Poor postoperative pain control may delay recovery and increase morbidity,1 and opioids remain the most frequently used drugs for postoperative analgesia. Because of the great potential for side-effects (nausea, vomiting, constipation, delirium, respiratory depression and postoperative cognitive dysfunction), other drugs or techniques are being investigated as alternatives to opioids.2 As part of a multimodal approach, local anaesthetics infused into the wound postoperatively through a multiholed catheter have been investigated for a range of surgical procedures, often showing reduced pain scores and reduced need for opioids as well as less nausea.3 During colorectal resection4 and nephrectomy,5 the technique has been shown to shorten time to recovery of bowel function. Following coronary artery bypass and after certain orthopaedic procedures, the length of stay in hospital was reduced.6–8 Both position of the catheter and volume infused have been subject to intense investigation. Some argue for a subcutaneous position of the catheter,9 whereas others have used a subfascial position.4,10,11 Wu et al.12 showed no effect after retropubic prostatectomy, using a regimen with no initial bolus infusion and a low infusion rate. As a higher infusion rate seems more appropriate, we, therefore, hypothesised that a large bolus dose of bupivacaine followed by infusion would result in a reduction in the need for opioids in patients undergoing retropubic prostatectomy.
Patients and methods
This prospective, randomised, double-blinded, placebo-controlled trial for patients undergoing radical retropubic prostatectomy was conducted in accordance with the Note for Guidance on Good Clinical Practice (GCP) (CPMP/ICH/135/95) and the Declaration of Helsinki. Ethical approval for this study was provided by the Central Denmark Region Committees on Health Research Ethics (De videnskabsetiske Komitéer for Region Midtjylland Skottenborg 26 DK-8800 Viborg Lena Danvøgg, reference code; M-20080019) on the 4th of April 2008. The article has been prepared in accordance with the Consort statement. Written informed consent was obtained from all patients before enrolment.
Consecutive patients older than 17 years scheduled for elective radical retropubic prostatectomy at the Department of Urology of Aarhus University Hospital (Skejby, Denmark) were considered for inclusion in the present study. Exclusion criteria were known allergic reactions to bupivacaine, preoperative opioid requirement and contraindication to non-steroidal anti-inflammatory agents (allergy, peptic ulcer, renal insufficiency or heart failure). The surgical procedure was performed by one experienced surgeon using a standardised retropubic approach.
All patients were anaesthetised with propofol and remifentanil, with cisatracurium to facilitate tracheal intubation. Anaesthesia was maintained with propofol and remifentanil and all patients were ventilated to maintain normocapnia with an oxygen/air mixture, FiO2 40 to 50%. At least 40 min before the expected end of surgery, morphine 0.2 mg kg−1 (maximum 15 mg) was given intravenously for postoperative analgesia. After removal of the prostate and with acceptable haemostasis, ketorolac 30 mg was given intravenously.
No prophylaxis against postoperative nausea and vomiting was given.
Fluids were administered according to institutional guidelines.
Study design and randomisation protocol
Participants were randomly assigned using a sealed opaque envelope system to active treatment or placebo. The envelope was opened by a person not participating in the study who also prepared a 30-ml syringe and an elastomeric infusion pump (On-Q, Pain Buster; I-Flow LLC, Lake Forest, USA), according to randomisation, with either bupivacaine 2.5 mg ml−1 (SAD; Amgros I/S, Copenhagen, Denmark) or isotonic saline (Natriumklorid isotonisk 0.9%; DAK, Roskilde, Denmark). The study vehicle was brought to the operating room labelled with a case-specific randomisation number.
At the end of surgery, the surgeon placed a multihole plastic-catheter ‘On-Q, Pain Buster’ subfascially, and after closure of the wound, 30 ml of either bupivacaine 2.5 mg ml−1 (B-group) or saline (S-group) was given through the catheter as a bolus dose. The pump was set to infuse 5 ml h−1 of either isotonic saline (S-group) or the study drug bupivacaine 2.5 mg ml−1 (B-group) for 48 h. During the study period, all staff were blinded to the content of the study vehicle.
All patients began oral paracetamol 1 g every 6 h before the start of surgery, and oral diclofenac 75 mg every 12 h from the first postoperative night.
In the postanaesthesia care unit (PACU), additional morphine (0.05 mg kg−1) was given intravenously when patients had pain, defined by a verbal numerical rating scale (NRS 0 to 10) more than 3 at rest, NRS more than 5 with activity (defined as deep cough) or at request. The time interval between repeated doses was decided by the attending nurse according to normal routine. Patients were discharged from the PACU to the surgical ward according to institutional guidelines. Upon arrival at the ward, patients were provided with two tablets of oxycodone 5 mg and supplemented if needed with patient-controlled analgesia. If the patient was not able to swallow a tablet because of nausea or vomiting, morphine was given intravenously. In case of nausea and/or vomiting, ondansetron 1 mg, repeated if necessary, was given intravenously.
The presence of nausea and vomiting was recorded for each patient on arrival in the PACU, 2 and 8 h after the end of surgery as well as twice a day during the following 2 days.
The primary study outcome was the opioid requirement. Further prespecified outcomes were pain scores (NRS) at rest and with activity, nausea, vomiting (yes/no), operating time, blood loss and fluids during the operation. Data were recorded on arrival in the PACU, 2 and 8 h postoperatively, as well as twice a day (at 8 a.m. and 8 p.m.) on postoperative days 1 and 2.
All statistical analyses were performed using the statistical program Sigma Stat 4 (Systat Software Inc., San Jose, California, USA). We defined a 30% reduction in opioid requirement as clinically relevant. Based on a sample size calculation with 2α = 5%, β = 20% and a standard deviation estimated from pilot experiments, 26 patients were required in each group. To adjust for possible dropouts, we planned to enrol 60 patients. Groups were pretested for equal standard deviations using the method of Bartlett and were estimated to follow a Gaussian distribution based on the Kolmogorov–Smirnov test. Between-group variables were evaluated by means of the unpaired t-test or Mann–Whitney rank-sum test as a non-parametric test.
Between April 2008 and May 2010, a total of 60 patients were recruited for the study. Of these, 10 were excluded due to insufficient data, or withdrawal of informed consent, or protocol deviation resulting from additional pain medication taken prior to surgery (Fig. 1). Patient characteristics and intraoperative data are listed in Table 1. There were no differences between the two groups with regard to age, weight, operating time, blood loss, fluid infusion or duration of stay in the PACU. Similar amounts of morphine were required during the postoperative observation period (P = 0.49) in the two groups (placebo group 12 mg, 25 to 75% percentile 5 to 18 and bupivacaine group 10 mg, 25 to 75% percentile 0 to 16). The total amount of oxycodone administered during the same time period was the same (P = 0.99) in the two groups (5 mg; 25 to 75% percentile, 5 to 10). Most of the morphine was administered within the first 2 postoperative hours, whereas oxycodone was used throughout the observation period (Fig. 2a and 2b). No statistically significant differences between the groups were detected at any time point.
At 2 h postoperatively, a significantly (P = 0.0488) higher number of patients in the placebo group required additional morphine (24 of 25 in the placebo group and 18 of 25 in the bupivacaine group). Numerical rating scores for patients at rest and during activity did not differ significantly between the groups at any time during the observation period (Table 2).
Presence of nausea is presented in Table 2. No significant differences in nausea and vomiting (data not shown) between the two groups were detected. No catheter infections or other adverse effects were observed in the groups.
The only detectable difference in opioid consumption was seen in the postanaesthesia care unit: a significantly lower number of patients in the bupivacaine group required morphine in the first 2 postoperative hours. Otherwise, no significant difference in opioid consumption was observed. This means the total amount of morphine and oxycodone was similar among the groups. Additionally, no differences in pain score or nausea/vomiting between the study groups could be demonstrated.
Despite promising results with other surgical procedures,3–8 the use of wound catheters in radical retropubic prostatectomy seems unwarranted in this setting. Our study confirmed the results of a randomised controlled trial based on 100 patients from Wu et al.12 In that study, bupivacaine dosage was only slightly lower at 10 versus 12.5 mg h−1 in our study, whereas the infusion volume was significantly lower at 2 versus 5 ml h−1 in our study. Increasing the infused volume of bupivacaine does not seem to increase the efficacy of wound catheters. Pain control may be better with higher total dosage. The negative results of the study may be due to the fact that standard morphine-ketorolac treatment and paracetamol along with diclofenac constitute an effective analgesic baseline that obscures the effect of any additional measures.
The administered dose of bupivacaine might be too low to elicit a significant effect. In the present study, the dose was based upon previous positive studies.13 It is also possible that the pain experienced after radical retropubic prostatectomy is dominated by visceral components that do not respond to a superficially placed wound catheter.
Our results contrast with other studies that have shown a marked benefit from wound catheters. The difference in morphine consumption between the groups in the first 2 postoperative hours suggests that the subfascially administered bupivacaine was therapeutic. Throughout the rest of the study, no differences were observed. The initial reduction in morphine requirement may be related to the administration of bupivacaine and would justify our hypothesis, but the effect seen could probably be observed after single-shot wound infiltration by local anaesthetic without the use of a catheter. However, the reduction is modest and is not reflected in the total amount of morphine given in the two groups. Thus, the clinical relevance of this observation seems questionable. It is possible that a larger study population might have revealed an effect in the first 2 postoperative days, but this begs the question: does the need for a large sample reflect a modest effect, attainable with simpler means?
Based on a sample size calculation, 26 patients in each group were required to observe a significant change in the primary outcome. Due to an unexpectedly large number of dropouts, 25 patients in each group reached data analysis. Adding one patient to each group would, however, not change the overall results and conclusions of the present study.
Many studies investigating the effect of local pain management use pain intensity scores as outcome variables. In the present study, a reduction in opioid use was chosen as the primary outcome as it represented a clinically relevant indicator of a potential beneficial effect from local wound infusion of bupivacaine. The majority of morphine was administered within the first 2 postoperative hours. We can speculate that single bolus wound infiltration with bupivacaine 2.5 mg ml−1 at the end of surgery would achieve identical results in an easier, cheaper and less invasive way.
Side-effects caused by insertion of wound catheters were not investigated in the present study. However, Baig et al.14 treated 70 patients with a catheter similar to the one used in the study. The number of adverse events including wound infection was reported as acceptable, even with a 30-day follow-up.
In conclusion, in the present perioperative setting, additional use of wound catheters in patients undergoing radical retropubic prostatectomy does not significantly reduce total opioid requirement. These findings call for further investigations in larger clinical trials.
Assistance with the study: this study was supported by the Department of Anaesthesiology and Intensive Care, Aarhus University Hospital Skejby, Denmark.
Financial support and sponsorship: wound catheters were supplied by the manufacturer.
Conflicts of interest: none declared.
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