cellular and Molecular Biological Technology: From Recombinant DNA to Transgenic Animals / 259 The Molecular Organization of the Cells / 263 Novel Treatment Strategies in Modern Surgical Care / 267 Summary / 269 References / 269

13. Physiologic Principles in Preparing Patients for Surgery / 271 Henry J. Schiller, Kara C. Kort, and Lelan F. Sillin Introduction / 271 General Aspects of Preoperative Preparation / 271 Specific Aspects of Preoperative Preparation / 273 Risks of Hematologic Disease / 286 Prophylaxis Against Thromboembolism / 289 HIV Infection and AIDS / 289 Summary / 290 References / 290

Bobby S. Glickman and Jon S. Thompson Introduction / 369 Fluid and Electrolyte Secretion and Absorption / 369 Overview of Digestion / 371 Protein Absorption / 372 Carbohydrate Absorption / 374 Fat Absorption / 376 Vitamins and Minerals / 377 Regulation / 378 Diarrhea and Malabsorption / 378 Summary / 379 References / 379

17. Circulation and Vascular Disorders of the Splanchnic Vascular Bed / 381 Stuart I. Myers and Patricia A. Lowry Introduction / 381 Normal Anatomy and Collateral Circulation / 381 Physiology of Intestinal Circulation / 384 Reperfusion Injury of the Intestine / 386 Clinical Evaluation of Intestinal Blood Flow / 392 Radiologic Evaluation of Patients with Acute Mesenteric Ischemia / 393 Intraoperative Assessment of Intestinal Viability / 396 Diseases That Affect the Visceral Vessels / 397 Miscellaneous Diseases That Affect the Viscera / 403 Summary / 406 References / 408

18. Inflammatory Disorders of the Small Bowel and Colon / 415 Douglas J. Turner and Barbara L. Bass Introduction / 415 Inflammatory Bowel Disease / 415 Appendicitis / 419 Meckel’s Diverticulum / 421 Jejunoileal Diverticuli / 421 Colonic Diverticular Disease / 422 Clostridium difficile Colitis / 423 Radiation Enteritis / 423 Summary / 424 References / 424

PART TWO: THE ALIMENTARY TRACT & Liver, Biliary Tract, Pancreas, and Spleen & Esophagus and Stomach

14. Physiologic Dysfunction of the Esophagus / 295 Nahid Hamoui and Peter F. Crookes Introduction / 295 Anatomy and Physiology / 295 Symptoms of Esophageal Disease / 296 Physical Examination / 297 Investigations / 297 Esophageal Diseases / 304 Esophageal Motor Disorders / 316 Esophageal Emergencies / 321 Esophageal Tumors / 323 Summary / 328 References / 328

19. Hepatic Physiology / 427 Jose M. Prince and Timothy R. Billiar Introduction / 427 Embryology / 427 Histology / 428 Anatomy / 429 Hepatic Functions / 431 Metabolic Homeostasis / 432 Pathophysiology / 435 Diagnostic Testing / 436 Regeneration / 438 Future / 438 Summary / 438 References / 439

Contents

20. Portal Hypertension / 443

26. The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain / 539

Alexander S. Rosemurgy and Emmanuel E. Zervos Introduction / 443 Anatomy / 443 Variceal Hemorrhage / 443 Summary / 452 References / 452

21. Calculous Disease of the Gallbladder and Common Bile Duct / 455 Lillian S. Kao and Terrence H. Liu Introduction / 455 Epidemiology / 455 Bile Physiology / 455 Pathogenesis of Gallstones / 459 Clinical Manifestations of Gallstone Disease / 461 Treatment / 463 Summary / 465 References / 465

22. Normal Exocrine Function and Inflammatory Diseases of the Pancreas / 469 David J. Bentrem and Raymond J. Joehl Introduction / 469 Embryology / 469 Gross Anatomy / 469 Acinus / 470 Pancreatic Exocrine Function / 470 Control of Pancreatic Secretion / 471 Acute Pancreatitis / 471 Treatments / 475 Summary / 479 References / 479

23. The Jaundiced Patient / 483 Attila Nakeeb and Henry A. Pitt Introduction / 483 Bilirubin Metabolism / 483 Classification of Jaundice / 483 Pathophysiology of Jaundice / 484 Diagnostic Approach / 487 Patient Management / 492 Benign Disease / 495 Malignant Disease / 497 Summary / 499 References / 499

24. The Spleen / 503 Haytham M. A. Kaafarani and Kamal M. F. Itani Introduction / 503 Gross Anatomy / 503 Embryology / 503 Histology / 504 Physiology and Function of the Spleen / 505 Hematologic Disorders and Splenectomy / 507 Malignancies and Splenectomy / 511 Miscellaneous Conditions / 513 Splenic Trauma / 515 Splenectomy / 520 References / 522

Kathryn A. Richardson, Ryan M. Wolfort, and Richard H. Turnage Introduction / 539 Types of Abdominal Pain / 539 Anatomy and Physiology of Abdominal Pain / 539 Pathophysiologic Stimuli for Somatic and Visceral Nociceptors / 541 Evaluation of Patients with Acute Abdominal Pain / 541 Prototypical Examples of Acute Abdominal Pain / 547 Abdominal Pain in Special Patient Groups / 550 Summary / 553 References / 553

27. Neoplastic Disorders of the Gastrointestinal Tract / 555 Carlos A. Murillo, Kenneth J. Woodside, Lindsey N. Jackson, and B. Mark Evers Introduction / 555 Cellular and Molecular Biology of GI Cancers / 555 Neoplastic Diseases of the Stomach, Small Bowel, and Colorectum / 562 Summary / 579 References / 580

28. Mechanical Disorders of the Stomach, Duodenum, and Intestine / 587 Sean P. Harbison and Daniel T. Dempsey Introduction / 587 Mechanical Disorders of the Stomach and Duodenum / 587 Mechanical Disorders of the Small Bowel / 590 Mechanical Disorders of the Colon / 595 Summary / 597 References / 597

29. Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor / 599 Janette Gaw and Walter E. Longo Introduction / 599 Anorectal Anatomy / 599 Normal Physiology of the Anus and Rectum / 603 Colonic Function and Anorectal Physiology Testing / 604 Disordered Anorectal Physiology / 605 Neoplasms of the Anal Canal and Anal Margin / 611 Summary / 613 References / 613

30. Derangements in Gastrointestinal Function Secondary to Previous Surgery / 617 Jeannie F. Savas, Thomas A. Miller, and David W. Mercer Introduction / 617 Gastric Dysfunction / 617 Intestinal Dysfunction / 625 Summary / 628 References / 629 Index / I-1

VOLUME 2 PART THREE: THE CARDIOTHORACIC SYSTEM

& Other Conditions

& Lung

25. Gastrointestinal Hemorrhage / 527

31. Pathobiology of Surgically Relevant Pulmonary Disease / 631

Kevin Bruen and Leigh Neumayer Introduction / 527 Initial Evaluation and Management / 527 Upper Intestinal Bleeding / 528 Lower Intestinal Bleeding / 532 Occult Bleeding / 535 Summary / 536 References / 536

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Daniel G. Tang, Jonathan Kiev, and Neri M. Cohen Introduction / 631 Anatomy and Physiology / 631 Perioperative Pulmonary Assessment / 636 Common Pulmonary Disorders / 637 Neoplastic Conditions / 643 Lung Transplantation / 645

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Contents Summary / 646 References / 647

& Heart

32. Normal Cardiac Function / 649 Andrew C. Fiore and Andrew S. Wechsler Introduction / 649 Molecular Mechanisms in Contraction and Relaxation / 649 Mechanics of Isolated Muscle / 651 Function of the Intact Heart / 653 Heart Failure / 660 Summary / 661 References / 661

33. Heart Failure and Resuscitation / 663 Heinrich Taegtmeyer Introduction / 663 Heart Failure / 663 Resuscitation / 671 Summary / 673 References / 674

34. Mechanical Support for the Failing Heart: Current Physiologic Concepts of Management / 677 Sina L. Moainie and Bartley P. Griffith Introduction / 677 Cardiac Support in End-Stage Heart Failure / 677 Summary / 683 References / 683

35. Congenital Heart Lesions / 685 Ralph S. Mosca and Edward L. Bove Introduction / 685 Adjustments in the Circulation After Birth / 685 Congestive Heart Failure / 685 Obstructive Lesions / 686 Left-to-Right Shunts / 689 Right-to-Left Shunts / 691 Inadequate Mixing / 693 Hypoplastic Left Heart Syndrome / 695 Summary / 695 References / 696 Further Reading / 697

38. Urinary Tract Obstruction / 767 J. Robert Ramey and Deborah T. Glassman Introduction / 767 The Upper Urinary Tract / 767 The Lower Urinary Tract / 770 Summary / 772 References / 772

39. Neurogenic Lower Urinary Tract Dysfunction / 775 Hari Siva Gurunadha Rao Tunuguntla and Unyime O. Nseyo Introduction / 775 Anatomy and Physiology of Continence and Micturition / 775 Pathophysiology of LUT Dysfunction / 780 Definition of Common Terms in Neurogenic Voiding Dysfunction / 781 Specific Neurologic Lesions / 781 Classification of NLUTD / 783 Diagnosis of NLUTD / 783 Management of NLUTD / 787 Device Therapy / 791 Urinary Diversion / 792 Quality of Life / 792 Follow-Up / 792 Summary / 793 References / 793

PART FIVE: THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

40. Pathophysiology and Management of Head Injury / 795 Egon M. R. Doppenberg, M. Ross Bullock, and William C. Broaddus Introduction / 795 Pathophysiology / 795 General Considerations in the Care of the Head-Injured Patient / 798 Specific Management of the Head-Injured Patient / 799 Monitoring the Injured Brain / 802 Summary / 802 References / 802

41. Spinal Cord Injury / 805 36. Acquired Cardiac Disorders / 699 Dipin Gupta, Andrew C. Fiore, and Glenn J. R. Whitman Introduction / 699 Ischemic Heart Disease / 699 Valvular Heart Disease / 709 Heart Failure / 715 Cardiac Dysrhythmias / 716 Pericardial Disease / 719 Cardiac Tumors / 721 Summary / 721 References / 722

Kangmin Lee and R. Scott Graham Introduction / 805 Epidemiology / 805 Pathophysiology / 805 Evaluation / 807 Classic Injury Patterns / 807 Imaging / 812 Management of Acute SCI / 812 Rehabilitation / 814 Advanced Therapies / 814 Restoration of Function / 814 Summary / 814 References / 814

PART FOUR: THE URINARY SYSTEM

37. Urine Formation: From Normal Physiology to Florid Kidney Failure / 725 Akinsan Dosekun, John R. Foringer, and Bruce C. Kone Introduction / 725 Overview of Renal Physiology / 725 Acute Kidney Failure / 735 Chronic Kidney Disease / 740 Renal Transplantation / 755 Summary and Conclusions / 761 References / 761

42. Injuries to Peripheral Nerves / 817 Irvine G. McQuarrie, Thomas C. Chelimsky, and Karen Bitzer Introduction / 817 Anatomy and Physiology / 817 Pathology / 820 Assessment of the Deficit / 821 Treatment Approach / 824 Rehabilitation After Neurorrhaphy / 826 Summary / 828 References / 828

Contents

PART SIX: THE PERIPHERAL VASCULAR SYSTEM

PART SEVEN: THE ENDOCRINE SYSTEM

43. Physiology of Arterial, Venous, and Lymphatic Flow / 831

49. Calcium and Phosphorus Metabolism and the Parathyroid Gland / 927

Dennis F. Bandyk and Paul A. Armstrong Introduction / 831 Peripheral Arterial System / 831 The Venous System / 841 Lymphatic System / 846 Summary / 847 References / 848 Further Readings / 848

Fiemu E. Nwariaku Introduction / 927 Calcium Homeostasis / 927 Hormonal Regulation of Extracellular Calcium Concentration / 928 Disorders of Calcium Metabolism / 931 Phosphate Metabolism / 937 The Parathyroid Glands / 938 Multiple Endocrine Neoplasia Syndromes / 944 Summary / 945 References / 945

44. Aorta and Arterial Disease of the Lower Extremity / 849 Christopher K. Zarins and Sheila M. Coogan Introduction / 849 Atherosclerosis / 849 Pathophysiologic Processes Affecting the Aorta and Lower Extremity Arteries / 851 Arterial Occlusive Disease of the Aorta and Peripheral Arteries / 852 Evaluation of Peripheral Vascular Occlusive Disease / 854 Treatment of Peripheral Vascular Occlusive Disease / 856 Aneurysmal Disease of the Aorta / 862 Peripheral Artery Aneurysms / 865 Complications of Vascular Procedures / 865 Summary / 866 References / 866

45. Cerebrovascular Disease and Upper-Extremity Vascular Disease / 869 Bruce L. Gewertz and James E. McKinsey Introduction / 869 Cerebral Blood Flow / 869 Clinical Presentation of Cerebrovascular Disease / 871 Types of Cerebrovascular Disease / 872 Upper-Extremity Vascular Disease / 876 Summary / 880 References / 880

46. Venous and Lymphatic Abnormalities of the Limbs / 883 Jose R. Parra and Julie A. Freischlag Introduction / 883 Anatomy / 883 Venous Physiology / 884 Venous Disorders of the Lower Extremity / 884 Venous Disorders of the Upper Extremity / 891 Lymphedema / 892 Summary / 894 References / 894

50. Pituitary Dysfunction / 947 Henry Ty and Kathryn Holloway Introduction / 947 Anatomy of the Pituitary Gland / 947 Physiology of the Pituitary Gland / 948 Hormones of the Adenohypophysis / 948 Hormones of the Neurohypophysis / 950 Regulation of Hormone Secretion / 950 Hypopituitarism / 952 Sellar and Parasellar Lesions / 954 Syndrome of Inappropriate Secretion of ADH / 960 Summary / 961 References / 961

51. Adrenal Glands / 965 Maria A. Kouvaraki, Douglas B. Evans, Ana O. Hoff, and Jeffrey E. Lee Introduction / 965 Embryology, Anatomy, and Histology / 965 Physiology / 966 Neoplasms of the Adrenal Gland / 968 Controversies in the Surgical Management of Adrenal Disease / 982 Adrenal Insufficiency / 983 References / 984

52. The Thyroid Gland / 989 Ronald C. Merrell and Lucian Panait Introduction / 989 Thyroid Anatomy / 989 Physiology / 990 Assessment of Patients with Thyroid Disease / 993 Sick Euthyroid Syndrome / 994 Hyperthyroidism (Thyrotoxicosis) / 995 Hypothyroidism / 997 Thyroiditis / 997 Thyroid Nodule / 998 Thyroid Cancer / 999 Summary / 1003 References / 1003

47. Diseases of the Thoracic Aorta / 897 Michael P. Macris and O. Howard Frazier Introduction / 897 Intrinsic Thoracic Aortic Disease / 897 Traumatic Pseudoaneurysms / 902 Summary / 903 References / 904

53. Endocrine Pancreas / 1005

48. Secondary Hypertension: Pathophysiology and Operative Treatment / 907 James C. Stanley and Gerard M. Doherty Introduction / 907 Adrenal Disease and Hypertension / 907 Renal Artery Occlusive Disease and Hypertension / 912 Summary / 922 References / 922

Ronald C. Merrell, Giacomo P. Basadonna, and Cristiana Rastellini Introduction / 1005 Anatomy and Embryology of the Islets / 1005 Physiology of the Islets / 1007 Islets in Health and Disease / 1010 Endocrine Tumors of the Pancreas / 1016 Summary / 1020 References / 1021

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Contents

54. Multiple Endocrine Neoplasia: Types 1 and 2 / 1025 Frank J. Quayle and Jeffrey F. Moley Introduction / 1025 Multiple Endocrine Neoplasia Type 1 / 1025 Multiple Endocrine Neoplasia Type 2 / 1028 Summary / 1032 References / 1032

Metabolic Alterations / 1091 Organ System Alterations / 1093 Resistance to Infection / 1095 Pulmonary Consequences of Thermal Injury / 1096 Physiologic Considerations in Managing the Burn Patient / 1097 Summary / 1101 References / 1102

PART EIGHT: THE INTEGUMENT AND BODY WALL

55. The Biology of Wound Healing / 1035 Dorne R. Yager and Ashley E. Ducale Introduction / 1035 Phases of Healing / 1035 Other Aspects of Repair / 1038 Wound-Healing Pathologies / 1038 Wound Management / 1040 Summary / 1044 References / 1044

56. Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States / 1047 Rakhshanda Layeeque and V. Suzanne Klimberg Introduction / 1047 Physiology of Development / 1047 Pregnancy / 1050 Physiology of Lactation / 1051 Lactogenesis / 1052 Breast-Feeding / 1053 Physiology of Involution / 1053 Clinical Approach to Breast Pathology / 1054 Work-Up of Common Clinical Symptoms / 1055 Treatment of Benign Breast Pathology / 1057 Treatment of Malignant Breast Pathology / 1058 Summary / 1062 References / 1062

57. Hernias of the Abdominal Wall and Its Contents / 1067 Philip E. Donahue Introduction / 1067 Concepts and Definitions / 1067 Pathophysiology of Hernia Development / 1068 Types of Abdominal Wall Hernias / 1070 Summary / 1082 References / 1083

58. Pathophysiology of Thermal Injury / 1085 Ronald M. Barton, Evan R. Kokoska, David J. Wainwright, and Donald H. Parks Introduction / 1085 The Burn Wound / 1085

PART NINE: SPECIAL PHYSIOLOGIC CONSIDERATIONS

59. Physiologic Problems in the Pediatric Surgical Patient / 1107 Daniel J. Ostlie, Shawn D. St. Peter, Sheilendra S. Mehta, and George K. Gittes Introduction / 1107 Physiologic Considerations / 1107 Glucose, Fluid, and Electrolyte Management / 1107 Thermoregulation / 1109 Pulmonary and Cardiac Transitional Physiology / 1109 Nutritional Support / 1110 Specific Pediatric Surgical Conditions / 1111 Summary / 1123 References / 1124

60. Physiologic Considerations in the Elderly Surgical Patient / 1129 Ronnie Ann Rosenthal and Melissa F. Perkal Introduction / 1129 Physiology and Pathology of Aging / 1129 Preoperative Evaluation, Risk Assessment, and Outcome / 1141 Summary / 1144 References / 1145

61. Surgery for Morbid Obesity / 1149 Eric J. DeMaria, Ramzi Alami, and Robert E. Brolin Introduction / 1149 Etiology and Pathophysiology / 1149 Risks and Complications of Severe Obesity / 1150 Treatment of Severe Obesity / 1151 Patient Management / 1156 Results of Surgical Treatment / 1158 Summary / 1161 References / 1161 Index / I-1

Contributors

Ramzi Alami, MD Fellow in Advanced Laparoscopic Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A. Joseph F. Amaral, MD President and CEO, Rhode Island Hospital, Professor of Surgery, Brown University Medical School, Providence, Rhode Island, U.S.A. Paul A. Armstrong, DO Clinical Assistant Professor of Surgery, Department of Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Dennis F. Bandyk, MD Professor of Surgery, Director, Division of Vascular Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Ronald M. Barton, MD Associate Professor of Surgery Emeritus, Director of the Burn Center Emeritus, Division of Plastic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Giacomo P. Basadonna, MD Professor of Surgery, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Barbara L. Bass, MD Professor of Surgery, Department of Surgery, Weill Medical College of Cornell University, New York, New York; Carolyn and John F. Bookout Chair, Department of Surgery, The Methodist Hospital, Houston, Texas, U.S.A. David J. Bentrem, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A. Timothy R. Billiar, MD The George Vance Foster Professor and Chair, Department of Surgery, Presbyterian University Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Karen Bitzer, OTR/L, CHT Musculoskeletal Division Coordinator, Department of Rehabilitation Services, University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Mark Bloomston, MD Fellow in Surgical Oncology, Ohio State University Medical Center, Columbus, Ohio, U.S.A. Edward L. Bove, MD Helen and Marvin Kirsh Professor of Surgery, Professor and Section Head, Cardiac Surgery, Director, Pediatric Cardiac Surgery, University of Michigan, C. S. Mott Children’s Hospital, Ann Arbor, Michigan, U.S.A.

of Bariatric Surgery, University Medical Center at Princeton, Princeton, New Jersey, U.S.A. Kevin Bruen, MD Resident in Surgery, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A. M. Ross Bullock, MD, PhD Reynolds Professor, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A. Michael D. Caldwell, MD, PhD Director of Marshfield Medical Research and Education Foundation, Director of the Wound Healing Clinic, Marshfield, Wisconsin, U.S.A. Thomas C. Chelimsky, MD Associate Professor of Neurology, Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A. G. Patrick Clagett, MD Professor and Chairman, Division of Vascular and Endovascular Surgery, Department of Surgery; Ian and Bob Pickens Distinguished Professorship in Medical Science; Director, Center for Vascular Disease, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Neri M. Cohen, MD, PhD Chief, Division of Thoracic Surgery, Greater Baltimore Medical Center Health Care, Baltimore, Maryland, U.S.A. Sheila M. Coogan, MD Assistant Professor of Surgery, Vascular Surgery Service, Palo Alto Veterans Affairs Hospital, Stanford University School of Medicine, Palo Alto, California, U.S.A. Peter F. Crookes, MD Associate Professor of Surgery, Director of Bariatric Surgery Program, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A. Eric J. DeMaria, MD Professor and Chief, Endoscopy and Bariatric Surgery, Vice Chair, Network General Surgery, Chief, Duke General Surgery at Durham Regional Hospital, Duke University Medical Center, Durham, North Carolina, U.S.A. Daniel T. Dempsey, MD Professor and Chairman, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Gerard M. Doherty, MD Norman W. Thompson Professor of Surgery, Head, Section of General Surgery; Chief, Division of Endocrine Surgery, University of Michigan, Ann Arbor, Michigan, U.S.A.

William C. Broaddus, MD, PhD Hord Professor, Department of Neurosurgery, Virginia Commonwealth University Health System; Chief of Neurosurgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Philip E. Donahue, MD Professor of Surgery, Department of Surgery, University of Illinois Medical Center at Chicago; Chairman, Division of General Surgery, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, U.S.A.

Robert E. Brolin, MD Adjunct Professor of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, Director

Egon M. R. Doppenberg, MD Former Chief Resident, Department of Neurosurgery, Virginia Commonwealth University

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Contributors

Health System, Richmond, Virginia; presently in neurosurgery private practice in Chicago, Illinois, U.S.A. Akinsan Dosekun, MD Associate Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ashley E. Ducale, MPT, PhD Post-Doctoral Fellow, Department of Surgery, Wound Healing Laboratory, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Rodney Durham, MD Professor of Surgery, Department of Surgery, Division of Trauma and Critical Care, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A. Douglas B. Evans, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. B. Mark Evers, MD Professor and Robertson-Poth Distinguished Chair in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Peter J. Fabri, MD Professor of Surgery, Associate Dean for Graduate Medical Education, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Andrew C. Fiore, MD Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, St. Louis University School of Medicine; Chief of Cardiothoracic Surgery, Cardinal Glennon Children’s Hospital, St. Louis, Missouri, U.S.A. John R. Foringer, MD Assistant Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. O. Howard Frazier, MD Professor of Surgery, University of Texas Health Science Center at Houston; Professor of Surgery, Baylor College of Medicine; Chief of Cardiopulmonary Transplantation; Director of Cardiovascular Surgery Research, Texas Heart Institute, Houston, Texas, U.S.A. Julie A. Freischlag, MD William Stewart Halstead Professor of Surgery, Chair, Department of Surgery; Surgeon-in-Chief, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

Deborah T. Glassman, MD Clinical Assistant Professor, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Bobby S. Glickman, MD Instructor of Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A. R. Scott Graham, MD Associate Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Bartley P. Griffith, MD Professor of Surgery, Chief, Division of Cardiac Surgery, Director, Heart and Lung Transplantation, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Dipin Gupta, MD Fellow, Cardiovascular Surgery, New York University School of Medicine, New York, New York, U.S.A. Carl E. Haisch, MD Professor of Surgery, Department of Surgery, East Carolina University Brody School of Medicine, Director of Surgical Immunology and Transplantation; Attending Surgeon, Pitt County Memorial Hospital, Greenville, North Carolina, U.S.A. Nahid Hamoui, MD Assistant Professor of Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A. Sean P. Harbison, MD Associate Professor of Surgery, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Kenneth S. Helmer, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ana O. Hoff, MD Assistant Professor of Endocrinology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kathryn Holloway, MD Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System; Neurosurgical Director of the Southeast Parkinson’s Disease Research, Education and Clinical Care Center of Excellence (PADRECC) at Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Janette Gaw, MD Former Chief Resident, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; presently in colorectal surgery private practice, Fort Myers, Florida, U.S.A.

Kamal M. F. Itani, MD Professor of Surgery, Boston University Medical Center, Chief of Surgery, VA Boston Health Care System, Boston, Massachusetts, U.S.A.

Bruce L. Gewertz, MD Dallas B. Phemister Professor and Chair, Department of Surgery, The University of Chicago, Chicago, Illinois, U.S.A.

Lindsey N. Jackson, MD Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A.

Rafik M. Ghobrial, MD, PhD Professor of Surgery, Director, Liver, Pancreas and Small Bowel Transplantation, The DumontUCLA Transplant Center, David Geffen School of Medicine of the University of California at Los Angeles, Los Angeles, California, U.S.A.

Mark R. Jackson, MD Former Associate Professor of Surgery, Division of Vascular Surgery, University of Texas Southwestern Medical School, Dallas, Texas; presently in vascular surgery private practice, St. Francis Hospital, Greenville, South Carolina, U.S.A.

George K. Gittes, MD Surgeon-in-Chief, Children’s Hospital of Pittsburgh, Professor of Surgery, Division Chief, Pediatric Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Raymond J. Joehl, MD Professor of Surgery, Program Director General Surgery Residency, Department of Surgery, Loyola University Medical Center, Maywood; Chief, Surgical Service and Manager, Surgery Service Line, The Charles B. Puestow Surgical Service, Edward Hines, Jr VA Hospital, Hines, Illinois, U.S.A.

Contributors

xv

Haytham M. A. Kaafarani, MD Resident in Surgery, Department of Surgery, University of South Florida Medical School, Tampa, Florida, U.S.A.

Walter E. Longo, MD Professor and Vice Chairman, Chief, Division of General Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

Lillian S. Kao, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Patricia A. Lowry, MD Associate Professor of Radiology, Department of Radiology, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Gregory Kennedy, MD Chief Resident in Surgery, Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin, U.S.A.

Michael P. Macris, MD Medical Director, Cardiovascular Surgery, Memorial Hermann Northwest Hospital, Houston, Texas, U.S.A.

Jonathan Kiev, MD Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. V. Suzanne Klimberg, MD Professor of Surgery, Department of Surgery, Director, Breast Surgical Oncology, University of Arkansas for Medical Services and the Arkansas Cancer Research Center, Little Rock, Arkansas, U.S.A. Evan R. Kokoska, MD Assistant Professor of Surgery, Department of Surgery–Pediatric Surgery Service, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A. Bruce C. Kone, MD The James T. and Nancy B. Willerson Chair, Chairman, Department of Medicine, Professor of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Kara C. Kort, MD Assistant Professor of Surgery, Department of Surgery, State University of New York–Upstate Medical University, Syracuse, New York, U.S.A. Maria A. Kouvaraki, MD, PhD Fellow in Endocrine Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Rosemary A. Kozar, MD, PhD Associate Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Rakhshanda Layeeque, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology Section, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, U.S.A. Jeffrey E. Lee, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kangmin Lee Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A.

Ajai K. Malhotra, MD Assistant Professor of Surgery, Division of Trauma and Critical Care, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. James F. McKinsey, MD Associate Professor of Clinical Surgery and Site Chief of Vascular Surgery, Columbia University of New York Presbyterian Hospital System, New York, New York, U.S.A. Irvine G. McQuarrie, MD, PhD Associate Professor of Neurosurgery and Neuroscience, Department of Surgery, School of Medicine, Case Western Reserve University; Cleveland VA Medical Center, Cleveland, Ohio, U.S.A. Margaret M. McQuiggan MS, RD, CNSD Clinical Instructor, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Sheilendra S. Mehta Former Research Fellow in Pediatric Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. David W. Mercer, MD Professor of Surgery and Vice Chairman, Department of Surgery, The University of Texas Health Science Center–Houston; Chief of Surgery, Lyndon Baines Johnson General Hospital, Houston, Texas, U.S.A. Ronald C. Merrell, MD Professor of Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Thomas A. Miller, MD Ammons Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Chief of Surgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Sina L. Moainie, MD Resident in Cardiothoracic Surgery, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Jeffrey F. Moley, MD Professor of Surgery and Chief, Endocrine and Oncologic Surgery, Washington University School of Medicine; Associate Director, Alvin J. Siteman Cancer Center; Attending Surgeon, Barnes-Jewish Hospital, St. Louis, Missouri, U.S.A.

Denise Lester, MD Assistant Professor, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Director, Chronic Pain Clinic, Anesthesiology Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frederick A. Moore, MD Professor of Surgery and Vice Chairman, Department of Surgery, Medical Director, Trauma Services, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Terrence H. Liu, MD Associate Clinical Professor of Surgery, Residency Program Director, UCSF–East Bay Surgery Program, University of California San Francisco School of Medicine, East Bay Campus, Oakland, California, U.S.A.

Ralph S. Mosca, MD Associate Professor of Surgery, Columbia University College of Physicians and Surgeons; Associate Attending Surgeon, New York Presbyterian Hospital/Columbia University Medical Center, New York, New York, U.S.A.

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Contributors

Carlos A. Murillo, MD Resident Instructor, Department of Surgery, Texas Tech University Health Sciences Center, El Paso School of Medicine, El Paso, Texas, U.S.A.

Jose M. Prince, MD Surgical Resident, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Stuart I. Myers, MD Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frank J. Quayle, MD Resident in Surgery, Department of Surgery, Division of General Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Attila Nakeeb, MD Associate Professor of Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Lena M. Napolitano, MD Professor of Surgery, Director, Surgical Critical Care; Associate Chair, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, U.S.A. Leigh Neumayer, MD Professor of Surgery, Program Director, Utah Building Interdisciplinary Research Careers in Women’s Health, University of Utah Medical Center, Salt Lake City, Utah, U.S.A. John E. Niederhuber, MD Acting Director, National Cancer Institute, Bethesda, Maryland; Former Director, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, U.S.A. Unyime O. Nseyo, MD Adjunct Professor, Department of Urology, University of Florida School of Medicine; Chief, Urology Section, Malcom Randall VA Medical Center, Gainesville, Florida, U.S.A. Fiemu E. Nwariaku, MD Associate Professor and Vice Chairman, Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Daniel J. Ostlie, MD Associate Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Lucian Panait, MD Former Postdoctoral Research Fellow, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Donald H. Parks, MD Professor and Chief, Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Jose R. Parra, MD Former Assistant Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

J. Robert Ramey, MD Chief Resident in Urology, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Cristiana Rastellini, MD Associate Professor, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Lorita Rebellato, PhD Associate Professor of Pathology, Department of Pathology, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A. Kathryn A. Richardson, MD Assistant Professor, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Alexander S. Rosemurgy, MD Professor of Surgery and Medicine, Director, Division of General Surgery, Surgical Director, Tampa General Hospital Digestive Disorders Center, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Ronnie Ann Rosenthal, MS, MD Associate Professor of Surgery, Yale University School of Medicine, New Haven; Chief, Surgical Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, U.S.A. Shawn D. St. Peter, MD Assistant Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Jeannie F. Savas, MD Associate Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Henry J. Schiller, MD Associate Professor of Surgery, Department of Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota, U.S.A. Lelan F. Sillin, MD, MS(Ed) Professor of Surgery, Vice Chair for Educational Affairs, Department of Surgery, University of Rochester Medical Center, Rochester, New York, U.S.A.

Christina Paylan, MD Former Fellow in Trauma and Critical Care, Department of Surgery, University of South Florida College of Medicine, Tampa General Hospital, Regional Trauma Center, Tampa, Florida, U.S.A; presently in plastic surgery private practice, Tampa, Florida, U.S.A.

Michael Sobel, MD Professor and Vice Chairman, Department of Surgery, University of Washington; Professor and Chief, Puget Sound Veterans Affairs Health Care System, Seattle, Washington, U.S.A.

Melissa F. Perkal, MD Assistant Professor of Surgery, Director, Veterans Affairs Hospital Surgical Intensive Care Unit, Director, Surgical Preceptor Program, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

James C. Stanley, MD Handleman Professor of Surgery, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A.

Henry A. Pitt, MD Professor and Vice Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Heinrich Taegtmeyer, MD, DPhil Professor of Medicine, Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Contributors

xvii

Daniel G. Tang, MD Chief Resident in General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Glenn J. R. Whitman, MD Professor of Surgery, Division of Cardiothoracic Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Jon S. Thompson, MD Professor and Vice Chairman, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.

Charles Williams, MD Associate Professor, Vice Chair for Veterans Affairs, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Chief, Anesthesiology Service, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Hari Siva Gurunadha Rao Tunuguntla, MD, MBBS, MS (Surgery), MCh Resident, Department of Urology, University of Miami, Miller School of Medicine, Miami, Florida, U.S.A. Richard H. Turnage, MD Professor of Surgery and Chairman, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Douglas J. Turner, MD Assistant Professor of Surgery, Division of General Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Henry Ty, MD Former Chief Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia; presently in neurosurgery private practice, North Andover, Massachusetts, U.S.A.

Ryan M. Wolfort, MD Resident in Surgery, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Kenneth J. Woodside, MD Chief Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Dorne R. Yager, PhD Associate Professor of Surgery, Physiology and Biochemistry, Director, Wound Healing Laboratory, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

Kathryn M. Verbanac, PhD Professor of Surgery, Division of Transplantation, Department of Surgery, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A.

Christopher K. Zarins, MD Chidester Professor of Surgery, Chief, Division of Vascular Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A.

David J. Wainwright, MD Associate Professor of Surgery, Division of Plastic and Reconstructive Surgery; Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Emmanuel E. Zervos, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A.

Jian-Ying Wang, MD, PhD Professor of Surgery and Pathology, Associate Chair for Basic Research, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Andrew S. Wechsler, MD Stanley K. Brockman Professor and Chairman, Department of Cardiovascular Medicine and Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania, U.S.A.

Yuan Zhai, MD Assistant Professor of Surgery, Department of Surgery, Section of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, U.S.A. Huiping Zhou, PhD Assistant Professor, Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

medwedi.ru

PART ONE: General Considerations in the Management of Surgical Patients

1 Metabolic Response to Starvation, Stress, and Sepsis Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller

INTRODUCTION The metabolic response to stress, starvation, and sepsis should be viewed as a complex series of neuroendocrine reflexes resulting in an integrated attempt by the organism to mobilize energy substrates, to preserve oxygen and substrate delivery, and to maintain essential body functions (1). These alterations involve changes in the distribution and use of water, proteins, fats, and carbohydrates. As such, an understanding of normal body composition is essential to make discussion of the metabolic response meaningful.

BODY COMPOSITION Body composition has been defined by Moore (2) as ‘‘the study of the total mass and volume of body components in relation to body size, body configuration, age, sex, disease, and concentration changes.’’ It can be considered from several aspects, including tissue anatomy, chemical composition, and metabolic structure (Fig. 1), with the latter two being the most important with regard to energy stores and ‘‘intermediary metabolism.’’

Chemical Composition

for the relatively high boiling point of water, its relatively high freezing point, and its high specific heat (the energy required to raise the temperature of 1 g of a substance by 1 C). This latter property allows water to exert a major role in temperature regulation, because a large amount of heat is lost as water evaporates (perspiration) and a large amount of heat is required to raise the temperature of water. The extensive hydrogen bonding of water also makes it important in establishing the tertiary structure of proteins and other molecules. Total body water (TBW) is divisible into two components: intracellular water (ICW) and extracellular water (ECW). These two components are separated by cell membranes. Measurement of body fluid compartments uses dilution techniques, based on the concept that a substance that distributes itself equally and exclusively throughout a given compartment (e.g., TBW) can be used to determine the volume of that compartment. This procedure is done by injecting a known amount of the substance and measuring its concentration at steady state, as well as measuring the amount excreted during the period of time required to reach steady state. Thus: Volume ¼

All living organisms may be considered as complex and organized arrangements of fats, proteins, carbohydrates, minerals, and electrolytes in an aqueous environment. Although the percentage of each of these chemical groups varies among and within species, by far the largest component of all living organisms is water.

Amount injected Amount excreted Steady state concentration

Because the amount lost is usually negligible, the convention is to use: Volume ¼

Amount injected Steady state concentration

Water Water is an important substance involved in virtually all physiologic processes. Its physiochemical properties result largely from its electron structure. The hydrogen ions have a slightly positive charge, whereas the oxygen molecule, with its lone pair of electrons, has a negative charge. This difference allows extensive hydrogen bonding and a relatively high dipole moment (5) that causes the water molecules to orient themselves in an external electric field in such a way that they act as an electric buffer. When ionic substances are placed in water, a hydrational shell forms around the individual ions, reducing their electrochemical attraction and thus forming a solution (5). Water thus keeps electrolytes and other polar molecules in solution and allows them independent motion, which is critical to nutrient transport. The extensive hydrogen-bonding capacity of water molecules causes them to orient themselves in a highly organized structure similar to ice. This structure accounts

Numerous substances are available that allow measurement of various fluid compartments (Fig. 2). Generally, the TBW is the most accurately measured compartment. The TBW varies with age, sex, body build, physical activity, disease, and state of hydration. The TBW can be measured accurately using deuterium oxide or tritiated water. For a healthy man, TBW constitutes approximately 60% of total body weight, and for a healthy woman, it constitutes approximately 50% (Table 1). The differences in the proportion of TBW reflect the quantity of skeletal muscle and adipose tissue present in the two sexes. Adipose tissue contains little ICW, whereas skeletal muscle has one of the largest water contents of all tissues (Table 2). Women, with their larger adipose tissue stores and smaller skeletal muscle mass, have less TBW than men. Similarly, the TBW of young, lean athletes is greater than that of elderly, obese nonathletes. The TBW as a percentage of body weight decreases steadily with age (Table 1). Newborns have the highest

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2

Part One: General Considerations

Table 1 Distribution of Total Body Water in Infants, Children, and Adults 100

CHO Mineral

Other

Other nitrogen

Protein

Vital organs

Fat

Blood Nerve

Hydrogen Carbon

Fat

Skin Adipose

% 50

Extracellular water

Extracellular mass

Intracellular water

Body cell mass

Oxygen

Bone

Muscle

0 TISSUE

CHEMICAL

METABOLIC MOLECULAR

Figure 1 Body composition in adult man. Source: From Refs. 3, 4.

percentage, with 75% to 80% of body weight representing water. This percentage decreases during the first few months after birth to approximately 65% of the body weight, where it remains for the remainder of infancy and childhood. This reduction in TBW is primarily the result of reduction in ECW (Fig. 3). Until the age of 12, no difference in TBW is noted between boys and girls. With advancing age, TBW as a percentage of body weight decreases to a low of 52% and 47% in males and females, respectively (2). This results primarily from a decrease in

ECF

ICF

PlasRBC ma ISF

RBC Plasma

Cr54

T1824

131

I ECF

Inulin Sucrose

Mannitol S2O3

TBW (%) Age

Men

Women

0–1 day 1–10 days 1–3 mo 3–6 mo 6–12 mo 1–2 yr 2–3 yr 3–5 yr 5–10 yr 10–16 yr 17–39 yr 40–59 yr 60 þ yr

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 58.9 60.6 54.7 51.5

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 57.3 50.2 46.7 45.5

Abbreviation: TBW, total body water. Source: Adapted from Ref. 7.

ICW, because ECW remains unchanged (5). The size of the ECW space depends on the method used for determining it. Large molecules such as insulin, mannitol, or sucrose appear to underestimate the ECW compartment because of the slower diffusion of these larger molecules into noncellular spaces (5). An ECW space of 15% to 16% of body weight is usually reported with these methods (5). Assessment of the ECW with small molecules such as 35SO4,82Br, and 24Na appears to overestimate the ECW space because of the ability of these small ions to diffuse into cells. An ECW space of 21% to 27% of body weight is usually reported when these methods are used (5). In general, it is estimated that the ECW occupies 20% of the body weight (and therefore 30–40% of TBW). It is divided into plasma (5% of body weight) and interstitial fluid (15% of body weight). The interstitial fluid occupies a rapidly equilibrating functional space between cells and a slowly equilibrating (or nonequilibrating) space composed of epithelial cell secretions, connective tissue, joint space, and cerebrospinal fluids, the so-called transcellular space (9). The functional interstitial fluid accounts for 90%, and the transcellular space accounts for 10% of the total interstitial fluid. The transcellular space should not be equated with the ‘‘third space.’’ The transcellular fluids are a normal component of the ECW and do not affect the functional volume of the extracellular space. The third space results

SO4 Br

Table 2 Distribution of Water in the Various Tissues of a 70 kg Man

Cl Na SCN D 2O

TBW

THO Antipyrine

RBC Plas- ISF ma ECF

Conn. tissue ICF

Figure 2 Substances used to measure the body fluid compartments. Abbreviations: ECF, extracellular fluid; ICF, intracellular fluid; ISF, interstitial fluid; RBC, red blood cell; TBW, total body water; THO, titrated water. Source: From Ref. 6.

Tissue Skin Muscle Skeleton Brain Liver Heart Lungs Kidneys Spleen Blood Intestine Adipose tissue Source: From Ref. 8.

Water (%)

Body weight (%)

Liters of water per 70 kg

72 75.6 22 74.8 68.3 79.2 79 82.7 75.8 83 74.5 10

18 41.7 15.9 2 2.3 0.5 0.7 0.4 0.2 8 1.8 10

9.07 22.1 2.45 1.05 1.03 0.28 0.39 0.25 0.1 4.65 0.94 0.7

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

3

Table 3 Electrolyte Composition of the Body Fluid Compartments Serum Serum water (mEq/L) (mEq/L)

100 90

Electrolytes

BODY WEIGHT (%)

80

Total body water (TBW)

70 60

Intracelluar fluid (ICF)

50 40

Extracellular fluid (ECF)

30 20

+

+

+

10 2 4 6 8 Birth 6 12 3yr 6yr 9yr 12yr 15yr Adult mo mo AGE

Figure 3 Distribution of body fluids in children as a function of age and sex. Source: From Ref. 6 and courtesy of Pediatrics 1961; 28:169.

Interstitial fluid (mEq/L)

Intracellular fluid (muscle) (mEq/kg of H2O)

Cations Sodium (Naþ) Potassium (Kþ) Calcium (Ca2þ) Magnesium (Mg2þ)

142 4 5 2

152.7 4.3 5.4 2.2

145 4

10 156 3.3 26

Total cations

153

165

149

195

102 26

109.7 28

114 31

2 8

2

2.2

95

1 6 16

1.1 6.5 17.2

20

Anions Chloride (Cl) Bicarbonate (HCO2 3 ) Phosphate (HPO2 4 ) Sulfate (SO2 4 ) Organic acids Protein Total anions

153

165

55 145

180þ

Source: Adapted from Ref. 7.

from abnormalities in the permeability of cells, such as the abnormalities seen after ischemia and those seen with inflammation that increases the size of the extracellular space but not, a priori, the volume of the ECW. Third-space size is proportional to the severity of the injury. Because fluid and electrolytes in the third space are derived from functional extracellular fluid, the increase in size of the space reduces the functional extracellular volume. Direct measurement of the ICW compartment is extremely difficult, because substances that equilibrate only in the intracellular space have not been defined. Consequently, the ICW space is estimated as the difference between TBW and ECW. The ICW space varies from individual to individual. In healthy normal adults, it constitutes approximately 30% to 40% of body weight (55% of TBW). Because fat has little ICW and skeletal muscle has the highest percentage of ICW, athletic muscular individuals have a higher proportion of ICW; but women, the obese, and the elderly have a smaller muscle mass and therefore have a smaller percentage of their body weight as ICW. The electrolyte composition of the various fluid compartments is noted in Table 3. The major cations are sodium and potassium, and the major anions are chloride and bicarbonate. The absolute amount of a particular ion can only be measured by cadaveric analyses, but the total exchangeable amount of an ion can be estimated by dilution with a labeled

form of the compound. Total exchangeable sodium is not equivalent to total body sodium. A large amount, approximately 1000 mEq, is present in a nonexchangeable form in bone (10). The total exchangeable potassium is more closely equivalent to the total body potassium (TBK) (less than 0.5% is nonexchangeable) (10). Sodium is the major extracellular cation, and potassium is the major intracellular cation (Table 4). The ECW space is approximated by the total body sodium, the ICW space by the TBK, and the TBW by the sum of total body sodium and TBK. Moore (10) has used this relationship to estimate TBW from total exchangeable sodium (Nae) and potassium (Ke) using the following formula: TBM ¼

ðNae þ Ke Þ þ 70 ð2LÞ 163

The differing ionic compositions of the various fluid compartments are the result of variations in the permeabilities and active transport mechanisms present great diversity among the transcellular fluids in this regard (Table 5).

Fat (Lipids) Until the 1950s, lipids, the second largest chemical constituent of the body, were considered to be relatively inert

Table 4 Total and Exchangeable Amounts of Electrolytes in Fluid Compartments of Adult Man Sodium

Potassium

Compartment Total extracellular Total intracellular Total body Total exchangeable Total body intracellular concentration (milliequivalent per liter intracellular water)

Magnesium

Chloride

Bicarbonate

27.8 5.2 33 33 14.4

6.8 5.9 12.7 12.7 16.4

(mEq/kg of body weight) 52.8 5.2 58 41 14.4

2.5 51.3 53.8 52.8 14.3

21.8 8.2 30 3.4, 4.9, 10a 22.8

a

Equilibrated for 24, 48, and 89 hours, respectively. Total exchangeable magnesium is a function of time of equilibration. Source: From Ref. 11.

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Table 5 Mean Electrolyte Composition of Transcellular Fluids Fluid Saliva Gastric juice Bile Pancreatic juice Ileal fluid Cecal fluid Cerebrospinal fluid Sweat

Na (mEq/L)

K (mEq/L)

Cl (mEq/L)

HCO3 (mEq/L)

Hþ (mEq/L)

33 60 149 141

20 10 5 5

34 130 101 77

0 0 45 92

– 90 – –

129 80 141

11 21 3

116 48 127

29 22 23

– – –

45

5

58

0

–

Source: Adapted from Ref. 12.

substances that served as a source of protection and insulation. They now are recognized as essential components of energy metabolism (providing 9.3 kcal/g), hormonal synthesis (steroids), hormonal regulation and action (prostaglandins), and neural transmission (sphingomyelins). In addition, they are required for general cellular integrity and stability (cell membrane phospholipids and cholesterol). Many of the functions of lipids require fatty acids that cannot be synthesized by human beings. The three major essential fatty acids are arachidonic acid, linoleic acid, and linolenic acid. Total body fat (TBF) varies inversely with TBW in normal individuals. During the first four months of life, there is a decrease in the percentage of TBF, expressed as percent of total body weight (Table 6). After puberty, the TBF content increases, with the increase being greater in girls than in boys. In healthy men, TBF accounts for approximately 25% of body weight, and in healthy women, fat accounts for approximately 35% of body weight. With age, there is an increase in the percentage of body weight occupied by fat. However, it is of note that body weight often remains unchanged with age. Because total body weight equals body fat plus fat-free tissues, a decrease in fat-free tissue is thought to occur with aging (14). The percentage of body weight occupied by fat is also inversely related to the level of physical activity. Muscular athletic individuals have a greater muscle mass and smaller percentage of body fat than sedentary individuals of similar body weight (15). However, these changes are somewhat adaptive. For example, a long-distance swimmer benefits from the buoyancy and insulation provided by fat and often has a greater amount of fat than a long-distance runner of equivalent body build (15). This presumably results from a difference in caloric intake between these two groups. Approximately 50% of the fat in human beings is located in the subcutaneous tissue, but the distribution of the subcutaneous tissue varies with age, sex, and physical activity (14). Children have a large amount of subcutaneous

Table 6 Body Composition of Infants and Children as Function of Age

Age (mo) Birth 4 12 24 36

Whole body (g/100 g)

Body weight (kg)

Water

Protein

Lipid

Other

3.5 7 10.5 13 15

75.1 60.2 59 61 62

11.4 11.4 14.6 15.7 16.4

11 26.3 23.9 20.6 18.3

2.5 2.1 2.5 2.7 3.3

Source: From Ref. 13.

tissue over their triceps, but only a small amount of subcutaneous tissue in their abdominal walls. The distribution is reversed in adults. Changes in the body fat distribution occurring as a result of weight gain are not equally distributed (14). For this reason, serial measurement of an isolated anthropometric index may not adequately reflect body composition changes in malnourished individuals who are being repleted. However, changes in the body fat distribution occurring as a result of weight loss are equally distributed. A 10% loss in triceps skinfold is accompanied by a concomitant 10% loss in the size of the subcutaneous tissues of other areas such as the hips, abdomen, thighs, and breasts (14). TBF is defined as the difference between total body weight and fat-free mass (see the equation given below). Fat contains very little water and virtually no potassium. On the other hand, the total water content of fat-free tissue averages 73.2% of TBW (16), and the potassium content of fat-free tissues averages 68.1 mEq/kg (14). Consequently, fatfree tissue may be approximated from either TBW or total exchangeable potassium (Ke), and the TBF is estimated by inference. Equations for these calculations are: For TBW: TBF ¼ BWt ðTBW=0:732Þ

and

%TBF ¼ 1 ð%TBW=0:732Þ For Ke : TBF ¼ BWt ðKe Þ=68:1 and %TBF ¼ ½BWt ðKe =68:1Þ=BWT where BWt is body weight. It should be noted that these methods assume that the hydration and potassium content of that portion of the body that is fat free is constant. However, these assumptions are not always valid because the hydration of the fat-free tissue can vary considerably (e.g., greatest in edematous states and least in dehydrated states). A third method used in calculating TBF involves the measurement of the specific gravity of the individual by underwater weighing procedure (14,15,17,18). This method is based on the findings that normal human fat has a density of 0.9 g/mL and nonfat tissue has an average density of 1.1 g/mL at 37 C. At 37 C, the density of an average reference male containing 15.3% body fat is 1.064 g/mL (19). With the use of these values, the percentage fat in an individual can be determined by measuring the density (D) in water as indicated by the equation: %Fat ¼ ½ð4:570=DÞ 4:142 100 Although the density of human fat changes only with temperature, the density of fat-free tissue changes with age, degree of obesity, and degree of hydration (14). When estimates of TBF made by densitometric methods are compared to calculations of TBF made from TBW, the densitometric methods give a higher estimate of TBF (15,17). Densitometric methods give a lower estimate of TBF when compared to calculations of TBF made from total exchangeable potassium (17,20). A fourth method used to calculate TBF involves the measurement of the uptake of an inert, highly fat-soluble gas such as cyclopropane or krypton (21). The assumption made in this technique is that the gas will only go into fat cells. Thus it should yield a more accurate measurement of TBF than the other methods noted. When compared to measurements made by TBW determination, similar results

5

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

protein turnover per kilogram of body weight are the result of a decrease in skeletal muscle mass. TBP may be estimated by one of two methods: (i) measurement of total exchangeable potassium or (ii) measurement of total body nitrogen (TBN) by neutron activation. TBN is linearly related to total exchangeable potassium in both normal and decreased conditions (26,27). The average exchangeable potassium to nitrogen ratio in tissue is 3 mEq/g nitrogen (10). Thus:

are obtained (22). When compared to total exchangeable potassium measurements or densitometric measurements, lower values are obtained (23). However, no data are available comparing the inert gas method with cadaver analyses.

Proteins Proteins are chains of amino acids. Proteins and amino acids form essential components of all living cells and are involved in virtually all body functions. These molecules serve as enzymes, hormones, neurotransmitters, immunoglobulins, and transport molecules. They are also essential components of all cell membranes and various cellular components, including receptors, transport systems, and contractile elements. As such, they are necessary for the metabolism, growth, regulation, replication, protection, repair, communication, and motion of individual cells and the coordinated function of the entire organism. Consequently, it is somewhat remarkable that total body proteins (TBPs) account for only 15% of the body weight in a healthy man and that over 80% of the TBP is present in skeletal muscle and connective tissue. Unlike fat, there are no storage depots for protein. All the body’s protein is functional. As a result of its numerous and varied functions, protein, unlike fat, undergoes considerable daily turnover. Approximately 2.5% of the TBP (250 g in a 70 kg man) is broken down and resynthesized each day (23). More than half this turnover is accounted for by daily secretory processes, white cell turnover, hemoglobin turnover, muscle-protein turnover, and plasma protein turnover. The total turnover rate of body protein diminishes progressively with age (24). The protein synthesis rate per kilogram of body weight decreases from 25 g/kg/day in the neonate to 7 g in a one-year-old infant. In the average man and woman, protein synthesis is 3.2 and 2.6 g/kg of body weight per day, respectively; in an elderly man and woman, it is 2.6 and 1.9 g, respectively. The synthesis rate of transport protein, such as albumin, remains unchanged with increasing age, but the breakdown rate (and presumably synthesis rate) of skeletal muscle decreases (Table 7). If the total turnover rate of protein is expressed per lean body mass rather than body weight, an increase in turnover is noted with aging. Because the lean body mass decreases with aging as a result of a reduction in skeletal muscle mass and the synthesis rate of albumin is unchanged, it is apparent that the changes in

TBN ¼ Ke =3 where Ke equals exchangeable potassium. TBP is directly proportional to TBN by a factor of approximately 6.25. Thus: TBP ¼ ð6:25ÞðTBNÞ ¼ ð6:25ÞðKe =3Þ ¼ 2:08 Ke TBN can also be measured using neutron activation analysis (26,28). When tissues are irradiated with neutrons from either a cyclotron or a plutonium source, gamma rays specific for a substance capturing the neutron are emitted. For nitrogen, gamma rays of 10.83 meV are emitted. Consequently, measurement of the gamma rays produced after neutron activation allows determination of TBN. In general, the results obtained with either method correlate well with each other.

Carbohydrates Carbohydrates serve as the energy source of the body when energy is rapidly required, providing approximately 4 kcal/g. They also play important roles in cell membrane function and stability (glycoproteins and glycolipids), in hormone function (glycoproteins), and as precursors of lipid and nonessential amino acid synthesis. In addition, the brain, RBCs, WBCs, and wounds are to a large extent glucose-dependent tissues. Of the three major sugars found in the human body (glucose, fructose, and galactose), glucose is the primary carbohydrate. In addition to ingested carbohydrates, glucose is readily available from pyruvate and lactate, gluconeogenic amino acids (alanine and glutamine), the glycerol moiety of lipids, and its storage form, glycogen. Most of the body’s glycogen is stored in the liver, skeletal muscle, and cardiac muscle. Muscle glycogen is used primarily by the muscle itself, because muscle lacks

Table 7 Comparison of Whole Body Protein Breakdown with Estimates of Muscle-Protein Breakdown and Albumin Synthesis in Young and Old Adult Human Beings Whole body protein breakdowna (g/day) Group Males Young Old Females Young Old

Muscle-protein breakdownb (g/day)

Albumin synthesisc (g/day)

Mean age (yr)

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

22 70

2.94 2.64

6.7 7.5

115 163

0.76 0.53

1.74 1.50

30 32

0.19 0.15

0.39 0.40

7 8.4

20 76

2.35 1.94

6.1 6.6

103 166

0.64 0.31

1.69 1.05

28 26

– –

– –

a

Measured by administration of 15N-glycine. Measured as 3-methylhistidine output in urine and computed as muscle protein. c Measured by administration of 15N-glycine. Abbreviation: BCM, body cell mass. Source: From Ref. 25. b

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6

Part One: General Considerations

glucose-6-phosphatase. In contrast, hepatic glycogen is primarily used in providing glucose to glucose-dependent tissues. Because only a little glycogen is stored in the liver, the hepatic stores of glycogen are rapidly depleted by an overnight fast. Cahill (29) has estimated the total hepatic glycogen content of a 70 kg man to be 75 g, and the total muscle glycogen content to be 105 g. The total carbohydrate content of the body is approximately 300 g (30). Except by cadaver analysis, no method is available to measure total body carbohydrate. However, it is of note that the daily intake of carbohydrate approximates the total body stores.

Lean Body Mass and Body Cell Mass Based on densitometric measurements, Behnke (17) and Behnke and Wilmore (15) proposed the division of total body weight into fat and lean body mass. The lean body mass was defined as that portion of the body mass with the least amount of essential body fat compatible with health. The essential body fat was thought to represent 2% to 10% of the total body weight. However, because the essential body fat cannot be differentiated from the nonessential body fat, most investigators have redefined lean body mass as the portion of body mass devoid of all fat, the so-called fat-free body (14). Although ‘‘fat-free body’’ and ‘‘lean body mass’’ are often used interchangeably, there is a small (2–10%) difference between them (Table 8). This chapter subsequently refers only to the fat-free body, but it should be kept in mind that the same statements are generally true for lean body mass. Because the total body weight is equal to TBF plus the fat-free body, the size of the fat-free body can be determined by the same methods used to determine the size of the TBF.

The fat-free body is divisible into the extracellular mass, composed primarily of water, and the body cell mass (BCM), composed of all the metabolically active cells in the body (2,10). The cells in the BCM are actively involved in energy exchange, protein synthesis, enzyme replication, and morphogenesis (2). Therefore the BCM is composed of the skeletal muscle mass (60%), visceral cell mass (20%), and the peripheral cell mass (20%) (Table 8) (10). The peripheral cell mass includes blood cells and connective tissue cells. Although the BCM cannot be measured directly, it can be calculated from the exchangeable potassium, the exchangeable sodium, the TBN, or the ICW. Because more than 98% of the TBK is intracellular, a linear relationship exists between BCM, TBK, total exchangeable potassium, and ICW. Histochemical analysis has demonstrated that approximately one-fourth of the wet weight of cells is protein (31). Consequently: BCM ¼ ðTBKÞð4Þ ¼ ð2:08 Ke Þð4Þ ¼ 8:33 Ke BCM ¼ ðTBNÞð6:25Þð4Þ ¼ 25ðTBNÞ Because the average cell has 150 mEq of intracellular potassium per liter (10) and because each cell is composed of 25.8% solids (74.2% water) (31), BCM is also equivalent to: Ke ð1000=0:732Þ=150 ¼ ðKe Þð9:10Þ or ICW=0:742 Each of these methods yields a different value for the BCM of a given individual. This is most obvious when

Table 8 Comparison of Body Cell Mass, Lean Body Mass, and Fat-Free Body BCM Anatomy

All body cells Protoplasm Nucleus Membrane [ICK]av ¼ 150 mEq/LICW

LBM

g

g

Function

Composition

Cellular metabolism Respiration Oxidation Synthesis Cretion Mitosis [Ke ECK] f ¼ BCM f ¼ 7.510 or Ke 8.33 ¼ BCM 70 kg man 3200 8.33 ¼ 26.6 kg Calories 2.73.6 kcal/hr/kgBCM

FFB

All body cellsg BCM Plus: Plasma ECF ECF TCF Tendon ECT Fascia Collagen Elastin ECS Dermis Skeleton ‘‘2% ¼ 10% essential lipid’’: Fat Cellular metabolism Support Transport Circulation Protection Integument Density ¼ 1100 % LBM ¼ 100 495/d 450 70 kg man Approximately 50 kg Calories 110 kcal/hr/kgLBM

Same as LBM but no lipid at all

g

Same as LBM

FFB ¼ TBW/f f ¼ 0.695 0.735 70 kg man 36.4/0.732 ¼ 49.7 Calories (same as LBM)

Abbreviations: BCM, body cell mass; ECF, extracellular fluid; ECK, extracellular potassium; ECS, extracellular supporting structure; ECT, total extracellular space; f, coefficient; FFB, fat-free body; ICK, intracellular potassium; ICW, intracellular water; Ke, exchangeable potassium; LBM, lean body mass; TBW, total body water; TCF, total cellular fluid. Source: From Ref. 10.

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

2400

× 2100

× ×× × ×

1800 IRME (cal/day)

the two methods presented for total exchangeable potassium are used. However, any of these methods provide accurate estimates of sequential changes in an individual or differences among populations, if the same method is used throughout the study. Measurements of total exchangeable potassium by whole body 40K counting or of TBN by neutron activation are difficult to perform and require equipment that is expensive and not readily available. To avoid these practical problems, Shizgal et al. (32) developed a method to estimate total exchangeable potassium from isotope dilution measurements of TBW and total exchangeable sodium. As noted previously, TBW is approximately equal to the sum of the total exchangeable sodium and potassium. Thus:

7

×

1500 1200

×

900

× ×

× ×× × ××

= Healthy young males = Healthy young females = Healthy elderly males × = Surgical patients

× ×

600 300

TME = –8.99 = 10–5Ke + 250

Nae þ Ke =TBW ¼ R

400 800 1200 1600 2000 2400 2800 3200 3600 4000 4400 4800 Ke (mEq)

where R is constant. Total exchangeable sodium and TBW can be easily measured by isotope dilution with deuterium oxide or tritiated water and 22Na. The constant, R, can be approximated by measurement of the sodium, potassium, and water of whole blood. Thus:

Figure 4 Relationship of total body energy expenditure to the total Ke. Abbreviations: Ke, exchangeable potassium; IRME/TME, total metabolized energy. Source: From Ref. 34.

Ke ¼ ½ðRÞðTBWÞ Nae energy expenditure when compared to total exchangeable potassium because skeletal muscle at rest contributes significantly to total exchangeable potassium but not to total metabolic energy expenditure.

and BCM ¼ 8:33 Ke or 9:10 Ke As might be expected, BCM increases with age until the middle years of life. With advancing age, the percentage of body weight composed of the BCM decreases as a result of a decrease in skeletal muscle mass. In addition, men generally have a greater percentage of body weight composed of BCM than women; athletic individuals have a greater percentage of body weight composed of BCM than sedentary individuals; and lean individuals have a greater percentage of body weight composed of BCM than obese individuals. Thus the BCM varies from 20% of body weight in morbidly obese individuals to 54% in lean athletic men (33). A direct correlation exists between total energy expenditure and BCM, whereas other measurements of body composition such as total body mass and fat-free body demonstrate a variable or poor correlation (34). Kinney et al. (34) have demonstrated an oxygen consumption of 8 to 10 mL oxygen per kilogram BCM and an energy expenditure of 2.7 to 3.6 kcal/kg/hr: As noted in Figure 4, total exchangeable potassium (and therefore BCM) is linearly related to the total metabolic energy expenditure in healthy adults and surgical patients until 1800 cal/day are expended. However, when measurements of total metabolic energy expenditure greater than this are included, the relationship is parabolic. This relationship is believed to reflect the lower resting metabolic rate of skeletal muscles per milliequivalent intracellular potassium when compared to visceral tissues. Skeletal muscle, which provides approximately 50% of the TBK, accounts for only 15% of the body’s resting energy expenditure. On the other hand, visceral tissues, such as brain, heart, and kidneys, which provide only 10% of the TBK, account for 70% of the body’s resting energy expenditure (35). Consequently, individuals with a small BCM have less skeletal muscle mass and a good correlation of total exchangeable potassium with total metabolic energy expenditure. In contrast, individuals with a large BCM have a smaller increase in total metabolic

Changes in Body Composition with Stress, Sepsis, and Starvation The body composition of a human being at any given moment is influenced significantly by the individual’s age, sex, physical activity, and previous nutritional status, as well as by concurrent infections, injuries, and disease processes. Changes produced by age, sex, and physical activity have been discussed at length. Tables 9 and 10 and Box 1 provide a summary of the formulas derived from multiple body composition studies of normal individuals (2,10). These formulas can be applied to any healthy adult under normal circumstances to estimate the components of body composition. Ultimately, body composition is the net result of the total chemical constituents taken in minus the total chemical constituents used and excreted. Because carbohydrates and lipids primarily serve as a source of calories, this relationship can be estimated by: DBC ¼ ½ðCin þ Nin þ WSin Þ ½ðCout þ Nout þ WSout Þ where D is change, BC is body composition, C is calories, N is nitrogen, W is water, and S is solutes (electrolytes and Table 9 Estimation of Total Body Water by Age, Sex, and Body Weight Sex

Age (yr)

TBW (L)

95% conf. limits (%)

Males

16–30 31–60 61–90 16–30 31–90

0.4 (BWt) þ 13 0.4 (BWt) þ 11 0.34 (BWt) þ 12 0.31 (BWt) þ 11.6 0.33 (BWt) þ 8.84

16 17 16 13 21

Females

Abbreviations: TBW, total body water; BWt, body weight. Source: From Ref. 10.

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Part One: General Considerations

Table 10 Estimation of Total Exchangeable Potassium by Age, Sex, and Body Weight Sex

Age (yr)

Exchangeable potassium (mEq)

Males

16–30 31–60 61–90 16–30 31–90 61–90

38 (BWt) þ 735 26 (BWt) þ 1383 27 (BWt) þ 723 18 (BWt) þ 1250 17 (BWt) þ 1176 18 (BWt) þ 757

23 20 16 20 23 29

20–60 61–84

97.4 (TBW) 409 2 þ 77 (TBW)

10 17

Females

By TBW Males and Females

Injury and infection

Normal

95% conf. limits (%)

+110 +100 +90 +80

Abbreviations: BWt, body weight; TBW, total body water. Source: From Ref. 10.

minerals). Under normal steady-state conditions, the quantities of these components taken in equal the quantities used or lost, and there is no net change in body composition (BC ¼ 0). If the quantity of a component taken in is greater than the quantity used, this component either is stored (BC > 0), thus changing body composition, or is lost (BC < 0). For example, if caloric intake is greater than caloric loss or expenditure, energy is stored in the body in the form of lipids and carbohydrates. If water intake is greater than output, water is retained (e.g., edema). Fortunately, regulatory mechanisms exist that protect against an increase in body water (Chapter 2) and other nutrients. Consequently, for a net increase to be seen in TBW, there must be a neuroendocrine alteration present as well. Such is the case after trauma and surgery when elevated secretion rates of aldosterone and vasopressin promote the retention of salt and water. On the other hand, excess nitrogen intake is not stored, and, as already noted, maximum rates of protein synthesis exist in each individual. When the intake of nitrogen exceeds the need, the excess nitrogen is converted into urea and is excreted. There are five basic situations in which intake does not equal output—dehydration and the four catabolic stresses defined by Moore (2) as fasting, starvation, injury, and febrile illness. In dehydration, the loss of water exceeds the intake resulting in a reduction in TBW that is distributed throughout the ICW and ECW. In fasting and in starvation (prolonged fasting), caloric and nitrogen expenditures are the same or less than those of a normal individual, but the

Box 1 Estimation of Body Composition by Sex and Body Weight TBW ¼ 0.7945 (BWt) 0.0024 (BWt)2 0.0015 (age) (BWt) (males) TBW ¼ 0.6981 (BWt) 0.0026 (BWt)2 0.0012 (age) (BWt) (females) ICW ¼ 0.623 (TBW) 0.0016 (age) (TBW) (males) ICW ¼ 0.553 (TBW) 0.0007 (age) (TBW) (females) Fat ¼ BWt TBW/0.732 ECW ¼ TBW ICW Ke ¼ 150 (ICW) þ 4 (ECW) Nae ¼ 163.2 (TBW) Ke 69 Abbreviations: BWt, body weight; ECW, extracellular water; ICW, intracellular water; Ke, exchangeable potassium; Nae, exchangeable sodium; TBW, total body water. Source: From Ref. 2.

+70 +60

Third degree burns >20% BSA

+50 +40 +30 +20 Basal

Resting 10%

+10 Normal _10 _20 _30

Severe infection

Multiple fractures Postoperative Partial starvation

_40

Figure 5 Resting energy expenditure during injury and starvation in man. Abbreviation: BSA, body surface area. Source: From Ref. 36.

intake of these substrates is markedly reduced or absent. As a result there is a loss of total body lipids, carbohydrates, and nitrogen. In patients with injury or febrile illness, caloric and nitrogen expenditures are greater than those of the normal individual. The increase in energy expenditure produced by an injury or infection is in proportion to the severity of the insult. Burns are the most severe injury, and generalized sepsis is the most severe febrile illness (Fig. 5). A healthy adult undergoing an elective operation increases the resting energy expenditure by approximately 10%, but the same individual with a severe burn increases the resting energy expenditure by 40% to 120%, depending on the size and the degree of the burn injury (37). A minor febrile illness or a minor febrile complication after an elective operation increases the resting energy expenditure by 13% for each degree Celsius of temperature elevation (38), but generalized sepsis increases the resting energy expenditure by 15% to 50% (37). The changes in body composition resulting from an increase in caloric and nitrogen expenditure during injury and febrile illness are frequently compounded by reductions in intake as a result of anorexia and ileus. However, if the increased measurements are adequately met by exogenous substrate sources (enteral or parenteral), little change in the body composition occurs (10,28,39,40).

NORMAL METABOLISM: INTERMEDIARY METABOLISM AND SUBSTRATE INTERACTIONS Body composition remains in a steady state when four essential conditions are met: (i) energy is supplied in sufficient quantities to meet the metabolic demands of all the body’s tissues, (ii) carbohydrates are supplied in sufficient quantities to meet the requirements of glucosedependent tissues, such as those of the brain, RBCs, and WBCs, (iii) nitrogen is supplied in sufficient quantities to meet the obligatory synthesis of protein, and (iv) water

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

and solutes (electrolytes and minerals) are supplied in sufficient quantities to replace daily obligatory losses (water and electrolyte metabolism). In addition, these conditions must be met in the face of varying dietary intakes and varying daily energy requirements. This achievement is possible as a result of numerous substrate-to-substrate interactions (e.g., conversion of protein to carbohydrates) and the neuroendocrine regulation of intermediary metabolism.

Energy Metabolism All metabolic processes in cells either produce energy (exergonic reactions) or use energy (endergonic reactions). The energy required for the operation of all biologic processes in mammalian cells is derived from the inherent energy present in the structure of organic molecules (41). The chemical energy produced by the processing of these organic molecules is transferred to the phosphate bonds of purine nucleotides and other molecules with phosphate bonds such as phosphagens. As noted in Table 11, the hydrolysis of the phosphate bonds of adenosine triphosphate (ATP) or its precursors releases a considerable amount of energy that can be used to drive other biologic processes. The formation of these compounds with high-energy phosphate (HEP) group transfer potential is usually a result of the transfer of reducing equivalents from the substrate by reduction of nicotinamide adenine dinucleotide (oxidized form) (NADþ), flavoproteins, and other coenzymes followed by coupled oxidative phosphorylation of adenosine diphosphate (ADP) in the mitochondria (42). Although ATP serves as a carrier of chemical energy in all living cells, it is not a reservoir of energy (41). The intracellular concentrations of ATP are small, highly regulated, and rapidly depleted. Reservoirs of energy (phosphagens), such as phosphocreatine, do exist in some cells (41). These reservoirs accept HEP bonds when the intracellular concentration of ATP is high and transfer a phosphate group to ADP nucleotides when the availability of ATP is low (41). The intracellular concentrations of adenine nucleotides also provide the cell with a sensitive control mechanism for regulating energy-producing and energy-using processes in cells. Atkinson (43) has introduced the concept of energy charge to explain this regulatory mechanism. Adenylate energy charge (EC) represents the balance between energyusing processes and energy-producing processes. It is defined by the equation: EC ¼ ðATP þ 0:5ADPÞ=ðATP þ ADP þ AMPÞ A normal energy charge signals that energy-producing processes and energy-using processes are in balance. If the 0

Table 11 Energy Released (Go ) During Hydrolysis of High-Energy Phosphate Compounds 0

Reaction

Go (J/mol)

ATP þ H2O ! ADP þ Pi ADP þ H2O ! AMP þ Pi ATP þ H2O ! AMP þ PPi PPi þ H2O ! 2Pi AMP þ H2O ! A þ Pi

36,800 36,000 40,600 31,800 12,600

Abbreviations: A, adenine; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate. Source: From Ref. 41.

9

energy charge is increased, energy-producing processes are exceeding energy-using processes, and a resultant reduction of energy-producing processes occurs. If the energy charge is decreased, energy-using processes are exceeding energyproducing processes, resulting in a decrease in energy-using processes that may jeopardize cell survival. The major energy-producing processes include the catabolism of carbohydrates, proteins, and lipids. Each of these substrate groups can provide part of the energy present in their structure through cytoplasmic catabolic reactions (e.g., glycolysis). The remainder of the available energy present in these substrates is released during oxidation of the remaining carbon fragments in the intramitochondrial tricarboxylic acid (TCA) cycle. The final common pathway into the TCA cycle for carbohydrates, proteins, and lipids is through the formation of acetyl coenzyme A(CoA) (Figs.6–8). Foreachmolecule ofacetylCoA completely oxidized in the TCA cycle, two molecules of carbon dioxide, three molecules of nicotinamide adenine dinucleotide (reduced form) (NADH), one molecule of flavin adenine dinucleotide (FADH), and one molecule of guanosine triphosphate (GTP) are produced. In total, 12 HEPs are formed primarily by way of transfer of the reducing equivalents from NADH and FADH to oxygen in the electron transport system with the subsequent phosphorylation of ADP linked to this oxidative process (oxidative phosphorylation). Unlike carbohydrates and lipids, amino acids may directly enter the TCA cycle at one of the intermediate reactions (Fig. 6).

Carbohydrate Metabolism In the cytoplasm of all cells, one molecule of glucose is catabolized to pyruvate through the Embden–Meyerhof pathway to yield two molecules of pyruvate, two molecules of ATP, and one molecule of NADH (Fig. 7). The completion of glycolysis (i.e., glucose to lactate) uses one molecule of NADH in the conversion of pyruvate to lactate. Conversely, the conversion of pyruvate to acetyl-CoA produces one molecule of NADH. Because the oxidation of acetyl-CoA in the TCA cycle produces 15 HEPs, the complete oxidation of one molecule of glucose to carbon dioxide and water produces 26 HEPs [(2 12) þ 2] and four molecules of NADH. The latter molecules produce 12 HEPs (three HEPs per molecule of NADH) through coupled oxidative phosphorylation. Consequently, the total energy produced in the complete oxidation of one molecule of glucose to carbon dioxide and water is equivalent to 38 HEPs. This result is in contrast to glycolysis where only two HEPs are produced in the conversion of glucose to lactate. As noted in Fig. 7, there are two nonreversible reactions in glycolysis: (i) the conversion of glucose to glucose 6-phosphate, catalyzed by hexokinase, and (ii) the conversion of phosphoenolpyruvate to pyruvate, catalyzed by pyruvate kinase. These reactions are irreversible because they lose a considerable amount of energy as heat. It is the presence of these two nonreversible reactions that drives glucose to pyruvate. In addition, phosphofructokinase (PFK) and pyruvate kinase act as the major regulators of glycolysis (45). Once the catabolism of glucose has begun, it rapidly proceeds to pyruvate. Under aerobic conditions, most tissues oxidatively decarboxylate pyruvate to acetyl-CoA and then oxidize the acetyl-CoA in the TCA cycle. Under an anaerobic condition, pyruvate cannot be decarboxylated, and it is converted instead to lactate. As a result, elevated tissue and plasma concentrations of lactate (and pyruvate) are characteristic of ischemia and anoxia. Some tissues with a paucity of mitochondria, such as erythrocytes and leukocytes, are capable of glycolysis only. These cells lack

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10

Part One: General Considerations

Protein Glycogen

Proteolysis

Glucose Lactate

Glycolysis Pyruvate

Beta-oxidation

Fatty acyl-CoA

Phenylalanine Tyrosine Leucine Lysine Tryptophan

Cystine Glycine Alanine Serine Threonine

Fatty acid

Acetoacetyl-CoA

Acetyl-CoA

Cholesterol Oxaloacetate Malate Fumarate Succinate

Citrate

TCA cycle (15 ATP/TURN)

Ketone bodies

Isocitrate Alpha-ketoglutarate

Succinyl-CoA Glutamate

Phenylalanine Tyrosine

Isoleucine Methionine Valine

Aspartate Asparagine

the ability to oxidize pyruvate and acetyl-CoA even under aerobic conditions. Therefore they derive all their energy from conversion of glucose to pyruvate and lactate. Carbohydrates other than glucose can also be metabolized through glycolysis. For example, fructose, galactose, mannose, and triose sugars can enter glycolysis after modification by endergonic reactions. Similarly, pentose sugars may also enter the glycolytic pathway. As noted earlier, the total carbohydrate stores of the human body are limited and are rapidly depleted (31). In addition, RBCs, WBCs, and the brain are glucose-dependent tissues that are unable to use nonglucose energy substrates. Thus glucose must be made continuously available. The synthesis of glucose through a process called gluconeogenesis can proceed from lactate, pyruvate, and amino acids. Gluconeogenesis is not simply the reversal of glycolysis, because the unidirectional reactions make glycolysis irreversible. However, gluconeogenic tissues, such as the liver and the kidney, contain four enzymes that essentially allow glycolysis to proceed in reverse fashion from pyruvate (and lactate) to glucose (Fig. 8). The first of these enzymes, pyruvate carboxylase, in the presence of ATP, carbon dioxide, and biotin, converts pyruvate to oxaloacetate in the mitochondria. [Although it does not act as a cofactor, acetyl-CoA must be present in excess for this reaction to proceed (46).] Oxaloacetate is then converted to phosphoenolpyruvate by the cytoplasmic enzyme phosphoenolpyruvate carboxylase and GTP. Because the oxaloacetate is found in the mitochondria and phosphoenolpyruvate carboxylase in the cytoplasm, oxaloacetate must cross the mitochondrial membranes into the cytoplasm. However, because the mitochondrial membranes are relatively impermeable to oxaloacetate, it is thought that oxaloacetate leaves the mitochondria as either malate or aspartate, which

Arginine Histidine Glutamine Proline

Figure 6 Pathways for production and use of acetyl-CoA. Abbreviations: TCA, tricarboxylic acid; CoA, coenzyme A. Source: From Ref. 44.

can be transported through the mitochondrial membranes and then reconverted to oxaloacetate in the cytoplasm (47). Once phosphoenolpyruvate is formed, glycolysis can easily proceed in reverse fashion to fructose-1,6-biphosphatase. The enzyme fructose-1,6-bisphosphatase is required to form fructose 6-phosphate. This enzyme is present in the liver and kidney and to a lesser extent in skeletal muscle. However, it is not present in adipose tissue, smooth muscle, or cardiac muscle (48). Fructose 6-phosphate can then proceed to glucose 6-phosphate by the reversible glycolytic reaction catalyzed by glucose phosphate isomerase, but the conversion of glucose 6-phosphate to glucose requires the last of the gluconeogenic enzymes, glucose 6-phosphatase. This enzyme is present in the liver and kidney but not in skeletal, smooth, or cardiac muscle. Any glucose 6-phosphate that might be formed in skeletal muscle must be converted to glycogen, be used in glycolysis, or be used in the hexose monophosphate shunt, because skeletal muscle cannot release free glucose as a result of the absence of glucose 6-phosphatase. The glucose 6-phosphate formed in the liver and kidney can be converted to glucose and released into the circulation. Because there is a constant production of lactate and pyruvate in aerobic glycolytic tissues, in all tissues during anaerobic conditions, and from the reticuloendothelial system during sepsis and locally inflamed tissues, a constant source of lactate and pyruvate is available to gluconeogenic tissues such as the liver and kidney. In the liver and kidney, these substrates can be converted back to glucose and released into the circulation. The newly formed glucose is then available to glucose-dependent tissues for reconversion to lactate in the so-called Cori cycle (Fig. 9). However, it should be noted that this reconversion does not result in a net increase in glucose carbon, because lactate is itself derived from glucose (49).

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

Glycogen

11

Pyruvate + CO2 ATP Pyruvate carboxylase ADP

Glucose 1-phosphate

Oxaloacetate

ATP ADP

GTP Glucose

Glucose 6-phosphate Hexokinase

Phosphoenolpyruvate carboxylase

GDP

Glucose phosphate isomerase

Phosphoenolpyruvate

Fructose 6-phosphate ATP Phosphofructokinase

ADP

Fructose 1,6-diphosphate

Glyceraldehyde 3-phosphate NAD

Pi

NADH

Triose phosphate

Triose phosphate isomerase Dihydroxyacetone phosphate

Phosphoglycerate kinase Phosphoglyceromutase Enolase

ADP

Lactate dehydrogenase

Phosphoenolpyruvate ATP Pyruvate kinase ADP

Lactate

Pi Fructose 1,6-bisphosphate

Glyceraldehyde phosphate dehydrogenase

3 phospho-glycerol phosphate ATP

H 2O

Fructose-bisphosphatase Fructose 6-phosphate H2O Pi Glucose 6-phosphatate Glucose 6-phosphatase

Pyruvate NAD Pyruvate dehydrogenase

NADH NAD NADH

Glucose

TCA cycle

Figure 8 Gluconeogenic pathway in the liver and the kidney. Source: From Ref. 44.

CO2

Figure 7 Catabolism of glucose and major carbohydrate precursors. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD, nicotinamide adenine dinucleotide; NADH, reduced form of NAD; Pi, inorganic phosphate; TCA, tricarboxylic acid. Source: From Ref. 44.

Protein and Amino Acid Metabolism Energy and glucose can also be derived from the metabolism of amino acids. Although the partial catabolism and transformation of all a-amino acids to their a-keto acid derivatives can occur in most tissues, the complete oxidation of a-amino acids to urea and carbon dioxide occurs primarily in the liver and secondarily in the kidney (50). In general, the catabolism of all amino acids (except lysine) involves the removal of the a-amino acid group from the carbon skeleton to form ammonia and an a-keto acid. This is followed by the conversion of ammonia to urea and by the conversion of the a-keto acids to TCA-cycle intermediates or precursors (51,52). Removal of the a-amino group can occur by one of three processes: (i) transamination, (ii) oxidative deamination, and (iii) nonoxidative deamination (47,48). The most common mechanism is transamination. Transaminases (aminotransferases) interconvert a pair of amino acids and a pair of a-keto acids (Fig. 10). This process requires the presence of pyridoxal phosphate (vitamin B6) for the transfer of the amino group. These reactions are freely reversible and function both in synthesis and in catabolism. At least 12 of the amino acids undergo transaminations, including the branched-chain amino acids, valine, leucine, and

isoleucine. The most notable transaminases are glutamineoxaloacetic transaminase (or aspartate transaminase) and glutamic-pyruvic transaminase (or alanine transaminase). Through the collective action of all the transaminases, the a-amino groups are usually collected in the form of glutamate or alanine. Because a-ketoglutarate can accept the a-amino group of all the amino acids that are transaminated, including alanine, it serves as the final common amino group acceptor to form glutamate. Mallette et al. (53) have proposed and Felig (54) has expanded the concept of an alanine–glucose cycle similar to the Cori cycle (Fig. 9). In peripheral tissues, amino acids are transaminated with pyruvate to form alanine and an a-keto acid. The alanine is then transported to the liver, where it is transaminated with a-ketoglutarate to form pyruvate and glutamate. The pyruvate can then be converted back to glucose and released into the circulation, where it may be taken up by peripheral tissues and converted to pyruvate and lactate. The oxidative deamination of glutamate by glutamate dehydrogenase is an important mechanism in the liver for the removal of the amino group (Fig. 10). Because a-ketoglutarate is the common acceptor for all transaminases, substantial amounts of glutamate are formed. Consequently, the oxidative deamination of glutamine allows for the regeneration of a-ketoglutarate and the removal of free ammonia. Oxidative deamination of other amino acids is also possible through the action of a-amino

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12

Part One: General Considerations

Figure 9 Glucose–lactate (Cori) cycle and glucose–alanine cycle. Source: From Ref. 1.

acid oxidases that are present in the liver and kidney. However, with the exception of glutamate dehydrogenase, these enzymes do not appear to exert a major physiologic role in humans (50,52). Three amino acids, serine, threonine, and histidine, are primarily deaminated nonoxidatively (Fig. 10) (47). The former two amino acids undergo nonoxidative deamination by dehydration, whereas histidine undergoes direct deamination. The non–a-amino groups of glutamine and asparagine are removed by hydrolytic deamination (47). Free ammonia, even in small concentrations, is poorly tolerated by cells. Four mechanisms exist to handle the free

OXIDATIVE DEAMINATION Alpha-amino acid

Amino acid oxidase [Alpha-imino acid]

Flavin Flavin

H2O

H2

Alpha-Keto acid

ammonia produced by oxidative or nonoxidative deamination, thereby keeping the intracellular (and extracellular) concentration of this substance low. Free ammonia can be added to glutamate by glutamine synthetase to form glutamine. This is the primary mechanism for the elimination of ammonia in brain cells and muscle cells. The free ammonia may also be added to a-ketoglutarate, forming glutamate in the freely reversible reaction catalyzed by glutamate dehydrogenase. The resulting glutamate may be used as an amino acid in protein, as a precursor in arginine and citrulline syntheses, or as an a-amino group donor in transaminase reactions. A third mechanism for ammonia elimination is through its excretion by the kidney. Two-thirds of the ammonia excreted by the kidney is derived from the amide nitrogen of glutamine from renal arterial blood and one-third from the a-amino nitrogen of renal arterial amino acids (55). Although these three mechanisms remove a substantial amount of the ammonia formed, most of it is cleared by the liver, after which it enters into the urea cycle (Krebs– Henseleit cycle) (50). As noted in Figure 11, the urea cycle essentially involves the cleavage of a molecule of urea from arginine. The ammonia is first combined with carbon dioxide in the presence of ATP to form carbamylphosphate. Carbamylphosphate then condenses with ornithine to form citrulline, which, through a series of reactions, forms arginine. The arginine is then cleaved into urea and ornithine, thereby reestablishing the cycle. The net energy cost of this cycle is four HEPs, derived from three molecules of ATP. Atkinson and Bourke (56) have suggested an important role for ureagenesis in the maintenance of pH homeostasis. Because the oxidation of amino acids yields both bicarbonate and ammonium ions, the urea cycle promotes the neutralization of the bicarbonate ion by the proton of the ammonium ion during the formation of carbonyl phosphate. The remaining carbon skeletons of amino acid deamination or transamination are converted either to intermediates of the TCA cycle or to precursors of acetyl-CoA, such as pyruvate and acetoacetate. Consequently, all the carbon skeletons of amino acids can be oxidized in the TCA cycle to carbon dioxide and water. The carbon skeletons of all the amino acids may also be converted to glucose or fat. As such, they may be classified as glucogenic, ketogenic, or glucogenic and ketogenic (Table 12). Seven (alanine, serine, glycine, cysteine, cystine, proline, and hydroxyproline) of the 22 most common amino

NH3

NONOXIDATIVE DEAMINATION BY DEHYDRATION H2 O Amino acid oxidase Serine [Intermediates] Pyruvate H 2O

NH3

Pi Citrulline

2 ADP+Pi

DIRECT NONOXIDATIVE DEAMINATION Histidase Serine

CO2+NH4 ATP

[Histidine-enzyme]

Pyruvate

Aspartate ATP

Carbamyl phosphate

AMP+PPi Ornithine

UREA CYCLE

Argininosuccinate

NH3 HYDROLYTIC DEAMINATION OF NONALPHA AMINO GROUP Arginine

Asparaginase Asparagine

Aspartate

Urea

Fumarate

H2O NH 3

Figure 10 Mechanisms for removal of the amino group. Source: From Ref. 44.

Figure 11 Urea cycle. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; PPi, inorganic pyrophosphate. Source: From Ref. 44.

Chapter 1:

Table 12 Pathways for the Use of Amino Acid Carbon Fragments Gluconeogenesis Alanine Arginine Aspartic acid Asparagine Cystine Glutamic acid Glycine Histidine Hydroxyproline Methionine Proline Serine Threonine Valine

Ketogenesis Leucine

Gluconeogenesis and ketogenesis Isoleucine Lysine Phenylalanine Tyrosine Tryptophan

acids in proteins are converted to pyruvate. Depending on the redox state of the cell, the pyruvate can either be used for gluconeogenesis or converted to acetyl-CoA. Five amino acid carbon skeletons (phenylalanine, tyrosine, tryptophan, leucine, and lysine) form acetoacetate that may be converted to acetyl-CoA and either oxidized in the TCA cycle or used in fatty acid–synthesis. In addition, in the process of producing acetoacetate, phenylalanine and tyrosine are also cleaved to fumarate, and tryptophan is cleaved to alanine. Thus, phenylalanine, tyrosine and tryptophan may be used both in glucogenesis and in ketogenesis. Lysine may also be used both in glucogenesis and ketogenesis, but its precursor for gluconeogenesis is not known. In contrast, leucine forms one molecule of acetyl-CoA and one molecule of acetoacetate. Because neither acetyl-CoA nor acetoacetate can be converted to pyruvate, the carbon skeleton of leucine can only be used for ketogenesis or oxidation.

Metabolic Response to Starvation, Stress, and Sepsis

13

It should be apparent that any compound that enters the TCA cycle as acetyl-CoA cannot be used as a precursor of glucose. This relates to the fact that by the time it reaches malate, the acetyl-CoA that entered the TCA cycle has been completely oxidized. However, the carbon skeletons of amino acids that are TCA-cycle intermediates can be used for gluconeogenesis. In addition to phenylalanine and tyrosine, which enter the TCA cycle as fumarate, three amino acids enter as succinyl-CoA (isoleucine, methionine, and valine), and two other amino acids enter as oxaloacetate (aspartate and asparagine) and give amino acids that enter as a-ketoglutarate (glutamate, glutamine, proline, histidine, and arginine) (Fig. 12). Consequently, all these amino acids may be used either in gluconeogenesis or in oxidation. Quantitatively, in the isolated perfused liver, only alanine, serine, threonine, and glycine are used in significant amounts for gluconeogenesis (57). As noted previously, excess nitrogen cannot be stored. When the protein intake is excessive, the amino acids resulting from proteolysis are catabolized to nitrogen and a carbon skeleton. The nitrogen is converted to urea, and the carbon skeleton is converted to glucose, lipid, or carbon dioxide, depending on the needs of the cell and the redox state present. Similarly, when glucose is needed but unavailable, excess ingested proteins or existing body proteins are degraded. Although it may be imperceptible, the use of existing body protein for energy or gluconeogenesis always results in the loss of some cellular function.

Lipid Metabolism The final and greatest source of energy in the body is lipid. Stored in adipose tissues as triglycerides, lipids can be released on demand and transported to most tissues for use as an energy source. Tissues capable of using lipids include the liver, kidney, heart, and skeletal muscle; such use,

Figure 12 Pathways through which the carbon skeletons of a-amino acids enter the tricarboxylic acid cycle.

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Part One: General Considerations

however, must occur under aerobic conditions. Non–lipidusing tissues include erythrocytes, leukocytes, and nerve cells. Triglycerides are composed of three fatty acid–chains linked together by a glycerol molecule. During lipolysis, the fatty acids are sequentially cleaved off the glycerol moiety by lipases. The remaining glycerol moiety can then be used for glucose synthesis or converted to pyruvate (Fig. 7). In contrast, fatty acids themselves cannot be used as substrate for gluconeogenesis, because they are ultimately broken down to acetyl-CoA. The catabolism of fatty acids can be divided into two stages. These stages include b-oxidation in the outer mitochondrial membrane to produce molecules of acetyl-CoA, and the processing of acetyl-CoA in the mitochondria to produce carbon dioxide and energy or ketone bodies (Fig. 13) (58,59). Only the first step in fatty acid–catabolism requires energy. In this step, the enzyme thiokinase adds CoA to a fatty acid, producing a fatty acetyl-CoA (Fig. 13). After a sequence of reactions, the final two carbons on the fatty acetyl-CoA are cleaved, resulting in the production of one molecule of acetyl-CoA and a new fatty acetyl-CoA that is two carbon atoms shorter than the parent fatty acetyl-CoA. This process of b-oxidation yields five HEPs per acetyl-CoA formed and, with even-numbered fatty acid chains, continues until the entire fatty acid has been cleaved to acetyl-CoA. In the case of odd-numbered fatty acid chains, b-oxidation continues until a three-carbon fatty acetyl-CoA (propionyl-CoA) remains. The latter substance may then be converted to succinyl-CoA and enter the TCA cycle. The acetyl-CoA that results from the oxidation of fatty acids can be used in one of the three available pathways (Fig. 13) (58,60). The first involves the intramitochondrial oxidation of acetyl-CoA through the TCA cycle to two molecules of carbon dioxide and 12 HEPs. Thus the total

oxidation of a 20-carbon fatty acid, for example, yields: 169 HEPs ¼ ½ð10 5Þ þ ð10 12Þ 1 The second pathway involves the ketogenic pathway in the liver (Fig. 14). Through the action of the enzyme thiolase, two molecules of acetyl-CoA combine to form acetoacetyl-CoA in a freely reversible reaction. AcetoacetylCoA can then be converted to 3-hydroxy-3-methylglutaryl CoA, the precursor in cholesterol synthesis and ketone body formation. The three ketone bodies, acetoacetate, b-hydroxybutyrate, and acetone, are normally produced and released by the liver. Under conditions in which there is an abundance of hepatic glycogen, b-hydroxybutyrate predominates; under conditions in which the liver glycogen is low, acetoacetate predominates. The ketone bodies that are released by the liver can then be used by a variety of peripheral tissues, such as cardiac and skeletal muscle, as a source of energy by conversion back to acetyl-CoA. The final pathway for use of acetyl-CoA is in the synthesis of fatty acids and triglycerides (Fig. 13). This pathway is stimulated by neuroendocrine mechanisms and low cytoplasmic concentrations of fatty acids. Lipogenesis is a cytoplasmic process that requires malonyl-CoA. MalonylCoA is formed from acetyl-CoA by acetyl-CoA carboxylase. When fatty acid–levels are low, the rate-limiting enzyme in malonyl-CoA formation, acetyl-CoA carboxylase, is stimulated, leading to increased intracellular concentrations of malonyl-CoA (61). In turn, the elevated concentration of malonyl-CoA inhibits carnitine acetyl transferase, the enzyme necessary for transport of acetyl-CoA into the mitochondria (62), resulting in an increased concentration of cytoplasmic acetyl-CoA that can then be used for malonyl-CoA synthesis and ultimately for the synthesis of triglycerides and other lipids. In contrast, when the intracellular concentrations of

Figure 13 Metabolic pathways of fatty acid metabolism in the liver. Abbreviations: GAA, gossypol acetic acid; TCA, tricarboxylic acid. Source: From Ref. 1.

Chapter 1:

Acetyl-CoA Thiolase CoA

SH

Acetoacetyl-CoA H 2O HMG-CoA synthetase

Acetyl-CoA CoA

SH

3-Hydroxy-3-methylglutaryl CoA Acetyl CO2 CoA Acetone

HMG-CoA lyase

Acetoacetate

Beta-hydroxybutyrate dehydrogenase

Steroids

Cholesterol NADH NAD+

Beta-hydroxybutyrate

Bile salts

Cholesterol esters

Figure 14 Ketogenic pathway and cholesterol pathway in the liver. Abbreviations: CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; NADH, reduced nicotinamide adenine dinucleotide. Source: From Ref. 44.

fatty acids are elevated, the rate-limiting enzyme in malonylCoA synthesis (acetyl-CoA carboxylase) is inhibited. Malonyl-CoA concentrations decrease, thereby stimulating carnitine acetyl transferase and increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis (62). The inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through inhibition of PFK, the so-called Randle effect (45).

NEUROENDOCRINE REGULATORY MECHANISMS Stimuli and Mechanism of Action of the Neuroendocrine System The pathways of intermediary metabolism and substrateto-substrate interactions noted previously are under the local control of substrate availability, cellular redox potential, and cellular energy availability. The integration of this control is governed by the neuroendocrine system. This system may be thought of as a reflex physiologic network in which alterations in homeostasis are perceived by specialized receptors that are located both peripherally and centrally. The receptors

Metabolic Response to Starvation, Stress, and Sepsis

15

transmit their information to the central nervous system (CNS), where the afferent signals are processed and modulated, resulting in release or inhibition of numerous neuroendocrine effectors that produce physiologic changes aimed at correcting the alterations in homeostasis. In the absence of significant injury, sepsis, or starvation, alterations in homeostasis are small, and the responses of the neuroendocrine system to stimuli are directed at fine tuning and integrating the functioning of the organism. In the presence of significant injury, sepsis, or starvation, the stimuli are multiple and intensified, and the reflexes are directed at an integrated attempt by the organism to preserve oxygen delivery, mobilize energy substrates, and minimize pain (Fig. 15) (1). The major stimuli affecting neuroendocrine reflexes include (i) changes in the circulating body fluids; (ii) changes in the oxygen, hydrogen ion, and carbon dioxide concentrations in tissues and blood; (iii) changes in ambient and core temperature; (iv) changes in substrate availability; (v) emotional arousal; (vi) pain; and (vii) infection. Critical to the initiation of the neuroendocrine response is the perception of the stimulus. Paraplegics do not respond to stimuli below the level of cord transection. This lack of response is thought to be the result of the absence of afferent impulses reaching the brain (63). However, conscious perception of the stimulus is not required. An individual responds to a stimulus in the presence of anesthesia, but the response may not be the same as that in the absence of anesthesia. Changes in the circulating body fluids may result from the direct loss of blood (as in hemorrhage), from the loss of plasma volume (as in third-space losses and dehydration), or from the inability of the body fluids to circulate (as in cardiac failure or pulmonary embolism). The changes in circulating body fluids are sensed by high-pressure baroreceptors in the carotid arteries and aorta and by low-pressure stretch receptors in the right atrium. Under normal conditions, the afferent signals from these receptors exert a tonic inhibition of the release of many hormones and of the activities of the CNS and autonomic nervous system (64). When baroreceptor or stretch-receptor activities decrease (e.g., a decrease in blood pressure or blood volume), the tonic inhibition is released, resulting in the increased secretion of adrenocorticotropic hormone (ACTH), vasopressin, b-endorphin, and growth hormone through central pathways and resulting in the increased secretion of epinephrine, norepinephrine, renin, and glucagon through peripheral

Infection Pain

+

Hemorrhage plus ECF loss

Peripheral nerves

Baroreceptors + +

Hypoxemia

+

Fear and anxiety + + + Central _ nervous system +

+ Endocrine glands + + Sympathetic nervous system

Chemoreceptors – + Cardiac stimulation Vascular resistance Fluid shifts + Respiratory stimulation

medwedi.ru

Figure 15 Overview of the neuroendocrine reflexes induced by shock and trauma. Abbreviation: ECF, extracellular fluid. Source: From Ref. 1.

16

Part One: General Considerations

autonomic neural pathways. These responses bring about further neuroendocrine changes such as the inhibition of insulin secretion by epinephrine (65) and the stimulation of aldosterone secretion by renin and ACTH (66). Changes in blood concentrations of oxygen, hydrogen ion, and carbon dioxide initiate neuroendocrine responses through the activation of peripheral chemoreceptors. The chemoreceptors, which are located in the aortic and carotid bodies, have an extremely high–blood flow rate (67). Under normal conditions, these receptors are not activated. However, changes primarily in oxygen and secondarily in carbon dioxide and in hydrogen ions are sensed by these receptors, which result in the activation of neuroendocrine pathways. Because of the high blood flow through the chemoreceptors, the partial pressure of oxygen (PO2) of arterial blood, chemoreceptor tissue, and venous blood is nearly the same. However, a drop in blood flow increases the oxygen extraction by the chemoreceptor tissue, decreases the venous PO2, and through an unknown mechanism, activates the chemoreceptor (67). Consequently, a decrease in circulating volume or pressure not only inhibits baroreceptors and stretch receptors, but also activates chemoreceptors. Pain and emotion also activate the neuroendocrine system. The former acts through the projections of peripheral nociceptive receptors to the CNS, and the latter acts through projections from the limbic areas of the brain to the hypothalamus and lower brain stem nuclei (68). Through these pathways, pain and emotional arousal bring about increased hypothalamic, autonomic, adrenomedullary, and adrenocortical activities, the so-called fight- or-flight reaction of Cannon (69). Abnormalities in core and ambient temperatures, as well as infection, also stimulate neuroendocrine reflexes. Changes in the core temperature of the body are sensed in the preoptic area of the hypothalamus. These changes may result from alterations in ambient temperature, a loss of the normal insulating barrier of the skin (e.g., burns), or a reduction in hepatic thermogenesis produced by inadequate blood flow or substrate supply or in response to inadequate peripheral vasoconstriction or vasodilation. Infection may also decrease the core temperature through the action of endotoxin. Infection may further stimulate neuroendocrine reflexes through a direct action of endotoxin on the hypothalamus (70) or through secondary changes in blood volume, oxygen concentration, substrate concentrations, and pain. The primary substrate alterations that activate the neuroendocrine system are those induced by changes in the plasma glucose concentration. Plasma glucose alterations are sensed by receptors in the hypothalamus and the pancreas. A decrease in plasma glucose concentration stimulates the release of catecholamines, cortisol, growth hormone, and vasopressin through central mechanisms and stimulates the release of glucagon both by central pathways (autonomic nervous system) and peripheral pathways (direct pancreatic activation) (71). In addition, the secretion of insulin is inhibited through central pathways (autonomic nervous system) and directly by the pancreas itself (65). All these stimuli are commonly produced by injury, sepsis, and starvation. Furthermore, these stimuli rarely occur singly. Generally, the individual perceives multiple stimuli that occur both simultaneously and sequentially. Thus the neuroendocrine response is the summation of all the stimuli the individual perceives and processes. According to classic endocrine feedback mechanisms, the

elevation of serum cortisol resulting from one set of stimuli would be expected to inhibit the release of ACTH by a new set of stimuli. Following most injuries, this is not true. The secretion of ACTH is unchanged or increased (potentiated), and the secretion of cortisol may also increase. The mechanism of action of this physiologic facilitation is incompletely understood, but it appears to take 60 to 90 minutes to be of sufficient magnitude to offset the inhibition, and lasts for at least 24 hours (72). Physiologic facilitation and potentiation have been demonstrated with sequential hemorrhages (73) and repeated operations (74), in response to hypoxia and surgery (75), with pain and hemorrhage (20), and with elevated core temperature and hemorrhage (76). Consequently, the response to an injury or an alteration in homeostasis may be modified by previous stimuli, and the response to a second set of stimuli may be different if they had occurred first. The efferent limb of the neuroendocrine system arises from two primary areas, the hypothalamic–pituitary axis and the autonomic regions of the brain stem. The output from the former region involves the release of numerous pituitary hormones, and the output from the latter region involves changes in the neural activities of the sympathetic and parasympathetic nervous systems. Both sets of output either may cause direct changes in physiologic functions or may stimulate or inhibit the secretion of peripheral endocrine organs. The hormones secreted by endocrine organs and the autacoids produced by tissues fall into one of five chemical classes. These include the fatty acid–derivatives of cholesterol (cortisol and aldosterone) or arachidonic acid (prostaglandins), proteins (insulin and glucagon), glycoproteins [thyroid-stimulating hormone (TSH) and corticotropin], small polypeptides (vasopressin and enkephalin), and the amines (catecholamines and serotonin). All these agents act on cellular receptors that are either on the surface of cell membranes or in the cytoplasm of the cell. These cellular receptors are neither fixed nor unchangeable. Instead, they are in a dynamic state in which the number of receptors on cells can be increased (up regulation) or decreased (down regulation) according to need. Furthermore, the affinity of these receptors for their specific hormone can also be changed (77). Steroid hormones (and possibly thyroxine), which are freely permeable to cell membranes, bind to cytosolic receptors in target cells (78,79). The hormone–receptor complex migrates to the cell nuclei, where it interacts with DNA to modulate the transcription of messenger RNA and ultimately the synthesis of enzymatic, structural, and regulatory proteins (Fig. 16A) (78). This may, in part, explain the one- to two-hour delay in the action of steroid hormones. In contrast, the action of most peptide and amine hormones, which generally bind to cell surface receptors, is faster and of shorter duration. In general, these hormones act either through alterations in the intracellular concentrations of cyclic adenosine monophosphate (cAMP) or calcium, the so-called second messengers (81,82), or through other intermediates (growth hormone through somatomedins). The second messenger system of hormonal action operates primarily through the activation and inactivation of regulatory proteins and enzymes rather than through the synthesis of new proteins. This difference explains the faster onset of action and shorter duration of effect of hormones that operate through this system in contrast to those of steroid and other lipid-soluble hormones. The adrenergic receptor system may be considered the prototype for examining the mechanisms of second

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

17

Figure 16 (A) Proposed mechanism of action of steroid hormones. (B) Proposed mechanism of action of peptide hormones through the second messenger system. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; m, molecular; MW, molecular weight. Source: From Refs. 1, 80.

messengers, because all the second messenger pathways known are represented in the four adrenergic receptors (a1, a2, b1, and b2) (Fig. 16B). b1- and b2-receptors (differentiated on the basis of radioligand-binding affinity) both function through the activation of membrane-bound adenylate cyclase, which in turn leads to the production of cAMP (81). The increased intracellular concentration of cAMP activates an inactive protein kinase by attaching to a binding protein on the protein kinase molecule. The attachment of cAMP to the regulatory subunit protein results in the release of an active protein kinase that in turn phosphorylates an inactive phosphorylase kinase to an active form. The active phosphorylase kinase then phosphorylates dephosphoregulatory enzymes, possibly resulting in the activation of the regulatory enzyme (e.g., glycogen phosphorylase) or in its inactivation (e.g., glycogen synthetase) (Fig. 17) (83). In addition, active protein kinase may directly act on dephosphoregulatory enzymes without the activation of phosphorylase kinase. In contrast, a2-receptor activation inhibits membrane-bound adenylate cyclase, thereby decreasing the concentration of cAMP and active protein kinase. Activation of a1-adrenergic receptors results in an increase in phosphatidylinositol turnover that then mediates an increase in intracellular

calcium from intracellular and extracellular sources (81,84). The increase in intracellular calcium activates a calciumbinding protein kinase or phosphorylase kinase (Fig. 16B). The actions of intracellular cAMP and calcium in the coupling of receptor activation with hormonal action (stimulus–response coupling) are not independent. Instead, there is a duality to this system in which the actions of calcium and cAMP are highly interrelated, termed synarchic control by Rasmusen (81). As noted in Fig. 18 and Box 2, there are five basic patterns to the synarchic control of hormone-response coupling through cAMP and calcium. In co-ordinate control, a hormone activates both a calciumactivating receptor and a cAMP-activating receptor, either one of which may produce the response alone. In hierarchal control, separate stimuli activate independently the calcium and cAMP pathways that are both necessary for a given response. In sequential control, the activation of one of the two lines of the system leads to the activation of the other limb. Although the first limb can produce the response, activation of the second limb augments the response. In redundant control, two separate stimuli independently activate the two different limbs of the messenger system, either one of which can produce the response. Finally, in

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Part One: General Considerations

Box 2 Calcium–Cyclic AMP Interactions in Stimulus-Response Coupling

Figure 17 Activation of protein kinase leading to enzymatic or physiologic response. Activation of the dephosphoenzyme by phosphorylation may be brought about either directly by the active protein kinase or indirectly through the activation of a phosphorylase kinase by the active protein kinase. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. Source: From Ref. 80.

antagonist control, one stimulus activates one limb of the messenger system that leads to the response, and a second stimulus activates the second limb, which inhibits the ability of the first limb to produce the response. Although each of these control mechanisms can occasionally be found in cells in pure form, most of the presently known hormone– response coupling mechanisms involve mixed patterns (81).

1. Effects of calcium on cAMP messenger systems a. Stimulates cAMP production—brain, adrenal cortex, pancreatic islets, adrenal medulla, slime mold b. Stimulates cAMP hydrolysis—brain, heart, liver, kidney, fly salivary gland, many other tissues c. Activates phosphoprotein product of cAMP-dependent protein kinase, glycogenolysis in many tissues 2. Effects of cAMP on calcium messenger system a. Increases calcium entry across plasma membrane—heart, synapse b. Increases calcium release from mitochondria—kidney, liver, fly salivary gland, others c. Increases calcium uptake by microsomes—heart, uterus, liver, smooth muscles d. Increases calcium efflux across plasma membrane—smooth muscle, heart e. Decreases sensitivity of response elements to calcium—smooth muscle, heart f. Increases sensitivity of response element to calcium—phosphorylase beta kinase, liver, muscle 3. Interrelated activities a. cAMP-dependent and calcium-dependent protein kinases act upon same protein substrate—liver, brain, adrenal cortex b. Regulate sequential steps in metabolic or transport process—secretion in fly salivary gland, glycogenolysis Abbreviation: cAMP, cyclic adenosine monophosphate. Source: From Ref. 81.

Hormonal Regulation of Metabolism The neuroendocrine system is able to regulate metabolic reactions through three basic processes. First, it may increase substrate availability so that by simple stoichiometry (mass action), reactions proceed in a desired direction. This process can be brought about either by an increase in the plasma

COORDINATE CONTROL ++

R1

Ca

R2

cAMP

Response

H

HIERARCHICAL CONTROL H1

R1

++

Ca

+

Response

SEQUENTIAL CONTROL H

R

Ca

H2

R2

++

Response

+

cAMP

cAMP H

cAMP

R +

Ca

REDUNDANT CONTROL H1

R1

++

Ca

Response

++

ANTAGONISTIC CONTROL ++

H1

R1

Ca

H2

R2

cAMP

–

Response

Response H2

R2

cAMP

Figure 18 Patterns of synarchic regulation by calcium and cyclic adenosine monophosphate. Source: From Ref. 81.

concentration of a substrate or by alterations in blood flow and its distribution. Second, the neuroendocrine effectors can alter the membrane transport properties of cells for a given substrate so that more or less of the substrate enters or leaves the cell. Third, the neuroendocrine effectors can alter the activity or synthesis of key regulatory enzymes that are necessary for reactions to proceed. Most hormones operate through more than one of these processes. For example, insulin stimulates both glycogen synthetase and the transport of glucose into cells. In this manner, insulin not only activates the enzymatic mechanisms necessary for glycogenesis, but also increases the availability of the necessary substrates. It would be futile for a hormone to stimulate opposing processes in a given cell. If a hormone stimulated both glycogenesis and glycogenolysis, there would be no net effect. As a result, most hormones not only activate the enzymes necessary for one metabolic pathway, they also inhibit the enzymes necessary for the opposing process. Thus epinephrine, through an a-mechanism, activates glycogen phosphorylase and inactivates glycogen synthetase, whereas insulin inactivates glycogen phosphorylase and activates glycogen synthetase. The coordinated control of metabolism also requires that a hormone not have opposing actions in different tissues. Thus by increasing amino acid uptake in skeletal muscle and decreasing amino acid degradation in the liver, insulin promotes the availability of an abundant substrate supply for the enzymes of protein synthesis it activates. Cortisol produces an inhibition of amino acid uptake in skeletal muscle, increases amino acid uptake by the liver, and stimulates hepatic gluconeogenic enzymes. These processes ensure that an abundant supply of amino acids is available to the liver for cortisol-stimulated gluconeogenesis.

Chapter 1:

The primary hormones involved in the regulation of metabolism include insulin, cortisol, epinephrine, glucagon, growth hormone, vasopressin, and somatostatin. Insulin is the primary anabolic hormone promoting the synthesis of glycogen, proteins, and lipids. Cortisol, epinephrine, glucagon, and vasopressin are the primary catabolic hormones promoting the breakdown of glycogen, proteins, and lipids and the synthesis of glucose from gluconeogenic amino acids, lactate, and pyruvate. In contrast, the actions of growth hormone initially are anabolic, but its late effects are primarily catabolic.

Insulin, Glucagon, and Somatostatin Insulin, composed of two polypeptide chains, one containing 21 amino acids and the other 30 amino acids, and glucagon, a 29–amino acid polypeptide, are produced and secreted by the pancreatic B cells (beta islets of Langerhans) and A cells (alpha islets of Langerhans), respectively. The secretion of both of these hormones is under the control of at least three mechanisms: (i) circulating substrates (glucose, amino acids, and free fatty acids); (ii) the autonomic nervous system; and (iii) other circulating hormones. Under normal physiologic conditions, glucose is the most important regulator of insulin and glucagon secretion. When the plasma concentration of glucose increases, the secretion of insulin increases, and the secretion of glucagon decreases. When the plasma concentration ofglucosedecreases, the secretion of insulin decreases, and the secretion of glucagon increases. These changes are probably the result of a direct action of glucose on pancreatic islet cells and not a result of neuroendocrine modulation of the pancreas by other neuroendocrine effectors (85). The direct action of glucose on islet cell function may be mediated either through a glucoreceptor on the surface of the islet cell or through the intracellular metabolism of glucose in the islet cells (86). Elevations in the plasma concentration of amino acids stimulate the release of both insulin and glucagon. Most, if not all, of the amino acids increase insulin secretion, but the potency of amino acids in stimulating glucagon secretion is variable (87). In general, more gluconeogenic amino acids appear to stimulate glucagon secretion (87). High concentrations of fatty acids stimulate the secretion of insulin and inhibit the secretion of glucagon. Conversely, low concentrations of free fatty acids inhibit the secretion of insulin and stimulate the secretion of glucagon. The potency of fatty acids in regulating insulin and glucagon secretion is substantially less than that of glucose (87). The stimulation of insulin secretion and the inhibition of glucagon secretion after the administration of an oral glucose load are greater than that following the intravenous administration of glucose (88). Similarly, the stimulation of both insulin and glucagon secretion is greater after an oral protein or amino acid load than it is after the intravenous administration of amino acids and protein (89). This effect is thought to be the result of the higher concentrations of substrate in the pancreas, the potentiation by gastrointestinal hormones of the substrate effect on the pancreas, and the effect of neural input to the pancreas that has been stimulated by eating (87). The gastrointestinal hormones, cholecystokinin, gastrin, vasoactive intestinal peptide, substance P, neurotensin, and gastric inhibitory peptide (GIP), increase the secretion of both insulin and glucagon in pharmacologic concentrations (87,90). Although gastrin does appear to potentiate the release of glucagon and insulin induced by amino acids and GIP in physiologic concentrations and

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19

appears to augment the release of insulin by glucose (87), and the physiologic role of gastrointestinal hormones is not certain. The pancreatic A cells and B cells both have a- and b-adrenergic receptors that alter the secretion of insulin and glucagon. a-Adrenergic stimulation of the pancreas inhibits the secretion of both insulin and glucagon, whereas b-adrenergic stimulation of the pancreas stimulates the secretion of both insulin and glucagon (91,92). However, the a- and b-adrenergic receptor density of A cells and B cells is not the same. The b-adrenergic receptor density of A cells is greater than that of B cells (92). As a result, increased sympathetic stimulation of the pancreas or increased circulating concentrations of epinephrine or norepinephrine increase the secretion of glucagon but decrease the secretion of insulin (91,92). In contrast, isoproterenol infusion increases the secretion of both insulin and glucagon (92). In addition to sympathetic stimulation, the parasympathetic limb of the autonomic nervous system alters pancreatic hormone secretion. Both acetylcholine infusion and direct parasympathetic stimulation of the pancreas increase the secretion of both insulin and glucagon (87). In addition to the gastrointestinal hormones and the autonomic nervous system, other hormones alter the secretion of insulin and glucagon. b-Endorphin appears to directly increase the secretion of insulin and glucagon (93), insulin inhibits the release of insulin and stimulates the release of glucagon (87), and glucagon inhibits the release of glucagon and stimulates the release of insulin (87,94). Insulin and glucagon appear to exert their action both directly on islet cells and by the alterations they produce in circulating substrates (87). Cortisol stimulates the release of insulin and glucagon, but it appears to have no direct activity on the secretory ability of A cells and B cells. Instead, cortisol is believed to increase glucagon secretion through an increase in plasma amino acids and to increase insulin secretion by an increase in plasma glucose. In this regard, both cortisol and epinephrine are able to inhibit the peripheral actions of insulin, and both are thought to exert a major role in insulin resistance (95,96). Somatostatin, a tetradecapeptide, is a potent inhibitor of both insulin and glucagon secretion (90,97). In addition to its location in pancreatic D cells, somatostatin is found in the hypothalamus, limbic system, brain stem, spinal cord, other neural tissue, salivary glands, parafollicular thyroid cells, kidneys, and gastrointestinal tissue (90). Although somatostatin was originally named for its ability to inhibit growth hormone secretion, somatostatin is now recognized to inhibit the secretion of TSH, renin, calcitonin, gastrin, secretin, cholecystokinin, insulin, and glucagon (90). In addition, somatostatinergic nerve fibers are involved in the projection of impulses from peripheral sensory organs to the neuroaxis (90). The role somatostatin exerts in the physiologic regulation of insulin and glucagon secretion is not known precisely. The A, B, and D cells have somatostatin receptors that, when activated, inhibit the secretion of glucagon, insulin, and somatostatin, respectively. Although the mechanism of action of somatostatin is thought to be mediated primarily by the local diffusion of somatostatin from D cells to A cells and B cells (90,97), current evidence suggests that somatostatin reaching the pancreas through the blood stream may be more important (98). The effects of somatostatin on A cells are transient, but the effects on B cells are persistent (97). This persistence may account for the relative hyperglycemia that occurs in patients with somatostatinomas or after the longterm administration of somatostatin (97).

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The physiologic actions of glucagon occur primarily in the liver and are mediated through an increase in intracellular cAMP. The activation of glycogen phosphorylase and the inhibition of glycogen synthetase by glucagon promote the breakdown of glycogen to glucose (glycogenolysis) (45). In addition, glucagon stimulates gluconeogenesis through the stimulation of phosphoenolpyruvate carboxykinase, amino acid transport, and amino acid transamination (45,99). The net result is an increase in hepatic production and release of glucose that under basal conditions accounts for 75% of the glucose produced by the liver (100). Glucagon also exerts an important influence over hepatic lipid metabolism. In addition to stimulating lipolysis in adipose tissue and the liver, glucagon inhibits acetyl-CoA carboxylase, the enzyme that converts acetyl-CoA to malonyl-CoA (87). In turn, the reduction in malonyl-CoA produces inhibition of triglyceride synthesis and activation of carnitine acyl transferase. The latter increases fatty acid transfer to the mitochondria and therefore increases the oxidation of acetyl-CoA and ketogenesis (58,87). Peripheral actions of glucagon include the stimulation of lipolysis in adipose tissue, of glycogenolysis in skeletal muscle, and of myocardial contractility (101–103). However, these actions do not appear to be of physiologic significance in human beings (101–103). As a result of glucagon’s ability to increase hepatic glucose production, mobilize fat, and increase ketogenesis, glucagon is important in normal metabolism and more so in the metabolism of altered states. However, the effects of glucagon are evanescent (104). After 30 to 60 minutes, the activity assigned to glucagon decreases even if plasma glucagon concentrations remain elevated. Therefore it appears that an increase in glucagon concentration rather than the absolute amount of glucagon present is a key determinant of glucagon activity (104). This effect also appears to be true of other cAMP-mediated hormones (the burst effect). The physiologic activity of insulin is primarily in the liver, skeletal muscle, and adipose tissue, but insulin does affect many other peripheral tissues. Notable exceptions include erythrocytes and wounded tissue. Insulin promotes the entry of glucose into cells by stimulating the membrane transport of glucose. The increased intracellular concentrations of glucose are used in glycogen synthesis (stimulation of glycogen synthetase and inhibition of glycogen phosphorylase) and in glycolysis (stimulation of glucokinase, PFK, and pyruvate kinase) to produce energy (45). In addition, insulin inhibits gluconeogenesis through the inhibition of phosphoenolpyruvate carboxylase and the stimulation of PFK and pyruvate kinase (45). Insulin also increases the membrane transport of amino acids into the liver and peripheral tissues. The increased intracellular concentrations of amino acids are used in protein synthesis (stimulation of protein synthesis and inhibition of proteolysis). By inhibiting gluconeogenesis and amino acid oxidation, insulin further directs the intracellular amino acids to protein synthesis (99). In adipose tissue, insulin stimulates lipogenesis and inhibits lipolysis, as it does in the liver. By stimulating lipoprotein lipase, insulin also makes triglycerides more available for uptake from the plasma by adipose tissue. Glycerol synthesis and the action of the pentose-phosphate shunt also are increased by insulin in adipose tissue and the liver. Thus insulin is the primary anabolic hormone promoting the storage of lipid, glucose, and protein.

Although insulin and glucagon oppose each other in the metabolic processes each stimulates, a bihormonal response is necessary for maintenance of glucose homeostasis after a protein meal (90). If insulin were secreted alone in response to a protein meal, the increase in protein synthesis and decrease in hepatic glucose production would result in hypoglycemia. Conversely, if glucagon were secreted alone, the decrease in protein synthesis and the increase in hepatic gluconeogenesis would result in hyperglycemia. However, when a rise in glucagon is accompanied by an increase in insulin, hepatic glucose production remains unchanged and euglycemia is maintained. In this regard, Unger (105) has proposed the insulin/glucagon (I/G) ratio as a quantitative measure of hepatic glucose balance. When the I/G ratio is greater than 5, anabolism and protein synthesis are favored. When the I/G ratio is less than 3, glycogenolysis, gluconeogenesis, and lipolysis are favored. However, the validity of this relationship has been questioned (86).

ACTH, Cortisol, and Epinephrine The primary hormones released in response to any physiologic or psychologic stress are the glucocorticoids and catecholamines. These hormones are in large part responsible for the ‘‘fight-or-flight reaction.’’ The release of cortisol is under the control of ACTH, a 39–amino acid polypeptide released from the chromophobe cells in the anterior pituitary gland. In turn, the release of ACTH is itself under the inhibitory influence of cortisol and the stimulatory influence of corticotropin-releasing factor (CRF) produced by the hypothalamus. The release of CRF (and ACTH–cortisol) is stimulated by all the stimuli noted previously and is potentiated by vasopressin, oxytocin, and angiotensin II (106,107). ACTH acts directly on cells of the adrenal zona fasciculata, stimulating the production and release of cortisol through a cAMPmediated conversion of cholesterol to pregnenolone (108). The catecholamines (epinephrine, norepinephrine, and dopamine) are the prototypical neuroendocrine effectors that act as neurotransmitters and hormones (109). Epinephrine, produced almost exclusively by the adrenal medulla, functions primarily as a hormone, whereas norepinephrine and dopamine function primarily as neurotransmitters (109). Although the adrenal medulla may be viewed as a collection of postganglionic sympathetic neurons without axons that release their neurotransmitters into the general circulation, the activation of the sympathetic nervous system does not occur in an all-or-none fashion, and it is not synonymous with adrenomedullary secretion (110). Similarly, adrenomedullary stimulation is not synonymous with the complete activation of the sympathetic nervous system. Numerous stimuli have been identified that lead to increased secretion of catecholamines from the adrenal medulla (e.g., hypotension, hypoxia, hypoglycemia, pain, and fear), but the exact mechanisms involved in adrenomedullary control remain poorly understood (110). Both cortisol and epinephrine function as ‘‘counterregulatory’’ hormones, mediating catabolic processes throughout the body. In the liver, cortisol inhibits several key glycolytic enzymes (glucokinase, PFK, and pyruvate kinase), the pentose-phosphate shunt, and the actions of insulin (45,108). In addition, cortisol stimulates the hepatic uptake of amino acids, transaminases, and several gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase), as well as potentiating the actions of glucagon and epinephrine (45,95,111). As a result, the production of glucose, lactate, and pyruvate by the liver is increased.

Chapter 1:

The metabolic effects of epinephrine are similar to those of glucagon but are more widespread, affecting peripheral tissues and the liver. In the liver, epinephrine stimulates glycogenolysis (a1-mediated stimulation of glycogen phosphorylase and inhibition of glycogen synthetase) (81), lipolysis (b1-mediated activation of triacylglycerol lipase) (112), ketogenesis (b1-mediated inhibition of acetylCoA carboxylase leading to decreased malonyl-CoA and increased carnitine acyl transferase) (68), and gluconeogenesis (b1-mediated inhibition of PFK and hexokinase by the products of glycolysis and glycogenolysis) (113). Thus epinephrine serves to increase hepatic glucose production and lipid breakdown. Although both glucagon and epinephrine increase glucose production by the liver, glucose use by peripheral tissues is not the same in the presence of epinephrine as it is in the presence of glucagon (99). Glucagon promotes the use of glucose by peripheral tissues through the stimulation of insulin secretion. In contract, epinephrine inhibits both the release and the action of insulin, thereby decreasing glucose use in insulin-dependent peripheral tissues. However, epinephrine serves to increase glucose availability to insulin-insensitive tissues such as the brain, whereas glucagon does not shunt glucose to insulininsensitive tissues (99). In adipose tissue, epinephrine increases lipolysis (b-mediated activation of triacylglycerol lipase). In peripheral tissues, epinephrine stimulates glycogenolysis (a1) and inhibits stimulated glucose uptake through a b2- and a1-mechanism (114,115). As a result of increased substrate availability, glycolysis is increased in skeletal muscle, and large amounts of lactate are produced and released into the circulation. The lactate can then be taken up by the liver for subsequent gluconeogenesis (Cori cycle). Therefore during stressful conditions, epinephrine and cortisol both promote a rise in blood glucose and make glucose more available to glucose-dependent tissues. Both of these hormones also promote the breakdown of lipid and thereby its use as a source of fuel. Whereas the actions of epinephrine are direct, many of the actions of cortisol occur as a result of the potentiation or inhibition of other hormones, the so-called permissive action of cortisol.

Growth Hormone and Vasopressin Growth hormone is a 191–amino acid polypeptide that is released from acidophilic cells in the anterior pituitary gland. Its secretion is under the control of a releasing factor (growth hormone–releasing factor) and by an inhibiting factor (somatostatin) (116). Elevation of blood glucose or free fatty acids stimulates the release of growth hormone (116). In addition, the release of growth hormone is stimulated by vasopressin, ACTH, a-melanocyte–stimulating hormone, and estrogen; release of growth hormone is inhibited by cortisol, thyroxine, and growth hormone itself. In addition to its ability to promote protein synthesis and RNA synthesis and to increase linear growth, growth hormone exhibits an important role in the regulation of metabolic processes. Its effects are biphasic, composed of early effects of three to four hours duration and late effects of longer duration (116). In muscle and liver, growth hormone increases amino acid uptake and protein synthesis (117). In addition, growth hormone stimulates glucose uptake in skeletal muscle and antagonizes the lipolytic effects of catecholamines in adipose tissue while increasing protein synthesis (117). Therefore the early effects of growth

Metabolic Response to Starvation, Stress, and Sepsis

21

hormone are similar to insulin. In fact, growth hormone directly stimulates the secretion of insulin by pancreatic B cells during its early phase (66). The late effects of growth hormone include an increased mobilization of fatty acids and ketone bodies by adipose tissue as a result of increased lipolysis. This action of growth hormone occurs only in the presence of cortisol (118). In addition, growth hormone inhibits insulin-stimulated glucose uptake and use, thereby producing a profound stimulation of insulin release by hyperglycemia (66). Arginine vasopressin (antidiuretic hormone) is a nonapeptide that is released by the posterior pituitary gland. Although released primarily in response to an increase in plasma osmolality and to a reduction in effective circulating volume (98,119), vasopressin release is also stimulated by hypoglycemia through nonosmotic pathways (120). Vasopressin is a powerful stimulator of hepatic glycogenolysis (a-receptor) and also stimulates hepatic gluconeogenesis (121,122). As such, it may exert an important role in elevating the blood glucose after injury and during hypoglycemia.

METABOLIC RESPONSE IN STARVATION, INJURY, AND SEPSIS Fasting and Starvation In the absence of food, fasting humans must supply the energy required for daily activities, glucose for glucosedependent tissue, essential amino acids (Table 12), and essential fatty acids from existing body stores. Cahill (29) has estimated that the average resting 70 kg man using 1800 kcal of energy per day requires 180 g of glucose daily—for the metabolism of nervous tissue (144 g) and for other glycolytic tissue (RBCs, WBCs, and the renal medulla) (36 g) (Fig. 19). Because the available glycogen in the liver is only 75 g (Table 13), this amount will not suffice for either the energy requirements or the glucose needs of a fasting man. Although an additional 150 g of glucose is in skeletal muscle as glycogen, as noted previously, it cannot be released from skeletal muscle as free glucose as a result of the absence of glucose 6-phosphatase. Thus, it is apparent that the energy requirements and glucose requirements of fasting human beings must be supplied from noncarbohydrate sources and by gluconeogenesis. The daily energy requirements can be met by the mobilization of approximately 160 g of triglycerides from adipose tissue in the form of free fatty acids (19). The free fatty acids, as well as ketone bodies produced by the liver, are used throughout the body by nonglycolytic tissues such as the heart, kidney, muscle, and liver. In the liver, energy derived from b-oxidation of fat and from oxidation of acetyl-CoA is used to drive the necessary gluconeogenic processes. Gluconeogenic substrates are available from three sources (Table 14). First, the lipolysis of 160 g of triglycerides releases 16 g of glycerol that can be converted by the liver to glucose. Second, some glucose-dependent tissues (i.e., RBCs and WBCs) convert glucose to lactate and pyruvate that may then be reused in the liver by the Cori cycle to produce new glucose. In addition to the 36 g of lactate and pyruvate produced in this manner, skeletal muscle can also release lactate and pyruvate by the breakdown of glycogen and glucose. Third, approximately 75 g of skeletal muscle protein is degraded daily during starvation, and the resulting amino acids are used in the liver for gluconeogenesis. Consequently, the energy required during brief fasting is derived primarily from adipose tissue. In contrast, the

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Part One: General Considerations

FASTING MAN (24 hours, basal: –1800 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

Nerve Muscle protein 75 g

Amino acids Glycerol 16 g

Adipose tissue Triglyceride 160 g

40 g Fatty acid 160 g

144 g Glucose 180 g 36 g 36 g

Liver Glycogen Gluconeo genesis O2 H2O _P

Ketone 60 g

(Fatty acid) 120 g

glucose required is supplied from lactate, pyruvate, glycogen, and amino acids. During the first two to four days of fasting, there is a rapid increase in the urinary nitrogen excretion from 5 to 7 g/day to approximately 8 to 11 g/day (123). This increase is associated with the previously noted breakdown of 50 to 75 g of protein per day. The rapid proteolysis of skeletal muscle protein does not continue during more prolonged fasting. During the next 20 to 40 days of fasting, the urinary nitrogen excretion begins gradually to decline and eventually reaches its nadir of 2 to 4 g of nitrogen per day (123). This decline is the result of ketoadaptation to starvation. In this process, the brain, which does not normally use ketone bodies for fuel, adapts its metabolism and transport systems to use ketone bodies (124). This adaptation results in a significant reduction in the amount of glucose needed by this glucose-dependent tissue and consequently in the amount of amino acid substrate necessary for gluconeogenesis (Fig. 20). Protein conservation follows with only 20 to 30 g of protein catabolized per day (29). The molecular mechanisms responsible for these adaptive responses are incompletely understood. With respect to skeletal muscle proteolysis, an ATP-ubiquitin-proteasome pathway seems to be involved (125,126). Early in the starvation process, this pathway is activated so that muscle-protein degradation occurs during fasting. As the starvation is prolonged, down-regulation of this process occurs so as to conserve muscle protein stores. Concurrent with these adaptations to starvation is a reduction in the resting energy expenditure by as much as 31% (120). In part, the reduction in resting energy expenditure is the result of a reduction in BCM produced by the breakdown of muscle and other proteins. However, the reduction in body size is less than the reduction in resting energy expenditure (120,127). Other factors that may contribute to the reduction in resting energy expenditure include a reduction in voluntary work, a decrease in body temperature, a decrease in cardiac work, a decrease in sympathetic nervous system activity, and a decrease in muscle activity. The changes in metabolism accompanying fasting and starvation are primarily regulated by decreased concentrations of insulin and increased concentrations of glucagon in response to decreasing glucose concentrations (29,58,123). The decreased insulin concentrations promote an increase in lipolysis in adipose tissue and a decrease in glucose uptake

_P

CO2 + H2O

RBC, WBC, etc. _P Lactate and pyruvate O2 Heart, kidney, muscle, etc.

~P

CO2 + H2O

Figure 19 Flow diagram of fuel metabolism in normal fasted man. Abbreviations: RBC, red blood cell; WBC, white blood cell. Source: From Ref. 29.

in insulin-dependent tissues. The increased concentrations of glucagon promote hepatic gluconeogenesis. These changes (including the decreased secretion of insulin and increased secretion of glucagon) may be further augmented by slight increases in the concentrations of epinephrine, ACTH, cortisol, and growth hormone (103,128). However, an actual increase in these hormones is not necessary, because basal concentrations of the counter-regulatory hormones are unopposed by the reduced secretion of insulin that is stimulated by hypoglycemia. Thus through four major adaptive mechanisms, a reduction in resting energy expenditure, the use of protein for gluconeogenesis, the use of fat for energy, and ketoadaptation of the brain, a human is able to survive for prolonged periods of time without food. As a result of the decreased excretion of urea and nitrogen during prolonged starvation, water intake is also reduced. However, it is apparent that this condition cannot be maintained indefinitely. In the average 70 kg man, there are approximately 170,000 calories and 6000 g of protein (Table 13). If it could all be used, starvation for up to 100 days would be tolerated. However, this is not possible because of the loss of essential body functions as body protein is consumed and not replenished. In fact, acute weight losses of 30% to 40% of body weight are usually fatal and associated with a rapid increase in urinary nitrogen excretion and a rapid decline in plasma glucose (123,129,130).

Table 13 Fuel Composition of Normal Humans Fuel Tissues Fat (adipose triglyceride) Protein (mainly muscle) Glycogen (muscle) Glycogen (liver) Total Circulating fuels Glucose (extracellular fluid) Free fatty acids (plasma) Triglycerides (plasma) Total Source: From Ref. 29.

Weight (kg)

Calories

15 6 0.15 0.075

141,000 24,000 600 300 165,900

0.02 0.0003 0.003

80 3 30 113

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

23

Table 14 Amount of Glucose Produced from Lactate, Glycerol, and Amino Acids During Starvation Grams of glucose produced per day Glucose precursor Glycerola Lactate þ pyruvateb Amino acidsc Total glucose produced from above precursors by liver and kidney cortexd Maximum glucose available for oxidation by the brain (i.e., glycerol and amino acid as precursors)e Fuel requirement of brain (glucose equivalents)f Suggested alternative fuel to glucose for braing

3 or 4 days of starvation

Several weeks of starvation

19 39 41 99

19 39 16 74

60

35

120 Ketone bodies

120 Ketone bodies

a

Amount of glucose produced from glycerol is estimated from the amount of triglyceride hydrolyzed per day. In starvation, 190 g of triglyceride is required to satisfy the caloric needs of the subject. Because glycerol represents 10% of triglyceride, it can provide 19 g of glucose per day. This amount is confirmed by measurement of glycerol uptake by liver and kidney using catheterization techniques. b Amount calculated from glucose 1-C turnover studies in man that gives values between 27 and 58 g/day, and this is not affected by the dietary state. Also, the measurement of lactate and pyruvate uptake by the liver and kidney in man by catheterization techniques estimates glucose formation as 39 g/day. c Amount calculated from nitrogen excreted in urine (100 g protein produces 57 g glucose; 1 g nitrogen is equivalent to 6–25 g protein). In early stages of starvation approximately 12 g nitrogen is excreted per day, but this is decreased in prolonged starvation to 4 to 7 g/day. Catheterization studies in subjects undergoing prolonged starvation indicate an uptake of amino acids by liver and kidney that could theoretically produce 26 g glucose per day. d In prolonged starvation, the hepatic–renal glucose production as measured by catheterization techniques provides an estimate of 86 g glucose per day, which is in good agreement with the 74 g obtained in this calculation. e Catheterization techniques have been used to measure the arterio–venous (A–V) differences across the brain. In prolonged starvation, glucose oxidation by the brain (excluding glucose converted to lactate, which is converted back to glucose in the liver and kidney) is estimated as 24 g/day. f Oxygen uptake or total fuel use is measured by catheterization techniques. g The rate of ketone body uptake by the brain has been estimated from A–V differences using catheterization techniques. These studies strongly suggest that ketone bodies are the alternative fuel to glucose during starvation. Source: From Ref. 45.

Injury and Sepsis Cuthbertson (131,132), in his classic studies of the metabolic response to long-bone fractures, defined two phases of the metabolic response to injury—an ebb or shock phase and a flow phase. Moore (133) subsequently divided the flow phase into catabolic and anabolic stages. The ebb phase, constituting the first several hours after injury, is characterized by hyperglycemia and the restoration of circulatory

volume and tissue perfusion. Once perfusion is restored, the flow phase begins. It is characterized by generalized catabolism, negative nitrogen balance, hyperglycemia, and heat production. The flow phase is the best-studied phase and may last from days to weeks, depending on the severity of the injury, the previous health of the individual, and medical intervention. Finally, once volume deficits have been corrected, pain has been eliminated, wounds have been

FASTING MAN, ADAPTED (5_6 weeks) (24 hours, basal: – 1500 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

O2

47g

Muscle Protein 20 g

Glycerol 15 g Adipose tissue Triglyceride 150 g

O2 30 g

Fatty acid 150 g

H 2O –P

–P CO2 + H2O

44 g

Liver, kidney Glycogen Gluconeogenesis

Amino acids

Nerve

Glucose 80 g 50 g

Ketone 57g

(Fatty acid) 112 g

36 g

RBC, WBC, etc. –P 14 g

Lactate and pyruvate O2 Heart, kindly muscle, etc.

–P CO2 + H2O

Urine 10 g ketone = ~100 mEq

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Figure 20 Flow diagram of fuel metabolism in starved man after adaptation. Source: From Ref. 29.

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closed, infection has been controlled, and complete oxygenation has been restored, the anabolic phase begins (1). This phase can be divided into a slow but progressive reaccumulation of protein, followed by the reaccumulation of body fat. Because protein synthesis cannot exceed 3 to 5 g of nitrogen per day, the protein repletion phase may be considerably longer than the catabolic phase in which protein is broken down. The posttraumatic state is characterized by starvation, immobilization, and repair. Although starvation and immobilization are both associated with decreased energy requirements, reparative processes increase energy needs. As a result, the overall energy requirements of traumatized and septic individuals are increased. The increase in energy need varies directly with the severity of injury and the complications that develop. In this regard, the most severe injury is the burn, and the most severe complication is sepsis (Fig. 5). Despite the use of protein and carbohydrate for calories, most of the energy used after trauma and after sepsis is derived from fat. This use is reflected in the low respiratory quotients noted after injury and sepsis. For example, Wilmore et al. (134) found respiratory quotients of 0.70 to 0.76 after severe burns. In addition, septic injury appears to have a greater lipid dependence for energy than nonseptic injury (100,135). Increased lipolysis is seen in both the ebb phase and the flow phase of the metabolic response to injury. During the ebb phase, elevated concentrations of cortisol, catecholamines, glucagon, growth hormone, ACTH, increased sympathetic nervous system activity, and depressed concentrations of insulin favor lipolysis. The presence of cortisol appears to be necessary for the remainder of the hormonal agents to be effective (136,137). Elevated concentrations of glycerol and free fatty acids during the ebb phase are well documented (138–140). However, Kovach et al. (141) have noted that elevation of plasma free–fatty acids may not occur after severe hemorrhage as a result of intense vasoconstriction in adipose tissue, producing minimum blood flow. During the flow phase, net lipolysis persists despite an increase in the concentration of insulin. Increased free fatty acids have been documented after trauma, burns, and sepsis (100,133,142–146). The fatty acids are used throughout the body for energy. In both the ebb and flow phases, the high concentration of intracellular fatty acids and the elevated concentration of glucagon inhibit acetyl-CoA carboxylase, thereby decreasing malonyl-CoA concentrations and fatty acid synthesis. In hepatocytes, the decreased concentration of malonyl-CoA also stimulates carnitine acyl transferase, thereby increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis. However, the activity of ketogenesis after shock, injury, and sepsis is variable and correlates with the severity of injury (144–146). After major injury and sepsis, ketogenesis is low or absent, whereas after minor injury and sepsis, it is increased but to a lesser extent than is seen during nonstressed starvation (142,147). During starvation, the inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through PFK inhibition (Randle effect) (45). However, after shock and major injury, citrate does not accumulate (148,149). This lack of accumulation may play a role in the persistence of glycolysis after injury. Unlike fasting and starvation, hyperglycemia is a hallmark of the response to injury, sepsis, and stress. An increase in blood glucose occurs during both the ebb and

flow phases and is proportional to the severity of the injury (150,151). There is also an increased concentration of lactate, pyruvate, organic phosphates, total amino acids, glycerol, and free fatty acids. Changes in lactate, pyruvate, and alanine have also been found to correlate with the severity of injury (144). The rise in the concentrations of glucose and other solutes contributes to an elevated plasma osmolality after hemorrhage and injury that is thought to be critical in the complete restitution of blood volume and plasma proteins (119,152–155). The hyperosmolality appears to augment the transcapillary refill phase and the plasma protein– restoration phase of blood volume–restitution by mediating the movement of water from cells to the interstitium and ultimately to the plasma (153–155). The metabolic changes in carbohydrate metabolism arise primarily as the result of the actions and interactions of catecholamines, cortisol, glycogen, insulin, growth hormone, and somatostatin (65,95,96,150,156,157). It is apparent that the elevated blood glucose concentration results from increased hepatic production and from impaired peripheral uptake that are under endocrine control. Both the ebb and the flow phases are associated with hyperglycemia, increased gluconeogenesis, and hepatic and peripheral insulin resistance. However, the mechanisms involved in these carbohydrate ‘‘abnormalities’’ are different. During the ebb phase, plasma insulin is clearly depressed in relationship to the degree of hyperglycemia (111,150,158,159). This results from decreased B-cell sensitivity to glucose that is secondary to catecholamines, somatostatin, reduced pancreatic blood flow, and the increased activity of the sympathetic nervous system (92,115,139,160,162). However, during the flow phase, B-cell sensitivity returns to normal, and insulin concentrations rise to more appropriate values. Nevertheless, hyperglycemia persists (111,163). In both the ebb and the flow phases, there is a delayed rate of assimilation of a glucose load, glucosuria, and a resistance to exogenously administered insulin (156,160,164). Despite this ‘‘diabetes of injury,’’ glucose uptake and use by peripheral tissues in both the ebb and the flow phases have been demonstrated consistently to be greater than that under normal circumstances (111,165–169). The resistance to insulin is manifested in a decreased glucose clearance. Consequently, the high plasma glucose concentration and the attendant increase in plasma–tissue glucose concentration gradient appear to overcome the resistance of peripheral tissues to glucose entry. The insulin resistance that develops appears to result from the action of catecholamines, cortisol, and other factors (65,95,96,115,157). Hepatic carbohydrate metabolism is also affected by insulin resistance. During the ebb phase, elevated concentration of catecholamines, cortisol, and glucagon and a decreased concentration of insulin result in rapid glycogenolysis and an outpouring of glucose from the liver. In addition, these hormonal alterations stimulate gluconeogenesis from alanine, lactate, and pyruvate. Growth hormone also is involved in these processes by inhibiting glucose uptake through inhibition of glucokinase. During the flow phase, gluconeogenesis persists despite nearnormal concentrations of insulin. This persistence appears to result from insulin resistance and produces a continued flow of glucose from the liver. Therefore the hyperglycemia that occurs after injury results from a combination of increased glucose production and glucose release and from a peripheral resistance to the entrance of glucose. After injury and during sepsis, glucose must be provided not only to RBCs, WBCs, renal medulla, and

Chapter 1:

neural tissues, but also to wounded tissue (162,170,171). Glucose uptake in wounded tissue is increased by up to 100%. Wounds demonstrate a lack of insulin sensitivity and do not increase their glucose uptake or glycogenesis in response to insulin (60,172,173). The accelerated glucose uptake in wounded tissue and possibly in septic tissue appears to correlate with the degree of inflammatory cellular infiltrate (171). In addition, it has been demonstrated that the accelerated glycolysis of wounded tissue may be aerobic and not anaerobic, as thought previously (170). The aerobic glycolysis proceeds to lactate in the presence of adequate oxygen. Thus oxygen consumption and carbon dioxide production are normal, but lactate production is accelerated. Increased lactate production may be related to an inability of the NADH shuttle to transfer reducing equivalents from the cytoplasm to the mitochondrion (85,174). Metabolic derangements suggestive of aerobic glycolysis have also been seen in septic tissue (175). In this regard, it is of note that aerobic glycolysis is characteristic of the cellular infiltrate (176). As one might expect, negative nitrogen balance and net proteolysis are characteristic of the posttraumatic and the septic states (177,178). However, only 20% of the protein broken down is used for calories (71). The remainder is used in gluconeogenesis. As noted previously, the production of lactate in the presence of oxygen primarily results from the actions of cortisol, glucagon, catecholamines, and the decreased effectiveness of insulin. The rise in urinary nitrogen is associated with an increased excretion of urea, sulfur, phosphorus, potassium, magnesium, and creatinine, suggesting the breakdown of intracellular material (131,179). Isotope dilution studies suggest that this loss of protein results from the loss of cell mass rather than cell number (131). The nitrogen-to-sulfur and nitrogen-to-potassium ratios suggest that this loss occurs mainly from muscle (131). The marked increase in the urinary excretion of 3-methylhistidine during trauma, sepsis, and burns also suggests the importance of skeletal muscle in response (180,181). Analysis of the protein content and the incorporation of radiolabeled amino acids in visceral tissues and skeletal muscle confirm that it is skeletal muscle that is depleted and the visceral tissue (liver and kidney) is spared (182). This is the opposite of nonstress starvation in which visceral protein is used before muscle protein and has been termed visceral translocation of protein (37,182). In fact, one of the molecular tragedies associated with trauma, burns, and especially sepsis is that the proteolytic suppression accompanying prolonged starvation is not observed. Consequently, continued breakdown of protein results. The alterations in plasma amino acids are not well defined during the ebb and flow phases. During the ebb phase, little change in total amino acid concentrations were noted by Elwyn et al. (183) until the late phases of shock. In addition, it appears that these changes result primarily from a decreased hepatic uptake (183) and not an increased peripheral release as was thought previously (184). During the flow phase, alterations in plasma amino acids appear to be related to the severity of injury and the specific type of injury (121,185–187). Alanine, the major gluconeogenic amino acid, appears to be released from peripheral tissues and taken up by the liver for gluconeogenesis. Early in the flow phase, the concentration of alanine in plasma is increased; but as the injury persists, serum alanine decreases, presumably as a result of its lack of availability in peripheral tissues and its continued hepatic uptake.

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25

Branched-chain amino acids and aspartate and asparagine are transaminated in peripheral tissues, and their remaining carbon fragments are used in the TCA cycle. Nonetheless, muscle concentrations of amino acids generally reveal normal or elevated concentrations of all amino acids except alanine, glutamine, and arginine (188). The net catabolism of protein can result from increased catabolism, decreased synthesis, or a combination of the two. Available data on TBP turnover suggest that after injury the net changes in catabolism and synthesis depend on the severity of the injury (189). Elective operations and minor injury appear to result in a decreased rate of synthesis with a normal rate of protein catabolism (118,140). Severe trauma, burns, and sepsis appear to be associated with increases in both synthesis and catabolism but with a greater increase in the latter, resulting in net catabolism (122,189–191). In this regard, it is important to note that the accelerated proteolysis and a high rate of gluconeogenesis persist after injury and during sepsis (185,192). This persistence appears to result from an inhibition of ketoadaptation after injury and sepsis. Unlike starvation, ketogenesis is not prominent, and it does not fuel the brain in significant amounts. Therefore a high requirement for glucose and therefore gluconeogenesis persist. The mechanism for this inhibition of ketoadaptation is not understood presently. Clowes et al. (193) have presented evidence suggesting the involvement of a circulating peptide containing 33 amino acids in this response. In addition, Baracos et al. (194) have proposed that interleukin-1 (IL-1) (a human leukocyte pyrogen) may be responsible for the accelerated proteolysis that accompanies fever and sepsis (see section on ‘‘Cytokines’’). As noted previously, activation of an ubiquitin-proteasome pathway appears to be involved in skeletal muscle degradation during starvation (125,126). In septic states, rates of ubiquitination of muscle proteins are profoundly increased (125,195,196). Further, inhibition of this process significantly reduces proteolysis in septic conditions (197). The net catabolism of protein that occurs after any injury is dependent on the prior nutritional status and intake, sex and age of the individual, and the severity of the injury. Young healthy males lose more protein in response to an injury than do women or the elderly (40). In addition, the urinary excretion of nitrogen is less after a second operation if it closely follows the first (145,178). This decline is presumably the result of a reduction in available protein stores. Finally, negative nitrogen balance can be reduced or virtually eliminated by high caloric and nitrogen supplementation (34,156,191,198,199). Together, these facts suggest that the loss of protein that occurs after injury is not entirely obligatory to the injury, but is also a manifestation of acute starvation (146).

Local Wound Metabolism Injury is associated with a negative bodily balance of many substrates (200–203). Despite injury-induced abnormalities in cofactors and substrates known to be important in wound healing, most wounds heal after injury (203–205). The ability of the wound to heal in the face of varying hormone and substrate supply suggests that the wound has a biologic priority over the host. This concept of biologic priority of healing wounds was described by Moore and Brennan (206), who stated that 75% of wounds or surgical incisions healed to the point of tensile integrity during a period of negative energy and nitrogen balance. The other 25% healed in patients who returned to eating so rapidly that the

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period of negative balance was of minimal duration (206). It is therefore evident that during a period of postinjury hormonal alterations and general catabolism, the wound has a favored status. This concept suggests that the metabolic and functional determinants of normal wound repair are inherent within the local wound environment. This further suggests that the local wound environment is differently sensitive to substrate and hormonal alterations than are other organ systems.

Cellular Infiltrate as a Determinant of Biologic Priority Following injury, there is a local ordered infiltration of inflammatory cells and a characteristic pattern of cellular predominance within the wound over time. This ordered sequence of cellular predominance leads to characteristic alterations in extracellular substrate concentrations, temporal effects of wound fluid on wound cell function, an altered sequence of expression for peptide growth factors, and degradation of classical peptide hormones. It appears that the metabolism of the wound is determined by the cellular infiltrate and is independent of systemic hormonal and substrate alterations. This is supported by the following findings: 1. 2.

3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13.

A direct relationship exists between DNA content of wounded tissue and the cellular infiltrate (207). Wounded tissue metabolizes glucose rapidly through aerobic glycolysis. This unusual form of glycolysis is characteristic of the leukocytes that comprise the cellular infiltrate (170). A time course for glucose uptake and lactate production by wounded tissue appears to correlate with the development of the cellular infiltrate (207). Autoradiographic studies using [3H]-2-deoxyglucose reveal that the majority of the glucose uptake in wounded tissue occurs in the cellular infiltrate (208). Both wounded tissue and macrophages increase their glucose uptake in response to increasing glucose concentrations in the environment, and this glucose clearance is concentration independent. Thus the lack of saturation of glucose uptake of wounded tissue appears to be determined by the macrophages in the cellular infiltrate (209). A high PFK activity of wounded tissue can be explained by the PFK activity of the cellular infiltrate as measured by 5-[3H]-glucose (208). Macrophage glucose uptake and lactate production are independent of local epinephrine concentrations (208). Macrophages have a stimulatory effect on the HEP content of resident host tissue (210). A decreased HEP content of wounded tissue appears to be secondary to the dilutional effect of the cellular infiltrate (211). The presence of macrophages seems to explain the pattern of purine release from wounded muscle (212). Glutamine utilization by the cellular infiltrate appears to explain the decrease in glutamine content of wounded tissue (213). In the isolated perfused system, hormone and substrate profiles similar to those found following injury do not affect wound metabolism. A prior adrenalectomy does not affect wound metabolism despite substantial effects on noninjured tissue.

In addition, other investigators have shown a lack of effect of exogenous insulin on local wound metabolism in an incubated system (171). Thus there are substantial data to support the position of the wound as independent of circulating hormone and substrate concentrations. Yet it is known that several of the more common clinical examples of impaired wound healing involve systemic hormonal and substrate changes. Specifically, diabetes mellitus (214– 217), steroid therapy (218–220), amino acid deprivation (221,222), and hypophysectomy (223) have been shown to impair wound healing. In summary, generalized catabolism, hyperglycemia, persistent gluconeogenesis, protein wasting, negative nitrogen balance, heat production, and loss of the body mass that parallel the severity of the injury are characteristic after trauma and during sepsis. Most of the energy necessary for biologic processes to proceed is derived from fat. The net catabolism of 300 to 500 g of lean body mass per day is apparently required as a source of amino acids for gluconeogenesis. The persistence of the injury, particularly sepsis, through unknown mechanisms produces inhibition of the usual adaptive mechanisms that occur in starvation, resulting in the persistence of a highly catabolic state. This state in turn leads to protein wasting and malnutrition and ultimately in multiple organ failure (224) and death if the stimuli are not eliminated. (For further information on wound healing, the reader is referred to the chapter 55).

CYTOKINES In addition to the important role that neurohumeral mediators have been shown to play in the metabolic response to stress and injury, emerging evidence is also defining a role for cytokines (225,226). Often these two systems appear to work in tandem to carry out a particular response. Because cytokines are primarily proinflammatory agents, the magnitude of their involvement is related to the severity of the underlying stress or injury. For example, in an elective surgical procedure, the wound is the primary locus of the inflammatory response. Thus, cytokines involved in this response are targeted toward healing this wound; accordingly, their access to the systemic circulation is minimal and the resultant systemic response is modest or nonexistent. In a more traumatic situation in which massive tissue destruction has occurred (e.g., motor vehicle accident and blast injury), the local production of cytokines may be profound with an equally excessive egress of these substances into the systemic circulation. In this situation, the systemic response may result in hemodynamic instability and even distant organ failure. Cytokines comprise a family of small proteins or glycoproteins that alter the function of a target cell through an autocrine or paracrine process; rarely this targeting may be accomplished in an endocrine fashion. Many different cells may secrete cytokines but those commonly involved include lymphocytes, macrophages, Kupffer cells of the liver, and various components of the intestinal epithelium. The biologic response induced by cytokines is considerably diverse and will depend upon the particular cytokine secreted and the target cell affected. Since first being discovered in the 1970s, dozens of cytokines have been identified, and it is likely that many more will become recognized in the years to come. Accordingly, a comprehensive review of cytokines and their physiology is beyond the scope of this chapter [the reader is referred to several excellent references for this information

Chapter 1:

(225–228)]. This discussion will focus on those cytokines that have been shown to influence the metabolic response to stress. These include interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor [(TNF)/cachectin], and interferon-gamma. Cytokines are commonly categorized as being proinflammatory, anti-inflammatory, or both. This is based on their ability to invoke local or systemic inflammation and alter the immune response. The four cytokines involved in the metabolic response to stress are primarily proinflammatory, with the exception of IL-6, which possesses both proinflammatory and anti-inflammatory characteristics. Their effects on the immune response will not be discussed in this context, because this function is extensively covered in the chapter on immunity and the immunocompromised patient (Chapter 4). As mentioned above, cytokines can elicit both local and systemic effects. Because they are produced at the site of injury, their major action will be targeted to that site if the wound is uncomplicated. Thus, in situations such as setting a simple fracture, repairing an inguinal hernia, or removing a diseased gallbladder (particularly if done laparoscopically), a systemic response is highly unlikely. Rather, locally released cytokines will be confined to the site of injury to both induce and modulate the healing process. Important healing factors such as enhancement of blood flow through vasodilation, recruitment of neutrophils, monocytes, and other blood elements to the wound site to prevent or contain infection, maintenance of hemostasis through alterations in coagulation, and induction of angiogenesis and cell proliferation to issue adequate healing may all be cytokine mediated (226). TNF, for example, has been shown to induce microvascular angiogenesis, bone remodeling, and fibroblast proliferation (226). IL-1 induces procoagulant activity, collagenase activity, and collagen synthesis. Further, it has been shown to stimulate osteoclastic activity, which may be important in bone remodeling during injury (226). In situations where the injury is more severe, and particularly if extensive devitalization is present, excessive production of cytokines at the wound site results in their entrance into the systemic circulation that can often be measured. When this situation occurs, a variety of metabolic aberrations have been shown to occur. Release of IL-6 into the circulation appears to play a prominent role in many of these metabolic effects. Paramount among them is its induction of the acute phase response (229). This response is characterized by the reprioritization of hepatic synthesis and release of certain proteins into the blood during inflammation and sepsis and following severe injury (230). Thus, albumin and transferrin, which are normally important proteins synthesized by the liver, are reduced in favor of a number of acute phase proteins whose plasma concentrations increase substantially (sometimes as much as 10–1000-fold) (231). Examples of such proteins include C-reactive protein, a2 macroglobulin, a1 acid glycoprotein, amyloid, and fibrinogen. The physiologic role of many acute phase proteins is unknown, while emerging evidence has shown that others act as opsonins, influence coagulation mechanisms, and contain generalized tissue destruction. Acute phase proteins that possess antiprotease activity can significantly reduce tissue destruction from dead or dying cells. Similarly, fibrinogen can elicit thrombus formation to prevent bleeding in wounded tissue. It would appear, therefore, that an important role for the acute phase response is to set into motion a variety of survival mechanisms to contain the injury and/or associated infection and restore homeostasis (232).

Metabolic Response to Starvation, Stress, and Sepsis

27

Other cytokines that also have been shown to induce the acute phase response in the liver include TNF and IL-1 (226,233,234). Their role appears to be less important, and certainly less sustained, than that of IL-6. An explanation for this is the different half-lives of these cytokines. The half-life of TNF is 20 minutes or less whereas that of IL-1 is approximately six minutes (225). In contrast, IL-6 levels in the circulation are detectable within an hour after injury, reach peak levels within four to six hours, and can be sustained for a week or more (225). It may be that these three cytokines interact to initially induce the acute phase response and that IL-6 keeps it sustained. Because glucocorticoids also regulate hepatocyte biosynthetic activity, it has been proposed that such substances may be important cofactors to IL-6 and other cytokines in inducing and modulating the acute phase response (232). In support of this hypothesis is the finding that IL-6, TNF, and IL-1 stimulate the hypothalamic–pituitary–adrenal axis to secrete ACTH and glucocorticoids (235). Thus, there is likely to be a feedback mechanism involving glucocorticoids and cytokines (236,237). It is well known that injury and inflammation induce a metabolic response in skeletal muscle that results in net catabolism. Thus, amino acids released from skeletal muscle catabolism are preferentially taken up by the liver for gluconeogenesis and protein synthesis (especially acute phase proteins), as needed. Although the preponderance of evidence suggests that glucocorticoids are the major mediator of muscle proteolysis, various cytokines may also be involved (232). In differing models of sepsis, IL-1, TNF, and IL-6 have all been shown to stimulate muscle-protein breakdown (238–240). It would appear, therefore, that regulation of muscle-protein degradation following stress or injury is a multifaceted response. Conceivably, glucocorticoids may orchestrate the primary role, but cytokines may modulate this response in specific settings (232,241). During massive tissue destruction or endotoxemia, for example, cytokines may play a key role, whereas in other conditions such as starvation or differing forms of stress, glucocorticoids play the central role. An interesting effect of cytokines on protein catabolism is that induced by TNF. Chronic excessive production of this cytokine can lead to a state of profound cachexia (hence, its other name, cachectin). Administration of TNF to rodents induces nitrogen loss, decreased food intake, depletion of body lipid stores, and excessive weight loss (242–244). In a mouse model, tumors secreting TNF can cause profound weight loss and cachexia (245). IL-1 has also been shown to induce cachexia (242). Whether TNF or IL-1 are responsible, either alone or in combination, for the cachectic state observed in many cancer patients remains to be elucidated. TNF is also thought to be the primary mediator of many of the systemic manifestations of endotoxemia. In various animal models, administration of this cytokine in high doses can induce fever, tachypnea, tachycardia, hypotension, and death, not dissimilar to that observed in patients in septic shock (226). Pathologic findings are also characteristic of those reported in human septic shock, including pulmonary congestion, intestinal infarction, and adrenal necrosis (246). Other effects of cytokines include reductions in iron and zinc levels, which are commonly observed in septic patients. Both TNF and IL-1 have been shown to elicit these effects, which may actually confer a survival benefit by inhibiting the growth of various microorganisms and limiting the production of oxygen radical formation, both of which

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depend on trace metals (226). Finally, interferon-gamma can upregulate the number of TNF receptors on various cells, particularly monocytes. Although this interferon is primarily an immune modulator with antiviral activity, its TNF-related action may enhance cytotoxicity of devitalized tissue and thereby aid in the hearing of wounded tissue (226). It seems clear that cytokines play a major role in the metabolic response to injury and stress that is just now being unraveled. As our knowledge of this role is clarified, modulation of these substances and their physiologic and pathophysiologic mechanisms should prove beneficial in altering responses that are detrimental to recovery and survival.

SUMMARY Starvation, stress from injury or surgical procedures, and sepsis induce a series of metabolic changes that are regulated by neuroendocrine reflexes and cytokines and result in mobilization of substrates from endogenous tissue stores. These metabolic changes ensure that energy is available for vital functions, oxygen delivery is maintained, and reparative processes take place. An understanding of these complex metabolic interactions depends on an appreciation of normal homeostasis and the distribution of body water, proteins, fat, and carbohydrates. The role of each component of body tissue is important in periods of starvation, stress, and sepsis, especially when the ability to replenish endogenous food stores is impaired as a result of either the inability to consume adequate nutrients or the excessive consumption of tissue stores. The mechanisms described in this chapter illustrate the complexity of the metabolic response to stress, the interrelationships between the neuroendocrine responses, cytokine release and substrate mobilization and use, and the importance of adequate energy and tissue stores for survival and repair of the organisms under conditions of nutrient deprivation.

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178. Siegel JH, et al. Physiological and metabolic correlations in human sepsis. Surgery 1979; 86:163. 179. Frawley JP, Artz CP, Howard JM. Muscle metabolism and catabolism in combat casualties. Arch Surg 1955; 71:612. 180. Bilmazer C, et al. Quantitative contribution by skeletal muscle to elevated rates of whole-body protein breakdown in burned children as measured by 3-MEH output. Metabolism 1978; 27:671. 181. Williamson OH, et al. Muscle-protein catabolism after injury in man, as measured by urinary excretion of 3-methyl histidine. Clin Sci Mol Med 1977; 52:527. 182. Ryan NT. Metabolic adaptations for energy production during trauma and sepsis. Surg Clin North Am 1976; S6:1073. 183. Elwyn DH, et al. Interorgan transport of amino acids in hemorrhagic shock. Am J Physiol 1976; 231:377. 184. Engel FL. The significance of the metabolic changes during shock. Ann NY Acad Sci 1956; 55:383. 185. Clowes GHA, Randall H, Cha C. Amino acid and energy metabolism in septic and traumatized patients. JPEN 1980; 4:195. 186. Dale G, et al. The effect of surgical operation on venous plasma free amino acids. Surgery 1977; 81:295. 187. Woolfe LI, Groves AC, Moore JP. Arterial plasma amino acids in patients with serious postoperative infections and in patients with major fractures. Surgery 1976; 79:283. 188. Askanazi J, et al. Muscle and plasma ammo acids following injury. Ann Surg 1980; 192:78. 189. Birkhain RH, et al. Effects of major skeletal trauma on whole body protein turnover in man measured by L-[l,14C]-leucine. Surgery 1980; 88:294. 190. Long CL, et al. Muscle protein catabolism in the septic patient as measured by 3-methyl histidine excretion. Am J Clin Nutr 1977; 30:1349. 191. Stein TP, et al. Changes in protein synthesis after trauma: importance of nutrition. Am J Physiol 1977; 233:E348. 192. O’Donnell TF, et al. Proteolysis associated with a deficit of peripheral energy fuel substrates in septic man. Surgery 1976; 80:192. 193. Clowes GHA, et al. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med 1983; 308:545. 194. Baracos V, et al. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocyte pyrogen (interleukin-1). N Engl J Med 1983; 308:553. 195. Tiao G, Fagan J, Roegner V, et al. Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. J Clin Invest 1996; 97:339. 196. Hobler SC, Williams AB, Fischer D, et al. Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis. Am J Physiol 1999; 277:R434. 197. Tawa NE Jr, Odessey R, Goldberg AL. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying not skeletal muscles. J Clin Invest 1997; 100:197. 198. Schrier RW, Berl WT, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol 1979; 236:F321. 199. Stephens RV, Randall HT. Use of a concentrated, balanced, liquid elemental diet for nutritional management of catabolic states. Ann Surg 1969; 170:642. 200. Levenson SM, Green RW, Taylor FH. Ascorbic acid, riboflavin, thiamine and nicotinic acid in relation to severe injury, hemorrhage and infection in the human. Ann Surg 1946; 124:840. 201. Lund CC, Levenson SM, Green RW. Ascorbic acid, thiamine, riboflavin and nicotinic acid in relation to acute burns in man. Arch Surg 1947; 55:557. 202. Cuthbertson DP. Interrelationships of metabolic changes consequent to injury. Br Med Bull 1954; 10:33–37. 203. Moore FD. Metabolic Care of the Surgical Patient. Philadelphia: WB Saunders, 1959. 204. Hunt TK, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: AppletonCentury-Crofts, 1979:2. 205. Levenson SM, Seifter E, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: Appleton-Century-Crofts, 1979:286.

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206. Moore FD, Brennan ME. Manual of Surgical Nutrition, by the Committee on Pre- and Post-operative Care of the American College of Surgeons. Philadelphia: WB Saunders, 1975:169. 207. Daly JM, et al. Does wounded tissue regulate hepatic glucose production. Surg Forum 1987; 38:23. 208. Forster J, et al. Glucose uptake and flux through phosphofructokinase in wounded rat skeletal muscle. Am J Physiol (Endocrinol Metab 19) 1989; 256:E788. 209. Caldwell MD. Carbohydrate and energy metabolism in healing wounds. In: Barbul A, et al., eds. Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. New York: Alan R Liss, 1988:183. 210. Morris A, et al. A macrophage-mediated factor that increases the high energy phosphate content of skeletal muscle. J Surg Res 1985; 38:373. 211. Morris A, et al. Macrophage interaction with skeletal muscle: potential role of macrophages in determining the energy state of healing wounds. J Trauma 1985; 25(8):751. 212. Morris AS, et al. The role of purine metabolism in the macrophage mediated increase in high energy phosphates in skeletal muscle. J Surg Res 1986; 41:339. 213. Caldwell MD. Local glutamine metabolism in wounds and inflammation. Metabolism 1989; 38(suppl 1):34. 214. Goodson WH, Hunt TK. Studies of wound healing in experimental diabetes mellitus. J Surg Res 1977; 22:221. 215. Spanheimer RG, Umpierrez GE, Stumpf V. Decreased collagen production in diabetic rats. Diabetes 1988; 37:371. 216. Yue EK, et al. Effects of experimental diabetes, uremia, and malnutrition on wound healing. Diabetes 1987; 36:295. 217. Rosenberg CS. Wound healing in the patient with diabetes mellitus. Nurs Clin North Am 1990; 25:247. 218. Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg 1968; 167:324. 219. Hunt TK, et al. Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animal and man. Ann Surg 1969; 170:633. 220. Salmela K, et al. The effect of local methylprednisolone on granulation tissue formation. Acta Chir Scand 1980; 146:541. 221. Seifter E, et al. Arginine: an essential amino acid for injured rats. Surgery 1978; 84:224. 222. Barbul A. Arginine: biochemistry, physiology and therapeutic implications. J Parenter Enter Nutr 1986; 10:227. 223. Skottner A, et al. Anabolic and tissue repair functions of recombinant insulin-like growth factor l. Acta Paediatr Scand (Suppl) 1990; 367:63. 224. Hassett J, Border JR. The metabolic response to trauma and sepsis. World J Surg 1983; 7:125. 225. Lin E, Lowry SF, Calvano SE. Mediators of inflammation and injury. In: Norton JA, Bollinger RR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:69–94. 226. Fong Y, Lowry SF. Cytokines and the cellular response to injury and infection. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1603–1622. 227. Fink MP. The role of cytokines as mediators of the inflammatory response. In: Townsend CM Jr, ed. Sabiston Textbook, of Surgery. Philadelphia: Elsevier Saunders, 2004:45–66.

228. Bessey PQ. Metabolic response to critical illness. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1495–1520. 229. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265:621. 230. Koj A. Definition and classification of acute phase proteins. In: Gordon AH, Koj A, eds. The Acute Phase Response to Injury and Infection. New York: Elsevier, 1985:139–147. 231. Kushner I. The acute phase response: an overview. Methods Enzymol 1988; 163:373. 232. Hasselgren PO. Protein metabolism in surgery. In: Norton JA, Bollinger PR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:105–121. 233. Enayati P, Brennan MF, Fong Y. Systemic and liver cytokine activation. Arch Surg 1994; 124:1159. 234. Lin E, Calvano SE, Lowry SF. Cytokine response in abdominal surgery. In: Schein M, Wise L, eds. Cytokines and the Abdominal Surgeon. Austin: Landes, 1998:17–34. 235. Del Rey A, Besedovsky HO. Metabolic and neuroendocrine effects of pro-inflammatory cytokines. Eur J Clin Invest 1992; 22:10. 236. Besedovsky H, Del Rey A, Sorkin E, et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233:652. 237. Hocke GM, Barry D, Fey GH. Synergistic action of interleukin6 and glucocorticoids is mediated by the interleukin-6 response element of the A2-macroglobulin gene. Mol Cell Biol 1992; 12:2282. 238. Zamir O, Hasselgren PO, Higashiguchi T, et al. Tumor necrosis factor (TNF) and interleukin-l (IL-1) induce muscle proteolysis through different mechanisms. Mediat Inflamm 1992; 1:247. 239. Zamir O, Hasselgren PO, Kunkel S, et al. Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis. Arch Surg 1992; 127:170. 240. Goodman MN. Interleukin-6 includes skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205:182. 241. Mealy K, van-Lanschot JJ, Robinson BG, et al. Are the catabolic effects of tumor necrosis factor mediated by glucocorticoids? Arch Surg 1990; 125:42. 242. Fong YM, Moldawer LL, Marano MA, et al. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 1989; 256:R659. 243. Tracey KJ, Wei H, Manogue KR, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med 1988; 167:1211. 244. Moldawer LL, Anderson C, Gelin J, et al. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988; 254:G450. 245. Oliff A, Defeo-Jones D, Boyer M, et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 1987; 50:555. 246. Tracy KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470.

2 Pathophysiology of Fluid and Electrolyte Disorders Peter J. Fabri and Mark Bloomston

INTRODUCTION The human body can be likened to a sac of electrolyte-rich fluids in which is suspended or dissolved a complex network of solids known collectively as ‘‘organs.’’ The common medium of these fluids is water; the electrolytes are a mixture of primarily monovalent and divalent ions. The total volume of water, known as total body water, accounts for approximately 60% of total body mass. Substances are continually added to and excreted from this aqueous environment, and only through a system of homeostatic, protective mechanisms is the composition and distribution of this fluid-based system maintained. Disease, pharmaceuticals, and medical interventions all have the potential to disrupt the balance of this fluid medium and result in clinically evident fluid and electrolyte disturbances. To achieve the desired goal of preventing or treating such disturbances, the nature, composition, and interrelationships of these fluids and the homeostatic mechanisms that maintain them must be clearly understood.

MAINTENANCE OF THE INTERNAL MILIEU Total Body Water Water is the universal solvent of the human body. The total volume of this substance is subdivided into discrete parts known as intracellular, extracellular, and transcellular water (Fig. 1). These parts are separated by semipermeable membranes equipped with energy-consuming, work-producing pumps that are usually based on an adenosine triphosphatase (ATP-ase) enzyme system. These pumps are able to maintain electrochemical and concentration gradients across membranes, which result in a marked difference in composition between the intracellular and extracellular spaces. Water, on the other hand, passively follows the laws of osmotic and ionic equilibrium. It traverses these membranes freely to maintain an equal number of solute molecules (osmolality) and ionic particles (tonicity) per unit volume on each side of such semipermeable membranes. This difference between the control of solutes/ions and that of water results in marked differences in volume and electrolyte composition of the two spaces. The normal balance can be disturbed by changing the number of solute molecules on either side of the membrane (e.g., hypoalbuminemia and hyperglycemia) or by disrupting its enzyme-based pumps (e.g., shock and digitalis). The extracellular space can be considered an open system in that the alimentary tract serves as a mode of entrance and exit of water and solute, as shown in Figure 1. Similarly, the lungs, kidneys, and skin also serve as excretory conduits. Entrance and excretion of water and solute are

controlled by active systems that are under homeostatic (nervous or hormonal) control. Thus the composition of this open, extracellular system can be maintained within relatively tight limits (1). Nonstandard entrance routes, such as the administration of fluids intravenously, bypass the normal entry control mechanisms and directly add water and solute to the extracellular space. In this circumstance, the intrinsic ability of the excretory systems to maintain osmotic and ionic stability becomes the limiting factor in maintaining ionic stability and composition of the extracellular space. Failure of these excretory control mechanisms, by inability to either conserve or increase loss, threatens the chemical stability of the extracellular fluids. The intracellular space, on the other hand, is a closed space and is represented by the numerous cells floating within the extracellular water in Figure 1. The only route of entrance and exit is across the semipermeable cellular membrane and its contained enzyme systems. Therefore, extracellular space can be thought of as a conduit and buffer zone to the intracellular space. Only by transfer from or to the extracellular water can intracellular composition be changed. This complex system, richly furnished with active transport mechanisms and buffer zones, rigidly protects the stability of the body fluids and maintains constancy of

Figure 1 Conceptualized model of the human body. Note that everything enters into, is excreted from, and is sampled in extracellular water.

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Table 1 Normal Distribution of Body Water as Percent of Body Weight

Total body water Extracellular water Intracellular water a

a

Men (%)

Women (%)

60 15 45

55 15 40

Values are less than equivalent for men because women have a relatively greater amount of adipose tissue.

the internal milieu. Although not depicted accurately in our model, two-thirds of total body water is intracellular and one-third is extracellular. This translates to about 40% and 20% of total body weight for the intracellular and extracellular compartments, respectively (Table 1).

Extracellular Water The extracellular space is composed of the intravascular space (blood cells plus plasma) (comprising about 8% of total body weight) and the extravascular space (interstitial fluid and lymph). Cerebrospinal fluid is a specialized subspace of extracellular fluid. The vascular and extravascular spaces are in relative continuity, separated only by the rather permeable basement membranes of the blood vessel walls. When these vessels are intact, the formed cellular elements of the blood remain contained in the intravascular space, whereas the aqueous, noncellular plasma undergoes continuous ‘‘filtration’’ through the relatively leaky vessel walls into the extravascular space. The extravascular space, however, is continuously ‘‘drained’’ by a system of lymphatic channels that return protein-rich extracellular fluid to the vascular space through the lymphatic ducts. This continuous-cycle system results in moment-to-moment renewing of the interstitial, pericellular space, bringing fresh nutrients from and carrying waste products to the vascular space, which is in direct continuity with normal routes of intake and excretion. The volume of intravascular fluid (blood) is determined by the oncotic effect of blood cells and large molecules such as albumin, as well as the rate of return of lymph. The volume of the extravascular fluid space depends on the balance between ‘‘filtration’’ of plasma and ‘‘drainage’’ of lymph. Plasma is continuously filtered across the vascular pores, particularly at the capillary level. The rate of filtration is governed by Starling’s law, which takes into account net hydrostatic pressure, net oncotic pressure, and pore size (reflectance and permeability). Fluid shifts across the vascular membrane are controlled by the summed effect of hydrostatic and oncotic pressures. Hydrostatic pressure exists in both the vessel (mean capillary pressure) and the tissue (mean tissue pressure). The difference results in a vector force that typically acts to drive fluid into the extravascular space. Simultaneously, this vector is offset by an oncotic pressure vector, which is the net difference between plasma oncotic pressure and tissue oncotic pressure adjusted for a permeability factor (reflectance) that varies as the ‘‘size’’ of the pores changes. Ordinarily, these vectors, on the average, tend to cancel, and there is only a small flux of fluid across the membrane. However, alteration in any of the main forces can lead to marked derangement in fluid distribution and the development of increased interstitial fluid, a condition recognized as clinical edema. The balanced forces in Starling’s equation result in the passage of fluid across the vascular membrane into the interstitial (extravascular) space. Not addressed in Starling’s equation is the ‘‘drainage’’ effect of the lymphatic system that tends to remove filtered plasma

from the interstitium. Obstruction of lymphatics by conditions such as tumor and infection can further impair fluid clearance and result in localized edema or lymphedema.

Osmolality and Tonicity The composition of extracellular water is reflected by the concentration of solutes. Ordinarily, extracellular composition is maintained within narrow limits by accurate renal control mechanisms [e.g., antidiuretic hormone (ADH) and aldosterone]. These control mechanisms, however, tend to respond to the concentration of a given substance rather than to the total amount of all substances. Concentration represents the combined effect of the amount of a given substance (numerator) dissolved in a given amount of water (denominator). Thus abnormalities in concentration may represent changes in the amount of solute, amount of water, or both. The concentration of total solute is most easily measured by plasma osmolality (mOsm/kg). This value indicates the ratio of solute to water in the plasma and in the extravascular space. Because extracellular water is in equilibrium with intracellular water, shifts of membrane permeable water result in maintenance of osmotic equality throughout total body water. In other words, accumulation of intracellular solute is compensated by a shift in water from the extracellular space to the intracellular space until osmolality is equal and vice versa. The concentration of total ions, indicating ionic strength, is approximated by assessing the concentration of the principal extracellular cation, sodium. Changes in sodium concentration represent changes in tonicity, a term related to but not synonymous with osmolality. Typically, tonicity and osmolality change together, and hyperosmolality usually includes hypertonicity (2). However, any substance that has a low molecular weight and a sizable concentration will contribute to serum osmolality. Thus conditions such as hyperglycemia, azotemia, hyperlactatemia, and accumulation of ethanol, which add solute but not ions, will raise osmolality without a change in tonicity. The contributing factors to osmolality can be understood more clearly by determining the osmolal gradient. This represents the difference between calculated (Osm[c]) and measured (Osm[m]) osmolality. Calculated osmolality is estimated by the formula Osm½c ¼ 1:86½Na þ Glu=18 þ BUN=2:8 where Na is serum sodium concentration in mequiv/L, Glu is serum glucose in mg/100 mL, and BUN is blood urea nitrogen in mg/100 mL. [1.86 is twice the osmotic activity coefficient of a monovalent ion; 18 is the molecular weight of glucose divided by 10 (a correction factor to convert mg/dL to mg/L); and 2.8 is the molecular weight of urea nitrogen divided again by the correction factor 10.] Ordinarily the osmolal gradient is less than 10 mOsm/kg where Osmolal gradient ¼ Osm½m Osm½c A gradient greater than 10 mOsm/kg represents the accumulation of some unmeasured, osmotically active (low molecular weight) substance such as lactate, ethanol, or mannitol. A common error in clinical practice is to assume that a change in measured osmolality represents an increase or decrease in water. As might be anticipated, osmolality is a concentration term and therefore can be disrupted by a change in amount of solute (e.g., azotemia) or amount of water (e.g., dehydration) or both (e.g., hyperosmolar coma).

Chapter 2:

Table 2 Electrolyte Composition

Total body content (mequiv/kg) Exchangeable content (mequiv/kg) Intracellular concentration (mequiv/L) Plasma water concentration (mequiv/L) Serum concentration (mequiv/L)

Na

K

Cl

Ca

Mg

67

58

42

940

32

41

44

30

–

–

10

160

3

2

26

152

5

110

5

3

142

5

103

5

–

Because measured osmolality equals the ratio of solute molecules to water: Osm ¼ solute=water

Pathophysiology of Fluid and Electrolyte Disorders

35

only part of the system that is able to ‘‘control’’ its output. Accepting that fact, it is helpful to think of renal homeostasis as ‘‘throwing the baby out with the bath water, and catching the baby before it goes down the drain.’’ In other words, glomerular filtration, the frontline initiator of renal excretion, is relatively nonspecific. It only limits excretion of substances that are associated with large proteins and therefore too big to pass through the renal vascular pores. Glomerular filtrate, therefore, is an ultrafiltrate of plasma. This ultrafiltrate passes through the proximal tubule where approximately 95% of most solutes and water are reabsorbed. In effect, control of excretion to this point is really a question of ‘‘what isn’t reabsorbed.’’ Final modification of urinary composition takes place in the distal tubule and collecting duct, where sodium is, in a matter of speaking, ‘‘exchanged’’ for hydrogen or potassium and the remaining water is either reabsorbed or not (8–11).

Sodium and Water Homeostasis

By rearrangement, the amount of solute determines the osmolality multiplied by total body water (which can be estimated as 60% of total body weight), as shown by the formula: Solute ¼ Osm 0:6 wt Estimation of this variable allows assessment of changes in total body solute, and, by comparison, permits an appraisal of relative changes in body water versus body solute.

Electrolyte Composition As previously indicated, intracellular and extracellular fluids vary in concentration of electrolytes. The total body content of each electrolyte (3) has been estimated by direct assay (4) and by radionuclide exchange (exchangeable ion) (5–7). The distribution of these electrolytes is unequal and results in marked concentration differences throughout the body (Table 2). Most of the difference between total body content (gravimetric) and exchangeable content is accounted for as substance in bone. As a glance at Table 2 will confirm, and contrary to the impression gained from evaluating serum electrolytes, the content of total exchangeable sodium (Na) is roughly equal to the content of total exchangeable potassium (K). The sum of these ions (exchangeable Na þ K) validly estimates total body cations that are roughly equally divided between intracellular and extracellular water. Accordingly, the serum sodium concentration (or conversely the intracellular potassium concentration) represents the ratio of total body cations to total body water, as shown below: Na ðserumÞ ¼ ðNa þ KÞ=ð0:6 wtÞ By a process analogous to osmolality, cross-multiplying serum sodium concentration by an estimate of total body water yields total body exchangeable cations. An estimate, therefore, of total body water, total body solute, and total body cations allows a more detailed serial assessment of fluid and electrolyte balance for patients in whom derangements are suspected.

HOMEOSTATIC CONTROL MECHANISMS General Concepts The kidney is the cornerstone of the homeostatic mechanisms controlling fluid and electrolyte balance. Although it is true that fluid losses from the skin, lungs, and gastrointestinal (GI) tract may be impressive, the kidney is the

Intracellular water is in equilibrium with extracellular water through osmotic and ionic neutrality. A small gradient is accounted for by anion proteins, which results in a concentration inequality referred to as the Gibbs–Donnan distribution. Extracellular water is controlled largely by plasma volume and serum sodium concentration. Sodium and water conservation must be considered together because their control mechanisms are inseparable. Water deficits or excesses are compensated by changes in ADH release from the pituitary, and its effects within the renal collecting duct (12–14). Changes in sodium composition are accompanied by both ADH and mineralocorticoid responses. A decrease in plasma volume stimulates baroreceptors located in sites such as the right atrium and carotid body, as well as in the juxtaglomerular apparatus and macula densa of the kidney (15). The baroreceptor response results in an increase in ADH release from the posterior pituitary and causes decreased loss of solute-free water in the collecting duct of the kidney. Conversely, as the serum sodium concentration falls, ADH release will be inhibited, and further water conservation will be blunted. The simultaneous effects of decreased glomerular filtration leading to decreased sodium delivery to the juxtaglomerular apparatus results in renin release, which subsequently causes cleavage of angiotensinogen into the decapeptide angiotensin I. This latter substance is converted in the lung to the octapeptide angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is a very potent vasoconstrictor that also directly stimulates aldosterone release from the zona glomerulosa of the adrenal cortex. The resultant increase in circulating aldosterone increases sodium reabsorption in the distal tubule of the kidney, in exchange for potassium and/or hydrogen ions. As serum sodium concentration changes, release of ADH from the posterior pituitary is altered by osmoreceptors in the hypothalamus. Very small changes (e.g., 2 mOsm) can predictably result in a measurable change in plasma ADH levels. Corresponding changes in thirst perception and in the permeability of the collecting duct of the kidney to water also occur. In the case of hypernatremia, thirst increases, and maximum retention of solute-free water occurs in the kidney. This can be corroborated by a high measured urine osmolality (usually >500 mOsm). During hyponatremia, ADH release is inhibited, the stimulus for water conservation in the collecting duct ceases, and solute-free water (‘‘free water’’) is excreted, resulting in hypotonic (< 280 mOsm/kg) urine and a return of serum sodium to normal. In addition, the zona glomerulosa

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Part One: General Considerations

of the adrenal appears to be sensitive to changes in serum sodium concentration, resulting in feedback control of aldosterone release.

Potassium Homeostasis Control of serum potassium levels is quite unlike that of sodium. Sodium is controlled at both the intake and excretion level, whereas potassium intake is unregulated. Potassium, then, is controlled entirely by excretion. Potassium is primarily an intracellular ion, with a concentration many fold greater than plasma. Yet, the extracellular concentration is extremely important in maintaining electrochemical gradients across cell membranes that facilitate depolarization of electrically active cells such as cardiac muscle and specialized conduction cells. Therefore control of extracellular potassium is vitally important. Typically, mammalian diets contain very large amounts of potassium, such that conservation of potassium is not usually a problem unless losses are excessive (diuresis and diarrhea) or renal mechanisms are abnormal (hyperaldosteronism). Potassium conservation and excretion tends to be a direct contrast to sodium conservation. Excess potassium, for example, stimulates the release of aldosterone from the adrenal, whereas too little sodium would result in the same response (16,17). While the majority of potassium reabsorption (like sodium) occurs in the proximal tubule, it is excreted in the distal tubule in response to the aldosterone stimulus. Sodium can be reabsorbed almost entirely within the nephron, whereas potassium conservation is less complete until profound body deficits occur. Distal tubular flow rate is also a major factor in potassium homeostasis. As flow rates increase, potassium excretion becomes inappropriately high. Although total body potassium distribution is greatly affected by renal mechanisms, it is also subject to exchange mechanisms at the cell surface of all cells such that, as sodium (or hydrogen) is transported out, potassium reenters the intracellular fluid (probably insulindependent). Likewise, in severe acidosis or alkalosis, plasma potassium levels may change as a result of the fluxes of potassium that are consequent to the hydrogen ion shifts.

Calcium Homeostasis The majority of calcium in the human body is complexed within the rigid crystal lattice of bone. This phase of calcium hydroxyapatite and phosphate is in equilibrium with three other forms of calcium: protein-bound, ionic complex, and ionic. Only the latter, ionic calcium, is physiologically active. In normal physiology, this very small amount of calcium is responsible for a large number of functions, including extracellular, transcellular, and intracellular communication; coordination of protein structure, including clotting factors; electrical triggering of active cells, such as myocytes; second messenger function together with calmodulin; activation of enzymes; and many others. Because of the many life-critical functions of calcium, its concentration is very tightly controlled and the cell is capable of functioning normally in an environment with little calcium intake. Consequently, normal homeostatic mechanisms do an admirable job at maintaining calcium-dependent physiologic processes in a wide variety of situations. Said another way, clinical abnormalities of calcium metabolism are very rare except in specific circumstances. Normal laboratory measurement of calcium assays all three components of nonbone calcium, yet only the ionized fraction is active. Numerous nomograms and algorithms have attempted to allow the physiologic fraction to be estimated based on serum protein concentrations, but

recent studies suggest that such estimates have little clinical utility and that ionized calcium must be measured to identify clinical hyper- or hypocalcemia. Calcium in the serum is regulated by the interplay of two hormones, parathyroid hormone (parathormone, PTH) and 1,25 dihydroxyvitamin D3. Calcitonin, which is important in other animal species, has not been identified as being of importance in calcium homeostasis in humans. PTH is produced as a very large macropeptide, undergoes posttranslational cleavage to the smaller 84–amino acid peptide, and is released by the parathyroid glands. The parathyroid glands, in turn, have calcium receptors (CaR), which recognize the level of ionized calcium in the extracellular fluid within the parathyroids. Even a small decrease in ionized calcium produces an immediate increase in PTH release and, if of long duration, hyperplasia of the parathyroids themselves. Similarly, a small increase in ambient calcium turns off PTH release and, if of long duration, regression of the parathyroids. This increase in PTH increases the mobilization of calcium from bone, increases the resorption of calcium in the renal tubule, and enhances excretion of phosphate in the renal tubule. Additionally, prolonged increase in PTH elevation induces an increase in hydroxylation of vitamin D in the kidney. 1,25 dihydroxyvitamin D3 increases the absorption of both calcium and phosphate from the intestine. A second hormone, parathyroid hormone–related peptide, homologous with PTH, is often produced in tumors, particularly squamous cell neoplasms, and leads to tumoral hypercalcemia. This must be distinguished from an alternative form of malignancy-related hypercalcemia seen in advanced disease where the tumor is actively invading the bone, leading to osteoclast and osteoblast mobilization and subsequent hypercalcemia. Hypercalcemia can also be produced by diseases that cause an increase in active vitamin D, such as lymphoma, granulomatous diseases including sarcoidosis, and excessive intake of vitamin D in the diet or supplements. When a patient is identified with hypercalcemia, the urgency of correction must be established. Mild hypercalcemia or intermittent hypercalcemia rarely produces physiologically important abnormalities or even symptoms and therefore does not require management. Calcium levels above 12 mg/dL have traditionally been considered urgent, requiring aggressive treatment, and above 14 mg/dL, as a medical emergency (hypercalcemic crisis). Saline diuresis and inhibition of bone resorption with biphosphonates or calcitonin is the mainstay of treatment. Hypercalcemia, if persistent, produces a physiologic equivalent of nephrogenic diabetes insipidus, resulting in volume loss and hypernatremia, with the symptoms of polydypsia and polyuria. Treatment with fluids alone will correct the electrolyte abnormalities but will not correct the underlying cause of the hypercalcemia (18). Hypocalcemia is often seen in critically ill individuals and in individuals who have hypoalbuminemia. Because serum calcium levels are often measured in the basic metabolic panel used in hospitalized patients, the treatment of hypocalcemia as an electrolyte problem is often considered. Current evidence suggests that the hypocalcemia seen in hospitalized patients (except hypoparathyroidism following thyroid or parathyroid surgery) is almost never of clinical significance and does not require treatment. Furthermore, evidence is accumulating that PTH release and responsiveness of the CaR are altered as part of the acute injury response, suggesting that hypocalcemia is actually a programmed component of acute injury (19).

Chapter 2:

In the final analysis, ionized calcium is very tightly controlled and is not often a fluid and electrolyte issue. Treatment of asymptomatic hypocalcemia does not appear to be needed and may even be detrimental. Although the discovery of hypercalcemia clearly requires the establishment of a diagnosis, mild hypercalcemia also does not usually require treatment as a fluid and electrolyte issue unless the calcium level is greater than 12 mg/dL.

Acid/Base Conservation With the exception of several specialized body fluids, the pH of body water is very closely guarded in a narrow range. Normal plasma pH (7.4 0.05) generally is representative of the pH of total body water, although the pH of fluids such as cerebrospinal fluid and intracellular fluid may transiently diverge from that of plasma because of differing controlling factors and influences. For practical purposes, however, the pH of all compartments of body water can be assumed to be equal. To appreciate the intricacies of acid/base balance, a solid understanding of the basic chemical concepts of acids, bases, and dissociation is essential. Acids are substances that have the capability of donating protons (hydrogen ions and hydronium ions). Bases, conversely, are substances that have the ability to accept protons during chemical reactions. Both acids and bases are ionic compounds that, when dissolved in water, have the ability to dissociate into cationic and anionic species. For most organic acids and bases in the body, dissociation is only partial, and the ratio of dissociated to nondissociated forms is determined by the dissociation constant. Acids, when dissociated, contribute hydrogen ions (Hþ) and a corresponding anion (An) to the total ionic composition of the solution. Bases typically contribute a cation and a hydroxyl (OH) ion. A typical acid (or base) dissociation can be described by the chemical reaction: HAn ¼ Hþ þ An: The dissociation constant is determined by the ratio of products to reactants; therefore: K ¼ ½Hþ ½An=½HAn; where the brackets represent concentration in solution. Taking the logarithm of both sides of this equation results in a useful and familiar form of the dissociation equation: logK ¼ log Hþ þ logð½An=HAnÞ pK ¼ pH logð½An=½HAnÞ pH ¼ pK þ logð½An=½HAnÞ: The dissociation constant (and consequently the pK) takes into account the simultaneous equilibrium of water. In the human, many acid/base pairs (buffer pairs) exist in simultaneous equilibrium. This means that the ambient pH of the body determines the ratio of anion to dissociated acid for a number of acids present in the body. Although substances such as phosphoric acid, proteins, and amino acids are all present in abundance and could be used as estimates of acid/base status, the carbonic acid/bicarbonate buffer system is most commonly used for this purpose. Bicarbonate is not the major buffer in the human body (pKa ¼ 6.1). In fact, hemoglobin and proteins make up the bulk of the buffering capacity (maintenance

Pathophysiology of Fluid and Electrolyte Disorders

37

of pH within narrow limits). The reason for measuring the bicarbonate/carbonic acid component of the buffer system is clear. Again, the organic acids and bases in extracellular water are in equilibrium with each other, so any pair could be used to evaluate acid/base status. The major homeostatic mechanisms of acid/base control are pulmonary (the excretion of carbon dioxide) and renal (the conservation of bicarbonate and excretion of hydrogen ions). Consequently, this buffer pair reflects the efficacy of the homeostatic mechanisms that are operative in compensating for changes in the gain or loss of acid or base. In addition, bicarbonate and carbon dioxide (pCO2) are easily measured in plasma. The general dissociation equation, when applied to the bicarbonate/carbonic acid buffer system, is known as the Henderson–Hasselbach equation: pH ¼ 6:1 þ logð½HCO 3 =½H2 CO3 Þ; where [HCO 3 ] is the concentration of bicarbonate and [H2CO3] is the concentration of carbonic acid. Because the concentration of carbonic acid is determined by the partial pressure of carbon dioxide, and the solubility of carbon dioxide in water is 0.03 pH ¼ 6:1 þ logð½HCO 3 =0:03 pCO2 Þ and ½Hþ ¼ 24ðpCO2 =½HCO 3 Þ: Current technology allows the direct measurement of pH and pCO2 in arterial (or venous) blood, enabling the estimation of bicarbonate concentration by the above equation. Alternatively, measurement of bicarbonate concentration and pH would enable calculation of pCO2. In normal circumstances, the ratio of [HCO 3]/0.03 pCO2 is 20/L. Other electrolytes enter the body pool only by ingestion (or injection), but acids (and bases) are rarely present in the diet. Acid is a product of metabolism of other substances and is added to total body water as a function of the rate of metabolism and the fractional use of acidproducing metabolites (Table 3). In general, net acid production is approximately 1 mequiv/kg/day (2 to 3 mequiv/kg/day in infants) and is primarily caused by the production of sulfuric acid from metabolism of thiols; phosphoric acid from metabolism of organic phosphates; and other organic acids from the metabolism of proteins, carbohydrates, and fats. Any addition of base (e.g., antacids) or compounds that generate base (e.g., citrate and lactate) will tend to offset the daily endogenous acid load. Table 3 Physiologic Factors Affecting Plasma Acidity Through plasma bicarbonate changes Rate of hydrogen ion input Rate of hydrogen ion or bicarbonate loss (gastrointestinal) Availability of buffers Bicarbonate space of distribution Rate of net renal acid excretion

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Through plasma pCO2 Rate of carbon dioxide production Rate of alveolar ventilation

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Part One: General Considerations

To maintain acid/base equilibrium, the body must excrete a quantity of acid equal to endogenous production (plus any exogenous acid and minus any exogenous base). This is accomplished primarily by renal excretion of fixed acid in the form of phosphates and ammonia. Ammonia is actively produced by metabolism of glutamine in the kidney and subsequently excreted into the renal tubular lumen. Simultaneously, monohydrogen phosphate is filtered at the glomerulus. Hydrogen ions, filtered or secreted, are trapped by the buffering capability of these two proton acceptors and excreted. In addition, through a carbonic anhydrase– dependent system, the tubular epithelial cell is capable of generating a hydrogen ion and a bicarbonate ion from carbonic acid (dissolved carbon dioxide) and reabsorbing the bicarbonate while the hydrogen ion is excreted. This regenerates the bicarbonate pool and facilitates acid/base stability. If the bicarbonate pool becomes excessive, renal excretion of bicarbonate is increased by a complex mechanism dependent on the decreased hydrogen ion in the tubular fluid. In effect, therefore, the kidney is able to directly influence acid excretion by three mechanisms: excretion of phosphate (affected by glomerular filtration and parathyroid hormone), synthesis of ammonia, and control of the directional flow of bicarbonate. The last of the three mechanisms just enumerated requires further comment. Because of the ready availability of carbon dioxide and water (and consequently carbonic acid), the kidney, through carbonic anhydrase, can control the abundance of hydrogen ions and bicarbonate. By directing the excretion of hydrogen ions into the tubular lumen and the return of bicarbonate to plasma, the kidney has a great capacity to excrete acid and control base levels. Only when the renal mechanisms responsible for reabsorption of base or excretion of acid are compromised does the renal contribution to acid/base balance become limited. In normal circumstances, the rate at which the kidney returns bicarbonate to the body is equivalent to the rate of sodium/hydrogen exchange in the distal tubule. Although the proximal tubule is quantitatively the most important site of bicarbonate reabsorption in the kidney, with a small contribution from the loop of Henle, the distal segment is capable of ‘‘fine-tuning’’ the acid/base excretory balance.

Acute Injury Response Since the discovery of interleukin-1 in 1981, we have continued to learn about the system of cytokines and chemokines, which mediates what is often called the ‘‘acute injury response.’’ Current evidence suggests that the macrophage reacting to surface receptor signals from infectious agents, allergens, trauma, chemokines, and other agonists initiates a vigorous biochemical response leading to a cascade of interrelated events that alter metabolism, body temperature, cellular response, hepatic protein synthesis, and renal handling of fluid and electrolytes (20). More recent evidence suggests that many, if not all, of the observations usually referred to as ‘‘sepsis’’ can actually be explained by the human response to activation of a cell receptor (toll-like receptor). This would imply that what historically has been considered to be an effect of gram-negative endotoxin may actually be the host response to the presence of chemical substances (lipopolysaccharide from the cell wall) rather than a toxic effect of the substances themselves. The impact on fluid and electrolyte balance appears to be primarily mediated by a ‘‘nonphysiologic’’ release of ADH and mineralocorticoids. This increase in the substances that control the reabsorption of salt and water in the distal portion of

the nephron results in decreased renal excretion (often manifested as oliguria) in an attempt to protect the volume and composition of extracellular water. The recognition of the importance and ubiquity of this acute injury response may result in a change in our methods of intravenous fluid therapy as we more fully understand the significance of this hormonal response to injury.

Effect of Medications It is beyond the scope of this chapter to address specific effects of drugs used in clinical practice. It is nevertheless important to recognize that commonly used pharmaceutical agents can produce significant fluid and electrolyte abnormalities. One hundred fifty-two separate drugs are identified as having hyponatremia as a major side effect. These are broadly categorized as agents that cause loss of sodium in the kidney (e.g., diuretics) or that enhance the retention of water in the renal collecting duct [e.g., syndrome of inappropriate antidiuretic hormone (SIADH)]. Hypokalemia is also commonly produced by drugs. Loop-active diuretics, amphotericin B, and drugs producing metabolic alkalosis are commonly responsible. It is prudent to consider the possibility of an adverse drug effect early in the course of evaluating new onset fluid and electrolyte abnormalities (21–24).

PATHOPHYSIOLOGY AND TREATMENT OF SPECIFIC ELECTROLYTE AND ACID/BASE ABNORMALITIES To understand abnormalities of electrolyte homeostasis, some attention must be given to normal daily requirements (Table 4) (25). Although it is true that a state of electrolyte balance requires that intake be equal to losses (and losses can be minimized), realistically there will be daily excretion of electrolytes of a fairly predictable magnitude, allowing a range of estimated daily needs. Under normal conditions, water losses occur primarily through urinary excretion, evaporation from the skin, and water losses through the lungs. The latter two sources are referred to as insensible losses because they are not visible or readily measurable and amount to 500 to 800 mL [300 mL/m2 body surface area (BSA)] of water daily, with almost negligible amounts of sodium and chloride. Urine is the major sensible loss (one that is visible and measurable) and averages between 1200 and 1500 mL of water daily, with 10 to 30 mequiv of sodium and 20 to 60 mequiv of potassium. Another sensible loss is water loss through the feces, which is usually quite minimal. Losses greater than those routinely encountered (e.g., diarrhea) will result in corresponding increases in requirements; increases in normal excretion rates (e.g., renal failure) will necessitate a reduction in intake.

Abnormalities of Water Balance Disturbances in the amount and distribution of total body water are common in clinical practice. Because water Table 4 Adult Daily Requirements Normal Water (total) Water (insensible) Sodium Potassium Chloride Calcium Magnesium Source: From Ref. 25.

2

1500 mL/m 500 mL/m2 0.7–3.6 mequiv/kg 0.7–2.1 mequiv/kg 0.7–3.6 mequiv/kg 0.4–1.1 mequiv/kg 0.3–0.7 mequiv/kg

Minimal 870 mL/m2 – 0.3 mequiv/kg 0.3–0.5 mequiv/kg 0.3 mequiv/kg 0.2 mequiv/kg 0.2–0.4 mequiv/kg

Chapter 2:

distributes throughout the body, restricted in its movement only by osmotic and ionic barriers, abnormalities in amount, with maintenance of normal electrolyte concentrations (i.e., isotonic), are frequent. An isotonic increase in total body water results in edema, whereas an isotonic decrease produces clinical dehydration. Because electrolyte conservatory mechanisms are extremely efficient, deviation from isotonicity is uncommon except at the extremes of age, when compensatory mechanisms are less adequate or access to water or salt is restricted. In infants and the elderly, therefore, hypertonic (sodium > 145 mequiv/L) and hypotonic (sodium < 135 mequiv/L) abnormalities are more common and require that attention be given to the volume as well as the concentration problems. It is important to realize that isotonic abnormalities in total body water are more prevalent than other fluid derangements in adults, only because compensatory mechanisms maintain the concentration of important solutes. In circumstances where a coexistent problem compromises these compensatory mechanisms (e.g., renal disease, inappropriate ADH secretion, diuretic use, and adrenal insufficiency), a superimposed fluid loss or gain may very well not be isotonic. Dehydration is an absolute decrease in total body water and usually represents a balanced loss between intracellular and extracellular volume. Dehydration can be assessed on clinical grounds alone, and in fact, there is no readily available ‘‘test’’ that identifies dehydration unless there is a coexistent abnormality of concentration. Blood urea nitrogen and consequently osmolality are frequently elevated, however, and may be supportive of the diagnosis when the creatinine concentration is normal and the blood urea nitrogen/creatinine ratio is greater than 20. Up to a 5% decrease in total body water can escape clinical detection, without appropriate suspicion by history. Thirst is usually present, however, and is an accurate sign of water deficit. Losses greater than 5% usually lead to conditions such as sunken eyes, loss of skin turgor with tenting of presternal skin, and dry mucous membranes. Greater than 10% dehydration will commonly demonstrate hemodynamic changes with tachycardia and postural hypotension. Treatment of dehydration requires an understanding of the composition of the fluid deficits. Isotonic dehydration reflects a loss of all fluid compartments (and their contained electrolytes) and is corrected by intravenously infusing a balanced salt solution such as Ringer’s lactate (Table 5). Concomitant abnormalities in concentration or tonicity are best assessed by the serum sodium concentration; such electrolyte abnormalities should be treated simultaneously with management of the volume deficit. For example, in hypernatremic dehydration (Table 5), water alone as 5% dextrose in water is used for replacement of the water deficit and a balanced salt solution, for volume restoration. The appropriate intravenous fluid should be administered to correct one-half of the estimated abnormality over 24 hours. This

39

Pathophysiology of Fluid and Electrolyte Disorders

approach is used because most deficits develop over a period of days or weeks and the patient has usually adjusted to them. Rapid replacement of losses may actually impose a greater risk than the deficit itself. Edema can be related to an underlying disease (cardiac, renal, or hepatic) or, as is common in modern practice, to abundant or excessive intravenous fluid administration. Excesses in extracellular fluid typically are susceptible to gravity and hence are most pronounced in dependent areas. Conditions such as pretibial and ankle edema are common in the upright patient. Presacral edema or pitting of the skin overlying the iliac crest is more likely in the recumbent patient. Water intoxication represents a specific abnormality of water balance. Ordinarily, large amounts of ingested or administered water can be excreted quantitatively, without a resultant volume excess or ionic dilution. Very marked amounts, however, particularly in a setting of compromised homeostatic mechanisms, can result in edema, hyponatremia, and dilution of other electrolytes as well (for a further discussion, refer to section on hyponatremia). Treatment of fluid excess requires an understanding of the cause and an assessment of the integrity of homeostatic mechanisms, particularly renal, hepatic, and central nervous system (CNS) function. In the setting of normal compensation, simple fluid restriction or decreased administration is likely to be effective. When simultaneous abnormalities in renal, hepatic, adrenal, or cardiac physiology exist, careful attention to intake and output (an ‘‘accountant’’ approach) is indicated. Only by specific accounting of all volumes, concentrations, and amounts can aggravation or creation of abnormalities be prevented.

Abnormalities of Sodium Because sodium is the major cation within extracellular water and is regularly analyzed in the laboratory, it is surprising that abnormalities in sodium concentration are not discovered more frequently. Although hypernatremia and hyponatremia are seen, they are rigorously prevented by compensatory mechanisms within the kidney. In fact, very small changes in sodium concentration (and subsequently osmolality) result in a measurable change in ADH release in the same direction. When renal concentrating mechanisms are defective (2) (e.g., wash out of renal medullary concentration gradient as with diuretics, partial tubular dysfunction from incipient or resolving acute tubular necrosis, or massive sodium loss in interstitial nephritis), abnormalities in serum sodium are more common.

Hyponatremia Virtually all acute, stressful situations (e.g., infection, anesthesia, and surgery) are accompanied by release of ADH and conservation of free water (26,27). This homeostatic mechanism is very effective in preserving extracellular volume, when combined with sodium conservation, which

Table 5 Composition of Common Solutions Used for Intravenous Therapy Solutions 5% Dextrose and water 0.9% Sodium chloride (normal saline) 0.45% Sodium chloride (half-normal saline) 3% Sodium chloride (hypertonic saline) Lactated Ringer’s solution

Glucose (g/L)

Na (mequiv/L)

Cl (mequiv/L)

HCO3 (mequiv/L)

K (mequiv/L)

Ca (mequiv/L)

50 – – – –

– 154 77 513 130

– 154 77 513 109

– – – – 28a

– – – – 4

– – – – 2.7

Exists in solution as lactate and is ultimately metabolized to bicarbonate (HCO3).

a

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depends on a decrease in perfusion pressure or delivered sodium at the juxtaglomerular apparatus (28,29). Consequently, hyponatremia in adult patients at the time of admission for elective surgery is distinctly uncommon. However, once a patient has received intravenous administration of hypotonic fluids (e.g., 0.45% saline), the inability to excrete the ‘‘free’’ water due to an obligatory ADH release will frequently result in a dilutional decrease in serum sodium to some degree. When hyponatremia is present, spurious causes must be excluded. This is accomplished most simply by evaluating the serum osmolality. Because osmolality measures the amount of solute per ‘‘mass’’ of water instead of volume, it is independent of the amount of water in a volume of serum. Normally, serum is 94% water. Increases in protein or lipid concentrations can, however, alter the amount of water and lead to an analytic error in sodium determination. Osmolality is not affected so. Consequently, hyponatremia in the setting of normal osmolality would raise the suspicion of paraproteinemia (e.g., multiple myeloma and macroglobulinemia) or hyperlipidemia. Alternatively, an increase in an extracellular solute such as glucose (or mannitol) causes a shift in water from the intracellular to extracellular space, to conserve osmotic equality. This results in a subsequent ‘‘dilution’’ of extracellular sodium, but a maintained osmolality because of the presence of another osmotically active substance, glucose. Identification of hyperglycemia in the setting of normal osmolality will explain a fall in sodium levels of approximately 1.6 mequiv/L for each 100 mg/100 mL rise in blood sugar above normal. When true hyponatremia does occur (low sodium plus low osmolality), evaluating how the kidney is behaving allows a rational interpretation of the probable pathophysiology. A careful assessment of overall fluid and electrolyte status (weight change, input and output summaries, presence or absence of edema, etc.) is essential (30). Characterizing the patient as ahead or behind in volume by clinical assessment allows appropriate interpretation of the renal response, which is best ascertained by measuring the urinary osmolality and sodium concentration. During active sodium conservation, urinary sodium is typically low (< 5 mequiv/L). This indicates either that there is a true deficit in sodium or that the kidney ‘‘thinks’’ there is one. The latter occurs when circulating substances (e.g., aldosterone) are inappropriately present in edematous states such as cirrhosis and chronic congestive heart failure (28,31). In each of these settings, however, the patient is edematous and probably has ascites. In the absence of either of these findings, true sodium depletion is probably present. Sodium administration should be guided by an estimate of the deficit, which must be considered independently of (added to) volume deficits that are isotonic (Na ¼ 140 mequiv/L). The sodium deficit approximates 0.6 mequiv/kg per milliequivalent fall in serum sodium. Unless neurologic symptoms are present, which would mandate urgent treatment, the sodium replacement should take 24 to 48 hours. After one-half of the deficit has been replaced, serum electrolyte levels should be rechecked. When urinary sodium is increased (>20 mequiv/L), simple sodium depletion can be excluded. Sodium conservation either will not or cannot take place. This occurs in the setting of abnormal ADH release, adrenal insufficiency, severe hyperthyroidism, recent use of diuretics, or intrinsic renal tubular dysfunction as in renal failure or interstitial nephritis. This can be clarified by measuring urinary osmolality.

Because the normal response to hyponatremia and hypo-osmolality is excretion of solute-free water (or dilute urine), the finding of a urine osmolality above that of serum, plus hyponatremia, indicates an abnormal ADH response (27,32). This implies a continued release of ADH in spite of a hypo-osmolar state. If this is present at the time of admission or in the absence of intravenous fluids, it implies a CNS abnormality (e.g., head trauma and intracranial tumor) or an ectopic site of production (e.g., bronchogenic carcinoma). In the patient receiving hypotonic fluids, this finding more commonly reflects the release of ADH associated with a central ‘‘acute phase response’’ or ‘‘systemic inflammatory response’’ to stress or illness. In either event, fluid balance will be ‘‘ahead’’ as is the total amount of sodium in the body. The hyponatremia means that water is ‘‘more ahead’’ than sodium. This paradoxic increased total sodium in the face of decreased serum sodium concentration results in a high urinary sodium excretion (>20 mequiv/L) and a high salt excretion fraction (>5%) (33). The finding of isosthenuria (urine osmolality equals serum osmolality) implies intrinsic renal dysfunction or pharmacologic dysfunction from diuretics. The finding of low urine osmolality and high urine sodium, however, suggests that ADH release is appropriately terminated, but that sodium is not being conserved. This situation is seen in mineralocorticoid insufficiency. Laboratory evaluation of the renal response to hyponatremia can be enlightening but does not replace clinical assessment. Because hyponatremia means either a decrease in sodium or an increase in water, appropriate interpretation of readily available data should allow discrimination. A decrease in sodium requires the presence of a route of loss and usually is associated with weight loss. Alternatively, an increase in water should be manifested by a gain in weight and excess fluid intake over output. In the patient who is not receiving intravenous fluids, a serum sodium below 135 mequiv/L constitutes hyponatremia and deserves investigation. In the patient who is receiving hypotonic fluids, however, mild hyponatremia is common enough to be expected. Although it is not normal, mild hyponatremia down to 130 mequiv/L can probably be ignored. A sodium level of 125 to 130 mequiv/L justifies vigorous diagnostic efforts to identify the cause. A serum sodium level of 120 to 125 mequiv/L necessitates vigorous institution of appropriate therapy. A sodium level of less than 120 mequiv/L is a medical emergency and frequently requires careful administration of hypertonic saline for correction. It is not the low sodium per se that is detrimental, but rather the increase in the intracellular fluid compartment, which accompanies this circumstance. This intracellular volume increase is especially detrimental to brain cells because the brain is contained within a fixed space with little or no room for expansion. When brain cells swell, an increase in intracranial pressure ultimately develops and presents clinically as a variety of manifestations, including apathy, confusion, weakness, nausea, and occasionally vomiting. If this water intoxication is not corrected, it will ultimately lead to convulsions, stupor, and possibly even death. When hyponatremia occurs in the setting of brain injury or intracranial surgery (particularly for cerebral aneurysms), the term ‘‘cerebral salt wasting’’ is often applied (34). The hypothesis is that humoral substances are released from the injured brain, either directly or as a result of the injury, which leads to an excessive loss of sodium in the kidney (35). More recent studies question whether this is actually a specific syndrome, or whether it is a manifestation

Chapter 2:

of increased ADH release in patients who have received very large amounts of isotonic crystalloid solutions. Although it is not clear which explanation is correct, it is certainly true that hyponatremia occurs in neurosurgical patients and that this hyponatremia may be multifactorial. Central to appropriate treatment is the assessment of actual fluid status (hypervolemia vs. hypovolemia) and a decision whether to administer fluids containing a high concentration of sodium or to restrict the amount of water being administered. In the absence of objective evidence of a sodium deficiency, it may be more appropriate to restrict water intake, as in the syndrome of increased ADH release, seen both in SIADH and in the acutely injured patient.

Pathophysiology of Fluid and Electrolyte Disorders

41

the very narrow range of normal potassium concentration in plasma and the relatively massive adjacent intracellular pool (5) (with exchange influenced by variables such as pH and drugs) make control of serum potassium both important and tenuous. This importance is underscored by the critical nature of severe potassium abnormalities on the cardiac, neural, and muscular systems and evidenced by the diligent monitoring of potassium concentrations, which occurs in operating suites and intensive care units. An understanding of the common circumstances leading to potassium abnormalities will facilitate maintenance of normal homeostasis and simplify treatment of abnormalities (16).

Hyperkalemia Hypernatremia The body rigorously defends itself against hyperosmolality. Even a small rise results in increased ADH release and subsequent free-water retention by the kidney, unless, of course, ADH release cannot occur (e.g., diabetes insipidus), ADH is ineffective (e.g., nephrogenic diabetes insipidus), or the patient is denied access to water (e.g., infants, geriatric patients, and unconscious or restrained patients). A simple review of the clinical situation will often identify the cause. Because hypernatremia implies either an increase in sodium or a decrease in water, both must be considered. An increase in sodium can result from aggressive administration of normal saline or sodium bicarbonate. A decrease in water can occur by renal or extrarenal mechanisms. Nonrenal causes should be clinically apparent and include such symptoms as diarrhea and excessive sweating. In addition to the forms of diabetes insipidus (pituitary dysfunction or nephrogenic), renal sources must include osmotic diuresis with obligatory ‘‘free-water’’ loss. In all cases, treatment is simple. Administration of hypotonic solutions will restore sodium concentration, and, when sodium excess is a component, judicious diuretic use will hasten sodium excretion. Care in treating hypernatremia must be exercised, however, because a rapid change in sodium concentration is of greater clinical importance than the actual sodium concentration (36). Too rapid a correction of sodium abnormalities can result in dramatic CNS effects, including seizures secondary to rapid changes in intracellular volume. Accordingly, treatment should be planned to correct one-half of the estimated deficit over 24 hours. In the case of hypernatremia, this usually translates into the administration of 2 mL of free water/kg over 24 hr for each milliequivalent of planned decrease in serum sodium concentration. In the patient with head injury or recent neurosurgical intervention with accompanying diabetes insipidus, unless actual hypophysectomy has been performed, early administration of vasopressin should be avoided. Careful replacement of losses will maintain fluid and electrolyte balance until the usually transient abnormality resolves. Accordingly, hypernatremia should be avoidable. If permanent diabetes insipidus is anticipated, however, administration of vasopressin or its synthetic analog, desmopressin acetate (DDAVP), should be instituted. Serious complications of diabetes insipidus (or inappropriate ADH secretion) are not a function of difficulty in treatment, but rather failure of recognition. Anticipation of such problems will greatly simplify their subsequent management.

Abnormalities of Potassium Because mammals usually ingest large amounts of potassium, it is not surprising that most abnormalities in potassium balance are the result not of intake, but of excretion. Further,

Because the kidney is the major site of potassium excretion, compromised renal function is almost always a factor contributing to hyperkalemia (9,11,13). Although increased potassium levels can occur from either excess intake or decreased excretion, the former is quite rare, is usually iatrogenic, and occurs in the setting of administering very large intravenous doses of potassium (or potassium-containing drugs such as penicillin) or giving potassium to a patient receiving a drug that inhibits potassium excretion (e.g., spironolactone, triamterene, and ACE inhibitors). Abnormalities of excretion are common and can be caused by intrinsic abnormalities of renal function (acute oliguric renal failure), disturbances in hormonal control of potassium exchange (hypoaldosteronism, adrenal insufficiency, etc.), or alterations in the potassium exchange mechanism per se (drugs, acidosis, etc.). Occasionally serum potassium is factitiously elevated (compared to plasma potassium) because of in vitro Kþ release from platelets during phlebotomy, in the setting of thrombocytosis (37). Hyperkalemia produces predictable clinical consequences that affect neuromuscular function (weakness, irritability, etc.) and cardiac conduction (peaking of T waves, prolongation of PR and QT intervals, widening of QRS complexes, and eventual heart block). Monitoring of the electrocardiogram provides a simple, noninvasive method of assessing change in the hyperkalemic or potentially hyperkalemic patient. Predictable changes, beginning with T-wave peaking, are the harbingers of subsequent complications, which are evidenced by alterations in the shape and duration of the major electrocardiogram complexes. Because hyperkalemia poses a life-threatening problem, urgent and definitive correction is imperative (17). A transient decrease in serum potassium can be accomplished by translocating extracellular potassium back into cells with glucose and insulin, and the membrane effects of hyperkalemia can be offset by the administration of calcium. In the rare patient with reasonable renal function and the need for a rapid decrease in serum potassium, a potassium diuresis can be induced by the use of loop-active diuretics. More commonly, potassium is removed from the body by the use of potassium-exchanging resins [sodium polystyrene sulfonate (Kayexalate)] that can be given by mouth or rectum and will predictably lower serum potassium. This is accomplished, however, through exchange with sodium and may alter fluid and sodium balance. Institution of peritoneal or hemodialysis is clearly the most effective, long-term approach to potassium control in the patient with renal compromise. It is important to remember, however, that continued administration of hypertonic glucose, as in parenteral nutrition, will result in a predictable and sustained fall in serum potassium because the egress of potassium associated with catabolism is prevented.

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Hypokalemia Hypokalemia is a common electrolyte abnormality in both hospitalized and ambulatory patients (16,38). Although it may be precipitated by an underlying disease (mineralocorticoid excess as in Cushing’s syndrome, potassium loss from a colonic villous adenoma, potassium wasting in renal disease, etc.) or by decreased potassium intake (low-potassium diet), most hypokalemia is iatrogenic in that it is induced pharmacologically by agents having potassium wasting as a side effect (36,39,40). Most notable are the diuretic agents currently used in the management of hypertension and fluid overload. The loop-active agents in particular are associated with a substantial potassium loss in the urine. Other classes of drugs, however, can also induce hypokalemia (21,41). The recent increased use of amphotericin B in the treatment of immune-compromised patients has uncovered a profound and difficult-to-manage hypokalemia (42). Use of newer synthetic penicillins in ultrahigh concentration is also associated with increased renal potassium loss and subsequent hypokalemia. Hypokalemia may manifest itself in various ways (e.g., muscle weakness and paralysis). More frequently, however, hypokalemia produces myocardial irritability and subsequent arrhythmias such as frequent premature contractions, sustained tachycardias, and potentiation of digitalis toxicity. Although these complications are more feared than common, they are serious complications and justify both respect and careful monitoring. Treatment is simple. Administration of potassium as the chloride salt will correct the usual associated chloride-dependent alkalosis, decrease renal potassium loss, and correct the hypokalemia. Beware, however, because the degree of hypokalemia is very poorly correlated to the magnitude of potassium deficit. Therefore, strict guidelines for replacement are dangerous. Because the hazards of hypokalemia appear to be virtually eliminated by institution of treatment rather than total correction, the identification of the abnormality and institution of treatment are more important than the rapidity of treatment. Frequently, discontinuation of the offending drug or control of the underlying disease will be necessary for long-term potassium control.

Abnormalities of Chloride Because chloride is the most abundant anion in plasma and extracellular water, it is not surprising that its range of variation is large and its mechanism of variation somewhat passive. The high concentration of chloride in gastric juice accounts for the hypochloremia that accompanies the metabolic alkalosis of conditions such as gastric outlet obstruction, repetitive vomiting, and pyloric stenosis. Chloride is absorbed in large quantities from the gut, and its level is controlled by urinary excretion. Most reabsorption of chloride occurs in the proximal tubule of the kidney, in association with sodium reabsorption. A considerable component is also actively reabsorbed in Henle’s limb (43). Alterations in proximal tubule absorption (osmotic diuretics) or Henle’s limb (loop-active diuretics) can lead to hypochloremia and metabolic alkalosis. In addition, in the presence of ‘‘hormone-dependent’’ (e.g., aldosterone) alkalosis, the fraction of chloride that is reabsorbed is decreased. This interaction of chloride and bicarbonate is important in the evaluation of the patient with metabolic alkalosis. Chloride is present in abundance in GI secretions. Substantial chloride loss can result from GI fluid losses from the upper tract (e.g., gastric outlet obstruction) or lower tract

(e.g., diarrhea). Assessment of the chloride deficit provides complementary information in the evaluation of volume depletion, secondary to GI losses.

Abnormalities of Calcium The most important factor in assessing calcium as an electrolyte is that clinically important abnormalities are very, very rare and easily categorized into hypocalcemia caused by hypoparathyroidism and hypercalcemia caused by hyperparathyroidism, tumors, systemic diseases, and medications. Hypocalcemia is rarely of clinical importance, except following parathyroid and thyroid surgery, and therefore infrequently requires treatment. Hypercalcemia, when the serum calcium is greater than 12, can be treated with aggressive saline administration, loop-active diuretics to minimize the fluid overload, and biphosphonates to reduce resorption of calcium from bone. Identification of the specific cause of the hypercalcemia (by measurement of ionized calcium, PTH, parathyroid hormone related peptide (PHRP), and 1,25-dihydroxyvitamin D3) is necessary to effect long-term control of the calcium level (18).

Isolated Acid/Base Abnormalities The availability of routine measurement of ‘‘arterial blood gases’’ has resulted in a much clearer understanding of the nature and treatment of acid/base disturbances in clinical practice. On the basis of the normal physiologic determinants previously described and the pathophysiologic mechanisms that will be enumerated, acid/base disturbances can be classified into acidosis or alkalosis. Both of the categories can be further subdivided into metabolic and respiratory, as well as combined metabolic/respiratory. Tables, nomograms, and algorithms have been developed for the assessment of the excess or deficit of acid (or base) to assist the clinician in management. Unfortunately, all of these aids are of only limited practical value because of the concurrent and efficient efforts of the compensatory mechanisms of the body to correct the acid/base disturbance. In other words, the onset of a disturbance in pH (by change in either HCO3 or pCO2) results in very rapid initiation of respiratory and/or metabolic compensatory mechanisms to partially correct the pH. It is essential in planning the treatment of acid/base disturbances to keep this compensation in mind, lest overaggressive management result in new, iatrogenic acid/base disturbances in the opposite direction.

Acidosis As described previously, acidosis can occur by the absolute gain in acid or loss of base from the body. Because the buffering system of the body is ‘‘open’’ in the sense that the CO2/HCO 3 system uses both respiratory and renal control systems, all but the most acute form of acidosis will be combined with compensatory adjustments. Consequently, all respiratory disturbances will have a metabolic compensatory component, and metabolic imbalances will stimulate respiratory compensation. Frequently, the pH is remarkably well corrected, and only a careful review of the historical facts associated with the illness will allow a clear analysis of the inciting cause. Occasionally, the cause is so elusive that only by disturbing the system with exogenous alkali and observing the respiratory response (or lack thereof) will the primary problem become apparent.

Respiratory Acidosis Pure respiratory acidosis is the simplest of the acid/base disturbances conceptually, because it results from a decrease

Chapter 2:

in effective alveolar ventilation (relative to carbon dioxide production). Normal carbon dioxide production from metabolic processes is approximately 450 L/day (20,000 mmol). Whenever carbon dioxide elimination lags behind production, respiratory acidosis ensues. The consequent laboratory abnormalities include a decrease in pH and an increase in pCO2. It is important to consider the pH first, because compensatory hypercapnea (increase in serum pCO2) in the setting of profound metabolic alkalosis is not uncommon, particularly in patients receiving mechanical ventilation by an intermittent (synchronized intermittent mandatory ventilation, pressure support ventilation, etc.) modality. Once respiratory acidosis is identified, a differential consideration of causes must include central respiratory depression (e.g., narcotics and intrinsic CNS disease), mechanical causes of decreased ventilation and/or increased dead space (e.g., tension pneumothorax, hemothorax, and massive pleural effusions), or pathophysiologic causes of increased carbon dioxide production. The common causes of acute or chronic respiratory acidosis are summarized as follows: & & & & & &

Airway obstruction Respiratory center depression Neuromuscular defects Restrictive lung diseases Smoke inhalation Inadequate mechanical ventilation

Appropriate treatment logically follows identification of the underlying mechanism and may include ventilatory assistance to enhance alveolar ventilation to eliminate the retained carbon dioxide and thereby correct the acidic pH. Occasionally, respiratory acidosis is produced by an increase in carbon dioxide production, because of either marked increase in oxygen consumption (active rewarming after heart surgery) or alteration in the respiratory quotient (excessive administration of carbohydrate-based parenteral nutrition). Because the pCO2 is proportional to the ratio of carbon dioxide production and minute alveolar ventilation, pCO2 ¼ kðV CO2 Þ=ðV AlvÞ; recognition of a high pCO2 and a high minute ventilation should assist in identifying patients with excessive carbon dioxide production.

Metabolic Acidosis In marked contradistinction to respiratory acidosis, metabolic acidosis can result from a variety of causes that include the gain of metabolic acids above excretion rates or the loss of bicarbonate greater than its rate of regeneration (44–47). Again, clinical evaluation and elucidation of the underlying mechanism greatly simplifies the task of evaluating the data. Also, it is important to avoid jumping to a conclusion of acidosis on the basis of only a decrease in the bicarbonate concentration of the serum, because this finding may also represent a normal metabolic compensation for a respiratory alkalosis. As is true with all biologic systems, electrical neutrality is maintained in all fluid compartments throughout the body by balancing the total number of cations with the total number of anions. In the extracellular compartment under normal conditions, the concentration of the cation sodium roughly equals the sum of the concentrations of the anions, chloride and bicarbonate, except for a small anion gap of

Pathophysiology of Fluid and Electrolyte Disorders

43

12 2 mequiv/L. An increase in this gap can give an important clue concerning the cause of acidosis. Thus it is helpful to subdivide metabolic acidosis into those categories that manifest an increase in unmeasured anions (increased anion gap) and those that do not and subsequently have a normal anion gap (nonanionic gap). As a generality, metabolic acidosis associated with the accumulation of organic acid will have an associated increased anion gap, whereas that caused by a loss of bicarbonate will have a normal or decreased anion gap. The distinction is important. Although both causes may require replacement of bicarbonate to correct the acidosis, the former group will require correction of an associated metabolic abnormality, and the latter will require attention to the site of bicarbonate loss (e.g., fistula).

Increased Gap Acidosis Any metabolic acidosis that is caused by the accumulation of organic acid (which is not measured by routine electrolyte analysis) will have a calculated anion gap that is greater than normal (uremia, diabetic ketoacidosis, lactic acidosis, and drug ingestion/poisoning). In some circumstances, e.g., diabetic ketoacidosis, combined mechanisms are operative, and the component caused by ketoacids is proportional to the anion gap. The presence of an acidosis with an anion gap greater than 14 mequiv/L implies either ingestion of an organic substance or an endogenous metabolic abnormality. Of the four commonly ingested ‘‘toxins’’ (methanol, ethylene glycol, ethanol, and isopropanol) only methanol (formic acid) and ethylene glycol (oxalic acid) produce a metabolic acidosis. Ethylene glycol also produces oxaluria, whereas methanol ingestion usually produces rapid retinal blindness. Acetylsalicylic acid (aspirin) and paraldehyde can also produce metabolic acidosis if ingested in large amounts, although paraldehyde is no longer available in the United States. Endogenous production of organic acid in excess of excretory capacity is seen in uremia, diabetic ketoacidosis, and lactic acidosis. Each is usually identifiable by the company it keeps: acidosis caused by renal failure is associated with the clinical and metabolic abnormalities of uremia; diabetic ketoacidosis is usually seen in known diabetics and is associated with hyperglycemia, dehydration, and ketosis in urine and serum (48); lactic acidosis can be caused by a variety of clinical states, but usually represents some form of hypoperfusion, such as sepsis or trauma (49). Lactic acidosis is associated with an increase in lactate in the blood (>4 mequiv/L) and an altered ratio of lactate to pyruvate (>30:1) and other oxidation–reduction pairs [e.g., acetoacetate/ betahydroxybutyrate and reduced nicotinamide adenine dinucleotide (NAD)/oxidized nicotinamide adenine dinucleotide (NADH)]. The actual cause of the increased lactic acid concentration is impairment of electron-to-oxygen transfer and subsequent accumulation of NADH, which shifts the equilibrium of pyruvate and lactate in the direction of lactate. Lactate serves as a reservoir or ‘‘cul de sac’’ during periods of deficient electron-to-oxygen transfer. Restoration of NADþ levels results in a prompt conversion of lactate back to pyruvate. It is often erroneously assumed that lactic acid is part of the pathophysiology of ‘‘lactic acidosis,’’ whereas it is actually only a secondary biochemical consequence of the underlying oxidation–reduction disorder. It is a quantitatively useful test to confirm the diagnosis and estimate the magnitude, however. Because it is often included in the battery of tests known as ‘‘blood gases,’’ it is important to confirm that a metabolic acidosis with an increased anion gap is

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present before suggesting a diagnosis of lactic acidosis, because lactate levels may be elevated in the absence of lactic acidosis. When lactic acidosis is present, attention needs to be paid to the underlying cause of the inadequate delivery of oxygen to tissues. It is also important to recognize that lactic acid may also be a component of the metabolic acidosis caused by diabetic ketoacidosis, methanol poisoning, and salicylate intoxication. Treatment of all forms of anion gap acidosis is both supportive (restore circulation, correct acidosis with bicarbonate, etc.) and specific (correct underlying abnormality). Bicarbonate should be given in adequate quantities to keep the pH above 7.2 and/or the bicarbonate level above 15 mequiv/L. Situations with ongoing tissue hypoxia may require substantial replacement, whereas transient problems such as postictal lactic acidosis usually correct themselves spontaneously. When bicarbonate is required, the bicarbonate deficit can be determined by a variety of formulas. An easy-toremember fact is that the bicarbonate space (apparent volume of distribution of the effective buffering system) corresponds roughly to one-half of total body water (approximately 30% of total body weight in kilograms). Thus: HCO 3 deficit ¼ 0:3 wt ð24 HCO3 Þ:

Usually one-half of the calculated deficit is replaced to avoid overcorrection, following which blood gases are repeated before infusing additional bicarbonate. In patients with compromised renal function and metabolic acidosis, it is important to remember that disorders associated with levels of potassium, magnesium, and phosphate are commonly found and should be sought. In lactic acidosis produced by hypovolemic shock, the treatment should focus on restoring circulation and perfusion, rather than on correcting the acidosis itself.

in conditions such as sepsis and hypovolemia) can be estimated by the following formula: pCO2 ¼ 1:5ðHCO 3 Þ þ D; where HCO3 is mequiv of HCO 3 and D is 8 2 mequiv/L. Recognition of this compensatory phenomenon will assist in preventing iatrogenic metabolic alkalosis from overtreatment with bicarbonate. It is also helpful to test whether the change in pCO2 is of an appropriate amount, because each increase or decrease of pCO2 of 10 torr should result in a change in pH in the opposite direction of 0.08.

Alkalosis As is the case with acidosis, alkalosis may be either respiratory or metabolic in origin. In contradistinction to acidosis, it is the metabolic component that is rather simple to define and correct, whereas respiratory alkalosis may have a myriad of causes.

Respiratory Alkalosis Respiratory alkalosis is probably the most common acid/ base disturbance in clinical medicine and can be induced by a multitude of underlying conditions. The pathophysiologic mechanism is excess alveolar ventilation above the requirements of carbon dioxide production. This abnormality typically represents some form of CNS overstimulation but may include as causes the factors summarized below: & & & & & &

Nonanion Gap Acidosis (Hyperchloremic) Causes of metabolic acidosis with a normal anion gap include bicarbonate loss, inability to excrete hydrogen ion, or administration of exogenous HCl or NH4Cl. Most commonly, there is either a recognized source of bicarbonate loss or an abnormality in the kidney (or adrenal). Recognized bicarbonate loss is usually from the GI tract distal to the pylorus and may include duodenal fistula, biliary drainage, pancreatic fistula, small intestinal fistula, ureterosigmoidostomy, and diarrhea. Intrinsic renal losses of bicarbonate include interstitial nephritis, renal tubular acidosis, adrenal insufficiency, hypoaldosteronism, and acetazolamide administration (50). Treatment of nonanion gap acidosis requires correction of the existing acidosis plus routine administration of a bicarbonate source on a regular basis. The dosage of bicarbonate required will depend on the underlying disease, its magnitude, and the need for dialysis. Guidelines for acute correction are the same as for anion gap acidosis: calculate the bicarbonate deficit (base deficit), estimate the bicarbonate space, and administer only as much as should correct one-half of the predicted deficit over a period of 24 hours. As indicated previously, compensation for metabolic acidosis is usual and is manifested as hyperpnea, tachypnea, nasal flaring, or even Kussmaul’s respiration. The degree of compensatory hyperventilation in a stable, chronic metabolic acidosis (as opposed to the acute changes seen

& & & &

Anxiety Fever Salicylate intoxication CNS disorders Intrathoracic processes Hypoxemia Hepatic insufficiency Gram-negative septicemia Pregnancy Mechanical hyperventilation

Treatment of respiratory alkalosis must be directed at correcting the underlying cause (e.g., correct fever with antipyretics). In patients requiring assisted ventilation, use of intermittent or partial ventilation systems will tend to minimize the overventilation that is often seen with controlled or assist/controlled ventilation. Other attempts at increasing pCO2, such as inspired carbon dioxide, rebreathing devices, and added mechanical dead space, are relatively ineffective.

Metabolic Alkalosis The fundamental abnormality in pure metabolic alkalosis is an absolute or relative excess of base (primarily bicarbonate) in extracellular fluid (44,51,52). This excess tends to be offset by a compensatory decrease in minute alveolar ventilation with subsequent hypercarbia. The mechanisms underlying metabolic alkalosis include the loss of hydrogen ion (with chloride), gain of exogenous base, or extracellular fluid–volume contraction. Identification of the latter two mechanisms should be straightforward by clinical evaluation, although gain of exogenous base may be masked as in blood or fresh frozen plasma transfusions (citrate is converted to bicarbonate) or excessive infusion of lactated Ringer’s solution.

Chapter 2:

The most common, clinically important forms of metabolic alkalosis are a result of loss of hydrogen ion and chloride from the stomach or hydrogen ion alone from the kidney. These two varieties can be separated by attention to the amount of chloride measured in the urine. Low urinary chloride (<10 mequiv/L) indicates a ‘‘chlorideresponsive’’ alkalosis. When there is insufficient chloride in the proximal nephron to maintain electroneutral reabsorption of sodium, bicarbonate is reabsorbed, leading to alkalosis, but with no chloride in the urine (53). When the abnormality occurs in the distal tubule (caused by hyperaldosteronism, increased plasma desoxycorticosterone, exogenous corticosteroids, licorice ingestion, or carbenoxolone therapy) the urine chloride will be greater than 20 mequiv/L, which confirms that chloride depletion is not the cause and therefore will not correct the abnormality by itself (54). More specifically, chloride-resistant alkalosis of renal origin can be thought of as excessive stimulation of the distal tubular, mineralocorticoid-mediated cation exchange mechanism resulting in increased excretion of Hþ and Kþ (55). This latter variety is perpetuated by (although not initiated by) hypokalemia, and correction of the potassium deficit is essential to restoration of acid/base balance (56,57). Active reabsorption of potassium (initiated by hypokalemia-induced hyperaldosteronism) in the distal renal tubule in ‘‘exchange’’ for Hþ, leads to the paradox of acid urine in the face of hypokalemic alkalosis (paradoxic aciduria). Occasionally, massive doses of potassium are required to achieve equilibrium; so the kidney does not have to work so hard reabsorbing it. When clinically significant hypoventilation develops as compensation for metabolic alkalosis, more rapid treatment may be needed (58). Two approaches are effective, including administration of acid and inducing renal tubular acidosis with acetazolamide, but neither will correct the underlying cause of the alkalosis. Recent experience with 0.1N HCl infusions (or as high as 0.2N) has shown this form of treatment to be quite safe if administered through a central venous line. The dose of Hþ should be calculated by determining base excess (or increase in bicarbonate above 28 mequiv/L), and multiplying it by one-half of estimated total body water (0.3 weight in kg). One-half of this calculated amount is then administered over 24 hours. Although repeated acetazolamide administration is effective in the treatment of severe metabolic alkalosis, correction of the excessive mineralocorticoid stimulation or maintenance of a high serum potassium is required to prevent recurrence.

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Table 6 Identification of Isolated Acid-Base Disturbances Disturbance Metabolic acidosis Metabolic alkalosis Respiratory acidosis (acute) Respiratory acidosis (chronic) Respiratory alkalosis (acute)

Respiratory alkalosis (chronic)

Effect pCO2 should fall by 1 to 1.5 times the fall in HCO3 PCO2 should rise by 0.5 to 1 times the rise in HCO3 Plasma HCO3 should be <30 mequiv/L Plasma HCO3 should rise by 4 mmol/10 mm Hg rise in pCO2 Plasma HCO3 should fall by 2.5 mmol/10 mm Hg fall in pCO2 (usually >18 mequiv/L) Plasma HCO3 should fall at least as much as acute but not <15 mequiv/L

Abbreviations: HCO3, Bicarbonate; pCO2, carbon dioxide partial pressure. Source: From Ref. 59.

clinical settings in which they are likely to occur are summarized below: Respiratory acidosis and metabolic alkalosis occur in patients with chronic respiratory acidosis with coexistent congestive heart failure, requiring diuretics. b. Respiratory acidosis and metabolic acidosis occur in patients with cardiopulmonary arrest, chronic lung disease in shock, or chronic renal failure with respiratory insufficiency. c. Respiratory alkalosis and metabolic acidosis may occur in hepatic failure with respiratory overstimulation or renal failure in sepsis. d. Respiratory alkalosis and metabolic alkalosis occur in hepatic cirrhosis with hyperventilation associated with vomiting or in chronic respiratory failure following institution of vigorous mechanical ventilation. e. Metabolic acidosis and metabolic alkalosis can be sequential rather than simultaneous abnormalities, although this may not be obvious. This situation is identified when the anion gap is numerically greater than the estimated HCO3 deficit and occurs with progressive contraction alkalosis caused by vomiting when hypovolemia becomes manifest. a.

PRINCIPLES OF FLUID THERAPY

Combined Acid/Base Disorders It is crucial to realize that acid/base disorders are in no way limited to a single pathophysiologic derangement at a time. Consequently, combinations of abnormalities are common. To distinguish single from combined disturbances, an objective approach is essential. Most standard texts contain graphs (e.g., Goldberg graphs) that indicate the 95% probability range for single acid/base disorders, i.e., the laboratory values that are 95% likely to represent a single pathophysiologic abnormality. In addition, numerous empiric equations have been developed to identify compensatory changes as opposed to coexistent abnormalities. Characteristics of isolated acid/base disturbances are listed in Table 6 (59). Certain combinations of acid/base disturbances are encountered commonly enough clinically to also justify listing. The components of these combinations and the

In any patient requiring intravenous fluid therapy, three categories of fluid loss must be taken into consideration. These include losses related to normal body maintenance (insensible plus urine), continuing losses of fluid and electrolytes, and preexisting fluid deficits resulting from the patient’s underlying disease. These should be thought of as a combination of maintenance and replacement fluids. As indicated in an earlier section of this chapter, all patients have normal maintenance requirements related to daily sensible and insensible losses. These losses will vary somewhat depending on the person’s age, body build, and sex, but generally average between 2000 and 2500 mL of fluid every 24 hrs (1500 mL/m2/day). The major sensible loss is urine, and the major insensible loss is related to evaporative losses from the skin and water losses through the lungs. All of these are primarily water losses, containing only small

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Table 7 Composition of Gastrointestinal Secretions

Stomach Pancreas Bile Intestine (primarily small)

Volume (mL/24 hr)

Na (mequiv/L)

K (mequiv/L)

Cl (mequiv/L)

HCO3 (mequiv/L)

1000–2000 300–800 300–600 2000–4000

60–100 135–145 135–145 120–140

10–20 5–10 5–10 5–10

100–130 70–90 90–130 90–140

– 95–120 30–40 30–40

amounts of electrolytes. If an individual patient requires intravenous therapy for only short periods of time, replacement of electrolyte losses is generally unnecessary, and maintenance volume losses can be replaced with solutions of 5% dextrose and water (Table 5) or 5% dextrose and half normal saline. If prolonged intravenous therapy is expected, the small but consistent daily electrolyte losses will need to be taken into account and can generally be managed by giving 2 mequiv/kg of body weight of sodium, chloride, and 1 mequiv/kg of potassium daily. Thus if a patient requires 2500 mL of fluid to meet normal maintenance needs, 1500 mL could be provided as dextrose and water, and the remaining 1000 mL could be given as half normal saline with the addition of appropriate amounts of potassium chloride (Table 5). Losses arising from the patient’s underlying disease must also be replaced. In surgical patients, these losses are almost always from some portion of the GI tract. As a general rule, intestinal secretions, bile, or pancreatic juice can be replaced on a volume-to-volume basis with a balanced salt solution such as Ringer’s lactate (although pancreatic replacement may require additional bicarbonate). Losses from an actively secreting stomach (emesis or nasogastric (NG) losses) require significant amounts of chloride (normal saline or half normal saline with potassium chloride added) (Table 5). The actual amount of potassium loss from GI secretions is small, although alkalosis can result in significant potassium loss from the kidney. Generally, vomiting or NG losses produce this abnormality (Table 7). To prevent the development of problems with hypokalemia, 20 to 40 mequiv of potassium for every liter of fluid loss from any of these sites should be administered. If long-term intravenous therapy is required, these requirements may increase and should be monitored by the determination of serum electrolyte values periodically. Another source of abnormal losses is an increased evaporative loss from the skin and respiratory tract in patients who are febrile. Loss of as much as 1000 mL daily may occur over and above normal insensible losses, if the body temperature is markedly elevated. In patients with persistent temperature elevations above 101 F (38.4 C), 500 to 1000 mL of additional fluid may be required daily (10% per C increase). Because such fluid loss is primarily water, it can generally be replaced with a ‘‘dextrose and water’’ intravenous solution or as water through a feeding tube. In critically ill patients receiving ventilatory support, respiratory losses (one-third of insensible loss) are no longer present because of the use of warm, humidified air, and fluid replacement should be reduced accordingly. Finally, preexisting solute or volume deficits must also be corrected. Again, such deficits generally arise from the GI tract and are the result of such problems as vomiting, diarrhea, or sequestration of fluid as may occur in patients with bowel obstruction. A correct estimate of these losses is often difficult, but careful attention to physical findings and important historical information from the patient, summarizing the duration of disease and the

frequency and amount of fluid losses (e.g., through vomiting or diarrhea), are usually helpful in deriving an appropriate estimate of the magnitude of underlying deficits. As emphasized previously, only one-half of this calculated estimate should be replaced in a given 24-hour period, and the patient reassessed clinically and with supporting laboratory data before attempting any further deficit replacement. If the principles just enumerated are followed, the large majority of patients requiring intravenous therapy can be managed without difficulty. Especially pertinent in such management is the frequent reassessment of the patient clinically and daily review of the patient’s input and output records to ensure that the proper amount and type of fluid is being given. Daily weight assessment are especially helpful in this regard and can give valuable clues as to whether abrupt or even subtle changes in fluid balance (either fluid overload or fluid deficit) are occurring. Further, attention to such detail helps prevent the development of any major imbalances that may occur insidiously before they become clinically obvious.

SUMMARY Plasma is a subset of the total fluid (extracellular fluid) that bathes the cells. As such when sampled, it allows an indirect look at the cellular events and the interaction between the cells and the extracellular fluid. Fluid and electrolyte disorders are legion and commonplace. The correct, critical interpretation of laboratory parameters to identify the pathophysiologic mechanisms underlying these abnormalities requires a willingness to go beyond the obvious. A logical analytic approach to the meaning of the observed laboratory disturbances should lead to an insight into the significance of the observation. A cookbook approach to ‘‘correct’’ the abnormal test result may actually worsen the situation. It is critical to appreciate that a concentration actually represents a ratio of the amount of a substance to the amount of fluid in which it is dissolved or suspended. Abnormalities in concentration can be caused by a change in either component. Attention to a variety of clinical factors (weight changes, vital signs, nursing notes, even history and physical examination, etc.) often provides the insight necessary to identify the true problem and chart its solution.

REFERENCES 1. Pitts R. Physiology of the Kidney and Body Fluids: Volume and Composition of the Body Fluids. Chicago: Year Book Medical Publishers, 1968. 2. Halperin ML, Bohn D. Clinical approach to disorders of salt and water balance. Emphasis on integrative physiology. Crit Care Clin 2002; 18:249–272.

Chapter 2: 3. Gruber UMA. Water and electrolyte balance. In: Diem K, ed. Documenta Geigy, Scientific Tables. Ardsley, NY: Geigy Pharmaceuticals, 1970. 4. Forbes R, Mitchell H, Cooper A. Further studies on the gross composition and mineral elements of the adult human body. J Biol chem 1956; 223:969. 5. Corsa L, et al. Measurement of exchangeable potassium in man by isotope dilution. J Clin Invest 1950; 29:1280. 6. Moore F. Determination of total body water and solids with isotopes. Science 1946; 104:157. 7. Moore F, et al. Body composition: total body water and electrolytes: intravascular and extravascular phase volumes. Metabolism 1956; 5:447. 8. Prough DS. Physiologic acid-base and electrolyte changes in acute and chronic renal failure patients. Anesthesiol Clin North Am 2000; 18:809–833, ix. 9. Beck LH. The aging kidney. Defending a delicate balance of fluid and electrolytes. Geriatrics 2000; 55:26–28, 31–32. 10. Miller M. Fluid and electrolyte homeostasis in the elderly: physiological changes of ageing and clinical consequences. Baillieres Clin Endocrinol Metab 1997; 11:367–387. 11. Jorgensen PL. Sodium and potassium ion pump in kidney tubules. Physiol Rev 1980; 60:864–917. 12. Kreimeier U. Pathophysiology of fluid imbalance. Crit Care 2000; 4:S3–S7. 13. Samson WK. Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu Rev Physiol 1999; 61: 363–389. 14. Frazier SK. Neurohormonal responses during positive pressure mechanical ventilation. Heart Lung 1999; 28:149–165; quiz 166–167. 15. Cadnapaphornchai MA, Gurevich AK, Weinberger HD, Schrier RW. Pathophysiology of sodium and water retention in heart failure. Cardiology 2001; 96:122–131. 16. Gennari FJ. Disorders of potassium homeostasis. Hypokalemia and hyperkalemia. Crit Care Clin 2002; 18:273–288, vi. 17. Williams ME. Endocrine crises. Hyperkalemia. Crit Care Clin 1991; 7:155–174. 18. Kinder B, Stewart A. Hypercalcemia. Curr Probl Surg 2002; 39:349–448. 19. Fulop M. Algorithms for diagnosing some electrolyte disorders. Am J Emerg Med 1998; 16:76–84. 20. Ward P. Role of complement, chemokines, and regulatory cytokines in acute lung injury. Ann N Y Acad Sci 1996; 796:104–112. 21. Polderman KH, Girbes AR. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002; 28:520–522. 22. Madhusoodanan S, Bogunovic OJ, Moise D, et al. Hyponatraemia associated with psychotropic medications. A review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev 2002; 21:17–29. 23. Liberopoulos EN, Alexandridis GH, Christidis DS, Elisaf MS. SIADH and hyponatremia with theophylline. Ann Pharmacother 2002; 36:1180–1182. 24. Fanestil DD, Park CS. Steroid hormones and the kidney. Annu Rev Physiol 1981; 43:637–649. 25. Goodenough RD, Burke JF. Fluid, electrolyte, and acid-base homeostasis in surgery. In: Burke JF, ed. Surgical Physiology. Philadelphia: WB Saunders, 1983. 26. Patel GP, Kasiar JB. Syndrome of inappropriate antidiuretic hormone-induced hyponatremia associated with amiodarone. Pharmacotherapy 2002; 22:649–651. 27. Diringer MN. Sodium disturbances frequently encountered in a neurologic intensive care unit. Neurol India 2001; 49(suppl 1): S19–S30. 28. Porcel A, Diaz F, Rendon P, et al. Dilutional hyponatremia in patients with cirrhosis and ascites. Arch Intern Med 2002; 162:323–328. 29. Oh MS, Carroll HJ. Disorders of sodium metabolism: hypernatremia and hyponatremia. Crit Care Med 1992; 20: 94–103.

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30. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ 2002; 166:1056–1062. 31. Milionis HJ, Alexandrides GE, Liberopoulos EN, et al. Hypomagnesemia and concurrent acid-base and electrolyte abnormalities in patients with congestive heart failure. Eur J Heart Fail 2002; 4:167–173. 32. Wong LL, Verbalis JG. Systemic diseases associated with disorders of water homeostasis. Endocrinol Metab Clin North Am 2002; 31:121–140. 33. Espinel CH. The FENa test. Use in the differential diagnosis of acute renal failure. JAMA 1976; 236:579–581. 34. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2002; 50: 749–755; discussion 755–766. 35. Singh S, Bohn D, Carlotti AP, et al. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med 2002; 30:2575–2579. 36. Riggs JE. Neurologic manifestations of electrolyte disturbances. Neurol Clin 2002; 20:227–239, vii. 37. Johnson C, Hughes K. Pseudohyperkalemia secondary to postsplenectomy thrombocytosis. Am Surg 2001; 67:168–170. 38. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin 2001; 17:503–529. 39. Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci 2002; 970:134–144. 40. Elisaf M, Liberopoulos E, Bairaktari E, Siamopoulos K. Hypokalaemia in alcoholic patients. Drug Alcohol Rev 2002; 21:73–76. 41. Preuss H, Burris J. Adverse metabolic effects of antihypertensive drugs. Implications for treatment. Drug Saf 1996; 14: 355–364. 42. Ural A, Avcu F, Cetin T, et al. Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients? Eur J Clin Pharmacol 2002; 57:771–773. 43. Rocha AS, Kokko JP. Sodium chloride and water transport in the medullary thick ascending limb of Henle. Evidence for active chloride transport. J Clin Invest 1973; 52:612–623. 44. Sirker AA, Rhodes A, Grounds RM, Bennett ED. Acid-base physiology: the ’traditional’ and the ’modern’ approaches. Anaesthesia 2002; 57:348–356. 45. Story DA, Poustie S, Bellomo R. Estimating unmeasured anions in critically ill patients: anion-gap, base-deficit, and strong-iongap. Anaesthesia 2002; 57:1109–1114. 46. Hatherill M, Waggie Z, Purves L, et al. Correction of the anion gap for albumin in order to detect occult tissue anions in shock. Arch Dis Child 2002; 87:526–529. 47. Frangiosa A, De Santo LS, De Santo NG, et al. Acid-base state in patients after cardiac transplantation. Am J Nephrol 2002; 22:332–337. 48. Felig P. Diabetic ketoacidosis. N Engl J Med 1974; 290: 1360–1363. 49. Mizock B, Falk J. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80–93. 50. Rothstein M, Obialo C, Hruska K. Renal tubular acidosis. Endocrinol Metab Clin North Am 1990; 19:869–887. 51. Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001; 93: 811–816. 52. Hodgkin JE, Soeprono FF, Chan DM. Incidence of metabolic alkalemia in hospitalized patients. Crit Care Med 1980; 8: 725–728. 53. Wesson D, Dolson G. Enhanced HCO3 secretion by distal tubule contributes to NaCl-induced correction of chronic alkalosis. Am J Physiol 1993; 264:F899–F906. 54. Hanna J, Scheinman J, Chan J. The kidney in acid-base balance. Pediatr Clin North Am 1995; 42:1365–1395.

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55. Gill JR Jr., Bartter FC. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter’s syndrome. Am J Med 1978; 65: 766–772. 56. Jacobson H, Seldin DW. On the generation, maintenance, and correction of metabolic alkalosis. Am J Physiol 1983; 245:F425–F432.

57. Khanna A, Kurtzman NA. Metabolic alkalosis. Respir Care 2001; 46:354–365. 58. Palmer B, Alpern R. Metabolic alkalosis. J Am Soc Nephrol 1997; 8:1462–1469. 59. Schrier RW, ed. Renal and Electrolyte Disorders. Boston: Little Brown, 1980.

3 Surgical Nutrition Rosemary A. Kozar, Margaret M. McQuiggan, and Frederick A. Moore

INTRODUCTION It has been said that outward appearances do not always convey things as they really are. This is certainly true with respect to surgical nutrition. In our society, where fast food diets have become the norm and a sedentary lifestyle is all too commonplace, protein-calorie malnutrition is being increasingly recognized in patients requiring hospitalization, despite how healthy a patient appears outwardly. Failure to identify this problem prior to embarking on a surgical procedure can have devastating effects on the outcome, not only from the standpoint of postoperative complications, but also, unfortunately and all too frequently, whether survival is impacted as well. Thus, it behooves the surgeon to have a thorough understanding of those factors that contribute to both good health and malnutrition and an understanding of how an operation or other stressful events can alter the adequacy of nutritional balance, and what strategies need to be employed to ensure that a healthy nutritional environment is maintained to minimize postoperative morbidity and mortality. The present chapter addresses these issues.

METABOLIC RESPONSE TO STRESS VS. STARVATION Endogenous supplies of carbohydrates, fat, and protein, are used to supply energy needs during starvation. In acute starvation, carbohydrates are initially utilized but stores are limited and quickly depleted. The body then depends heavily upon the breakdown of protein to provide amino acids as a primary energy source and as a source of new glucose for glucose-dependent tissues. These pathways provide about 85% of energy needs in this setting. Fat is a major fuel source available for gluconeogenesis and may also be oxidized to ketone bodies for use by the liver and other tissues. During brief starvation (approximately 72 hours), this process may be easily interrupted by providing exogenous substrate. After this, adaptive changes favor the mobilization of fat and reduce the breakdown of protein to a low level (30% of energy requirements). Fat, rather than protein, becomes the principal source of energy. With longer starvation, protein is further protected by a fall in total energy requirements. As with brief starvation, the process is quickly and easily reversed by providing exogenous glucose alone (which returns the patient to the brief starvation pattern) or exogenous glucose and amino acids. A variety of conditions, such as trauma, major elective surgery, burns, or sepsis, lead to a metabolic response called the ‘‘injury stress response.’’ This is an endocrinemediated response that increases circulating levels of

the counter-regulatory hormones, catecholamines, corticosteroids, and glucagon, and alters the metabolism of carbohydrates, protein, and fat. More recent evidence suggests that the systemic inflammatory response syndrome (SIRS) and its associated mediators [e.g., tumor necrosis factor (TNF)a, interleukin (IL)-1, IL-2, IL-6] also play an important role in the injury stress response. The best option to control the initiating insult is to provide high-risk patients exogenous substrates that support the metabolic environment. The injury stress response increases resting energy expenditure (REE). The increase in REE is dependent upon the type as well as the severity of the insult. It can increase as much as 100% after burns, 50% after sepsis, 40% after trauma, and 30% after major surgery (1–3). Similar to what occurs in starvation, endogenous substrates are mobilized. Glucose stores are quickly depleted and gluconeogenesis (principally in liver, but also in kidney) produces glucose that is shunted to glucose-dependent tissues (brain, erythrocytes, inflammatory cells, and wound tissue). Adipose tissue is stimulated to release free fatty acids and glycerol. The rate of lipolysis, however, exceeds lipid oxidation. As a result, plasma triglyceride levels increase and considerable reesterification occurs in the liver. This requires energy and creates futile cycles. The increase in protein catabolism is the most dramatic effect. Skeletal muscle proteins and later constitutive protein stores (such as albumin) are broken down and the released amino acids become the substrate for acute-phase protein synthesis, gluconeogenesis, and energy production. Metabolic differences between chronic starvation and the injury stress response are summarized in Table 1. Nutritional support needs to be tailored to the metabolic environment of the patient. The stressed intensive care unit (ICU) patient requires more nonprotein calories (25 kcal/kg/day) and more protein (1.3 g/kg/ day) compared to the starved patient (20 kcal/kg/day and 1.0 g/kg/day, respectively). As stress increases, patients become more catabolic and less tolerant to glucose. Therefore the amount of protein administered is increased (1.5–2.0 g/kg/day) and the percent of nonprotein calories delivered as glucose is decreased

Table 1 Metabolic Response of Starved vs. Stressed Patients Metabolic response

Prolonged starvation

Injury stress

Resting energy Primary fuel Proteolysis Gluconeogenesis Ketone production

Decreased Fat Increased (þ) Increased (þ) Increased (þþþ)

Increased Mixed Increased (þþþ) Increased (þþþ) Increased (þ)

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(80–70%). Thus the nonprotein calories to gram of nitrogen ratio is decreased from 120:1 to 80:1 with increasing metabolic stress.

RATIONALE FOR NUTRITIONAL SUPPORT The rationale for providing nutritional support is threefold: first, to prevent acute protein malnutrition, second, to modulate the immune response, and third, to promote vital gut function.

Prevention of Acute Protein Malnutrition Persistent hypercatabolism dominates the metabolic response to critical illness. Initially, amino acids demands are met by skeletal muscle proteolysis. However, in a short period of time, this depletes crucial constitutive structural elements as well as circulating proteins. The resulting acute protein malnutrition is associated with cardiac, pulmonary, hepatic, gastrointestinal, and immunologic dysfunction. Delayed infections then extend hypercatabolism with the progression to full-blown multiple-organ failure (MOF). A number of clinical studies have clearly demonstrated that early enteral nutrition improves outcome, as measured by improved nitrogen balance and constitutive protein levels, improved immune function, decreased incidence of infections, and decreased length of stay (4–7). However, these studies were performed in trauma and burn patients, an easily identified and cohesive group of patients who also tend to be young and free of comorbid disease. Whether these observations can be generalized to other ICU patient populations is not clear.

Modulation of Immune Response Despite tremendous advances in ICU care, nosocomial infections continue to be an unsolved problem. In large part, these late infections occur due to failure of local and systemic host defenses. While exact causes of late immunosuppression are not clear, it is now believed to occur in part as a result of dysfunctional regulation of inflammation (8). An initial insult, whether secondary to sepsis, trauma/burns, or major operation, can precipitate early systemic hyperinflammation (i.e., SIRS), which when intense can precipitate early MOF. Certain components of this early SIRS response are endogenously downregulated to prevent unnecessary, potentially auto-destructive inflammation. This is referred to as the compensatory anti-inflammatory response syndrome (i.e., CARS). The resulting delayed immunosuppression, however, sets the stage for secondary infection, which can either worsen early MOF or trigger late MOF. While no strategy can prevent or eliminate this dysfunctional inflammatory response, the delivery of specific immune-enhancing nutrients (generally via the gut) may prove beneficial.

Promotion of Vital Gut Function The dysfunctional gut is believed to be the ‘‘reservoir for pathogens’’ that cause late MOF-associated infections. The initial insult (via ischemia/reperfusion, sepsis, or inhibitory neuroendocrine reflexes) and emergency laparotomy (via anesthesia and bowel manipulation) cause an early ileus. Disuse (parenteral instead of enteral nutrition) and common ICU therapies (e.g., H2-antagonists, narcotics, and broadspectrum antibiotics) promote further gut dysfunction, characterized by progressive ileus, colonization of the upper gut, increased permeability, and decreased gut-associated lymphoid tissue function. Consequently, the upper gut becomes

a reservoir for pathogens, and local and systemic defense mechanisms that prevent the spread of these organisms become impaired; the primary route of dissemination (i.e., aspiration vs. translocation) is not clear. Although there is good epidemiologic evidence for this sequence of events, prospective randomized controlled trials (PRCT) of gutspecific therapies such as early enteral nutrition and, recently, immune-enhancing enteral formulas have consistently demonstrated a reduction in nosocomial infections and provide the most convincing evidence (7,9). Thus, the provision of early enteral nutrition to promote more normal gut function is believed to prevent the occurrence of this cascade of events.

INITIATION OF NUTRITIONAL SUPPORT Nutritional Assessment A nutritional assessment is completed early in the hospital stay. Physical assessment of the patient includes evaluation of body composition, edema, wound healing, nutrient composition of fluid losses through wounds or drains, and review of the laboratory and medication profile. A recording of the height and preadmission weight is obtained and information on chronic disease, activity level, medications, previous dietary restrictions, psychosocial data, and drug and tobacco patterns is elicited. A history of 10% weight loss over three months is considered significant. However, weight loss combined with physiologic impairment may be clinically more important, as this can be associated with more septic complications, pneumonia, and a longer hospital stay (10). Functional impairment may be assessed by crude measures such as physical assessment of muscle bellies and triceps skinfold, decreased prehospital activity, perception of fatigue, strength of handshake, strength of cough, and skin integrity. More sophisticated measures such as caliper measurements of skin folds, bioelectrical impedance analysis, indirect calorimetry, and dual-energy X-ray absorptiometry for bone mineral density, hand-grip dynamometry, and respiratory muscle strength may also be performed. Body protein stores as assessed by muscle mass and serum proteins correlate more closely with survival than adipose stores. The normal age-related loss of skeletal muscle is well recognized. Protein-energy malnutrition is a major predictor of mortality in elderly patients (11). Beginning in the second decade, there is a reduction in the total muscle fiber numbers that, with advancing age, produces a 40% reduction in muscle cross-sectional area (12). The malnourished, elderly patient undergoing a catabolic illness may reach a critical cardiac or respiratory threshold earlier than expected (13). Loss of lean body mass, predominately skeletal muscle, in the ICU after stress or sepsis may approach 1% daily (14). Thus, a healthy young person might approach a lethal decline in lean body mass (40%) in 40 days, while a 60-year-old would reach that level in 30 days, and a person over 70 years in 20 days. Reduced immunocompetence accompanies loss of lean body mass. Assessment of serum protein status is conducted upon admission and periodically throughout the hospital stay. Acute-phase proteins, such as C-reactive protein, rise markedly within 48 to 72 hours after sepsis, injury, or surgery, while the constitutive proteins—albumin, prealbumin, and transferrin—all decline (Table 2). Measuring both categories of proteins concurrently helps to determine the degree of physiologic stress and the return of anabolism.

Chapter 3: Surgical Nutrition

Table 2 Serum Proteins that Aid in Nutritional Assessment Protein

Site of synthesis

Half-life

Liver Liver Liver Liver

21 days 2–4 days 8–10 days 48–72 hours

Albumin (g/dL) Prealbumin (mg/dL) Transferrin (mg/dL) C-reactive protein

Table 4 Urinary Nitrogen Loss as a Function of Stress Type of protein Constitutive Constitutive Constitutive Acute-phase reactant

Once the acute-phase response has resolved, the constitutive proteins should rise on provision of adequate nutrition.

Energy Requirements The Harris–Benedict equation is a common method to estimate energy expenditure and thus determine caloric requirements. This equation was derived using healthy males and estimates basal energy expenditure (BEE) based on age, sex, height, and weight. The Harris–Benedict equations are as follows: Men : BEE ¼ 66 þ ð13:7 weightÞ þ ð5 heightÞ ð6:8 ageÞ Women : BEE ¼ 665 þ ð9:6 weightÞ þ ð1:9 heightÞ ð4:7 ageÞ where weight is actual or adjusted (kg), height is in cm, and age is in years. The BEE represents energy requirements in the fasted, resting, nonstressed state. In the presence of metabolic stress, the BEE must be multiplied by an empirically derived stress factor to obtain an estimate of the caloric requirement. The usual stress multiplication factors range from 1.2 to 1.6 times the BEE. Current recommendations for estimated caloric support are reviewed in Table 3. In general, most patients should receive 25 to 30 kcal/kg/day and 1.5 to 1.75 g/kg/day of protein. Needs may decrease as patients move farther from the initial surgery or trauma.

Monitoring Response to Therapy Urinary Urea Nitrogen Urinary urea nitrogen (UUN) is measured as an indicator of the protein catabolic rate (i.e., stress) and is used to determine the nitrogen balance. It represents 60% to 90% of the nitrogen excreted in the urine, and therefore, is a rough approximation of total urinary nitrogen. As the stress level increases, the concomitant increase in protein catabolism results in an increase in urinary nitrogen. Estimated urinary losses for various clinical conditions are reviewed in Table 4. However, in patients with compromised renal function (creatinine clearance <50 mL/min), measurement of UUN is not Table 3 Estimated Caloric Requirements in Surgical Patients by Body Weight Weight class Underweight Normal Overweight Obesitya Extreme obesitya a

BMI (kg/m2) < 18.5 18.5–24.9 25–29.9 30–34.9 35–39.9 40

Use adjusted body weight.

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Obesity class

Caloric intake (kcal/kg/day)

I II III

40 25–30 25–30 20–25 20–25 10–20

Level of stress Nonstressed Mild stress Moderate stress Severe stress

Clinical condition

Urinary nitrogen loss (g/day)

Starvation Elective surgery Trauma Sepsis

<8 8–12 13–18 > 18

valid and calculations of protein catabolism rates are necessary. These require serial measurements of blood urea nitrogen and weights, and calculations of interdialytic time period and urinary losses of nitrogen. Additionally, UUN is not useful in patients with spinal cord injury because obligatory losses due to disuse muscle wasting are generally extraordinary regardless of the level of support and persist for up to seven weeks postinjury (15). Nitrogen balance is the difference between nitrogen intake and nitrogen output. Nitrogen intake is determined from dietary intake per day, while nitrogen output per day is determined by measuring UUN in a 24-hour urine collection and adding 4 g to approximate nonurea nitrogen loss in the urine plus other insensible N2 losses. Ideally patients should be in positive nitrogen balance (3–5 g/day). Nitrogen balance is calculated as follows: Nitrogen balance ¼ ðg protein intake=6:25Þ ðg nitrogen in UUN þ 4Þ

Metabolic Gas Analysis Also known as indirect calorimetry, metabolic gas analysis is a tool that can measure REE. Oxygen consumption ðVO2 Þ and carbon dioxide production ðVCO2 Þ are measured, and the REE is then calculated from the Weir equation: REE ¼ 3:9 þ VO2 þ 1:1 VCO2 2:8 UUN Care, however, must be taken to ensure that a steady state (less than 10% change in VO2 and VCO2 during five consecutive minutes of the test) was achieved before relying on results (16). The REE obtained should then be used as the patient’s nutritional goal. No activity factor or thermogenesis factor (unless the patient is fasted or on intermittent feeds) needs to be added. Indirect calorimetry may be helpful when (i) overfeeding would be undesirable [as in diabetes, obesity, or chronic obstructive pulmonary disease (COPD)], (ii) underfeeding would be especially detrimental (renal failure, or large wounds), (iii) physical or clinical factors promote energy expenditure deviant from normal, (iv) drugs are used that may significantly alter energy expenditure (paralytic agents, beta-blockers, or corticosteroids), (v) patient response to calculated regimens is suboptimal, and (vi) body habitus makes energy expenditure predictions challenging (morbid obesity or quadriplegia). Although more commonly utilized in ventilated patients, indirect calorimetry can also be performed on spontaneously breathing patients. The second variable obtainable from indirect calorimetry is the respiratory quotient (RQ). This is calculated as follows: RQ ¼ VO2 =VCO2 ¼ CO2 production=O2 consumption RQ is a gross measurement of substrate utilization (Table 5) and should be used to verify the accuracy of the study (17).

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Table 5 Respiratory Quotient (RQ) for Various Substrates RQ 0.7 0.8 0.85 1.0 > 1.0

Substrate Fat Protein Mixed Carbohydrate Lipogenesis

Any test with an RQ value outside of the physiologic range (less than 0.67 or greater than 1.3) should be checked for accuracy. When an RQ value 1 is obtained and the patient is on total parenteral nutrition (TPN), CO2 production may be increased by one of two mechanisms: either a high proportion of nonprotein calories are being supplied as glucose (carbohydrates have RQ of 1) or the patient is being provided excess calories. With overfeeding, excess glucose is converted to fat and lipogenesis (RQ > 1) occurs.

Body Proteins that Aid in Nutritional Assessment Serum proteins that correlate with nutritional status should be assessed (Table 2). The liver normally produces a number of constitutive proteins that are helpful in nutritional assessment. Albumin is useful for evaluation of chronic malnutrition, but not in the acute setting as it has a long half-life. To determine if nutritional support is having an impact, proteins such as prealbumin and transferrin are more useful due to their shorter half-life. However, during the acutephase response, the liver undergoes reprioritization and downregulates the constitutive proteins and upregulates acute-phase proteins such as C-reactive protein. Measurement of proteins such as albumin and prealbumin are therefore not helpful as indicators of the adequacy of the nutrition support during the acute stress response. C-reactive protein is a sensitive acute-phase reactant that increases from a normal level near zero up to 20 to 30 mg/dL within 48 to 72 hours of injury. It can be used as an indicator of the severity of injury, inflammation, and sepsis. Only when this level begins to decline, can the liver begin to again synthesize constitutive proteins. Once C-reactive protein falls below 10 to 15 mg/dL, a prompt increase in prealbumin typically occurs (0.5–1.0 mg/dL daily). If not, then the adequacy of the support regimen should be reevaluated and other factors that are preventing anabolism should be investigated.

Impact of Nutritional Status on Surgical Outcome Clinical studies have clearly documented the predictive value of preoperative serum albumin levels on postoperative morbidity and mortality. In fact, albumin was the single best predictor of postoperative outcome in several large studies conducted by the Department of Veteran Affairs (18–20). Recently Kudsk et al. (21) demonstrated that albumin as well as the operative site was important in predicting postoperative complications. Patients undergoing colectomy and gastrectomy tolerated greater degrees of malnutrition than those patients undergoing pancreatectomy and esophagectomy. Interestingly, patients with the lowest preoperative albumin levels sustained the longest delays in resuming oral intake postoperatively, compounding the preexisting malnutrition. Despite these findings, preoperative malnutrition remains under-recognized and under-treated and suggests that additional prospective preoperative nutritional studies should be conducted with high-risk patients.

Special Considerations in the Obese Patient Overview of Obesity and Nutrition Obesity affects one-third of Americans and is associated with a number of comorbid conditions. Obesity and morbid obesity are increasingly encountered in the surgery patient and may increase risk for morbidity and mortality. Trauma patients with a body mass index (BMI) > 31 were found to have an eightfold higher rate of mortality following blunt trauma, frequently due to pulmonary complications (22). While controversial, hypocaloric feeding in the obese patient has also been suggested to lessen infectious complications secondary to hyperglycemia. Comparable nitrogen balance is achieved in this patient population when hypocaloric feeds are administered (23). Monitoring for clinical evidence of overfeeding (hypercapnea, hyperglycemia, insulin resistance, hypertriglyceridemia, diarrhea, and distention) is used to refine predictions. Obesity is defined as a BMI 30 (Table 3). Energy needs should be based on adjusted body weight (ABW) when actual body weight exceeds 120% of the ideal body weight (IBW) and is calculated as: ABW ¼ 0:25 ðactual body weight IBWÞ þ IBW: The ABW takes into account the increased lean body mass seen in obese patients and should be used in the Harris–Benedict equation or in caloric predictions (kcal/kg) of energy needs. Obese patients experience a similar metabolic response to critical illness but tend to be more resistant to insulin. Obese patients should be started on nutritional support as early as their nonobese counterparts. Hypocaloric feeding provides the obese individual with high protein (1.5–1.75 g/kg ABW) but low total calories (20–25 kcal/kg ABW).

Nutrition After Bariatric Surgery Nutritional treatment for uncomplicated bariatric procedures is somewhat standardized across the country, although little evidence-based research has been performed in this patient population. Immediately after surgery, most programs begin clear liquids for several days, which are consumed in 30 cc/hr increments. This is followed by a progressive diet (advanced every two weeks) of full liquids, then pureed, soft foods, and finally a regular diet as tolerated. Maintenance goals are set at 1000 to 1200 kcal daily. Protein goals are typically 60 to 80 g protein/day, which may deliver as little as 0.48 g protein/kg ABW, which is less than the recommended daily intake of 0.8 g/kg body weight of protein. Liquid multivitamins with mineral supplements, iron, vitamin C, vitamin B12, and calcium may also be added. The amount of nutritional follow-up and level of expertise varies greatly between programs. For the majority of patients, a standard bariatric diet can be followed. However, patients who develop postoperative complications necessitating admission to the ICU will generally require an alternative feeding regimen. If the complication is intra-abdominal, particularly if secondary to an anastomotic leak, nutrition will usually be provided by the parenteral route, as enteral access (to the small bowel) will generally require operative placement. An initial goal of adjusted weight at 10 to 20 kcal/kg and protein at 1.5 g/kg can be instituted, depending on the degree of insulin resistance. Indirect calorimetry is helpful and, if performed, feeds should be instituted at 60% to 75% REE. A UUN can then be used as a guide to achieve positive nitrogen balance. Type 2 diabetes is a

Chapter 3: Surgical Nutrition

frequent comorbidity and strict glycemic control (glucose < 110 mg/dL) should be employed in all patients. Intravenous lipids are not provided in the first one to two weeks, and then provided sparingly to prevent essential fatty acid deficiency. Enteral support typically requires a specialized combination of a high-protein polymeric formula with the addition of a protein modular product. A liquid multivitamin and mineral supplement may also be added. Bariatric patients who experience delayed complications or significant remote illnesses can pose a challenge. Many of these patients have been on the bariatric diet for a prolonged period of time and may have some degree of protein malnutrition from a low-calorie, low-protein diet. Due to malabsorption, micronutrient deficits may be present and the refeeding syndrome is likely to occur. Organ function may also be compromised through body cell mass depletion, and immunocompetence decreased via protein malnutrition. Kilocalorie and protein requirements can be extraordinary, especially with large wounds such as necrotizing fasciitis or decubiti. However, the approach is similar to that taken with early postoperative complications. Indirect calorimetry, 24-hour UUN, and sequential monitoring of C-reactive protein and prealbumin should be employed. If renal failure occurs, continuous dialysis is typically employed to facilitate adequate feeding. Depending on the length of time since the original surgery and the adequacy of postoperative nutritional follow-up, the patient may exhibit varying degrees of protein, iron, zinc, calcium, folate, and B12 deficiency.

ENTERAL NUTRITION Benefits of Enteral Nutrition Three prospective randomized controlled trials (PRCTs) performed in the 1980s had significant impact on clinical practice in surgical, and particularly trauma ICUs (4–6). These single-institution trials all randomized trauma patients to early enteral nutrition or TPN and all demonstrated that patients receiving early enteral nutrition had significantly fewer infectious complications. A meta-analysis that

53

combined data from eight PRCT (six published, two not published) was then conducted to assess the nutritional equivalence of enteral nutriton compared to TPN in highrisk trauma and/or postoperative patients (24). Similar to the single-institution trials, fewer infectious complications developed in patients receiving enteral nutrition. Even when patients with catheter-related sepsis were removed from the analysis, a significant difference in infections between groups remained. Taken together, these trials provide convincing evidence that enteral nutrition is preferred to TPN in patients sustaining major torso trauma. A recent meta-analysis evaluating the effect of early versus delayed enteral nutrition in acutely ill (medical and surgical) patients also confirmed a decrease in infectious complications in patients receiving early enteral nutrition (25).

Role of Immune-Enhancing Agents in Surgical Patients Recent basic and clinical research suggests that the beneficial effects of enteral nutrition can be amplified by supplementing specific nutrients that exert pharmacologic immune-enhancing effects beyond the prevention of acute protein malnutrition. There are at least 18 PRCT (Table 6) and three meta-analyses (24,26,27) where an immuneenhancing enteral diet is compared with a standard enteral diet or no diet, and where the patient outcome was a predetermined end point. Of the 18 PRCTs, 11 trials demonstrated improved outcome, four trials were highly suggestive of improved outcome, and three trials did not demonstrate any clinical outcome advantage. The majority of trials are in trauma and cancer patients, though a few trials include mixed ICU and septic ICU patients. The proposed immune-enhancing agents include glutamine, arginine, omega-3 polyunsaturated fatty acids (PUFA), and nucleotides, though the individual contributions of each have not been well investigated. Glutamine is actively absorbed across the intestinal epithelium and then metabolized in the small bowel to ammonia, citrulline, alanine, and proline, and serves as an energy source for the

Table 6 Patient Outcome in Prospective Randomized Controlled Trials Comparing IEDs vs. Standard Enteral Diets Author

Year, Journal

Patient type (Number)

Gottschlich Daly Brown Moore

1990, 1992, 1994, 1994,

JPEN Surgery Pharmacotherapy J Trauma

Burns (50) Cancer (77) Trauma (37) Trauma (98)

Bower Daly Kudsk Senkel Mendez Saffle Heslina Braga Atkinson Weimann Senkel Braga Snyderman Galban

1995, 1995, 1996, 1997, 1997, 1997, 1997, 1998, 1998, 1998, 1999, 1999, 1999, 2000,

Crit Care Med Ann Surg Ann Surg Crit Care Med J Trauma J Trauma Ann Surg Crit Care Med Crit Care Med Nutrition Arch Surg Arch Surg Laryngoscope JPEN

Mixed ICU (296) Cancer (60) Trauma (35) Cancer (154) Trauma (43) Burns (50) Cancer (154) Cancer (154) Mixed ICU (369) Trauma (32) Cancer (154) Cancer (206) Cancer (129) Septic ICU (181)

Results with IED (decrease in) Wound infection, LOS Wound complication, infections Infections Intra-abdominal infection, multiple organ failure Infections, LOS Wound complications, infections, LOS Antibiotics, infection, LOS Late infections * ARDS

Infections, LOS Ventilator days, LOS SIRS, multiple organ failure Late infections Infections Infections Late infections

a

Improved outcome Yes Yes Yes Yes ? Yes Yes Yes Yes No No No Yes ? Yes ? Yes Yes Yes Yes Yes

Compared IED to no diet. Abbreviations: ARDS, adult respiratory distress syndrome; ICU, intensive care unit; IED, immune-enhancing diet; SIRS, systemic inflammatory response syndrome; LOS, length of stay.

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enterocyte. Glutamine is therefore acknowledged to be the preferred fuel of the enterocyte, and stimulates lymphocyte and monocyte function. The demand for glutamine is increased during stressed states and supplementation at pharmacologic doses may be required. It also promotes protein synthesis, is a precursor for nucleotides as well as glutathione, and is thought to play a role in maintaining gut integrity. In a recent meta-analysis, glutamine (parenteral and enteral) administered to critically ill and surgical patients resulted in a lower mortality, less infectious complications, and shorter hospital stays (28). High-dose and parenteral glutamine had the greatest effect, though the study was not designed to examine these parameters. Additionally, a mixed patient population was included with limited (randomized) studies and clinical end points. A randomized trial of glutamine-enriched enteral nutrition in severely injured patients demonstrated a decrease in pneumonia, sepsis, and bacteremia (29). Arginine is a semiessential amino acid that is important for T-cell function and wound healing. Endogenous production is insufficient during periods of metabolic stress (such as illness) and exogenous supplementation is required for maximal function of the immune system. It is also a powerful secretagogue, increasing the production of growth hormone, prolactin, somatostatin, insulin, and glucagon. Additionally, arginine is the chief precursor of nitric oxide and has been shown to increase protein synthesis and improve wound healing (30). It is the association with nitric oxide production that has led to speculation that arginine may enhance the systemic inflammatory response and, therefore, be potentially harmful, particularly in septic patients (31). Sepsis increases levels of inducible nitric oxide synthetase (iNOS). Arginine is a substrate for iNOS, and in its presence arginine combines with molecular oxygen to produce citrulline and nitric oxide. The resulting nitric oxide could have numerous adverse effects in sepsis, including vasodilation, cardiac dysfunction, and direct cytotoxic injury by generating potent reactive oxygen species. Increased mortality has been demonstrated in some critically ill septic patients when receiving an immune-enhancing diet, and arginine has been implicated as the causative agent (32,33). Although traditional enteral products contain a high proportion of omega-6 PUFA, diets with a low omega-6 PUFA and high omega-3 PUFA content more favorably alter the fatty acid composition of membrane phospholipids toward reduced inflammation (34). Finally, nucleotides (purines and pyrimidines) are needed for DNA as well as RNA synthesis and may be necessary in stressed states to maintain rapid cell proliferation and responsiveness (35). In the setting of increased demand, most tissues can increase intracellular de novo synthesis of nucleotides. Lymphocytes, macrophages, and enterocytes, however, rely on increased salvage from the extracellular pool, which may be depleted during stress.

Contraindications to enteral nutrition can be divided into absolute and relative. Absolute contraindications would include functional complications such as bowel obstruction, peritonitis, progressive ileus, massive gastrointestinal hemorrhage, and gastrointestinal ischemia associated with shock and vasopressors. Relative contraindications include proven intolerance to enteral nutrition and intolerance associated with short-gut syndrome, high-output fistula, pancreatitis, and inflammatory bowel disease. A recent bowel anastomosis is not a contraindication. Laboratory data in fact suggests that healing may be hastened by early feeding (36).

Gastric Feeding Controversy exists as to the optimal site for delivery of enteral nutrients. Although there is a trend toward decreased ventilator-associated pneumonias with jejunal feeding, no significant differences have been demonstrated between postpyloric and gastric feeding (37–40). None of these studies, however, have been appropriately powered to demonstrate statistical significance. Additionally, a greater percentage of caloric goals are reached (37,41) and gastrointestinal complications are less frequent with postpyloric feeding. The stomach, but not the small bowel, commonly exhibits an ileus after surgery, major trauma, or other critical illnesses. Ritz et al. demonstrated that up to 45% of ventilated patients had delayed gastric emptying, impeding adequate delivery of gastric feeds (42). Several studies have shown that this can be modulated by the use of prokinetic agents (43,44). Erythromycin has a direct effect on the motilin receptors of the stomach and has been shown to improve the effectiveness of gastric feedings. Gastric feeding is appropriate for some surgical patients, particularly those farther out from their initial injury or insult. Prior to starting gastric feeds, however, patients should be screened for risk of aspiration (Table 7) (45). Aspiration is the second most common cause of nosocomial infection in hospitalized patients (46). The presence of an inflated endotracheal cuff does not preclude aspiration in intubated patients, as there is as high as a 50% to 75% incidence of aspiration in patients with endotracheal tubes and/or tracheostomies (47,48). Altered mental status, whether from dementia, sedation, or a closed head injury poses a risk as do neuromuscular disorders and stroke. Recent major abdominal surgery and the need for prolonged supine position can also increase the risk of aspiration. Persistently high gastric residual volumes have also been sited as a risk factor. What constitutes a high volume, however, has not been well defined. Approximately 1.5 L of saliva and 3 L of gastric secretions are produced daily and the stomach empties about a third to one-half of its contents hourly (49). Therefore, residual volumes approaching 500 cc/4 hr should be safe. To minimize the risk of aspiration, the head of the bed should remain elevated, oral care should be diligent,

Indications and Contraindications for Enteral Nutrition

Table 7 Factors Posing a Major Risk of Aspiration

Hospitalized patients who cannot adequately meet their nutritional goals by oral intake alone for a period of seven days should be considered for enteral supplementation. Additionally, early enteral nutrition should be considered for all acutely ill patients, such as patients with major torso trauma, chronically malnourished patients, and patients with limited physiologic reserve.

Endotracheal intubation Decreased level of consciousness Neuromuscular disorders or anatomical abnormalities of the upper gastrointestinal tract Recent stroke Recent major abdominal surgery Persistently high gastric residual volumes

Chapter 3: Surgical Nutrition

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tolerance should be regularly assessed, narcotics minimized, electrolyte abnormalities corrected, and glucose control optimized. Numerous strategies have been employed to identify occurrences of aspiration. Use of food, drug, and cosmetic (FD&C) blue No. 1 and methylene blue as means of visual detection for aspiration has been associated with clinically significant toxicity and this practice is discouraged (50). Furthermore, the presence of glucose in the tracheal aspirate has been found to be neither a reliable nor specific indicator of enteral feeding aspiration.

more partially digested macronutrients or combinations of nutrients and can be absorbed in patients with compromised gastrointestinal tracts), and modular formulas (which are composed of individual nutrients or combinations of nutrients, but are nutritionally incomplete and intended for use as supplements or in combination with other products). Unfortunately, with the exception of the immune-enhancing formulas, very little comparative data exists to guide clinicians in selecting the most appropriate formula. A recommended formula selection is reviewed in Table 9.

Obtaining Enteral Access

Administration of Feeds

Access can be divided into gastric (and duodenal) and jejunal with push, endoscopic, radiologic, and surgical options available (Table 8). For patients to be fed through an intragastric approach, a soft, nonsump nasogastric tube can be placed. For patients known to require long-term feeding access, a percutaneous endoscopic gastrostomy (PEG) can be obtained. For those patients identified as candidates for jejunal feeds, access can be obtained at the time of initial laparotomy, or at subsequent laparotomy if damage control is initially performed. The needle catheter jejunostomy (NCJ) is the preferred method of access and a commercially available kit containing a silastic 7 French catheter is available. Patients not undergoing laparotomy could have a ‘‘push’’ nasojejunal tube (Corpak Medsystems, Wheeling, Illinois) placed. If this is unsuccessful, an endoscopically placed nasojejunal tube can be placed through the biopsy channel of a flexible endoscope that has been advanced into the duodenum (51). Nasojejunal feeding may be done indefinitely, but if the need for long-term access becomes apparent, a PEG with a jejunal extension limb (PEG-J) can be placed.

Once enteral access has been obtained, feeds are begun at 15 cc/hr of full-strength formula and advanced by 15 cc/hr every 12 hours to a set goal of 60 cc/hr. To assure tolerance, this rate is maintained for 24 hours and then advanced by 15 cc/hr every 12 hours to a patient-specific targeted goal.

Formula Selection Many of the early clinical trials were performed using elemental formulas that were low in fat and surmised to be better tolerated. However, more recent studies suggest other formulas to be equally well tolerated. The numerous available formulas may be categorized into polymeric formulas (which contain nutrients in high-molecular-weight form, moderate fat loads, and require normal digestive and absorptive ability), predigested formulas (which contain one or

Complications of Enteral Nutrition Overview of Complications Technical complications that can be associated with the administration of enteral nutrition include aspiration, bowel perforation, clogged tubes, and tube malposition/dislodgement. Tube clogging can be prevented by routine saline irrigation of the tube and by administering only liquid medications through smaller bore tubes such as NCJs. Functional complications are the gastrointestinal manifestations frequently associated with intolerance and include emesis, nausea/ vomiting, cramping pain or distention, and diarrhea.

NCJ-Related Complications NCJs, although an ‘‘invasive’’ technique, are a safe and effective means to deliver jejunal feeds. Myers et al. reported only a 1% incidence of major complications and a 1.7% incidence of minor complications in a large study examining the safety of NCJs in patients undergoing major elective and emergency abdominal operations (52). The jejunostomyrelated complication rate in trauma patients has been reported to be slightly higher, with a major complications rate of 4% (53). However, the majority of these complications (10%) occurred in patients with a standard, open

Table 9 Formula Selection for Delivery of Enteral Nutrition Table 8 Options for Enteral Access Gastric tubes Manual Endoscopic Radiographic Surgical Jejunal tubes Manual Endoscopic

Radiographic

Nasogastric/nasoduodenal PEG Endoscopically placed nasoenteric (nasoduodenal tube) Fluoroscopy-guided nasoenteric tube PRG Open: Stamm, Witzel, or Janeway gastrostomy Laparoscopic gastrostomy ‘‘Push’’ nasojejunal tube PEJ PEG/JET Endoscopically placed nasojejunal tube PRG/PRJ PRG/JET

Abbreviations: JET, jejunal extension tube; PEG, percutaneous endoscopic gastrostomy; PRG, percutaneous radiographic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; PRG/PRJ, percutaneous radiographic gastrostomy/jejunostomy.

Immune-enhancing diet Patients who have sustained major torso trauma, undergone major upper gastrointestinal surgery, or have limited physiologic reserve and who are at known risk for septic complications and multiple organ failure Polymeric high-protein formula Patients who do not meet the criteria for an immune-enhancing diet, have normal gut function, and are believed to have increased nitrogen requirements due to major injury, illness, or surgery. A modular protein component may be used in addition to the polymeric high-protein formula for use in the morbidly obese patient or in any patient that requires protein supplementation Elemental formula Patients who are intolerant to a polymeric formula or are acutely ill and who have not received enteral feeds for prolonged period of time Renal failure formula A concentrated, reduced electrolyte formulation is selected for use only in patients requiring intermittent hemodialysis. Often a modular protein component is used in addition to the commercially available renal formula to meet the increased nitrogen demands of the critically ill patient

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jejunostomy (typically a 14 French catheter), rather than with a NCJ (5–7 French, 2% incidence of complications). Major complications reported included volvuli with infarction, small bowel perforation, intraperitoneal leaks, and nonocclusive small bowel necrosis.

Nonocclusive Bowel Necrosis A rare but devastating complication of bowel necrosis has been associated with the administration of enteral feeds. The clinical presentation is similar to that of neonatal necrotizing enterocolitis, though the consistent association with enteral nutrition suggests that the inappropriate administration of nutrients into a dysfunctional gut plays a pathogenic role. The incidence is less than 1%, but the mortality frequently exceeds 50% (54,55). Most cases of nonocclusive bowel necrosis occur in a delayed fashion in critically ill patients with a complicated course (pneumonia, sepsis, renal failure, etc.) that requires progressively higher acuity care. Gastrointestinal signs and symptoms tend to occur late and, as a result, clinical monitoring fails to detect this entity early in its course. Computed tomography scan may reveal pneumatosis intestinalis or thickened bowel. Although most cases will require exploratory laparotomy, less advanced presentations may be managed with cessation of feeds, broadspectrum antibiotics, and aggressive fluid resuscitation.

Enteral Nutrition Protocol Rationale for an Enteral Nutrition Protocol An enteral feeding protocol can assist in providing a systematic, evidence-based approach to enteral nutrition and in minimizing complications. Assessing tolerance parameters are an important part of any enteral protocol. Frequently identified indicators of intolerance are vomiting, abdominal distention or cramping/tenderness, diarrhea, and high nasogastric tube output (56). Symptoms can be graded as mild, moderate, or severe. Mild symptoms of intolerance, such as mild abdominal distention or diarrhea, can just be monitored by repeat physical examinations with no change in the current rate of feeding. Moderate symptoms are managed based on the particular symptom. For distention, enteral feeds should be stopped and the patient assessed for evidence of a mechanical obstruction. If distention remains moderate, an elemental formula should be considered. Moderate diarrhea can be managed by maintaining but not increasing the current feeding rate and repeat examinations. Finally, for severe distention, enteral feeds should be stopped, intravenous hydration begun, and the possibility of nonocclusive bowel necrosis should be considered. For severe diarrhea, tube feeds can be reduced and the patient should be evaluated for possible Clostridium difficile infection. Vomiting is managed by ensuring adequate gastric decompression and either stopping gastric feeds or decreasing the tube feed infusion rate by half for jejunal feeds. Additionally, high nasogastric output in patients fed into the small bowel can be managed by verifying postpyloric placement of the feeding tube and checking the nasogastric aspirate for glucose. Any amount of glucose is considered abnormal and enteral feeds should be withheld. In general, enteral feeds should be discontinued if vasopressors are instituted.

Results of an Enteral Nutrition Protocol The incidence of enteral tolerance while using a protocol was analyzed in a prospective multi-institutional study

(57). Early tolerance (during advancement of enteral feeds to a goal of 60 cc/hr) was good in 84% (41/49) of patients and moderate in 16% (8/49). No patients experienced poor tolerance or complete intolerance. Late tolerance (after standard goal rate was met) was good in 80% (39/49), moderate in 16% (8/49), and poor in 4% (2/49) of patients. The site of feeding (gastric vs. jejunal) was not dictated by the protocol. Moderate intolerance was primarily due to high gastric output in patients fed via the stomach. All patients were successfully maintained on early enteral nutrition using this standardized protocol.

Specialized Enteral Diets Formulas with reduced carbohydrate and increased fat loads are available for use in patients with diabetes to potentially improve glycemic control. These products have not, however, undergone PRCT to demonstrate superior outcome in ICU patients. The use of standard high-protein formulas in an isocaloric or hypocaloric load, combined with aggressive insulin therapy, may be the most effective treatment for insulin resistance in the stressed, diabetic patient as opposed to carbohydrate restriction. Additionally, gastric feedings in the diabetic patient with gastroparesis may be associated with delayed gastric emptying and increased risk of aspiration, especially when high in fat content. There is one PRCT that demonstrated superior outcome, as demonstrated by reduced days on the ventilator, reduced ICU length of stay, and decreased incidence of organ failure in patients with adult respiratory distress syndrome (ARDS) when provided a high omega-3 fatty acid enteral product versus a high omega-6 ‘‘pulmonary’’ formula (58). However, the control diet was not the standard of care and may worsen ARDS. High omega-6 fatty acids increase inflammation and production of lipid mediators, which can worsen V/Q mismatch and thus worsen oxygenation in these patients. Although an enteral diet high in omega-3 fatty acids may be beneficial in early ARDS (59), prior to recommending such a diet, additional studies need to be performed.

TOTAL PARENTERAL NUTRITION Indications for TPN Whenever possible, the gastrointestinal track should be utilized for nutritional support. Table 10 reviews the basic indications for the administration of TPN. In general, TPN should not be started for at least seven days postoperatively if the patient is well nourished at baseline. Critically ill patients should be started on TPN if they are unable to achieve adequate caloric intake by postoperative day 6. Unlike with enteral feeding, there is no benefit to early TPN. Patients with persistent ileus, bowel obstruction, short gut, high-output fistulas, and malabsorption, may all benefit from TPN. Additionally, patients unable to tolerate enteral Table 10 Indications for TPN Persistent or progressive ileus Bowel obstruction Massive bowel resection refractory to enteral diet High-output fistula refractory to elemental diet Malabsorption High risk for nonocclusive bowel necrosis if fed enterally (shock resuscitation, a-agonists, persistent severe distention, or cramping) Documented intolerance to enteral nutrition Abbreviation: TPN, total parenteral nutrition.

Chapter 3: Surgical Nutrition

nutrition or who are at high risk for nonocclusive bowel necrosis (hypoperfusion or high vasopressor requirements) may benefit from TPN.

Table 11 Trace Element Deficiencies Trace element Iron Zinc

Preoperative and Perioperative TPN It is well documented that malnourished patients are at an increased risk for septic complications, problems with wound healing, longer hospital stays, and increased mortality (60). The unproved contention is that preoperative TPN can improve nutritional status and thereby reduce postoperative morbidity and mortality. However, studies evaluating preoperative TPN and outcome are variable. Results of randomized trials and a meta-analysis suggest that preoperative TPN for 7 to 10 days in severely malnourished patients may be beneficial in reducing the rates of infectious complications (61–65). For the mild to moderately malnourished patients, however, the risks of preoperative TPN (increase in septic morbidity) appear to outweigh the potential benefits. One of the confounding variables in preoperative TPN trials is that many of the patients were undergoing resection of a gastrointestinal cancer. Cancer patients in general, and particularly those with gastrointestinal malignancies, have cancer-associated weight loss, which can be very difficult to reverse. Prospective randomized trials of patients undergoing gastrointestinal surgery also failed to demonstrate any benefit, with the TPN group experiencing higher complication rates. Thus, routine postoperative TPN is not indicated and should be reserved for patients who cannot resume a diet by postoperative day 6 (66).

Initiation of TPN Components of TPN Components of TPN include (i) dextrose, (ii) fatty acids, (iii) amino acids, (iv) electrolytes, (v) vitamins, (vi) trace minerals, and (vii) fluids. Protein is provided based on grams per kilogram body weight, lipid is provided to deliver approximately 10% of total kilocalories needed, and dextrose provides the balance of kilocalories. Dextrose monohydrate (caloric density 3.4 kcal/g) is the carbohydrate. Fat emulsions (caloric density 2.0 kcal/cc of 20%) made from either soybean oil or a mixture of soybean oil and safflower oil provide fat calories and are the source of essential fatty acids (linoleic, linolenic, and arachidonic acids). Protein (caloric density 4 kcal/g) is provided as crystalline amino acids. Standard amino acid solutions contain a balance of essential and nonessential amino acids. The electrolyte cations, which include sodium, potassium, magnesium, phosphorus, and calcium, are admixed into the TPN solution using one of several anions. Acid–base status may be affected by the amount of chloride or acetate used in providing sodium and potassium. The concentrations of calcium and phosphorus are limited to avoid precipitation of a calcium phosphate salt. Multivitamin products that meet American Medical Association recommendations contain vitamins A, C, D, and E and the B vitamins, including folate, but not vitamin K, which must be added separately. A multi–trace mineral product is added to provide copper, chromium, manganese, zinc, and selenium. Symptoms of trace mineral deficiencies are reviewed in Table 11. TPN solutions are hyperosmolar and must be delivered through a large-lumen vein. When central access is unavailable or undesirable, peripheral parenteral nutrition (PPN) with a dilute solution (less than 800 mOsm/L) may be delivered through a peripheral vein for 7 to 10 days. Infusion sites must be rotated often to

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Copper Chromium Selenium Manganese Molybdenum

Symptom of deficiency Anemia Maculopapular rash, poor wound healing, cutaneous anergy, alopecia Anemia unresponsive to iron, pancytopenia Sudden glucose intolerance during TPN Proximal neuromuscular weakness and cardiac failure Weight loss, altered hair pigmentation, nausea Nausea/vomiting, tachycardia, central nervous system disturbances

Abbreviation: TPN, total parenteral nutrition.

reduce the incidence of thrombophlebitis. This therapy is best reserved for younger patients with easy peripheral access. PPN is seldom utilized. The combination of amino acids, dextrose, and lipids is referred to as total nutrient admixture (TNA) or a 3-in-1 solution. Typically an 8.5% or 10% amino acid solution is employed, although a 15% solution is available for patients requiring fluid restriction, such as those with congestive heart failure, renal failure, or hepatic failure. Dextrose 50% is the usual carbohydrate solution, although 70% solution may be used to restrict volume. Lipids are available in 10%, 20%, and 30% and are needed to prevent essential fatty acid deficiency. Ten percent of total kilocalories will accomplish this goal. Additional lipids can be given to provide an alternative calorie source in patients intolerant of high glucose loads. If lipids are administered separately, they must be infused for no greater than over 12 hours to prevent bacterial growth. Lipids are stable in TNA for 24 hours because the osmolarity and pH are less favorable to bacterial growth. The following is an example of TPN in an 80 kg male patient with significant injuries requiring 2400 kcal (30 kcal/kg) and 140 g protein (1.75 g/kg). A typical institutional TPN form is shown in Table 12.

Calculations (see Table 13): 1. 2.

Establish the kilocalories and protein desired: 2400 kcal, 140 g protein. Select the appropriate amino acid formula and quantity: using 10% amino acids 10 gm=100 mL 140 gm ¼ 1400 mL

3.

Calculate 10% of kcal as lipid emulsion: using 20% lipids 10% 2400 ¼ 240 kcal 240 kcal 1 mL=2 kcal ¼ 120 mL

4.

Add the kcal from amino acids and fat and subtract from goal:

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acids ¼ 140 g protein 4 cal=g ¼ 560 kcal kcal from fat ¼ 240 kcal goal kcal ðamino acid þ fatÞ kcal ¼ 2400 ð800 þ 240Þ ¼ 1600 kcal

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Part One: General Considerations

Table 12 Example of a Standard TPN Order Sheet

This is the amount of dextrose kcal needed. To determine the volume, 1600 kcal=3:4 kcal=g glucose ¼ 470 g glucose 470 g glucose=50 g=100 mL ¼ 940 mL The patient’s electrolyte profile is reviewed. If it is relatively normal, infusion is started with standard electrolyte requirements.

Complications Complications of TPN can be divided into technical, infectious, and metabolic. Administration of TPN requires central venous access due to its hypertonicity. Administration

through a large, central vein allows rapid dilution and therefore prevention of venous sclerosis and thrombophlebitis, which will occur with peripheral venous administration. The insertion of a central venous line, however, is not without risk. More than 15% of patients receiving central lines have some type of complication (67). Technical complications range from injury to major veins, arteries, or nerves, and violation of the pleural space. Complications can be minimized by strict observation of well-established guidelines for insertion, including adequate supervision. If a major artery is punctured, the needle should be withdrawn and pressure applied. If the vessel has been cannulated and it is unclear into which vessel (artery or vein) the catheter has been inserted, the catheter should be transduced. A venous tracing should be seen and the measured pressure should be approximately 4 to 10 mmHg.

Chapter 3: Surgical Nutrition

Table 13 Sample TPN Order Nonstandard TPN solution Base solution Standard amino acid (10 g/100 mL) Dextrose 50% (50 g/100 mL:3.4 kcal/g) Volume of base solution to be delivered in 24 hr Electrolytes Sodium chloride Sodium phosphate Potassium acetate Calcium gluconate Magnesium sulfate Multivitamins Trace elements Fat emulsion 20% (1 kcal/mL) Infusion rate

1400 mL 940 mL 2300 mL

35 mEq/L 8.3 mEq/L 35 mEq/L 4.16 mEq/L 3.3 mEq/L 10 mL 1 mL 120 mL 101 mL/hr

Abbreviation: TPN, total parenteral nutrition.

The pathogenesis of infectious complications most commonly stems from colonization of the skin and catheter hub. Short-term, noncuffed catheters (such as single- or triple-lumen catheters) become colonized from skin flora that migrate from the insertion site along the external surface of the catheter to the catheter tip and lead to catheterrelated bloodstream infections. Long-term catheters such as cuffed, tunneled, silicone catheters (Hickmans or Broviacs) or implanted catheters (ports) become colonized as bacteria migrate through the lumen of the hub, which becomes contaminated by skin flora. Other less frequent sources of contamination include infusion of contaminated solutions or hematogenous seeding from a distal site of infection. Preventative measures can be broken down into three categories: (i) catheter insertion, (ii) catheter care, and (iii) catheter removal. Important components of catheter insertion include skin preparation (chlorhexidine is more efficacious than alcohol or povidone iodine) and the use of

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maximal sterile barriers (68). Although it is commonly believed that multiple-lumen catheters have a higher rate of catheter-related sepsis compared to single-lumen catheters, randomized studies have not confirmed this practice (69). Recent randomized trials indicate that catheter-related sepsis can be reduced by the use of antibiotic- or antisepticbonded catheters (70). However, these catheters are considerably more expensive, can be associated with anaphylaxis, and have the potential to cause resistant organisms. Therefore, they should be used in select patients whose catheters are going to be in place for extended periods of time. With regard to catheter care, dressings may be either a transparent, semipermeable, polyurethane dressing or gauze. Insertion site antibiotic or antiseptic ointments are not recommended because of the potential to promote antibiotic resistance and fungal colonization. A meta-analysis of 12 randomized trials of catheter replacement did not support scheduled exchange of catheters over a guide wire or scheduled, routine replacement at a new site (71). Metabolic complications can include hyper- or hypoglycemia, electrolyte abnormalities, acid/base abnormalities, liver function abnormalities, and trace mineral deficiencies (Table 14) (72). Critical illness is accompanied by increased plasma counter-regulatory hormone levels, which have multiple effects on glucose homeostasis. The end result is hyperglycemia with resistance to insulin. Other factors that contribute include obesity, inflammatory cytokines associated with the SIRS (such as TNFa, IL-1, IL-2, and IL-6), advanced age, exogenous steroid or catecholamines, increased free fatty acids, and nutritional support (parenteral route greater than enteral route). The resulting hyperglycemia can adversely affect outcome through several mechanisms, including glycosuria with inappropriate diuresis, increase risk of infection by impairing neutrophil and immunoglobulin function, and exacerbation of cerebral edema. Van Den Berghe et al. (73) have recently demonstrated in a prospective randomized fashion a reduction of mortality in critically ill surgical patients, from 8% to 4.6%,

Table 14 Metabolic Complications Associated with TPN Abnormality Electrolyte Hyperkalemia Hypokalemia Hyperphosphatemia Hypophosphatemia Hypercalcemia Hypocalcemia Hypermagnesemia Hypomagnesemia Glucose Hyperglycemia Hypoglycemia Amino acids Hypercholeremia Metabolic acidosis Fatty acid deficiency Bleeding Abnormal liver functions

Etiology

Correction # " # " # "

Renal insufficiency/failure Inadequate intake, diuresis, diarrhea, refeeding Renal insufficiency/failure Inadequate administration, refeeding Excessive administration Inadequate administration, hypoalbuminemia, refeeding, rapid phosphorus repletion Excessive administration, renal failure Inadequate intake, diuresis, refeeding

# Administration " Administration

Excessive administration, sepsis, inadequate secretion of insulin Abrupt cessation of TPN, liver dysfunction

Strict glucose control with exogenous insulin, consider reducing glucose calories Taper TPN rate, administer 5% or 10% dextrose

Excessive chloride administration Excessive chloride administration Sepsis, inadequate perfusion, renal failure Inadequate administration Vitamin K deficiency Excessive fat or glucose administration, amino acid imbalance

# Administration Administer acetate Reassess patient " Administration " Administration Reassess patient

Abbreviation: TPN, total parenteral nutrition.

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Administration Administration Administration Administration Administration Administration

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Part One: General Considerations

when glucose levels were strictly controlled between 80 and 110 mg/dL versus conventional therapy (120–180 mg/dL). In a follow-up analysis, the same investigators demonstrated that the reduction in critical illness polyneuropathy, bacteremia, inflammation, and mortality was related to the lowering of blood glucose levels and not the amount of infused insulin per se (74). These data strongly support the maintenance of normoglycemia. The refeeding syndrome is a dramatic example of a metabolic complication that can be associated with TPN administration. It occurs with rapid and excessive feeding of patients with severe malnutrition due to conditions such as starvation, alcoholism, delayed nutritional support, anorexia nervosa, hyperemesis gravidarum, and massive weight loss after bariatric surgery (75). As a result of ion fluxes into the cell with refeeding, serum phosphate, magnesium, potassium, and calcium levels can drop rapidly. In the case of blunted basal insulin secretion, severe hyperglycemia may arise. Symptoms include cardiac arrhythmias, confusion, respiratory failure, and even death. This can be prevented by initiating TPN at a rate lower than the required goal, primarily by reducing dextrose calories. Exogenous insulin is frequently required.

patients have poor response to chemotherapy, radiation, and surgery as well as increased morbidity and mortality. When feasible, use of the gastrointestinal tract is the preferable mode of feeding. Immune-enhanced enteral diets in patients with gastrointestinal cancers have been shown to decrease postoperative infections (78,79). A recent metaanalysis that carried out a separate analysis of patients with gastrointestinal cancer, similarly demonstrated a reduction in major infectious complications but not death in the postoperative period (26). Traditionally, concern exists that perioperative TPN may promote tumor growth, i.e., feed the tumor not the patient. However, many studies supporting this theory were performed in animals whose life span is much shorter than humans (80). Thus, a 10-day course of TPN would represent a far greater segment of an animal’s life. Furthermore, the tumor size in these studies was large, representing up to 30% to 40% of the animal’s body weight. Nonetheless, the use of TPN in this patient population offers little benefit and may increase infection rates (81). Severely malnourished patients receiving a bone marrow transplant may be one subset of patients who can benefit from perioperative TPN.

Monitoring TPN

Short Gut

This is done to (i) determine the efficacy of the TPN therapy; (ii) determine changes in metabolic status (stress level); and (iii) detect complications associated with TPN. Measurements of efficacy in the acute-care setting include weight, constitutive protein status (e.g., albumin, transferrin, and prealbumin), nitrogen balance, and wound healing. Metabolic status should be viewed first from the clinical perspective. The presence of SIRS, infection, or high ventilation requirements all indicate a high metabolic rate. Metabolic status can be further assessed by laboratory variables that evaluate substrate tolerance (e.g., blood glucose and serum triglyceride concentrations) as well as protein catabolic rate (24-hour UUN).

Specialized Amino Acid TPN Solutions These formulas are designed to meet organ-failure specific requirements and include high-branched-chain, hepatic failure (low aromatic amino acid), and renal failure (high essential amino acids) formulations. The use of these specialty formulas remains controversial because of the expense and lack of outcome data. Studies comparing high-branchedchain amino acid solutions with standard formulas in stressed patients have shown improvements in nitrogen retention, constitutive protein levels, and immune function, but have failed to demonstrate reduced morbidity or mortality (76). One recent trial in Europe was able to demonstrate a reduced mortality in septic patients receiving a high-branched-chain formula (77). The use of hepatic and renal formulas has also not shown any proven benefit.

DISEASE-SPECIFIC NUTRITION Nutrition and Cancer Many forms of cancer are associated with weight loss and wasting or cachexia. Intake can be impaired due to the disease process, physical anomalies related to surgery or to the cancer itself, side effects of therapy, and psychosocial factors. Utilization of nutrients may be altered by malabsorption, cytokine activity, or the preponderance of inefficient cycles for energy metabolism. Malnourished cancer

Mesenteric infarction, Crohn’s disease, radiation enteritis, tumors, and trauma are the leading causes of short gut in adults (82). Factors that influence the management of short bowel syndrome include (i) the extent of resection; (ii) the site of resection; (iii) the presence or absence of the ileocecal valve; (iv) the residual function of the remaining small bowel; (v) the adaptive capacity of the intestinal remnant; (vi) the primary disease that precipitated the bowel loss; and (vii) the amount and the activity of the residual disease in the remnant (83). The average adult has 25 cm duodenum, 240 cm jejunum, and 360 cm ileum (84). In adults, the minimal length of small intestine (distal to the Ligament of Treitz) required for adequate digestive function is approximately 75 cm, although there are interindividual differences (85). For lesser amounts, patients will require long-term TPN. Additionally, patients requiring TPN three months after surgical resection can be considered as having short gut regardless of the extent of resection. The small bowel is the site of absorption for a variety of nutrients and electrolytes. Duodenectomy results in malabsorption of calcium, folate, and iron. Although the proximal jejunum is the usual site for protein, carbohydrate, and fat absorption, jejunectomy usually results in no major change in macronutrient and electrolyte absorption because the ileum can take over this role (86). Because the jejunum is the site of hormones that inhibit gastric secretion such as gastric inhibitory peptide and vasoactive intestinal polypeptide, gastric hypersecretion begins within 24 hours after jejunal resection. This produces a high sodium load in the stomach and reduces pH downstream, thus inactivating digestive enzymes and increasing diarrhea. The ileum plays an important role in slowing intestinal transit and concentrating luminal contents. Both vitamin B12 and bile salts are normally absorbed from the ileum. Following resection, the liver increases production of bile salts to compensate for the loss of absorption. However, this production can never be fully compensated for and bile salt depletion occurs, leading to steatorrhea and cholelithiasis. Cholestyramine is sometimes employed to treat the ensuing diarrhea and cholecystectomy is commonly required within two years after

Chapter 3: Surgical Nutrition

bowel resection. Steatorrhea promotes calcium binding to fatty acids rather than oxalate and allows more oxalate to be absorbed, leading to oxalate stones. Three stages of intestinal adaptation after resection have been identified (84): Stage I is characterized by fluid and electrolyte loss and lasts for approximately two weeks. It is treated with electrolyte replacement, an H2 blocker (to minimize hypersecretion), and parenteral nutrition. Hypersecretion of gastrin may result in peptic ulcer disease, gastroesophageal reflux disease, and proximal small bowel inflammation, so that H2 antagonists are a mainstay of therapy after intestinal resection. Stage II is a period of adaptation where oral intake begins and lasts from a few months up to one year. Feedings are advanced as stool and/or ostomy output becomes manageable. Stage III is maximal adaptation where normal home life may resume, although some patients may still require TPN. The residual small bowel as well as the colon undergo dilatation, lengthening, and mucosal proliferation along the course of adaptation. Experiments in rats have demonstrated superior adaptation in animals fed TPN and complex enteral diets as opposed to elemental diets (87). Aggressive use of enteral nutrition is thought to maximize gut adaptation (88). Although somatostatin may slow intestinal transit and reduce fluid and electrolyte loss acutely, it may also decrease enteroglucagon release, which exerts beneficial effects in bowel adaptation after resection. Octreotide is a synthetic analog of somatostatin with a longer half-life (three hours vs. three minutes). Octreotide reduces splanchnic blood flow and inhibits gastric, pancreatic, and small bowel secretions. These mechanisms may limit intestinal adaptation after bowel resection and reduce dietary fat digestion. Bowel output is reduced due to decreased secretions rather than improved absorption. Octreotide is generally recommended for use in patients with severe diarrhea/ostomy output (greater than 4 L daily) that is intractable to antidiarrheal agents. The use of antimotility agents may prove helpful in this circumstance. Although glutamine has been recommended, its role in morphological adaptation after bowel resection remains to be elucidated. Administering probiotics, the addition of live bacteria to the gastrointestinal tract, may also be beneficial in short gut. Healthy bacteria may be altered due to antibiotics, antimotility agents, H2 blockers, proton-pump inhibitors, and narcotics. Growth of healthy flora decreases growth of enteropathogens that may adhere to the mucosa and initiate inflammatory or immune sequelae (89). Structured programs have emerged that are geared toward decreasing TPN dependence after intestinal resection (90). Therapy consists of TPN (when necessary), peptide-based enteral nutrition, a low-fat, low-oxalate, high-protein, high–dietary fiber oral diet, and enteral glutamine in dipeptide form. Recombinant human growth hormone is provided for a specified period. Long-term follow-up of patients after intestinal resection should consist of monitoring sodium, potassium, chloride, zinc, copper, magnesium, iron, B12, folic acid, and fat-soluble vitamins. Zinc losses in diarrhea are substantial and may require supplementation above the quantity provided by intravenous multi–trace element products. Intramuscular vitamin B12 should be given if more than 60 cm of terminal ileum is resected. Chronic complications of short bowel syndrome include liver failure, gallstones, nutrient deficiencies, osteopenia, catheter-related sepsis, and small bowel bacterial overgrowth. Surgical approaches to increase functional bowel, including transplantation, remain an option.

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Enterocutaneous Fistula Abdominal operations account for over 80% of enterocutaneous fistulae. The remainder are due to Crohn’s, cancer, radiation, and infection. The nutritional management depends on the location of the fistula, the health of the bowel distal to the fistula, and the amount of fistula output. The advent of TPN in the 1960s greatly reduced mortality from fistulae. Spontaneous closure depends on location, comorbid factors, and nutritional state. Ninety percent of fistulae that are likely to close spontaneously will do so in the first 30 days (91). If fistulae are in the proximal bowel, full enteral feeds may be delivered distally.

Pancreatitis Acute pancreatitis induces severe hypercatabolism and without exogenous nutritional support, acute protein malnutrition can quickly occur. Due to concerns that enteral feeding would stimulate further secretion of pancreatic enzymes and worsen autolysis, TPN has been the mainstay of nutritional therapy. However, recent studies have indicated that enteral feeding into the jejunum in patients with acute pancreatitis is both safe and effective. Initial trials of enteral support recommended low-fat, elemental formulas (92–95), again due to concerns over pancreatic stimulation. However, Duerksen et al. demonstrated that, in patients who underwent partial pancreatectomy with exteriorization of pancreatic stents, there was no statistically significant difference in pancreatic secretion between polymeric and elemental formulas (96). When compared with TPN, enteral nutrition is associated with an attenuation of the acute-phase response (97), reduced septic complications (94), and markedly decreased cost.

SUMMARY Protein-calorie malnutrition has become increasingly recognized in hospitalized patients and has been shown to be present in as many as 50% of patients requiring surgical procedures. Understanding the metabolic response to starvation and surgical stress, and how a suboptimal nutritional environment can adversely affect this response is mandatory if postoperative morbidity and mortality are to be lessened. Fortunately, the last several decades have unraveled an enormous amount of new knowledge regarding the role that malnutrition plays in altering fundamental metabolic pathways that are essential to good patient care. Further, the ability to provide nutritional support by way of enteral or parenteral routes has enabled the provision of optimal nutritional therapy in even the patient with profound malnutrition requiring surgical intervention. Such advances have greatly minimized the attendant negative effects that suboptimal nutrition would otherwise have on patient outcome and survival following operation.

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4 The Immune System and the Immunocompromised Patient Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch

INTRODUCTION The immune system functions to protect the body’s internal environment from a variety of potential insults such as foreign proteins, potentially adverse cells, microorganisms, and other noxious substances. Since immune competence plays such an important role in the insurance of good health and the response of a patient to surgical intervention, alterations in the immune system can greatly affect the outcome of an operation both in terms of morbidity and mortality. Immune competence reflects the highly integrated, carefully orchestrated homeostatic interplay of a number of physiologic processes whose primary function is to discriminate between substances that are part of the body’s own makeup (‘‘self’’) and those that are foreign to it (‘‘noself’’). The purpose of this chapter is to review the components of this immune system, how they interrelate, how this recognition of self and nonself occurs, and the impact that alterations in these processes can have on the surgical patient.

AN OVERVIEW OF THE IMMUNE SYSTEM In this section, we introduce the cellular components of the immune system, describe the initiation and effector stages of the humoral and cellular immune response, and discuss clinical assessment of immune function. This is to serve as a general introduction and review and to provide a basis for the clinical considerations that follow. There are several excellent textbooks on immunology, which should be referred to for a more comprehensive description of the immune system (1–5). In addition, we have cited key articles within each section that provide current reviews and references of the primary literature.

Cellular Components Leukocytes, the white blood cells that participate in the immune response, are derived from a common pluripotent stem cell in the bone marrow (Fig. 1). The mature cellular components of the immune system are distinguished on the basis of function and phenotype. Lymphocytes are distinguished from the other cells of the immune system because only lymphocytes exhibit diversity, specificity, memory, and self-/non–self-recognition. The cellular phenotype is principally defined by cell surface markers, the majority of which are designated cluster of differentiation (CD) antigens and are identified by monoclonal antibodies. Monoclonal antibodies serve as important immunological reagents for both the identification and quantitation of leukocyte and lymphocyte subpopulations that express these markers. There are currently 247 CD antigens that have been designated by the

International Workshops on Leukocyte Differentiation Antigens (6). Because the expression of cell surface antigens will vary qualitatively and quantitatively with both the maturation stage and activation state of the cell, monoclonal antibodies are also valuable for monitoring the phenotype of a specific leukocyte subpopulation (Table 1). Many of the cell surface antigens serve as specific receptors for ligands, thus ligand binding and receptor engagement have important immunological consequences. These ligands include immunoglobulins (Igs), complement, cytokines, viruses, and bacterial products.

B-Lymphocytes A schematic diagram of an Ig is presented in Figure 2. The development of the B-lymphocyte occurs predominantly in the bone marrow of mammals and is centered around the expression of membrane-bound Ig. Because the antigenbinding variable region of the membrane Ig is extracellular, it readily binds to soluble antigen. The expression of surface Ig will imbue the B-lymphocyte with both antigen specificity and memory. After antigen binding, signal transduction is mediated by another component of the B-cell receptor, a disulfide-bonded heterodimer that is noncovalently complexed with surface Ig and is designated as Ig-a/Ig-b or CD79a/CD79b (7). The DNA encoding antibody heavy chains, k light chains, and l light chains are located on different chromosomes. Within each chromosome, Ig sequences are present in germ line DNA as multigene families that contain numerous gene segments (Fig. 3). In progenitor and precursor B-cells, the variable region–D region–joining region (V-D-J) gene segments that comprise the variable region of the heavy chain undergo random gene rearrangement to form a functional Ig he