Boddy, Alexander P. BM, BCh; Mehta, Samir BM, BCh; Rhodes, Michael MD
Laparoscopic cholecystectomy is the treatment of choice for symptomatic cholelithiasis. Although there are clear benefits compared with open surgery, postoperative pain after laparoscopic cholecystectomy remains an issue. Pain can prolong hospital stay and lead to increased morbidity, which is particularly important now that many centers are performing this operation as a day-case procedure.
Administration of intraperitoneal local anesthetic (LA), either during or after surgery, is used by many surgeons as a method of reducing postoperative pain. This technique was first evaluated in patients undergoing gynecological laparoscopic surgery (1). Its application in laparoscopic cholecystectomy was initially examined in a randomized trial in 1993 (2). Since then, many trials evaluating the efficacy of intraperitoneal LA in laparoscopic cholecystectomy have been published worldwide. Although a number of these studies have reported a significant reduction in postoperative pain after the use of intraperitoneal analgesia, others have reported no benefit. We have performed a systematic review of the literature to evaluate the effects of intraperitoneal local analgesia on early postoperative abdominal pain after laparoscopic cholecystectomy.
We systematically identified reports of randomized, controlled trials assessing the use of intraperitoneal LA in the setting of laparoscopic cholecystectomy. MEDLINE, EMBASE, and the Cochrane Library databases were searched in June 2005 using the term: laparoscopic cholecystectomy AND intraperitoneal AND [local an(a)esthetic OR local an(a)esthesia OR lidocaine OR lignocaine OR bupivacaine OR levobupivacaine OR ropivacaine]. No language restrictions were imposed. Additional reports were identified from reference lists of retrieved papers.
Studies included were all double-blind, randomized comparisons of intraperitoneal LA versus placebo or no treatment, evaluating abdominal pain in the setting of laparoscopic cholecystectomy. Trials combining intraperitoneal LA with other interventions (e.g., port site infiltration or intraperitoneal nonsteroidal antiinflammatory drugs) were included as long as there were comparable treatment and control groups in which the only difference was instillation of intraperitoneal LA. Trials in which infusions of LA were administered after the patient had recovered from anesthesia were excluded. Papers that could not be supplied by the British Library were not included. The literature search, determination of studies meeting the inclusion criteria, and data extraction were performed independently by two authors. Consensus was reached by discussion.
The methodological quality of each eligible study was assessed using a 3-item, 5-point scale, which has previously been validated (3). Studies described as randomized were given either 1 or 2 points if the method of randomization was described and was appropriate. One point was deducted if randomization was inappropriate. Studies described as double-blind were either given 1 or 2 points if the method of blinding was described and was appropriate. One point was deducted if blinding was inappropriate. If the numbers were described and reasons for withdrawals offered, a further point was given. As only randomized, double-blind trials were included, the minimum possible score for each study was 2 and the maximum 5.
The principal outcome measure for quantitative analysis was abdominal pain score at 4 h after surgery. Only studies reporting pain scores on a visual analog scale (VAS) (0–100 mm or 0–10 cm) or an equivalent verbal pain score (0–10) were included. If both were given, the VAS was used in preference. Whereas many studies provided just one overall pain score, several studies reported pain scores at rest, with movement or coughing, and for visceral abdominal pain, superficial pain, and shoulder pain. In these cases, the pain score that best represented abdominal pain at rest was used. Most studies reported pain scores at various times during the postoperative period. If the score at 4 h was not reported, the nearest time point to 4 h was used (between 1 and 6 h). Mean pain scores and standard deviations for the control and intervention groups were extracted, either from the text or from tables or graphs included within the report. If the mean score was not given, the median score was taken as an approximation to the mean. In some cases, an estimation of standard deviation was made using Cochrane review methodology (4). Studies offering no measure of dispersion were not included in the pooled quantitative analysis. The weighted mean difference (WMD) between the treatment and control groups was calculated using Review Manager 4.2.8 software (The Cochrane Collaboration, Oxford, United Kingdom). The WMD is reported in millimeters (the units of the VAS for pain), and a negative value represents lower pain scores in patients in the treatment groups compared to the control groups.
Quantitative analysis was also performed on data given for additional analgesia requirements. The mean and standard deviation of the additional analgesia requirements (in milligrams) for the control and intervention groups were extracted from each report. Because different analgesic drugs with various potencies were used, comparison among studies required standardized mean differences to be calculated.
Because there was considerable clinical heterogeneity among trials (different quantities and concentrations of different LAs were used and different postoperative analgesia regimens were used), pooled analysis was performed using a random effects model. Studies that involved routine patient-controlled analgesia (PCA) regimens were assessed in a separate subgroup because it was expected that these patients would have less postoperative pain than patients who needed to ask the nursing staff for each dose of analgesia.
The initial electronic literature searches revealed 59 studies, and after review of the abstracts, 31 randomized trials were identified as potentially meeting the inclusion criteria. Of these, we were unable to retrieve the full papers of two trials (5,6). Four studies were excluded because there were differences between treatment and control arms aside from the instillation of intraperitoneal local analgesia (7–10), and one study was excluded because it examined the use of a postoperative infusion of intraperitoneal local analgesia (11).
Twenty-four studies were incorporated in this systematic review (2,12–34) (Table 1). Anesthetic drugs that were evaluated included bupivacaine, levobupivacaine, lidocaine, and ropivacaine. In some studies, bupivacaine or levobupivacaine was used in conjunction with adrenaline (epinephrine). Most studies used a set dose and concentration of LA. However, some studies based the quantity of LA used on the patient’s weight. In these cases, the figures given in Table 1 are based on the average weight of patients in the treatment arm. In one study, the total quantity of LA used was stated, but no mention was made of the strength or volume of the solution (23). The timing and location of instillation of local analgesia are also shown in Table 1.
Twelve of the 24 studies reported a significant improvement in pain during the early postoperative period. In one study, this occurred for pain during inspiration but not for pain at rest (34). In another study, no significant improvement in pain was noticed in the treatment arms that received a single bolus injection of LA, but a 4-h postoperative infusion did result in significantly lower VAS pain scores (30).
Four studies (18,26,30,32) had treatment arms in which the LA was instilled at different times in relation to surgery. However, only one of these studies reported a significant difference in pain scores between groups at different times (18). In this study, pain scores were lower in the group receiving LA before surgery than the group receiving LA after surgery. A third group receiving LA both before and after surgery had even lower scores.
Many of the studies reported additional analgesic use by patients, either as the number of patients requiring additional analgesia (15,16,20,22,29,31,34), the time to first analgesia request (27), the number of requests for analgesia (13), the number of doses of analgesic (25), or the mean and total dose of a single or combination of analgesic drugs (2,12,14,15,17–22,27,28,34). In the postoperative period, three studies used PCA IV regimens (14,17,28), whereas in the other studies, patients were provided with analgesia by the nursing staff.
Eight studies measured plasma levels after intraperitoneal administration of LA in 161 patients. Three of these trials studied bupivacaine (14,15,17), one levobupivacaine (33), one lidocaine (24), two ropivacaine (28,29), and one both lidocaine and bupivacaine (12). Potentially toxic plasma levels were reported in 4 patients overall: 1 patient after 50 mL of 0.25% bupivacaine (125 mg) (14), 1 patient after 0.6 mL/kg of 0.375% bupivacaine (17), and 2 patients after 40 mL of 0.75% ropivacaine (300 mg) (28). However, no patient in any of the trials included in this review suffered any adverse event attributable to the use of LA.
Two studies examined the effect of intraperitoneal LA on length of hospital stay. One reported that the use of intraperitoneal bupivacaine did not affect the length of hospitalization (15), but another, by combining treatment arms, reported a significant increase in the proportion of patients able to be discharged on the same day as surgery (32).
Two studies assessed respiratory function as an outcome measure. One found no difference in peak expiratory flow rates between patients receiving intraperitoneal bupivacaine and controls (23). However, the second study found that intraperitoneal lidocaine significantly reduced forced vital capacity at 4 h after surgery and increased hypoxemic periods in the 6 h after surgery when compared with controls (14).
All of the included studies used postoperative pain as an outcome measure. However, one study used a 4-point scale for recording pain and was therefore not included in any quantitative analysis (15).
Sixteen of the included studies reported results such that sufficient data could be extracted for quantitative analysis (12–14,17–20,22–24,27–29,31,33,34). Only one treatment arm per trial was included in the initial meta-analysis: if the trial compared different Las, different doses of the same LA, or different times at which the LA was instilled, the arm in which the effect was greatest was used for the pooled analysis. In total, there were 397 patients in the treatment arms and 400 patients in the control arms. There was a statistically significant overall WMD in VAS scores of –9 mm (95% confidence intervals [CI], −13 to −5) in favor of treatment (Fig. 1). As expected, there was a significant degree of heterogeneity among the studies, as demonstrated by an I2 value of 74.8% (I2 is a measure used to quantify heterogeneity and represents the percentage of the variability that is caused by heterogeneity rather than sampling error: a value more than 50% may be considered to represent substantial heterogeneity).
To further examine the effects of timing of instillation, the pooled quantitative analysis was repeated, grouping the studies according to when LA was used. Studies in which LA was instilled at the end of surgery were placed into Subcategory 1. Studies in which LA was instilled before any dissection (19,29), or in which there were two instillations of local analgesia—one at the beginning and one at the end of surgery (20,28)—were placed into Subcategory 2. In one study, data were available that were applicable to both subcategories (18). The WMD in VAS scores for Subcategory 1 (LA after surgery) was −6 mm (95% CI, −10 to −2), whereas the WMD for Subcategory 2 (LA before surgery) was −13 mm (95% CI, −19 to −8) (Fig. 2). This gives a significant difference in WMD between these subcategories of 7.0 mm in favor of LA before surgery (approximate 95% CI, 0.1–14.0).
The 10 studies that reported doses of additional postoperative analgesia to enable quantitative analysis are identified in Table 1. Pooled analysis of these studies was performed as shown in Figure 3. Overall, the standardized mean differences in analgesia use between treatment and control arms was not significant at −0.77 (95% CI, −1.65–0.12).
Laparoscopic cholecystectomy is one of the most frequently performed elective general surgical operations. It is an ideal candidate to be performed as a day-case or short-stay procedure, and therefore, the provision of adequate postoperative pain relief is of considerable importance. Instillation of intraperitoneal LA to reduce postoperative pain has been studied through randomized trials for more than 10 years, and this review has collated the available data both qualitatively and quantitatively.
We identified 24 studies that were suitable for qualitative analysis. In half of these, there was a significant improvement in postoperative pain relief after instillation of intraperitoneal LA. Meta-analysis revealed an overall WMD in VAS of −9 mm in favor of the treatment groups. Although statistically significant, this is slightly lower than the difference found in a meta-analysis (35) published in 2000. This previous review reported improved pain relief in 7 of 13 trials and a meta-analysis of 10 trials found an overall WMD in VAS of −13 mm in favor of the treatment groups. However, we did not find a significant effect of intraperitoneal LA on the total amount of analgesia delivered in the postoperative period. This might be explained by the fact that LA has its effects only over the initial few hours. In many of the studies, delivery of analgesia was measured over periods far in excess of this timescale.
The results of this meta-analysis highlight the considerable heterogeneity of results from available trials. Some of the factors that may be responsible for the clinical heterogeneity among trials are summarized in Table 2. These factors may either directly influence the efficacy of the LA or may affect postoperative pain independently (36), thus reducing the potential benefit from the administration of intraperitoneal LA. For example, patients in trials where PCA was used generally had lower pain scores than patients who had to request each dose of analgesia from medical or nursing staff. This may explain why, in trials where PCA was used, intraperitoneal LA resulted in a smaller reduction in early postoperative pain than in trials not using PCA (WMD, −6 versus −10 mm). However, we did not find that patients who received intraperitoneal LA used a significantly smaller total dose of PCA than control patients.
As well as differences in surgical and anesthetic technique, there were also differences in pain outcomes that different studies tried to measure. Although many studies reported only an overall abdominal pain score, several asked patients to distinguish visceral pain from superficial abdominal pain (2,13,26,28) or shoulder-tip pain (13,16,21,22,26,28,31,34) and also measured pain on movement (8,13,15,28), coughing (8,13,14,28), deep inspiration (14,34), and at rest. Although we tried to extract comparable data for the pooled quantitative analysis, these differences may have had an influence on the heterogeneity of the meta-analysis.
Some authors have suggested that the timing of LA administration has an important role in the success of the technique (18,29,37). It has been argued that postoperative pain is reduced if suppression of central neural sensitization by intraperitoneal LA occurs before nociceptive stimuli have triggered the activation of pain pathways, compared with afterwards. Pooled analyses seemed to support this view: the WMD in VAS scores for studies in which LA was only administered at the end of surgery was smaller than for studies in which at least some LA was administered before any dissection took place.
There is little evidence with regard to which type of LA is most effective because limited data are available for drugs other than bupivacaine. Bupivacaine itself (or levobupivacaine) is an excellent choice for intraperitoneal LA because of its long duration of action. Linear regression analysis of the VAS pain scores from all trials using bupivacaine or levobupivacaine suggested that there was a significant correlation (P = 0.02; R2 = 0.32) between the strength of bupivacaine used and difference in pain score between treatment and control groups, i.e., larger concentrations of bupivacaine resulted in larger reductions in pain score (Fig. 4). However, there was no significant correlation between the volume or total quantity of LA used and the WMD in pain score.
In this study, we calculated a WMD of 9 mm in favor of intraperitoneal instillation of LA. Although statistically significant, the clinical significance of this difference in pain perception is uncertain. Although 9 mm is less than the difference of 13 mm on a 0- to 100-mm VAS for acute pain that has been suggested to be clinically significant (38,39), it could be argued that any reduction in pain is beneficial for the patient if there are no adverse effects associated with it. In particular, a smaller difference in pain may be more significant for patients whose baseline VAS is relatively low (40) and may determine the difference between day-case discharge and an overnight stay in hospital. We identified only one trial that reported a same-day discharge rate as an outcome measure, and in this study, significantly more patients who received intraperitoneal LA were discharged on the day of the procedure (79% versus 43%; P < 0.02) (32).
Overall, this review does lend limited support to the use of intraperitoneal LA in laparoscopic cholecystectomy as part of a multimodal approach to pain management. The technique seems to be safe and results in a statistically significant reduction in early postoperative abdominal pain. It may be of particular benefit when the operation is planned as an ambulatory procedure to improve same-day discharge rates. Finally, there is some evidence to suggest that LA may be more effective if used at a larger strength and if at least some is instilled before any dissection.
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