Wound Infusion

ORIGINAL ARTICLE ANZJSurg.com

Wound infusion with local anaesthesia after laparotomy: a randomized controlled trial ans_5339

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Louis William Wang,† Shing Wai Wong,†‡ Philip John Crowe,†‡ Kok Eng Khor,§ Grazyna Jastrzab,§ Andrew David Parasyn† and William Robert Walsh‡¶ †Department of Surgery, Prince of Wales Hospital, New South Wales, Australia ‡University of New South Wales §Department of Pain Management, Prince of Wales Hospital, New South Wales, Australia ¶Surgical and Orthopaedic Research Laboratories, Prince of Wales Hospital, New South Wales, Australia

Key words anaesthesia, local, analgesia, patient-controlled, pain, post-operative, laparotomy, randomized controlled trial. Abbreviations PCA, patient-controlled analgesia; CI, confidence interval; D.F., degrees of freedom. Correspondence Dr Shing Wong, Department of Surgery, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Email: [email protected] L. W. Wang BSc(Med), MBBS(Hons); S.W. Wong MS, FRACS; P.J. Crowe DPhil, FRACS; K.E. Khor MMed(PM), FFPMANZCA; G. Jastrzab RN, MNEd; A.D. Parasyn MBBS FRACS; W.R. Walsh PhD. This research was presented at the Australia and New Zealand Medical and Surgical Gastrointestinal Week 2009, Sydney, Australia on 23rd October 2009. Accepted for publication 11 August 2009 doi: 10.1111/j.1445-2197.2010.05339.x

Abstract Background: The use of a continuous local anaesthesia infusion after laparotomy may reduce opioid requirements and facilitate earlier return of bowel function, independent mobilization and hospital discharge. Methods: We performed a double-blinded, randomized controlled trial on 55 patients who underwent laparotomy. Patients were randomly allocated to receive a continuous infusion of either 0.2% ropivacaine or normal saline into their midline abdominal wound at the fascial level. The end points of the study were: total opioid requirements at 24 and 48 h; time to first flatus, bowel movement and independent ambulation; length of hospital stay; complications; and daily mean patient-reported pain scores at rest and movement. Results: The two treatment groups were well controlled for factors that influence analgesia requirements, including age, weight, length of wound incision and type of operation. Patients allocated to ropivacaine infusion used, on average, 32 mg less morphine at 48 h (95% confidence interval 7, 57; P = 0.01). This was highly statistically significant after adjusting for age, gender and type of operation (P = 0.0006). Ropivacaine infusion was associated with a significantly decreased time to independent mobilization (P = 0.02), time to first flatus (P = 0.02) and reduced post-operative ileus (2/28 versus 9/27, c2 = 5.89, P = 0.02). There was no significant effect of ropivacaine infusion on time to first bowel movement (P = 0.94) nor length of hospital stay (P = 0.77). Conclusions: Local anaesthesia infusion at the fascial plane provides effective analgesia. This improves patient recovery through earlier return to bowel function and mobilization.

Introduction Infiltration of surgical wounds with local anaesthesia provides analgesia by preventing the depolarization of nerve axons required during nerve transmission.1 This effect has a limited duration of action, and as a result, continuous infusions of local anaesthesia have been used to achieve sustained analgesia. Intravenous opioids, on the other hand, act on multiple sites in both the central and peripheral nervous system to inhibit transmission of nociceptive stimuli.2,3 Although opioids are frequently used for the treatment of postoperative pain following laparotomy, their use is often associated

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with troublesome side effects.4 These include nausea, vomiting, over-sedation, confusion and delayed return of post-operative bowel function. Multi-modal treatment of post-operative pain is now the gold standard treatment for post-operative analgesia following laparotomy and is thought to improve analgesia by providing multiple mechanisms for reducing nociception and transmission.5 Side effects related to toxicity are reduced because the amount of each agent required to achieve analgesia is less when it is used in combination with other agents. Despite the theoretical advantages of multi-modal treatment for post-operative analgesia following laparotomy, opinion regarding © 2010 The Authors ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons

Wound infusion with local anaesthesia after laparotomy

the efficacy of continuous wound infiltration with local anaesthesia is still divided based on current evidence from randomized control trials.6–10 In this article, we report the results of a randomized controlled trial, which aimed at determining whether the use of a continuous local anaesthesia infusion reduced opioid analgesic requirements and facilitated earlier return to normal bowel function, independent mobilization and discharge from hospital.

Methods Approval for the study was obtained from the South Eastern Area Health Service Human Research Ethics Committee. Patients scheduled to undergo a midline laparotomy under a single surgeon (SWW) at Prince of Wales Hospital were recruited into this study. Patients were deemed eligible if they required an elective laparotomy and were expected to require post-operative patient-controlled analgesia (PCA) irrespective of the underlying pathology, age or other co-morbidities. Patients who had a previous adverse reaction to local anaesthesia or opioid analgesia were excluded from the study. Recruitment occurred between September 2005 and March 2008. After written informed consent, patients were randomized to receive either local anaesthesia (0.2% ropivacaine) or normal saline by continuous infusion into their midline abdominal wound via a commercial pump and catheter set (ON-Q PainBuster™; I-Flow Corporation, Lake Forest, CA, USA; Figure 1). A computer-generated randomization code was created using permutated blocks of four. Prior to surgery, the treatment solution containing either the ropivacaine or normal saline solution was loaded by the study pharmacist into a commercial bulb pump system. This was labelled with a ‘Painbuster Clinical Trial Study Solution’ sticker and then dispensed to the operating theatre. Solutions were

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identical in appearance. The same sticker was used to label both the intervention and control solutions. Allocation concealment was preserved as the randomization code was kept locked in the hospital pharmacy and was not made known to the inpatient surgical team who recruited the patients. The surgical team did not have physical access to the room where the randomization code was kept. The intervention assignment schedule was also blinded from patients, all staff administering the treatment (i.e. surgeon, surgical assistants and scrub nurses), as well as from those who monitored outcomes (i.e. doctors, nurses, allied health staff and members of the Acute Pain Service). At the end of each laparotomy procedure, the rectus abdominis muscle wound edges were closed with continuous 1-nylon or 1-polydioxanone suture. The surgeon then tunnelled the catheters subcutaneously approximately 5 cm from the midline wound. The two catheters were placed along the length of the wound between the sutures using an artery forceps, at the level of the musculo-fascial closure and not superficial to it. The catheter was then connected to a syringe pump, which was filled with 270 ml of study solution. This was delivered over 67.5 h at a rate of 4 ml/h. The following baseline characteristics were recorded: age, weight, gender, type of operation, and pre-operative renal function as measured by plasma creatinine. Other data collected included: length of laparotomy wound, histopathology of resected bowel, intraoperative analgesia administration and whether the patient required admission to the high dependency unit post-operatively. The end points of the study were: total opioid analgesia requirements (at 24 and 48 h), complications, time to first flatus, time to first bowel movement, time to independent ambulation, total length of hospital stay and daily mean patient-reported pain scores at rest and on movement (numerical rating scale from 0 to 10). These end points were all pre-specified and were stated on the application to the Human Research Ethics Committee. In this study, prolonged post-operative ileus was defined as no passage of flatus or stool by the end of the fifth post-operative day.11 Wound infection was defined as erythema of the wound site with positive microbiological culture and/or fever greater than 37.8 degrees Celsius. Pneumonia was defined as fever and radiological evidence of consolidation. Post-operative myocardial infarction was defined by the presence of chest pain with troponin elevation. Data was collected by ward staff (medical and nursing) and members of the Acute Pain Service, who reviewed patients daily while they were on PCA. The presence of any opioid-related side effects was recorded by the Acute Pain Service. This was recorded on a computer database for later statistical analysis.

Sample size

Fig. 1. ON-Q painbuster.

© 2010 The Authors ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons

Prior to this study, we conducted a pilot analysis which investigated the post-operative PCA requirements of 30 consecutive patients who underwent laparotomy. We analysed the amount of PCA morphine used in the second 24 h post-operatively. In this cohort, the range of morphine use was 6–101 mg (mean 37.9, standard deviation 23.48). Assuming that the ropivacaine infusion would reduce post-operative morphine requirements by 40%, we calculated that we would need to study 39 experimental subjects and 39 control subjects. This would allow us to reject, with a

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power of 0.8 and Type I error probability of 0.05, the null hypothesis that the mean post-operative morphine requirements of the experimental and control groups are equal. The plan was to recruit 100 patients (50 treatments, 50 controls) into this study, to allow for dropouts. However, recruitment was slow, and a decision was made to terminate the study in May 2008 because of the unlikelihood of achieving the recruitment target. In total, 55 patients were recruited. The revised power calculation was 0.63.

Statistical methods Data was tabulated on a Microsoft Excel 2003® (Microsoft Corporation, Redmond, WA, USA) and imported into the SAS 9.1® Software Package (SAS Institute Inc., Cary, NC, USA). Unadjusted results were first calculated. Student’s t-test was used to analyse differences in mean morphine PCA consumption and post-operative pain scores. The chi-squared test was used to test differences in proportions between randomization groups for outcomes such as post-operative ileus and wound infection, and a logrank statistic was used to analyse differences in time to first flatus, stool and independent mobilization, and post-operative length of stay. We also conducted multivariate analyses to ascertain the estimated effect of wound infusion with local anaesthesia after taking into account measurable confounders. Using SAS 9.1®, we created multivariate

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Cox proportional-hazard regression models for time to first flatus, time to first stool, time to first independent mobilization and length of stay. A multiple regression model was used to determine the effect of treatment allocation on total PCA use at 24 and 48 h; and how PCA use was influenced by treatment, type of operation (right hemicolectomy versus other), length of wound incision, age and weight. We also performed a sensitivity analysis to test whether the effect of ropivacaine solution was modified by gender or age, although these were not a priori hypotheses.

Results Recruitment and participant flow Figure 2 displays the flow of study participants. A total of 55 patients were recruited, of which 28 were randomized to receive ropivacaine and 27 to normal saline. In each arm, two patients received fentanyl PCA instead of morphine PCA. In three of these four patients, the reason was because of renal impairment. Fentanyl PCA was provided in the remaining patient because of a history of severe hallucinations with previous morphine use. Three patients in the control group had their PCA use terminated within the first 24 h. In two of these patients, this was because of language difficulties and their inability to use PCA despite the help of a translator. The remaining patient had her PCA ceased because of excessive confusion and

Fig. 2. Flow of study participants. PCA, patient-controlled analgesia.

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Table 1 Baseline characteristics by randomization group Intervention (n = 28)

Control (n = 27)

P-value

64.6 (58.6, 70.7) 70.5 (65.3, 75.7) 91 (78, 103) 25.4 (23.4, 27.4) 243 (210, 275) 16 (57%) 9 (32%) 8 (29%) 6 (21%) 22 (79%) 16 3 0 1 2 0 0

70.3 (64.5, 76.1) 67.8 (61.4, 74.2) 86 (73, 99) 25.6 (23.0, 28.2) 265 (203, 327) 14 (52%) 8 (30%) 11 (41%) 10 (37%) 17 (63%) 10 4 1 0 0 1 1

0.17 0.49 0.57 0.90 0.51 0.69 0.84 0.34 0.20 0.20 0.14 — — — — — —

Age in years (95% CI) Weight in kilograms (95% CI) Pre-operative creatinine in mmol/L (95% CI)† Wound length in centimetres (95% CI) Length of resected bowel in millimetres (95% CI) Number of males (%) High dependency unit admission post-operatively (%) Diagnosis of cancer (%) Right hemicolectomy (%) Other (%) Anterior resection Abdominoperineal resection Total colectomy Transverse colectomy Sigmoid colectomy Small bowel resection Reversal of Hartmann procedure †

Excluding one patient in the intervention group on regular haemodialysis. CI, confidence interval.

Table 2 Post-operative pain score, unadjusted and adjusted mean PCA morphine consumption by randomization group Intervention (n = 28)

Control (n = 27)

Mean difference (95% CI)

P-value

2.4 5.2 1.6 4.0 48.1 78.7 30.7 45.4 115.8

3.0 5.4 1.7 4.2 62.2 110.6 48.3 65.4 74.4

0.7 (-0.4, 1.8) 0.3 (-0.9, 1.4) 0.1 (-0.6, 0.8) 0.1 (-0.9, 1.2) 14.1 (-3.8, 32.0) 31.8 (7.1, 56.5) 17.7 (2.8, 32.6) 20.0 41.4

0.22 0.64 0.80 0.81 0.12 0.01 0.02 0.02 <0.001

Average pain score† Day 1 (rest) Average pain score† Day 1 (activity) Average pain score† Day 2 (rest) Average pain score† Day 2 (activity) Mean total PCA morphine at 24 h (mg) Mean total PCA morphine at 48 h (mg) Mean PCA morphine consumption in second 24 h (mg) Adjusted‡ mean morphine PCA use at 24 h (mg) Adjusted‡ mean morphine PCA use at 48 h (mg)

† Patient-reported, numerical rating scale from 0 (no pain) to 10 (most severe). ‡Adjusted for age, gender and operation. CI, confidence interval; PCA, patientcontrolled analgesia.

sedation. Twenty-six active treatment patients and 22 controls provided data for the per protocol analysis comparing total morphine use between treatment groups. An intention-to-treat analysis of all 55 patients was performed for all other end points including time to flatus, stool, mobilization, duration of PCA use, length of stay and complication events. The two treatment groups were similar with respect to key features which may determine analgesia requirement, including age, weight, length of wound incision and type of operation (Table 1).

Univariate analysis There was no statistically significant difference in rest or activity pain scores between the two groups (Table 2). The difference in mean total PCA morphine consumption at 24 h did not reach statistical significance (t46 = 1.59, P = 0.12). Patients randomly allocated to ropivacaine had significantly less total PCA morphine consumption in the second 24 h post-operatively (t46 = 2.39, P = 0.02), and this corresponded with a reduction in total PCA morphine consumption at 48 h (t46 = 2.59, P = 0.01). These results are also displayed in Table 2. The unadjusted mean morphine PCA use at 48 h was 79 mg for those who were given ropivacaine compared with 111 mg for controls, an average reduction of 32 mg (95% confidence interval (CI) 7, 57; P = 0.01). © 2010 The Authors ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons

Time-to-event analysis showed that the ropivacaine group experienced a decreased time to first flatus (Logrank c2 = 5.22 1 degree of freedom (D.F.), P = 0.02). The median time to flatus was 85 h (95% CI 68–93) for ropivacaine, and 89 h (95% CI 72–120) for controls. There was no significant effect of ropivacaine infusion on time to first bowel movement (Logrank c2 = 0.05, 1 D.F., P = 0.94), with a median time to first bowel movement of 115 h (95% CI 92–120) for active treatment, and 112 h (95% CI 94–142) for controls. Ropivacaine infusion was associated with a decreased time to independent mobilization (Logrank c2 = 5.56, 1 D.F., P = 0.02). The median time to independent mobilization was 94 h (95% CI 72–116) for ropivacaine and 127 h (95% CI 116–156) for controls. Ropivacaine infusion had no significant effect on total length of hospital stay (Logrank c2 = 0.08, 1 D.F., P = 0.77).

Multivariate analysis After adjusting for age, gender and type of operation (right hemicolectomy versus other operation), there was very strong evidence that mean morphine PCA use at 48 h differed between the two treatment groups (t43 = 3.70, P = 0.0006). The adjusted effect of ropivacaine was an average reduction in morphine use at 48 h of 41 mg (95% CI 19, 64). Age and gender also had independent and statistically significant effects on PCA use. After allowing for

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gender, treatment allocation and type of operation, the total morphine PCA requirements at 48 h was reduced by 1.2 mg (95% CI 0.5, 1.9) for every 1-year increase in age (t43 = 3.37, P = 0.002). Similarly, the total morphine PCA use at 48 h was, on average, 27 mg higher in males compared with females (95% CI 4.5, 49; t43 = 2.42, P = 0.02). Right hemicolectomy procedures appeared to reduce total morphine PCA at 48 h by 21 mg compared with other procedures (95% CI 5.1, 48), although this did not reach statistical significance (t43 = 1.63, P = 0.11). Nevertheless, the type of operation was included in the model because of an a priori opinion that the type of operation and extent of surgical dissection influences the amount of post-operative pain. This regression model accounted for 33% of the variability of morphine use. The amount of extra variability explained by the local anaesthesia infusion was 19%, suggesting that it played a moderately large role in determining post-operative morphine requirements. After allowing for gender, treatment allocation and type of operation, there was also evidence of a 20 mg reduction (95% CI 3.4, 36) difference in mean morphine PCA use at 24 h between the two treatment groups (t43 = 2.43, P = 0.02). Sensitivity analyses revealed that there was no interaction between treatment solution and age (P = 0.33) or gender (P = 0.54) at 48 h. Since the unadjusted Logrank tests were statistically significant for flatus and mobilization, a Cox proportional-hazards model was fitted to determine the effect of treatment, after adjusting for other variables thought to influence these outcomes (e.g. age, gender, type of operation and length of wound). In the crude analysis of time to flatus, allocation of treatment to either active treatment or control was the only significant predictor of time to flatus. After adjusting for the type of operation, there was evidence that the use of ropivacaine infusion decreased time to first flatus (c2 = 5.25, 1 D.F., P = 0.02). The adjusted hazard ratio was 2.0 (95% CI 1.1, 3.6) for the treatment group compared with placebo. Patients who had a right hemicolectomy also appeared to have shorter times to flatus, although this did not reach statistical significance (hazard ratio of 1.5, 95% CI 0.8, 2.8; c2 = 1.86, 1 D.F., P = 0.17). The allocation of either active treatment or control did not appear to have any effect on time to first stool, after adjustment for operation (c2 = 0.008, 1 D.F., P = 0.93). In the crude analysis of time to first independent mobilization, both age and treatment were significant predictors of time to flatus, with P-values of 0.0006 and 0.01 respectively. After adjusting for age and type of operation, there was evidence that those allocated to ropivacaine had a shorter time to first mobilization (c2 = 5.67, 1 D.F., P = 0.02). The adjusted hazard ratio was 1.9 (95% CI 1.1, 3.4) for the treatment group compared with placebo. There was also very strong statistical evidence that time to first independent mobilization increased with increasing age, with an adjusted hazard ratio of 0.7 (95% CI 0.6, 0.8) for every 10-year increase in age (c2 = 13.71, 1 D.F., P = 0.0002). Patients who had a right hemicolectomy also appeared to have shorter time to first mobilization, although this did not reach statistical significance with a hazard ratio of 1.7 (95% CI 0.9, 3.2; c2 = 2.95, 1 D.F., P = 0.09).

Adverse events An analysis of adverse events is shown in Table 3. In total, 5/55 (9%) patients developed post-operative wound infection, with no differ-

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Table 3 Post-operative complications by randomization group

Surgical complications Wound infection Post-operative ileus Intra-abdominal bleed Pneumonia Perioperative myocardial infarction Complications relating to PCA Nausea Vomiting Pruritis Confusion Sedation Hallucination Respiratory depression Any PCA complication†

Intervention (n = 28)

Control (n = 27)

P-value

2 2 0 1 0

3 9 1 1 1

0.61 0.02 — — —

11 2 1 0 4 0 0 15

7 1 2 2 4 1 3 14

0.29 — — — — — — 0.90

†

This refers to the number of patients experiencing any of the above complications. Some patients experienced more than one complication. PCA, patient-controlled analgesia.

ences in the two groups. Using the definition of post-operative ileus of at least 5 days without flatus or stool passage, there was a significant reduction in the incidence of post-operative ileus between ropivacaine and placebo groups (2/28 versus 9/27, c2 = 5.89, 1 D.F., P = 0.02). Treatment groups were similar with regards to other surgical and PCA-related complications. No local anaesthesia central nervous system or cardiovascular system toxicity was detected in any of our patients.

Discussion Continuous local anaesthesia wound infiltration has been used in multiple clinical settings, including orthopaedic, obstetric and gynaecological, cardiothoracic and general surgical procedures. A systematic review has shown that it is associated with many benefits including reduction in pain score, daily opioid requirements, the incidence of post-operative nausea and vomiting, and length of stay.12 Several randomized control trials studying the use of continuous local anaesthesia infusion in patients who have undergone laparotomy have been published.6–10 These studies have shown mixed results regarding efficacy. A systematic review of five randomized control trials, involving 542 laparotomy wounds, found that local anaesthesia wound infusion was associated with a significant decrease in total opioid consumption (P = 0.03), but no significant decrease in length of stay (P = 0.12) or return to bowel function (P = 0.45).13 One large randomized control trial involving 310 patients failed to detect any significant difference in morphine use, mobility or return to bowel function.9 The site of placement of the infusion catheters may explain the differences. Our practice of placing the catheters directly at the fascial wound edge, and not at the subcutaneous level, may have allowed greater penetration of the fascial layer and surrounding nerve fibres, thus improving the inhibition of nerve transmission. Pre-peritoneal infusion of local anaesthesia has been shown © 2010 The Authors ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons

Wound infusion with local anaesthesia after laparotomy

to be effective in reducing pain at rest and coughing, morphine use, and promoting faster recovery of intestinal transit.8 Our results support the concept that infusion at a deeper level (fascial or preperitoneal) may provide more effective analgesia than superficial subcutaneous infusions. No reductions in subjective pain scores at rest or activity were noted between the two groups. Hence, less PCA analgesia requirement in the treatment group did not result in patients having an increased level of pain. In this study, age and gender were shown to have independent statistically significant effects on PCA morphine requirements. Age and gender have previously been shown to be independent predictors of intravenous opioid use after colectomy.14 Differences in operations among study participants had the potential to confound our results. Patients undergoing a right hemicolectomy have been previously shown to require less post-operative intravenous analgesia than patients who have other types of colectomies.14 This has been attributed to right hemicolectomy requiring less extensive dissection. A greater proportion of patients in the normal saline group underwent right hemicolectomy than those allocated to the ropivacaine group. Morphine PCA use was still significantly less in the ropivacaine group despite this, even before we adjusted for the type of operation (right hemicolectomy versus other) in our multivariate analysis. In our study, ropivacaine wound infusion was associated with a shorter time to flatus and earlier time to mobilization, which was independent from important covariates such as age or type of operation. We also detected a statistically significant decrease in the incidence of post-operative ileus but not a decreased time to first bowel movement. These beneficial end points have also been reported by other studies.6,8,10 One study found that patients who underwent right hemicolectomy had a significantly shorter ileus.15 Another study demonstrated that time to first flatus and time to first bowel movement was influenced by amount of PCA use.16 In the same study, no correlation between incision length and morphine use or incision length and return of bowel function was found, which is consistent with our findings. Although wound infusion with local anaesthesia in this study resulted in earlier independent mobilization and earlier return to bowel recovery, these did not result in any reduction in length of hospital stay. Many factors other than direct recovery from the operation influence readiness for discharge from hospital. These include patient, surgeon and hospital factors. Patient factors include social support, pre-morbid health, attitudes and expectations. Surgeon factors include attitudes and expectations, especially relating to fast-track surgery, which may have been influenced by previous experiences. Hospital factors include discharge planning and support after discharge. There is conflicting evidence whether continuous local anaesthesia infusion increases the risk of wound infections. One study reported an infection rate of 4% after inguinal hernia repair.17 This infection rate was found to be 10 times the usual incidence in a retrospective audit. The rate of wound infection in our study was 9% (5/55), which is similar to that reported in the literature for laparotomy procedures.18,19 On the other hand, continuous local anaesthesia infiltration of wounds may be associated with a reduced incidence of wound infection. Local anaesthesia has been shown to © 2010 The Authors ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons

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improve tissue oxygen tension, which has been shown to be a strong predictor of the development of wound infection.20–22 This is possibly mediated by reduced sympathetic vasoconstriction at the level of the wound. Post-operative paralytic ileus remains a significant problem following laparotomy and is one of the most common reasons for delayed hospital discharge after abdominal surgery.23 Fast-track surgery, with the use of multi-modal pre-operative strategies and post-operative rehabilitation, has been shown to reduce postoperative ileus.23,24 Continuous local anaesthesia wound infiltration may have a place in fast-track surgery. Our results, with regards to paralytic ileus, should be interpreted with caution. Measurement of post-operative ileus is controversial as there is neither a universally accepted standard definition nor gold standard of diagnosis as (1) bowel sounds do not necessarily reflect propulsive bowel activity, (2) patients need to be conscious in order to be able to report flatus, and (3) bowel movements are dependent on intestinal content and recent diet.25 Wound infusion with local anaesthesia is thought to facilitate post-operative recovery of bowel function by reducing total opioid consumption and decreasing sympathetic tone, which may inhibit intestinal muscle contraction. Lignocaine, when co-administered intravenously at the start of surgery, has also been shown to significantly reduce duration of ileus and length of hospital stay.26 Several authors have postulated that local anaesthetic agents may have additional systemic effects in facilitating post-operative bowel function such as reducing inflammation and through direct potentiation of intestinal smooth muscle contraction.27,28

Critical review of the study Patients in this study were properly randomized. Emphasis was placed in ensuring that the randomization code was concealed from the surgical team recruiting patients thus preserving allocation concealment. It was also participant- and outcome–assessor-blinded. All patients who entered the trial were properly accounted for and attributed at its conclusion. An intention-to-treat analysis was used where possible during statistical analysis. However, this study also had several limitations. This study was prematurely terminated when it only recruited 55 out of its intended total of 100 patients. The study was terminated for a number of reasons. Recruitment of patients into this study was slow because it was a single-surgeon study. The increasing evidence supporting laparoscopic surgery for colorectal cancer and use of pre-peritoneal placement of catheters also contributed to the early termination of recruitment. Several patients were excluded from part of the analysis. Two patients were given fentanyl PCA in each arm, by the procedural anaesthetist, instead of the intended morphine PCA. On three of these occasions, this was because the patient had renal impairment. Fentanyl is often chosen instead of morphine because it is predominantly metabolised by the liver. These patients were excluded from the analysis comparing the association between treatment allocation and morphine use because there is no definite conversion ratio between fentanyl and morphine.29 This could have been avoided by excluding all patients with renal impairment before recruitment. Exclusions resulting from language difficulties could also have been

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Table 4 Differences in intra-operative and post-operative analgesia by randomization group

Intra-operative opioid administration Mean intra-operative morphine (mg) Mean intra-operative fentanyl (mg) Remifentanyl infusion (cases) Co-analgesics (cases) Paracetamol Parecoxib Tramadol Ketamine Clonidine

Intervention (n = 28)

Control (n = 27)

P-value

10.3 147 1

9.2 150 1

0.94 0.53 —

22 2 1 0 1

23 2 3 2 2

0.52 — — — —

which remained statistically significant after adjusting for age, gender and type of operation. There was no detectable difference in patient-reported pain scores, indicating that patients on ropivacaine attained the same level of analgesia with decreased amount of opioids. Ropivacaine infusion was associated with a shorter time to flatus, decreased risk of developing post-operative ileus and earlier time to independent mobilization. We did not find any corresponding decrease in time to first bowel movement or post-operative length of stay. Although this is a small study, our results support the concept that infusion at a deeper level (fascial or pre-peritoneal plane) may provide more effective analgesia than superficial subcutaneous infusion.

Acknowledgements avoided by not enrolling these patients. Patients unavoidably excluded from the study post-randomization comprised 11% (6/55) of the study population. Patients also differed with respect to the type and amount of intravenous opioid (fentanyl, morphine, remifentanil or combination), as well as the use of co-analgesia agents, both intra-operatively and post-operatively. Different anaesthetists were allocated to the operating list, and because of considerable variations in preferred individual anaesthetic practice, a rigid intra-operative analgesia protocol was not implemented. There was no statistically significant difference in the total amount of intra-operative opioid or proportion of patients administered with co-analgesia both intra-operatively and post-operatively (Table 4). Of patients in the active group, 22/28 (79%) received intravenous paracetamol compared with 23/27 patients (85%) in the control group (c2 = 0.40, 1 D.F., P = 0.52). On average, patients in the ropivacaine group had 2.7 mg less fentanyl (t52 = 0.08, 1 D.F., P = 0.94) and 1.1 mg more morphine than the placebo group (t52 = 0.64, 1 D.F., P = 0.94) intra-operatively. A systematic review found that co-administration of paracetamol in patients receiving PCA morphine resulted in 20% reduction in morphine PCA requirements in the first 24 h.30 Therefore, the presence of co-analgesia has the potential to confound our study results. We conducted a separate analysis to see whether there was still a significant difference in morphine PCA consumption between the two treatment groups after adjusting for both intra-operative opioid use as well as intra-operative and post-operative administration of co-analgesia agents. After adjusting for intra-operative opioid dose and use of paracetamol, clonidine, parecoxib, ketamine or tramadol in both the intra-operative and perioperative period, patients in the ropivacaine group still required, on average, 20 mg less morphine at 24 h (t36 = 2.35, P = 0.02) and 39 mg less morphine at 48 h (t36 = 3.32, P = 0.002) compared with placebo. Therefore, we conclude that intra-operative opioid administration and the post-operative administration of co-analgesia had a minimal impact on our results.

Conclusion In this study, post-operative local anaesthesia infusion of the midline laparotomy wound with ropivacaine was associated with a statistically significant decreased morphine PCA requirement at 48 h,

We thank Diane Davies (clinical trials pharmacist), as well as the surgical registrars, junior medical officers and members of the Acute Pain Service for their assistance during the implementation of the trial. I-Flow Corporation and its Australian distributor, Surgical Synergies, provided funding for the study but were not involved in the design, implementation, analysis and reporting of the study.

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