In 2011, nearly 29% of hospital stays and 48% of hospital costs in the U.S. involved operating room procedures (http://www.hcup-us.ahrq.gov/reports/statbriefs/sb165.jsp). Among the 15 procedures most commonly performed in U.S. were: cholecystectomy and common bile duct exploration (129.4/100,000 population), abdominal and vaginal hysterectomy (99.4/100,000 population), colorectal resection (97.4/100,000 population), excision or lysis of peritoneal adhesions (97.4/100,000 population), appendicectomy (93.3/100,000 population) and oophorectomy (71.3/100,000 population). Thus abdominal surgery represents a significant proportion of hospital stays and costs. Gastrointestinal paralysis and postoperative pain are 2 major issues needing to be taken care of after abdominal surgery.
Gastrointestinal paralysis following abdominal surgery may result in prolonged hospital stay and costs. Following laparotomy, laparoscopic cholecystectomy and colectomy, approximately 10.3% of the patients will have an ileus.1 An ileus occurs more frequently in colectomy than cholecystectomy and more often when performed by laparotomy. Ileus patients receiving opioids will have an increased hospital length of stay ranging from 4.8 to 5.7 days, total cost from USD 9945 to USD 13,055 and 30-day all-cause readmission rate of 2.3% to 5.3% higher compared to patients without an ileus.1
In 2000 the Joint Commission on Accreditation of Healthcare Organizations suggested that pain be considered as the fifth vital sign and that under-treatment of pain would constitute abrogation of a fundamental human right.2 Following this statement an increase in the use of opioids for acute postoperative pain treatment was observed as well as an increase in their side-effects.2 It was also observed that postoperative critical respiratory events were encountered more frequently during the first 24 hours after the introduction of opioid therapy.3
Epidural analgesia may promote a faster return in intestinal transit through various mechanisms including a reduction in opioid administration,4 blockade of the sympathetic gut innervation (creating a relative parasympathetic predominance) and a direct effect of systemic local anesthetics.5 Thörn et al6 demonstrated, in 14 participants, that the gastrointestinal electromyographic activity of the participants who received epidurally administered bupivacaine was different from those who received epidurally administered morphine.6 Oral acetaminophen absorption (as demonstrated by the area under the curve of acetaminophen blood concentrations from 0 to 60 minutes) was also higher in participants who received bupivacaine compared with those who received morphine.6 Thus an epidural containing a local anesthetic may promote faster gastrointestinal transit return compared to systemic opioids.
In undisturbed participants receiving patient-controlled morphine analgesia after surgery, abnormal breathing patterns with cyclic airway obstruction are extremely common.7 Provided that the pain relief would be at least equivalent to the one obtained with opioid therapy, by decreasing the amount of opioids administered,4 epidural analgesia with a local anesthetic would appear as an interesting alternative in the treatment of acute postoperative pain for the first days after an abdominal surgery, the time where pain is the most intense. Reducing the amount of opioids administered after the surgery may reduce the rare, but serious, adverse respiratory events associated with the administration of opioids for the treatment of postoperative pain.
The aim of this review was to compare the effects of postoperative epidural analgesia with local anesthetics to postoperative systemic or epidural opioids in terms of return of gastrointestinal transit, postoperative pain control, postoperative vomiting, incidence of anastomotic leak, hospital length of stay and cost in participants after abdominal surgery.
We included parallel randomized controlled trials (RCTs) in which an epidural containing a local anesthetic (with or without the addition of opioids) was added to general anesthesia and continued or not for postoperative analgesia or used for postoperative analgesia in 1 group, and where this group was compared with systemic or epidural opioid-based regimens in another group. We excluded quasi-randomized trials. We applied no language or publication status restriction. Those RCTs included adults (≥16 years old accepted) participants undergoing any abdominal surgery (open or laparoscopic) under general anesthesia. We excluded trials performed on children, trials performed outside the perioperative period (chronic pain, labor analgesia) and trials performed with participants undergoing surgery on other surgical sites (not abdominal surgery). Because some substances are not universally accepted as safe for injection in the epidural space, we did not retain in the analysis a trial (or subgroup) where anything else than an opioid or a local anesthetic or epinephrine was injected in the epidural space. We evaluated the differences between the treatment group and the control group on the following outcomes:
- Postoperative paralytic ileus as measured by first passage of flatus.
- Postoperative paralytic ileus as measured by first passage of feces (stool).
- Pain scores (any ascending scale) on movement at 24 hours.
- Incidence of postoperative vomiting: number of participants who had experienced vomiting on day 1.
- Gastrointestinal anastomotic leak.
- Length of hospital stay.
- Hospital costs.
We searched the following electronic databases to identify potential studies: Cochrane Central Register of Controlled Trials (CENTRAL; 2014 Issue 12), MEDLINE (OVID) 1950 to December 2014; and EMBASE (OVID) 1974 to December 2014 (Supplemental Digital Content, Supplemental Appendix 1, http://links.lww.com/AA/B527). Two review authors (J.G. and Dr. Dat Nut Nguyen [D.N.N., left the review before its completion]) scanned the titles and abstracts of all reports identified by electronic searching, retrieved full texts of those articles and independently extracted data (J.G., D.N.N. or M.N.). We resolved disagreements by discussion, the help of a third author was never required. The methodological quality of the selected studies was evaluated with the Cochrane tool by 2 authors (J.G., D.N.N. or M.N.) from the report with no assumption. We rated as unclear an element for which there was not enough information contained in the report to allow us to make a clear judgment. We extracted events and total numbers of participants in each group for dichotomous data when available. We extracted mean, standard deviation (SD) and number of participants in each group for continuous data when available. If results were unavailable in our favored format or provided on different scales, we extracted data as P values and number of participants for each group. We also extracted sites and dates of data collection (for exclusion of duplicate publication) and factors required for heterogeneity exploration (see assessment of heterogeneity). We contacted authors for additional information when we did not have enough information from the published articles to extract the data. We made no imputation. We considered clinical heterogeneity before pooling results and examined statistical heterogeneity before carrying out any metaanalysis. We quantified statistical heterogeneity using the I2 statistic. We qualified the amount as low (< 25%), moderate (50%) or high (≥ 75%) depending of the value obtained for the I2 statistic.8 We assessed publication bias with a funnel plot followed by Duval and Tweedie’s trim and fill technique. We analyzed data with RevMan (http://ims.cochrane.org/revman/about-revman-5) and Comprehensive Meta Analysis Version 2.2.044 (www.Meta-Analysis.com) with fixed (I2 < 25%) or random-effects models (I2 > 25%). For standardized mean differences (SMDs) we considered 0.8 as the cutoff limit for a large effect.9 For clinical equivalents, we multiplied the SMD by the SD of a study at low risk of bias and where a typical SD on a clinical scale was provided.10 For results where the intervention produced an effect, we calculated the number needed-to-treat for additional beneficial outcome or the number needed-to-treat for additional harm based on the odds ratio. When results were negative, we also calculated the optimal information size in order to make sure that there were enough participants included in the retained studies to justify a conclusion on the absence of effect.11 We explored any amount of heterogeneity >25% with the Egger’s regression intercept (to eliminate a small-study effect), sensitivity analysis, sub-grouping or meta-regression as appropriate. A priori factors for heterogeneity were the: level of the epidural (thoracic versus lumbar); type of drug used (local anesthetic alone [concentration in lidocaine equivalent potency calculated as follows: lidocaine = 1, bupivacaine = 4, chloroprocaine = 1.5, dibucaine = 4, etidocaine = 4, levobupivacaine = 3.9, mepivacaine = 0.8, prilocaine = 0.9, procaine = 0.5, ropivacaine = 3 and tetracaine = 412]) versus local anesthetic plus opioid (and type of opioid); timing (pre- versus post-surgical incision) and duration of administration (intraoperative only, <48 versus ≥ to 48 hours); site of surgery (bowel surgery, gynecologic, urologic or vascular); type of surgery (open versus laparoscopic); mean group age, American Society of Anesthesiologists physical status; and substance used and route of administration of analgesia in the control group (intravenous [with or without use of a patient controlled analgesia device] versus epidural [with or without the use of a patient controlled analgesia device] versus other routes). Sensitivity analysis (defined as excluding a study on the risk of bias or because it appeared as outlier on a forest plot) were performed. The quality of the body of evidence was judged according to the system developed by the GRADE working group13 and presented in a “Summary of findings” table for the all our outcomes.
The flow chart of the study selection is in Supplemental Appendix 2 (Supplemental Digital Content 2, http://links.lww.com/AA/B528). The risk of bias of the included studies is in Figure 1.
Postoperative Paralytic Ileus as Measured by First Passage of Flatus
Based on 22 trials that included 1138 participants,14–35 an epidural containing a local anesthetic reduced the time required for return of gastrointestinal transit after an abdominal surgery as measured by the time required before observing the first flatus: SMD −1.28 (95% confidence interval [CI], −1.71 to −0.86), I2 = 90% (random-effects model; Figure 2, Table). Egger’s regression intercept showed that part of the heterogeneity might be due to a small study effect (P < .0001; 2 tailed). Duval and Tweedie’s trim and fill analysis calculated that 2 trials might be missing to left of mean for an adjusted SMD of −1.47 (95% CI, −1.94 to −1.00; random-effects model). Keeping only trials where the local anesthetic was continued after the surgery14–17,19–22,24–33,35 would not affect statistical heterogeneity (I2 = 89%). Doing so, the effect size was similar whether an opioid was (SMD, −1.14 [95% CI, −1.73 to −0.56]; 11 trials including 575 participants) or was not (SMD, −1.19 [95% CI, −1.72 to −0.66]; 7 trials including 273 participants) added in the epidural infusion (mixed effects analysis): P value for heterogeneity between the 2 subgroups .92. For the same trials (local anesthetic continued after surgery), when trials are sub-grouped by the type of surgery, a large effect was seen for gastrointestinal (SMD, −1.26 [95% CI, −1.72 to −0.80]), abdominal aortic repair (SMD, −12.86 [95% CI, −15.98 to −9.73]), gynecologic (SMD, −1.24 [95% CI, −1.86 to −0.62]) and urologic (SMD, −0.83 [95% CI, −1.47 to −0.18]) surgeries only (mixed effects analysis). Although a high (gastrointestinal surgery) or moderate (gynecologic surgery) amount of heterogeneity still exists, this heterogeneity comes from the amplitude in effect since no trial favored the opioid based regimen over the epidural with a local anesthetic. For participants undergoing gastrointestinal, abdominal aortic repair, gynecologic or urologic surgery and for whom the infusion was used after the surgery, higher concentrations (in mg/mL) of local anesthetics infusions after the surgery increase the amplitude of the effect (P = .0008; Figure 3). For laparoscopic surgery (1 study with 50 participants28), SMD would be −0.81 (95% CI, −1.39 to −0.23). Based on Liu et al21 (mean ± SD of the control group 71 ± 13.86 hours) 54 participants (27 per group) could eliminate a 15% difference in a simple trial (α, 0.05; β, 0.2; 2-sided test) and the difference for gastrointestinal surgery would be equivalent to 17.5 hours. We rated the level of evidence as high (Table).
Postoperative Paralytic Ileus as Measured by First Passage of Stool
This outcome was available for 28 trials that included 1559 participants where the duration of local anesthetics infusion after the surgery was known.14,15,17,19,20,24–31,33,36–49 An epidural with a local anesthetic infusion after the surgery reduces the time required before observing the first feces (stool): SMD −0.67 (95% CI, −0.86 to −0.47); I2 69% (random-effects model). This effect was not seen in one trial where the local anesthetic was administered only during the surgery.37 This trial was excluded from the rest of the analysis. Excluding this trial, the effect size (SMD −0.71 [95% CI, −0.90 to −0.51]) and the heterogeneity would remain the same (I2 = 69%). Egger’s regression intercept showed no significant evidence of a small study effect. Duval and Tweedie’s trim and fill analysis showed no evidence of a publication bias. The addition of an opioid (SMD −0.66; 95% CI, −0.89 to −0.44, 16 trials for infusion of a local anesthetic with an opioid15,17,24,26–28,30,36,38,40–43,45,47,49) did not significantly modify the amplitude of the effect size (versus SMD −0.80; 95% CI, −1.21 to −0.40, 11 trials14,19,20,25,29,31,33,39,44,46,48; P value for heterogeneity between the 2 subgroups .56, mixed effects analysis). The effect was seen for gastrointestinal (SMD −0.78; 95% CI, −1.03 to −0.5314,15,20,24–26,28,30,36,38,42–46,48,49), gynecologic (SMD −0.62; 95% CI, −1.23 to −0.0119,29,33) and urologic surgery (SMD −0.87; 95% CI, −1.36 to −0.38,27,39 mixed effects analysis) without a statistically significant difference between those subgroups (P value for heterogeneity between the subgroups .82). This outcome was not available for aortic abdominal surgery. A thoracic epidural anesthesia was used for 21 of these trials, a lumbar epidural for 3 trials and this information was not available for 2 trials.40,46 The concentration of the local anesthetic used after the surgery did not affect the effect size. For laparoscopic surgery (4 studies with 188 participants28,42,44,48), the SMD would be −0.37 (95% CI, −0.75 to 0.00; I2 = 36%; random effects model). Based on Kudoh et al20 (mean and SD of the control group 114.5 and 28.2 hours respectively), 86 participants (43 per group) could eliminate a 15% difference (α, 0.05; β, 0.2; 2-sided test) and the difference for gastrointestinal surgery would be equivalent to 22 hours. We rated the level of evidence as low (Table).
Pain Scores on Movement at 24 Hours
Based on 35 trials including 2731 participants,15,21,28,35,38,42,45,48,50–76 an epidural infusion with a local anesthetic after an abdominal surgery decreases pain scores on movement at 24 hours: SMD −0.89 (95% CI, −1.08 to −0.70); I2 = 78% (random-effects model). Egger’s regression intercept showed the possibility of a small study effect (P = .004; 2-sided test). Duval and Tweedie’s trim and fill analysis showed that 6 trials might be missing to left of mean for an adjusted point of estimate SMD −1.07 (95% CI, −1.29 to −0.87; random-effects model). Trials were subgrouped by the type of surgery (Figure 4). An epidural with a local anesthetic decreases verbal/visual analogical scale (VAS) scores with movement at 24 hours after an abdominal surgery for a cholecystectomy (SMD −0.89 [95% CI, −1.62 to −0.15]), a gastrointestinal surgery (SMD −1.12 [95% CI, −1.43 to −0.80]) or an abdominal aortic repair (SMD −1.70 [95% CI, −2.43 to −0.98]). The effect on those 3 types of surgery was not different (P = .25; mixed effects analysis). Trials were subgrouped by the type of opioid added to the epidural infusion. An effect was seen when either fentanyl (SMD −0.95 [95% CI, −1.20 to −0.69]), morphine (SMD −1.19 [95% CI, −1.69 to −0.69]) or sufentanil (SMD −0.77 [95% CI, −1.14 to −0.41]) was added to the solution (random-effects model). There was no statistical difference between those 3 subgroups (P = .54; mixed effects analysis). Trials were subgrouped by the type of opioid in the control group. An effect was seen when an epidural containing a local anesthetic was compared with morphine (SMD −0.87 [95% CI, −1.05 to −0.69]), oxycodone (SMD −0.80 [95% CI, −1.33 to −0.26]) or tramadol (SMD −3.14 [95% CI, −4.31 to −1.97]) (random-effects model). Those 3 subgroups differed (P = .001; mixed effects analysis). For laparoscopic surgery (4 studies with 206 participants28,42,48,75), the SMD would be −0.78 (95% CI, −1.18 to −0.38; I2 = 49%; random effects model). Based on Peyton et al.70 (mean ± SD of the control group 5.5 ± 2.8 on a scale from 0 to 10), 248 participants (124 per group) were required to eliminate a difference of 1 in a simple trial (α, 0.05; β, 0.2; 2-sided test) and the decrease would be equivalent to 2.5. We rated the level of evidence as moderate (Table).
Incidence of Postoperative Vomiting: Number of Participants Who Had Experienced Vomiting on Day One
Based on 22 trials with 1154 participants,15,18,26,28,29,33,36,44,58,68,77–88 we did not find a difference in the number of participants who will experience vomiting during the first 24 hours after an abdominal surgery performed under general anesthesia: risk ratio (RR) 0.84 (95% CI, 0.57–1.23); I2 = 21%. Egger’s regression intercept showed no statistical significant small study effect. Duval and Tweedie’s trim and fill analysis showed 5 studies might be missing to right of mean for an adjusted point of estimate RR 1.05 (95% CI, 0.68–1.60; random-effects model). For laparoscopic surgery (4 studies with 160 participants,28,44,84,85 RR would be 0.50 [95% CI, 0.18–1.38; I2 = 39%; random effects model). For gynecologic surgery, 3 studies used a high lidocaine equivalent concentration (10 mg/mL29,33,84) and 1 study used a low lidocaine equivalent concentration (2.5 mg/mL88). The incidence was reduced when a high lidocaine equivalent concentration was used (112 participants: RR 0.13 [95% CI, 0.03–0.52; I2 = 0%). Assuming an incidence of 32%, the number needed-to-treat for additional beneficial effect for an epidural containing a lidocaine equivalent of 10 mg/mL would be 4 (95% CI, 4–7). Considering a basal rate of 17% in the trial population (Table), 1732 participants (866 per group) were required to eliminate a decrease of 25% in the incidence of vomiting (α, 0.05; β, 0.2; 1-sided test). We rated the quality of evidence as low (Table).
Gastrointestinal Tract Anastomotic Leak
Based on 17 trials with 848 participants,14,21,24,25,30,35,37,38,41–43,46,48,50,72,89,90 we did not find a difference in the incidence of anastomotic leak: RR 0.74 (95% CI, 0.41–1.32); I2 = 0% (Figure 5). Egger’s regression intercept showed no significant small study effect. Duval and Tweedie’s trim and fill analysis showed one study might be missing to right of mean for an adjusted point of estimate RR 0.79 (95% CI, 0.40–1.55). For laparoscopic surgery (2 studies with 118 participants42,48), RR would be 2.47 (95% CI, 0.34–18.12; I2 = 0%). Considering a basal rate of 6% in the study population (Table) 5466 participants (2733 per group) were required to eliminate a decrease of 25% in the incidence of anastomotic leak (α, 0.05; β, 0.2; 1-sided test). We rated the level of evidence as low (Table).
Length of Hospital Stay
Based on 34 trials with 2774 participants,15,21–24,27,29,30,33,35,38,41,42,44,45,47–49,57,66,71,72,75,77,90–99 an epidural with a local anesthetic does not reduce the hospital length of stay: SMD −0.13 (95% CI, −0.29 to 0.02); I2 = 69% (random-effects model). Egger’s regression intercept showed no statistically significant evidence of a small study effect. Duval and Tweedie’s trim and fill analysis calculated 9 trials might be missing to right of mean for an adjusted point of estimate SMD 0.05 (95% CI, −0.11 to 0.21). Epidural analgesia reduces hospital length of stay for open surgery (SMD −0.20; 95% CI, −0.35 to −0.04; I2 = 68%; 30 studies with 2598 participants) but not for laparoscopic surgery (4 studies with 176 participants,42,44,48,75 SMD 0.38 [95% CI, −0.06 to 0.82]; I2 = 49%; random effects model). For open surgery, there might be a small-study effect (P = .03; 2-sided test for Eger’s regression intercept) and Duval and Tweedie’s trim and fill analysis showed that 9 studies might be missing to right of mean for an adjusted point of estimate SMD 0.00 (95% CI, −0.16 to 0.16; random effects model). Based on Carli et al,38 (SD in the control group 5 days), 786 participants (393 per group) would be required in a simple trial to eliminate a difference of 1 day (from 8 to 7 days; α, 0.05; β, 0.2; 2-sided test) and the reduction for an open surgery would be equivalent to 1 day. We rated the quality of evidence as very low (Table).
Data for cost were available for 2 small trials only.24,34 One trial provided costs related to pain therapy only.45 Those 3 trials studied participants undergoing open abdominal surgery.
An epidural containing a local anesthetic will decrease the time required for return of gastrointestinal transit as measured by the time required to observe the first flatus after an abdominal surgery (Table; high quality of evidence; equivalent to 17.5 hours). The effect is seen for almost every type of abdominal surgery and is proportional to the concentration of local anesthetic administered after the surgery (Figure 3). The optimal concentration required to obtain the maximal effect without impeding ambulation by producing motor blockade of the lower limbs may need to be determined in future trials/reviews. Adding an opioid to the mixture does not reduce the benefit. The exact duration of administration required may also need to be determined in future trials/reviews. A reduced incidence of vomiting was seen only at relatively high local anesthetic concentrations and for gynecologic surgeries. Return of gastrointestinal transit is an important goal to achieve after abdominal surgery, as it is generally considered required before hospital discharge and postoperative ileus will increase hospital costs.1 Return of gastrointestinal transit as measured by time to first flatus or bowel movement is often chosen as an outcome measure in clinical trials evaluating recovery after surgery.100 In the present review, the positive effects on gastrointestinal transit translated in an interesting shortening of hospital length of stay for participants undergoing open surgeries (very low quality of evidence). Data on cost were too limited to allow us to make any comment on them.
In adults, regional analgesic techniques decrease postoperative opioid consumption,4 making them a potentially interesting alternative or adjunct to opioid-based regimens for treatment of postoperative pain, provided of course that the efficacy would be at least equivalent. An epidural with a local anesthetic has a clinically relevant effect on pain scores (moderate quality of evidence, Table). Not every patient will benefit from an epidural with a local anesthetic to the same extent. Many factors will either increase or decrease the beneficial effects. For patients themselves, the older the patient, the higher the difference in pain scores between an epidural with a local anesthetic and an opioid based regimen (pain scores at rest and on movement at 48 hours [results not shown here]101). For the type of surgery, patients undergoing abdominal aortic repair, gastrointestinal surgery or urologic surgery seem to be the ones for which an epidural containing a local anesthetic would be the most beneficial. The type of solution used also matters. Administering only a local anesthetic through the epidural catheter will not produce a decrease in pain scores compared to opioids based regimens, at least from 24 hours and after and this applies both to pain scores at rest and on movement. Fortunately, as mentioned above, adding an opioid to the mixture does not seem to decrease the benefit of the local anesthetic on acceleration of gastrointestinal transit return. For the opioid added to the local anesthetic morphine, fentanyl or sufentanil seem to be equally effective for pain on movement. When an opioid is administered in the epidural space, blood concentrations achieved will vary according to the type of opioid used. Therefore, a systemic effect of the opioid is to be expected. The type of opioid used in the control group as well as the route of administration may also increase or decrease the difference between an epidural containing a local anesthetic and an opioid based regimen on pain scores. Pain reduction was present regardless of the type of approach (open versus laparoscopic). Thus the decision to use epidural analgesia after an abdominal surgery versus other modalities has to be considered on a case by case basis taking into account age, associated comorbidities, relative contraindications and type of surgery.
When evaluating the benefit of an intervention, one has to also consider potential side effects. Because they may increase the risk of hypotension,102 some clinicians hypothesized that the secondary extra fluid administration could increase sutures edema and anastomotic dehiscence. We did not find a difference in the incidence on anastomotic leak (low quality of evidence). Severe complications such as paraplegia or death related to epidurals when used for perioperative pain treatment in adults are fortunately very rare (1.0 to 6.1 per 100,000 procedures103) and best evaluated by large prospective trials, being rarely reported in RCTs on neuraxial blocks.104
In conclusion, an epidural with a local anesthetic will accelerate the return of gastrointestinal transit by approximately 17 hours. The effect is proportional to the local anesthetic concentration. This effect will translate in shorter hospital length of stay for open surgeries only. An epidural with a local anesthetic also improves pain scores (open or laparoscopic surgeries). Adding an opioid to the solution of local anesthetic will improve pain scores without affecting its effect on gastrointestinal transit.
Name: Joanne Guay, MD.
Contribution: This author coordinated the review, screened search results, screened retrieved studies against inclusion criteria, appraised quality of studies, abstracted, analyzed and interpreted data, and wrote the review and attest having approved the final manuscript.
Name: Mina Nishimori, MD.
Contribution: This author screened retrieved studies against inclusion criteria, appraised quality of studies, abstracted and interpreted data, wrote the review, and attest having approved the final manuscript.
Name: Sandra L. Kopp, MD.
Contribution: This author interpreted data, wrote the review, and attest having approved the final manuscript.
This manuscript was handled by: Richard Brull, MD, FRCPC.
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