Effective postoperative pain management is important to reduce the neuroendocrine response to stress and occurrence of postoperative organ dysfunction.1 2
Open colorectal cancer (CRC) surgery induces severe and prolonged postoperative pain, especially after the patient becomes mobile.3 4–6 7–9
Continuous epidural analgesia (CEI) using local anesthetics has been demonstrated to be significantly more effective than systemic PCA with morphine for the management of pain during the first 2 postoperative days after colorectal surgery.10 , 11 12–14 15–19
The use of this technique after abdominal surgery has shown conflicting results for postoperative pain relief, particularly after major midline incision and when the infusion catheter was placed in the subcutaneous tissue or above the muscular fascia.20–22
Recent randomized clinical trials23–25 26
The need for comparative studies with other locoregional anesthetic techniques, especially epidural analgesia, has been emphasized to assess the potential efficacy of CWI, adverse effects, failures, and postoperative outcome.27
The aim of this study was to determine the efficacy of CWI analgesia compared to CEI with a local anesthetic for postoperative pain relief and quality of patient recovery after open CRC surgery.
METHODS
Study Design and Patient Characteristics
This multicenter randomized controlled trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Tripartite Guideline on Good Clinical Practice. Approvals from appropriate research ethics committees were obtained from each study center. The study was conducted from March 2010 to August 2011 at 4 different centers throughout Italy. All patients provided written informed consent before any study-specific procedure.
Patients of both sexes aged between 18 and 75 years who were candidates for open nonemergency CRC resection were eligible for participation. Patients aged 76 years and older were excluded from the study because of a possible increased risk of hypotension related to CEI of local anesthetics.11 , 12 2 , preoperative opioid consumption, concomitant planned urological or gynecological procedures during CRC surgery, contraindications or patient’s refusal of epidural analgesia, and inability to use a PCA device.
Patients were randomized using a computer-generated randomization schedule on a web-based system at a remote site made available to authorized researchers. Enrolled patients were allocated a subject number in sequential order of their enrollment into the trial and received CWI or CEI analgesia using the central randomization system.
Outcome Measures
For the primary outcome measure of assessment of noninferiority of preperitoneal CWI analgesia compared to CEI with a local anesthetic for postoperative pain control, at rest and coughing, a 100-mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (worst imaginable pain) at 2, 6, 12, 24, 48, and 72 hours after the end of wound closure (end of surgery) was used.
Secondary outcome measures of the study included the following:
Morphine titration and dosage required in the postanesthesia care unit (PACU)
IV PCA morphine consumption at 2, 6, 12, 24, 48, and 72 hours after the end of surgery
Time to first flatus noticed by the patient
Time to first bowel movement
Duration of hospital stay, defined as the period from the end of surgery to discharge from hospital; criteria for patient discharge were ambulatory ability, tolerance of solid foods, one bowel movement with fecal emission in the absence of diarrhea, apyrexia, and absence of signs of systemic inflammatory response syndrome28
Quality of night sleep assessed at 8:00 AM on postoperative days 1, 2, and 3, using a verbal numerical scale (VNS) ranging from 0 (poor quality) to 10 (excellent quality)
Patient satisfaction with the quality of postoperative analgesia 72 hours after the end of surgery, which was rated as poor, good, or excellent
Side effects recorded up to 30 days after discharge from hospital, i.e., incidence of postoperative hypotension requiring active vasoactive pharmacological treatment, central nervous system toxicity, postoperative nausea and vomiting (PONV) requiring pharmacological treatment, presence of motor block assessed by modified Bromage scale29
Study Procedures
Patients were randomly assigned to receive either CEI or CWI analgesia with ropivacaine 0.2% at 10 mL/h during the first 48 hours after surgery. All patients received IV morphine for a period of 72 hours with a PCA device (Pharmacia CADD 5800-R PCA Infusion Pump, Pharmacia Deltec, Inc., St. Paul, MN) programmed to deliver 1 mg/dose with a 10-minute lockout time without background infusion. Liberal IV ketorolac 30 mg 3 times daily or paracetamol 1 g 4 times daily was given as rescue analgesia if pain was not controlled by PCA (defined as a VAS score during coughing of >40). For patients with contraindications to nonsteroidal antiinflammatory drugs, only paracetamol was used.
A single-dose scale reduction of ropivacaine to 5 mL/h was planned for both groups of patients in case of hypotension not amenable to surgery (i.e., hemorrhage or major fluid loss) and requiring treatment with fluids and vasoactive drugs. If hypotension persisted, the ropivacaine infusion was stopped. In cases of symptoms suggestive of central nervous system toxicity, ropivacaine infusion was stopped.
Proper functioning of the elastomeric pump and collection of the patient’s postoperative pain evaluation was made by PACU and surgical ward nurses blinded to the study hypothesis. Before surgery, patients were trained to personally report the intensity of pain on the VAS and score the quality of night sleep on the VNS.
Anesthetic Technique
Patients received midazolam (0.02–0.04 mg/kg) as premedication. Anesthesia was induced with fentanyl (1.0–3.0 μg/kg), propofol (0.5–2.5 mg/kg), and atracurium (0.5 mg/kg) as muscle relaxant during tracheal intubation, and was maintained with a balanced technique using isoflurane, desflurane, or sevoflurane, continuous infusion of atracurium (0.4–0.5 mg/kg/h), and fentanyl (2.0–5 μg/kg/h on average), according to hemodynamic and neurovegetative responses. Reversal of residual neuromuscular relaxation was obtained with neostigmine and atropine at the end of the operation. Body temperature was maintained with a forced-air warming upper body blanket system. After surgery, patients were admitted to the PACU for recovery and initiation of analgesic therapy. After an initial loading dose of morphine (2–10 mg), IV PCA was started.
CEI Analgesia
The epidural catheter was placed via a median approach as close as possible to the surgical procedure via the intervertebral space (from T8 to L1) so that the affected dermatomes of the surgical wound would receive the benefits of ropivacaine infusion. Proper placement of the catheter was verified through an aspiration test and a small test dose of a local anesthetic (40–60 mg infused lidocaine). The epidural catheter was then secured with an occlusive transparent dressing. At the end of surgery, a 10-mL bolus of ropivacaine 0.2% was administered through the catheter and then connected to an elastomeric pump delivering a continuous fixed-rate infusion of ropivacaine 10 mL/h.
Preperitoneal CWI Analgesia
At the end of surgery and after the closure of the peritoneal layer, a 7.5-, 15-, or 30-cm 19-gauge multiholed catheter (PAINfusor® ; Baxter-Plan 1 Health, Amaro, Italy) was inserted 3 to 5 cm away from the lower end of the surgical incision through an introducer peel-away needle. The length of the catheter was established to guarantee homogeneous distribution of the holes all along the length of the incision of the fascia. The catheter was allocated above the peritoneum within the musculofascial layer and secured to the skin with an occlusive transparent dressing. The catheter was primed with a saline solution to control the patency of the holes and to prevent the presence of air bubbles in the catheter itself. Thereafter, muscular, subcutaneous, and skin layers were closed and the catheter was secured to the skin with a transparent film dressing. A 10-mL bolus of ropivacaine 0.2% was administered through the catheter and then connected to an elastomeric pump delivering a continuous fixed-rate infusion of ropivacaine 10 mL/h.
Postoperative Care Protocol
Postoperative management of patients was based on a conventional care not adhering to fast-track surgery programs. Nonetheless, early mobilization started on postoperative day 1, IV clear fluids were given liberally (2000–2500 mL/d) for 72 hours, oral fluid intake was allowed after the first 12 hours, oral liquid nutrition started after first postoperative flatus, and solid food intake started in the following 24 hours. Nasogastric intubation was maintained after surgery according to circumstances, and urinary drainage was removed on postoperative day 2 at the end of CEI or CWI analgesia.
Statistics
In this study, mean VAS pain scores with the 2 treatments (CEI and CWI analgesia) were compared. The objective was to demonstrate that the true reduction in mean VAS score for the CWI group does not occur below (exceed) the mean of the CEI group by more than a fixed amount Δ, the noninferiority limit.
Retrospective data from our institution indicate a mean VAS score after epidural analgesia evaluated over 2 postoperative days is 30.2 ± 10.6 at rest and 52.3 ± 10.5 after coughing. Given a clinically relevant difference between the mean VAS scores of −15%, the corresponding noninferiority limit is Δ = −4.5 and −7.8 at rest and coughing, respectively. Thus, the mean difference should be less than 4.5 and 7.8.
The study sample size was determined based on the primary end point, i.e., the evaluation of postoperative pain using mean postoperative VAS data recorded between 2 and 72 hours after the end of surgery.a α = 0.05 and a type II error β = 0.10, 108 patients were required in each study group.
Statistical testing of the difference between the mean VAS score at rest and after coughing in the CEI and CWI analgesia groups was conducted, accounting for the effect of multiple comparisons, by calculating the 2-sided 97.5% confidence interval (CI) for the parameter of interest Δ, and checking whether the lower 97.5% CI was above −Δ. The secondary hypotheses were evaluated statistically by using t test with unequal variances to compare differences in mean values of the studied interval covariates (i.e., morphine consumption, quality of night sleep, incidence of PONV), and Cox proportional hazard regression for time to events (i.e., time to first flatus, time to first evacuation, time to discharge from hospital). The proportional hazards assumption was evaluated graphically by plotting the cumulative hazards functions and the logarithm of the cumulative hazards functions for the 2 treatments. No departure from the assumption of hazards proportionality was detected. A P value <0.05 was considered statistically significant and no correction for the effects of multiple comparisons was applied. Differences not reaching statistical significance were abbreviated as NS.
Efficacy analysis was based on the intention-to-treat population. Descriptive statistics are reported as either mean (SD) or number (%) as appropriated.
Based solely on the slow accrual rate, unaware of the study outcomes, the Data Monitoring Committee decided to stop the trial at the accrual of 50% (108 patients) and the statistical analysis was performed on the randomized patients.
RESULTS
One hundred eight patients were recruited at 4 different study centers in Italy—55 at the National Institute for Cancer Research IST, Genova; 25 at the Centro di Riferimento Oncologico (CRO), Aviano; 24 at the Centro di Riferimento Oncologico Basilicata, Rionero in Vulture; and 4 at the Ospedale Monaldi, Napoli—and randomized to CEI (n = 54) or CWI (n = 54) postoperative analgesia. One patient from the CEI group was excluded from the study because he had a reintervention 24 hours after surgery for an anastomotic leak with acute septic peritonitis. One patient of the CWI group, for whom an unexpected abdominoperineal rectal resection was intraoperatively decided (noneligibility criteria), was excluded from the study. Thus, data from 53 patients per group were analyzed (Fig. 1 ).
Figure 1: Consort diagram. CRC = colorectal cancer.
Patient characteristics are listed in Table 1 . The 2 randomized groups were well matched for age, gender, height, weight, ASA physical status, and type of surgery. No significant differences were observed between the 2 groups for length of surgery.
Table 1: Baseline Patient Characteristics by Randomization Group, Analgesia Characteristics, and Surgical Intraoperative Data
Primary End Points
CWI was not inferior to CEI analgesia over the 72-hour period after the end of surgery. As shown in Figure 2 , the lower 97.5% confidence limits for the differences between mean VAS scores in the CWI and CEI groups at rest (1.89, 97.5% CI = −0.42, 4.19) and after coughing (2.76, 97.5% CI = −2.28, 7.80) were above the limits of noninferiority defined for pain control at rest (−4.5) and after coughing (−7.8). There was no difference between the 2 groups for postoperative VAS score, at rest and coughing, at 2-, 6-, 12-, and 24-hour evaluations. Conversely, there was a statistically significant reduction in VAS scores (Fig. 3 ) in the CWI compared with the CEI group at 48 hours (P = 0.01 and P = 0.001 at rest and coughing, respectively) and at 72 hours (P = 0.03 and P = 0.01 at rest and coughing, respectively).
Figure 2: Postoperative pain visual analog scale (VAS) noninferiority graphs. The shaded zones are the areas of equivalence and the dotted vertical lines are the limit of noninferiority defined as a 15% increased VAS score (i.e., −4.5 and −7.8) for pain assessed at rest and after coughing, respectively. The horizontal bars show the mean difference (1) between the epidural and preperitoneal infusion effect on pain over 72 hours after the end of surgery and the 97.5% confidence interval.
Figure 3: Postoperative visual analog scale (VAS) for pain assessment at rest (A) and after coughing (B) at different times after surgery (scale ranges from 0 = no pain to 100 = very severe pain). Vertical bars represent standard deviation. P values are indicated only for statistically significant differences.
Secondary End Points
Total IV morphine given in the PACU was 2.25 ± 2.35 mg and 2.53 ± 3.41 mg in the CEI and CWI groups, respectively (NS). Cumulative postoperative morphine consumption did not differ significantly between the CEI (17.17 ± 12.99 mg) and the CWI group (14.32 ± 10.74 mg).
Sixteen patients in the CEI group and 14 in the CWI group required rescue analgesia, ketorolac 30 mg or paracetamol 1 g. Requests per time period reported in Table 2 showed no significant between-group differences.
Table 2: Number of Requests for Rescue Analgesia per Time (Hours) After Surgery
For patients’ rating of the quality of postoperative pain control assessed at 72 hours after surgery, although more patients in the CEI than the CWI reported poor (7 and 3, respectively [13.2% vs 5.7%]) or good quality (42 and 26, respectively [79.2% vs 49.1%]), conversely, fewer patients in the CEI (n = 4) than the CWI group (n = 24) reported excellent quality (7.6% vs 45.3%).
Variables evaluating recovery of bowel function are summarized in Table 3 . Compared with the CEI group, there was a significant improvement in patients allocated to the CWI group; time to first flatus was 3.06 ± 0.77 days in the CWI and 3.61 ± 1.41 days in the CEI group (P = 0.002). Similarly, time to first stool was shorter in the CWI than the CEI group (4.49 ± 0.99 vs 5.29 ± 1.62 days; P = 0.001). There was no statistically significant between-group difference in duration of hospital stay; nonetheless, the mean time to hospital discharge was 0.64 day shorter for the CWI than the CEI group (7.40 ± 0.41 vs 8.04 ± 0.38 days) (NS).
Table 3: Comparison of Time to Recovery (Days) of Bowel Function and Discharge from Hospital After Surgery
Quality of night sleep evaluated using the VNS at daily intervals until 72 hours after surgery (Fig. 4 ) was somewhat better for the CWI group, particularly at the 72-hour evaluation (P = 0.009).
Figure 4: Quality of night sleep at different intervals evaluated with a verbal numerical scale (VNS) ranging from 0 (worst quality) to 10 (best quality) by randomization group. Vertical bars represent standard deviation. P values are indicated only for statistically significant differences.
The cumulative number and percentage of patients who experienced PONV are shown in Figure 5 . There was a statistically significantly lower incidence of PONV in the CWI than the CEI group at 24 hours (P = 0.02), 48 hours (P = 0.01), and 72 hours (P = 0.007) after surgery.
Figure 5: Percentage of patients in each treatment group with postoperative nausea and vomiting requiring pharmacological treatment with metoclopramide or ondansetron at different postoperative intervals by randomization group. Vertical bars represent standard deviation. P values are indicated only for statistically significant differences.
Adverse events are listed in Table 4 . Hypotension requiring ropivacaine dose-scale reduction occurred in 5 patients (9.43%) in the CEI group and in 2 patients (3.77%) in the preperitoneal group (NS). Two of 5 patients from the CEI group relapsed after ropivacaine infusion reduction to 5 mL/h and eventually discontinued CEI. Two patients in the CEI group had a catheter dislocation with a unilateral transient motor block that resolved after discontinuation of ropivacaine infusion. Two patients, 1 per group, had an accidental catheter removal. One patient in the CWI group had a catheter kinking. Minor complications of the abdominal wall (i.e., surgical wound infection, surgical wound hematoma, and cutaneous layer dehiscence) occurred in 2 patients in the preperitoneal group and in 3 in the epidural group (NS). No late adverse events or chronic pain was recorded at 30-day follow-up.
Table 4: Postoperative Adverse Effects by Randomization Group
DISCUSSION
Use of CWI with a local anesthetic has proven efficacy for postoperative pain relief with a very low toxicity and failure rate in many fields of surgery. Local anesthetics prevent and alleviate postoperative pain by reversibly blocking the conduction of nerve nociceptive impulses responsible for the sensation of pain. In laparotomic colorectal surgery, Beaussier et al.23 23 19 25 30 22 27
To our knowledge, this is the first study investigating the effectiveness of blocking parietal (i.e., peritoneum, fascia, and muscle) nociceptive inputs with a preperitoneal CWI analgesia technique compared with neuroaxial blockade of nociceptive inputs with epidural analgesia in open CRC surgery. The primary end point of our study was the comparative efficacy of postoperative pain relief by CEI and CWI analgesia. We demonstrated that CWI analgesia and peripheral block of nociceptive inputs ensures noninferiority compared with neuroaxial block with CEI. These results allowed us to reject the null hypothesis of superiority of CEI analgesia versus preperitoneal CWI analgesia for postoperative pain control after open CRC surgery. The effectiveness of CWI analgesia significantly improves over time, as shown by the 48-hour and 72-hour VAS results.
There are some possible explanations for this unexpected result. First, local anesthetics have prolonged antiinflammatory effects based on prostaglandin antagonism,31 32 33 34 , 35 34
There was no significant difference in postoperative morphine consumption between the 2 groups of patients, although the CWI group required a slightly lower total amount of morphine.
Postoperative recovery of bowel function remains a significant factor influencing the results of laparotomic surgery. In our study, it was faster in the CWI group with a significant reduction, by more than half a day, in time to first flatus and time to first production of feces. The length of hospital stay was 0.64 a day shorter in the CWI analgesia group. Although not significant, this is a marked period of time, especially considering the potential benefits and savings incurred when using this technique in a larger population of candidates for open surgery.
The significantly lower incidence of PONV in the CWI group seems to be associated with the faster recovery of bowel function more than with the slight reduction in morphine consumption. The lower incidence of PONV, longer-lasting pain control, and faster recovery of bowel function observed in the CWI group may have been due to a better quality of sleep and higher patient satisfaction with the quality of postoperative pain control treatment seen in this group.
Toxicity related to the amount, rate, and site (i.e., epidural or preperitoneal) of ropivacaine continuous infusion was never observed. Our results confirmed the safety of the continuous infusion of 0.2% ropivacaine 10 mL/h over 48 hours as previously reported in the preperitoneal,23 36 37 38 , 39
The incidence of catheter-related complications was very low in both groups. Whether continuous infusion of local anesthetics may increase the risk of wound infection has been a controversial issue. In our study, wound infection occurred in only 3 patients (2.8%) with no statistically significant between-group difference; this is in agreement with other study results.19 , 22 , 23
Some limitations of this study should be mentioned. First, many CRC procedures are conducted by laparoscopic surgery where the preperitoneal CWI technique is not applicable. Second, in the epidural arm, continuous infusion of ropivacaine was not associated with epidural opioid single-dose infusion, which is considered by some a standard practice for epidural analgesia. The use of opioids in the CWI group would be contraindicated because the local effect of morphine is negligible due to the shortage of morphine receptors in the abdominal layers. In addition, the study design would therefore be voided for methodological differences. It is worth mentioning that VAS results in the CEI group are similar to those previously reported in the literature.10 , 11
In conclusion, preperitoneal CWI with ropivacaine was an effective analgesic method not inferior to CEI infusion in open CRC surgery. It also provided long-lasting control of postoperative pain, faster recovery of postoperative ileus and bowel function with a lower incidence of PONV, and better quality of night sleep. In addition, patients expressed greater satisfaction with the quality of the postoperative analgesia. Continuous preperitoneal infusion may have an important role in laparotomic surgery for patients in whom epidural analgesia is not planned or is contraindicated, in vascular grafting surgery, in emergency and trauma abdominal surgery, and in pediatric patients. This analgesic technique should also be considered as a potential tool to improve fast-track surgery strategies. Moreover, it could therefore be used for video laparoscopic procedures that require conversion to open surgery.
DISCLOSURES
Name: Sergio Bertoglio, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Sergio Bertoglio has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Fabio Fabiani, MD.
Contribution: This author helped conduct the study.
Attestation: Fabio Fabiani has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Pasquale DeNegri, MD.
Contribution: This author helped conduct the study.
Attestation: Pasquale De Negri has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Antonio Corcione, MD.
Contribution: This author helped conduct the study.
Attestation: Antonio Corcione has seen the original study data and approved the final manuscript.
Name: Franco Domenico Merlo, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Franco Domenico Merlo has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Ferdinando Cafiero, MD.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Ferdinando Cafiero has seen the original study data and approved the final manuscript.
Name: Clelia Esposito, MD.
Contribution: This author helped conduct the study.
Attestation: Clelia Esposito has seen the original study data and approved the final manuscript.
Name: Claudio Belluco, MD.
Contribution: This author helped design the study and conduct the study.
Attestation: Claudio Belluco has seen the original study data and approved the final manuscript.
Name: Davide Pertile, MD.
Contribution: This author helped conduct the study.
Attestation: Davide Pertile has seen the original study data and approved the final manuscript.
Name: Riccardo Amodio, MD.
Contribution: This author helped conduct the study.
Attestation: Riccardo Amodio has seen the original study data and approved the final manuscript.
Name: Matilde Mannucci, BSc.
Contribution: This author developed and validated the e-CRF and helped to analyze the data.
Attestation: Matilde Mannucci has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Valeria Fontana, BSc.
Contribution: This author helped to analyze the data.
Attestation: Valeria Fontana has seen the original study data and approved the final manuscript.
Name: Marcello De Cicco, MD.
Contribution: This author helped design the study and conduct the study.
Attestation: Marcello De Cicco has seen the original study data and approved the final manuscript.
Name: Lucia Zappi, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Lucia Zappi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Spencer S. Liu, MD.
a Mean VAS scores for CWI and CEI groups were computed without adjusting for the unequally spaced postoperative times at which pain was recorded. Cited Here
REFERENCES
1. Kehlet H. Surgical stress: the role of pain and analgesia. Br J Anaesth. 1989;63:189–95
2. Kehlet H, Jensen TS, Wolf CJ. Persistent postsurgical pain risk factors and prevention. Lancet. 2006;367:1618–25
3. Liu S. Anesthesia and analgesia for colon surgery. Reg Anesth Pain Med. 2004;29:52–7
4. Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM. Effects of intravenous patient-controlled analgesia with morphine:continuous epidural analgesia:and continuous three-inone block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg. 1998;87:88–92
5. Jayr C, Beaussier M, Gustaffson U, Leteurnier Y, Nathan N, Plaud B, Tran G, Varlet C, Marty J. Continuous epidural infusion of ropivacaine for postoperative analgesia after major abdominal surgery: comparative study with i.v. PCA. Br J Anaesth. 1998;81:887–92
6. Borgeat A, Tewes E, Biasca N, Gerber C. Patient-controlled interscalene analgesia with ropivacaine after major shoulder surgery: PCIA vs PCA. Br J Anaesth. 1998;81:603–5
7. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534–40
8. McGrath B, Elgendy H, Chung F, Kamming D, Curti B, King S. Thirty percent of patients have moderate to severe pain 24 hr after ambulatory surgery: a survey of 5,703 patients. Can J Anaesth. 2004;51:886–91
9. Rawal N. Postoperative pain treatment for ambulatory surgery. Best Pract Res Clin Anaesthesiol. 2007;21:129–48
10. Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103:1079–88
11. Werawatganon T, Charuluxanun S. Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2005;1:CD004088
12. Christie IW, McCabe S. Major complications of epidural analgesia after surgery: results of a six-year survey. Anaesthesia. 2007;62:335–41
13. Popping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, PogatzkiZahn EM. Effectiveness and safety of postoperative pain management: a survey of 18,925 consecutive patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. Br J Anaesth. 2008;101:832–40
14. Viscusi ER. Emerging techniques in the management of acute pain: epidural analgesia. Anesth Analg. 2005;101:S23–9
15. White P, Rawal N, Latham P, Markowitz S, Issiui T, Chi L, Dellaria S, Shi C, Morse L, Ing C. Use of a continuous local anesthetic infusion for pain management after medial sternotomy. Anesthesiology. 2003;99:918–23
16. Weathley GH, Rosenbaum DH, Paul MC, Dine AP, Wait MA, Meyer DM, Jessen ME, Ring WS, DiMaio JM. Improved pain management outcomes with continuous infusion of a local anesthetic after thoracotomy. J Thorac Cardiovasc Surg. 2005;130:464–8
17. Rawal N, Gupta A, Hesling M, Grell K, Allvin R. Pain relief following breast augmentation surgery: a comparison between incisional patient-controlled regional analgesia and traditional oral analgesia. Eur J Anaesthesiol. 2006;19:1–8
18. Bianconi M, Ferraro L, Ricci R, Zanolli G, Antonelli T, Giulia B, Guberti A, Massari L. The pharmacokinetics and efficacy of ropivacaine continuous wound instillation after spinal fusion surgery. Anesth Analg. 2004;98:166–72
19. Forastiere E, Sofra M, Giannarelli D, Fabrizi L, Simone G. Effectiveness of continuous wound infusion of 0.5% ropivacaine by OnQ pain relief system for postoperative pain management after open nephrectomy. Br J Anaesth. 2008;101:841–7
20. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of continuous wound catheters delivering local anesthetic for postoperative analgesia: a quantitative and qualitative systematic review of randomized controlled trials. J Am Coll Surg. 2006;203:914–32
21. Polglase AL, McMurrick PJ, Simpson PJ, Wale RJ, Carne PW, Johnson W, Chee J, Ooi CW, Chong JW, Kingsland SR, Buchbinder R. Continuous wound infusion of local anesthetic for the control of pain after elective abdominal colorectal surgery. Dis Colon Rectum. 2007;50:2158–67
22. Gupta A, Favaios S, Perniola A, Magnuson A, Berggren L. A meta-analysis of the efficacy of wound catheters for postoperative pain management. Acta Anaesthesiol Scand. 2011;55:785–96
23. Beaussier M, El’Ayoubi H, Schiffer E, Rollin M, Parc Y, Mazoit JX, Azizi L, Gervaz P, Rohr S, Bierman C, Lienhart A, Eledjam JJ. Continuous preperitoneal infusion of ropivacaine provides effective analgesia and accelerates recovery after colorectal surgery. Anesthesiology. 2007;107:461–8
24. Wang LW, Wong SW, Crowe PJ, Khor KE, Jastrzab G, Parasyn AD, Walsh WR. Wound infusion with local anaesthesia after laparotomy: a randomized controlled trial. ANZ J Surg. 2010;80:794–801
25. Chan SK, Lai PB, Li PT, Wong J, Karmakar MK, Lee KF, Gin T. The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery. Anaesthesia. 2010;65:1180–6
26. Beaussier M, El’Ayoubi H, Rollin M, Parc Y, Atchabahian A, Chanques G, Capdevila X, Lienhart A, Jaber S. Parietal analgesia decreases postoperative diaphragm dysfunction induced by abdominal surgery: a physiologic study. Reg Anesth Pain Med. 2009;34:393–7
27. Kehlet H, Liu SS. Continuous local anesthetic wound infusion to improve postoperative outcome. Anesthesiology. 2007;107:369–70
28. . American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74
29. Breen TW, Shapiro T, Glass B, Foster-Payne D, Oriol NE. Epidural anesthesia for labor in the ambulatory patient. Anesth Analg. 1993;77:919–24
30. Rackelboom T, Le Strat S, Silvera S, Schmitz T, Bassot A, Goffinet F, Ozier Y, Beaussier M, Mignon A. Improving continuous wound infusion effectiveness for postoperative analgesia after cesarean delivery: a randomized controlled trial. Obstet Gynecol. 2010;116:893–900
31. Manku SH, Horrobin DF. Chloroquine:quinine:procaine:quinidine:tricyclic antidepressants:and methylxanthines as prostaglandin agonists and antagonists. Lancet. 1976;2:1115–7
32. Sasagawa S. Inhibitory effects of local anesthetics on migration:extracellular release of lysosomal enzyme:and superoxide anion production in human polymorphonuclear leukocytes. Immunopharmacol Immunotoxicol. 1991;13:607–22
33. Lavand’homme PM, Roelants F, Waterloos H, Collet V, De Kock MF. An evaluation of the postoperative antihyperalgesic and analgesic effects of intrathecal clonidine administered during elective cesarean delivery. Anesth Analg. 2008;107:948–55
34. Brennan T, Zahn P, PogatzkiZahn E. Mechanism of incisional pain. Anesthesiol Clin North Am. 2005;23:1–20
35. Kahokehr A, Sammour T, Soop M, Hill AG. Intraperitoneal use of local anesthetic in laparoscopic cholecystectomy: systematic review and meta-analysis of randomized controlled trials. J Hepatobiliary Pancreat Sci. 2010;17:637–56
36. Kahokehr A, Sammour T, Shostari KZ, Taylor M, Hill AG. Intraperitoneal local anesthetic improves recovery after colon resection. Ann Surg. 2011;254:28–38
37. Wang SC, Chang YY, Chan KY, Hu JS, Chan KH, Tsou MY. Comparison of three different concentrations of ropivacaine for postoperative patient-controlled thoracic epidural analgesia after upper abdominal surgery. Acta Anaesthesiol Taiwan. 2008;46:100–5
38. Dagtekin O, Hotz A, Kampe S, Auweiler M, Warm M. Postoperative analgesia and flap perfusion after pedicled TRAM flap reconstruction: continuous wound instillation with ropivacaine 0.2%—a pilot study. J Plast Reconstr Aesthet Surg. 2009;62:618–25
39. Bleckner LL, Bina S, Kwon KH, McKnight G, Dragovich A, Buckenmaier CC III. Serum ropivacaine concentrations and systemic local anesthetic toxicity in trauma patients receiving longterm continuous peripheral nerve block catheters. Anesth Analg. 2010;110:630–4
