Double-blind randomized sham controlled trial of intraperitoneal bupivacaine during emergency laparoscopic cholecystectomy

Birmingham, United Kingdom

Double-blind randomized sham controlled trial of intraperitoneal bupivacaine during emergency laparoscopic cholecystectomy

Keith J Roberts, Jeff Gilmour, Ruplay Pande, James Hodson, For Tai Lam and Saboor Khan

Birmingham, United Kingdom

BACKGROUND:Intraperitoneal local anesthesia (IPLA) during elective laparoscopic cholecystectomy (el-LC) decreases postoperative pain. None of the studies have explored the eff i cacy of IPLA at emergency laparoscopic cholecystectomy (em-LC). A longer operative duration, the greater frequency of washing, and the inf l ammation associated with cholecystitis or pancreatitis are a few reasons why it cannot be assumed that a benef i t in pain scores will be seen in em-LC with IPLA. This study was undertaken to assess the eff i cacy of IPLA in patients undergoing em-LC.

METHODS:Double-blind randomized sham controlled trial was conducted of 41 consecutive subjects undergoing em-LC. IPLA was delivered by a combination of injection to the diaphragmatic and topical wash over the liver and gallbladder with bupivacaine or saline. The primary outcome was visual analogue scale pain scores until discharge. Secondary outcomes included pain scores in theatre recovery and analgesic consumption.

RESULTS:One patient had a procedure converted to open and was excluded. There was no signif i cant difference in pain scores in the ward or theatre recovery. Analgesic use, respiratory rate, oxygen saturation, duration to ambulation, eating, satisfaction scores, and time to discharge were comparable between the two groups.

CONCLUSIONS:IPLA during em-LC does not inf l uence postoperative pain. Other modalities of analgesia should be explored for decreasing the interval between diagnosis of acute admission and em-LC.

(Hepatobiliary Pancreat Dis Int 2013;12:310-316)

gallbladder stone disease; gallbladder; cholecystectomy

Introduction

To improve patient's experience after laparoscopic cholecystectomy (LC) and to drive day case surgery, efforts to decrease postoperative pain include the induction of intraperitoneal local anesthesia (IPLA).[1]The majority of randomized trials to investigate the eff i cacy of IPLA demonstrate reduced pain scores in the treatment group.[2-17]There are several trials, however, in which no reduction of pain is observed.[18-26]Different local anesthesia (LA) agents, doses and mechanisms of administration may partly explain this variation. Shoulder pain is frequently experienced by patients and allegedly of diaphragmatic origin;[2]LA wash over the liver and gallbladder has little impact upon this expression of pain.[17]Diaphragmatic pain can be reduced by percutaneous injection[27]and intraperitoneal arosol of LA.[28]In a randomized trial comparing two different methods of IPLA with sham both direct injection of LA to the diaphragm and LA wash over the liver and gallbladder reduced postoperative pain in the immediate postoperative period.[12]A prolonged duration of benef i t was only observed in the group receiving diaphragmatic injection.

Patients with cholecystitis or gallbladder stone pancreatitis benef i t from LC during their emergency admission-emergency laparoscopic cholecystectomy (em-LC).[29,30]Patients undergoing em-LC have an improvement in quality of life at one month compared to those who are treated with delayed LC[31]and less time off work.[32]This strategy reduces the risk of repeated admission with further pain or pancreatitis.[33]The role of IPLA in patients undergoing em-LC is unknown with no data from randomized trials. Thisstudy was undertaken to assess the eff i cacy of IPLA in patients undergoing em-LC.

Methods

This randomized prospective double blind sham-controlled trial was approved by the Warwickshire Research Ethics Committee, UK. Following trial commencement there were no changes to the study protocol or methods. Written informed consent was obtained prior to the procedure in each patient. Consecutive adult patients admitted with cholecystitis or gallblader stone pancreatitis undergoing em-LC by one of two surgeons (RKJ or GJ) were eligible for inclusion to the trial. These two surgeons were responsible for participant enrolment. Cholecystitis was diagnosed with ultrasound conf i rmed gallbladder stones containing two of the following: an elevated neutrophil count (>7×109/L), pyrexia greater than 38 ℃ or a thickened gallbladder wall on ultrasonography with pain induced by compression of the ultrasound probe on the gallbladder. Gallbladder stone pancreatitis was diagnosed in patients with a serum amylase level, greater than 3 times the upper limit of normal values (>303 U/L at our institution), with gallbladder stones seen on ultrasonography and cholangiographic evidence of common bile duct stones (endoscopic or magnetic resonance imaging). Patients undergoing elective laparoscopic cholecystectomy (el-LC) were not eligible for inclusion in the study. Patients converted to an open procedure were excluded after allocation and not included on an intention to treat analysis due to the pain that would be predicted from this procedure.

The study hypothesis was that the test treatment, IPLA, would produce similar pain relief in patients undergoing em-LC compared with those undergoing el-LC. In a previous RCT, both diaphragmatic injection and wash over the liver and gallbladder with bupivacaine were associated with decreased postoperative pain compared to sham group.[12]LA was administered directly to the diaphragm and over the liver and gallbladder based upon the observed patterns of pain following LC.[2,17,20]These studies demonstrate that pain arises from parietal, somatic and diaphragmatic sources. The studies were powered (see below) to detect the same difference between a previously validated technique and a control group.

Study design

There were two groups - a sham group that received sham injections/wash of 0.9% sodium chloride and a treatment group that received IPLA injections/ wash of 0.25% bupivacaine. The trial technique of the wash/injection of sham or LA, randomization, blinding, surgical technique, anesthetic protocol and postoperative analgesia regimens were all the same as previously published in a trial of patients undergoing el-LC.[12]Brief l y, all patients received 20 mL of 0.25% bupivacaine to the port sites at the start of the operation. Intraoperatively prior to any dissection a topical wash of 10 mL LA or sham was administered over the anterior surface of the liver, gallbladder and porta hepatis. This was followed by subperitoneal injection into the right hemidiaphragm of 10 mL LA or sham. Randomization was performed by opening sealed sequential envelopes of a randomly generated sequence. Participants, surgeons (including those gathering data), ward nursing and medical staff were all blinded to the participants group allocation.

Outcome measures

The primary outcome measure was pain quantif i ed by postoperative visual analogue scale (VAS, 0-100 mm) pain scores on arrival to the ward, at 4 and 8 hours after the end of the operation. Patients received an information sheet and verbal training in completing the pain scores in the morning of the procedure before sedation. Secondary outcome measures were a three point verbal rating scale (VRS, 0-3) pain score recorded in theatre recovery room at 1, 5, 10 minutes and then at 10-minute intervals following the procedure until transfer to the ward. Time to oral intake of food, ambulation and duration of stay were recorded. At discharge, subjects were asked how satisf i ed they were with the experience in general during the admission and specif i cally with postoperative pain (VAS 0-100 mm). There were no changes in trial outcomes after the start of the study.

Statistical analysis

Data were assessed for normality, and continuous variables are expressed as mean±SEM, geometric mean (95% conf i dence interval) or median (quartiles), as applicable. Comparisons of baseline demographic variables between the treatment groups were made by independent samplesttest or Fisher's exact test for continuous and discrete variables, respectively. The preoperative VAS scores were subtracted from those taken at the ward and at 4 and 8 hours post procedure to calculate the change in the pain score brought about by the procedure. The resulting variables were compared between the sham and treatment groups using independent samplesttest. VRS pain scores in theatre recovery were then compared using the Mann-Whitney test. Signif i cance was accepted asP<0.05. IBM SPSS 19 (IBM SPSS Inc.) was used to perform analyses.

The randomization sequence (computer generated) and sample size calculation were kindly provided by Dr N Parsons, medical statistician, University of Warwick, UK. The sample size calculation was performed at the 5% level with 80% power based upon a clinically important difference in pain severity of 13 mm. This has been reported previously between control and topical wash groups[34,35]and corroborated by a meta-analysis[36]which provides the best estimate of the standard deviation (18 mm). Based on this calculation, a total sample size of 30 patients per group was recommended to ensure that analyses were suff i ciently powered.

Results

The trial had to be terminated early after an interim analysis demonstrating no difference between the trial groups. After the recruitment of 41 consecutive patients, em-LC was diff i cult to perform because of the change of theatre availability. A power calculation gave an expected power of 42.4% for the target sample size of 60 patients. This was largely due to the variability of the data that was greater than anticipated. Hence, the trial was terminated early because of futility. To this point, recruitment had been of consecutive patients agreeing to participate in the trial in a period of 50 weeks (June 2009-June 2010). One patient whose operation was converted to open was excluded after randomization (randomized to receive LA). The remaining patients completed the study (CONSORT diagram) (Fig. 1).

Patient age, gender, smoking habit, ethnic origin, and preoperative daily use of analgesics or antidepressants were comparable. No signif i cant differences in operation duration, spillage of bile or blood, use of peritoneal irrigation or placement of a drain were observed between the groups (Table 1).

Pain scores

Before the operation there was no signif i cant difference in VAS pain scores between the groups (sham: 8 [0-41], bupivacaine: 17 [4-20]; median [IQR];P=0.380). Immediately after the operation there was no signif i cant difference between the groups using a threepoint VRS pain score measured at any time point (Fig. 2). In addition to this, no signif i cant differences between the groups were detected in the increase of pain scores from the preoperative period to arrival at the ward (P=0.357), 4 and 8 hours after the operation (P=0.639 and 0.849, respectively) or at discharge (P=0.772) (Fig. 3).

Analgesic use

Fig. 1.The CONSORT diagram.

Table 1.Preoperative and operative characteristics of the groups

No signif i cant difference was seen in the total analgesic use in theatre recovery and in the ward after the operation and before discharge between the groups (P=0.879). The total number of doses received by each patient in the sham and treatment groups in the postoperative period was 7 (3-20) and 8 (2-15) respectively (median [IQR]). There was no signif i cant difference in the use of opiate or non-opiate analgesics (data not shown) between the groups.

Return of function, duration of stay and complications

Fig. 2.Three point VRS pain scores following arrival in theatre recovery. For each time point measured pain scores for the sham and treatment groups are presented withPvalues from the Mann-Whitney test. Bup: bupivacaine.

Fig. 3.Changes in VAS pain scores. Error bars represent SEM, andPvalues are from independent samplesttest. Preop: preoperation; Postop: postoperation.

Table 2.Summary of secondary outcome measures

No difference was observed in the time to take oral food (P=0.286), ambulate (P=0.319) or discharge (P=0.684), nor in respiratory rate or oxygen saturation at any time point between the groups (Table 2). There were no surgical complications. Patients were subjected to a clinical examination by the anesthetist at the end of the operation. No evidence of pneumothorax was identif i ed at this time or before discharge. Routine chest radiography showed no hemorrhage or hematoma in the patients after subperitoneal injection.

Discussion

In this study, we compared postoperative pain scores between patients receiving intraperitoneal delivery of LA and those receiving a sham treatment during em-LC. No signif i cant effect was observed on pain scores, use of analgesic, or time to recovery. We used two techniques of IPLA: a topical wash (liver and gallbladder surface wash) which has been validated in several clinical trials[2-17]and a subperitoneal diaphragm injection. Previously we found diaphragmatic injection was effective, but not more than topical wash to reduce postoperative pain.[12]The techniques were combined to block visceral, parietal and diaphragmatic pain pathways. There are several explanations why no difference has been observed in the present study. First, the rate of wash was higher in this study than in previous studies, indicating the nature of em-LC. Topical LA was administered at the start of the procedure but not re-administered after wash in this study or previous studies. Topical wash provided at the end of the operation provides inferior analgesic benef i t compared to insertion of the wash at the start of the operation.[4,36]However, a wash would have no impact upon the diaphragmatic injection and is thus not the sole explanation. Second, inf l ammation associated with cholecystitis or pancreatitis may have reduced the effect of topical LA. Inf l ammatory mediators directly decrease the eff i cacy of LA in a pH dependent manner.[37,38]Third, in the present study, 20 mL of 0.25% bupivacaine was divided in two 10 mL applications: one to wash over the liver and the second to inject the right diaphragm. In the previous study this same dose was administered either as a wash or diaphragmatic injection where bothwere associated with a signif i cant decrease in pain. It is possible that by keeping the dose the same but dividing it between two locations resulted in subtherapeutic levels of analgesic at both sites. Forth, preoperative pain scores were different between the groups in the present study and the previous study of subjects undergoing el-LC (18±4 in the present study compared to 6±2 in our previous study of patients undergoing el-LC;[12]mean± SEM) ref l ecting the presence of an acute inf l ammatory process in the emergency group.

In the case of pancreatitis, IPLA will have little or no effect on peripancreatic inf l ammation and in cholecystitis it may be that residual inf l ammatory mediators at the gallbladder bed, which would not have been exposed to LA at the time of wash, continue to be expressed after cholecystectomy. Diaphragmatic LA may be effective, but the overall pain experience for the patient may not be altered signif i cantly.[5]A further difference is the nature of the patients' hospital experience which may affect their interpretation and expression of pain. Patients in an elective setting are admitted specif i cally to undergo LC. In the acute setting they are admitted primarily to treat cholecystitis or pancreatitis and when it is possible an em-LC is performed. For the majority of these patients, LC is not performed at the index admission.[39,40]The availability of surgeons with suitable experience and theatre time appear to be the main inf l uences on the rate of em-LC.[39-41]Thus, in patients who do undergo em-LC there may be variable episodes of delay between consenting the patient for the procedure and when it has been performed, which may affect the expectations and experience of patients. In the present study, the median time from admission to LC was 3 days (range 0-7). The statistical power of the analysis may also have contributed to the non-signif i cance of the difference between the treatment groups. This was lower than anticipated because of the combination of the standard deviation in the pain scores being higher than expected and the fact that the trial was terminated early. However, this trial was based upon data used for a randomized trial of bupivacaine versus sham in el-LC. In that study, two separate arms that used bupivacaine both demonstrated signif i cantly lower pain scores versus sham. However, in this trial of IPLA at em-LC no difference was observed and thus we conclude that the addition of IPLA during em-LC is not benef i cial.

The origins of pain after el-LC are multifactorial and include visceral pain from dissected peritoneum surrounding the gallbladder,[20]somatic pain from retained intraperitoneal blood or bile, insuff l ation of carbon dioxide with distension of the parietal peritoneum and with traumatic injury related to the trocars.[42]IPLA appears to be effective at el-LC; however, in the emergency setting it is not associated with a decrease in postoperative pain. Given the benef i ts of reduced hospital stay and reduced risk of further episodes of biliary colic, cholecystitis or pancreatits[29,30,43]in performing LC at index admission for acute presentations of biliary disease, we suggest that efforts should be concentrated at increasing the proportion of those patients who undergo LC and at improving techniques of providing postoperative analgesia.

Acknowledgments:The authors kindly thank Jenny Abrahms for assistance with data collection and Dr B Murthy for assistance with the anesthetic and analgesic regimes/protocols.

Contributors:RKJ proposed the study, collected the data and drafted the paper. HJ analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. RKJ is the guarantor.

Funding:None.

Ethical approval:This study was approved by the Warwickshire Research Ethics Committee, United Kingdom and trial registration #: NCT01528722 www.clinicaltrials.gov.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received September 4, 2012

Accepted after revision November 5, 2012

AuthorAff i liations:Department of Hepatopancreatobiliary Surgery, University Hospitals Coventry and Warwickshire, United Kingdom (Roberts KJ, Gilmour J, Pande R, Lam FT and Khan S); and Wolfson Laboratory, University Hospitals Birmingham, United Kingdom (Hodson J)

Keith J Roberts, PhD, FRCS, Consultant Surgeon, 3rd Floor Nuff i eld House, University Hospitals Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom (Tel: 07801658505; Email: j.k.roberts@bham.ac.uk)

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60049-1