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* From the Departments of Anesthesiology,
Surgery, and
Center for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Address correspondence to: Dr. Ken Kardash, Anesthesia Department, Room A335, SMBD-Jewish General Hospital, 3755 Cote Ste. Catherine, Montreal, Quebec H3T 1E2, Canada. Phone: 514-340-8222, ext. 5701; Fax: 514-340-8108; E-mail: kenneth.kardash{at}mcgill.ca
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Abstract |
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Methods: This randomized, double-blind trial studied 40 men undergoing elective inguinal hernia repair under spinal anesthesia. All patients received 19 mL of lidocaine 1% infiltrated in the operative field before incision. Patients were randomized into two groups of 20. The surgical site group received ketorolac 30 mg added to the lidocaine infiltration. In the control group, ketorolac 30 mg was injected subcutaneously in the contralateral abdominal wall. Numeric rating scores (0–10) of pain at rest and with movement were recorded at the time of discharge from the recovery room and at 24 hr postoperatively. Time to first analgesia, postoperative iv morphine use, total time in the recovery room, and total oral analgesic use in the first 24 hr were also compared.
Results: There were no significant differences between groups with respect to any of the measured variables. In both groups, pain scores were low at rest (1.9 ± 1.4 vs 2.2 ± 1.8, surgical site and systemic groups, respectively) and moderate with movement (5.3 ± 2.2, 5.0 ± 1.8) after anesthetic recovery. Pain scores were similar at 24 hr (1.1 ± 1.3, 1.9 ± 1.6 at rest; 5.7 ± 2.0, 6.2 ± 2.2 with movement).
Conclusion: Adding ketorolac to lidocaine infiltration for hernia repair does not improve or prolong postoperative analgesia compared to systemic administration.
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Introduction |
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Inguinal hernia repair continues to be one of the most painful ambulatory surgeries, with almost half of patients reporting moderate to severe pain 24 hr later.7 At our institution, outpatient hernia repair is performed routinely under spinal anesthesia with local anesthetic wound infiltration to optimize postoperative analgesia. We sought to determine if peripheral administration of ketorolac would improve analgesia in this setting. Our primary interest was to test pain relief outcomes at 24 hr, because of the practical benefit this would have in simplifying ambulatory analgesia.
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Methods |
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Patients were prospectively randomized using blocks of four into two treatment groups. In the surgical site group, 1 mL of ketorolac 30 mg•mL–1 (Sabex 2002 Inc., Boucherville, QC, Canada) mixed with 19 mL of lidocaine 1% was infiltrated in the operative field by the surgeon before incision, and 1 mL of saline was injected subcutaneously in the contralateral abdominal wall. In the systemic control group, 1 mL of saline was mixed with the 19 mL of 1% lidocaine for pre-incisional infiltration, and 1 mL of ketorolac 30 mg was given subcutaneously on the contralateral side. All study drugs were prepared by the pharmacy in advance in a sterile fashion and stored at room temperature until use. Ketorolac has been shown to be stable when mixed with lidocaine for at least one week at 37°C.8
Intraoperatively, all patients received iv normal saline. Standard anesthetic monitoring was employed. Spinal anesthesia was performed in the sitting or decubitus position at the mid-lumbar level using a 27-gauge Whitacre needle. Hyperbaric bupivacaine 9 mg with fentanyl 10 µg were administered and the patient immediately laid supine. Infiltration of study drugs at the surgical site was achieved using 25-gauge Quincke-tipped spinal needles. Contralateral 1 mL injections were made using a 25-gauge hypodermic needle (all needles from BD Medical Systems, Franklin Lakes, NJ, USA). No opioids were given before or during surgery. At the discretion of the attending anesthesiologist, propofol in incremental doses of 20 mg was given for sedation during the procedure. Duration of surgery was defined as time from incision until arrival in the recovery room.
Postoperative pain in the recovery room was treated with morphine 2 mg iv every five minutes prn, based upon nurses’ assessment. At discharge, patients received a prescription for oxycodone 5 mg with acetaminophen 325 mg, one or two tablets every four hours prn, and were asked to record the total number of tablets taken. Arrangements were made in advance for a telephone follow-up at 24 hr. An 11-point numeric rating scale (NRS) was used by the anesthesiologist to assess postoperative pain intensity (0 = none, 10 = worst imaginable) at discharge from the recovery room and at 24 hr postoperatively. At both time points, NRS was assessed both at rest and with movement (standing up).
The primary outcome was pain intensity with movement at 24 hr. Secondary measures of analgesia were: time to first analgesic dose (TTFA), as measured from the beginning of surgery; total dose of iv morphine administered in the recovery room; pain intensity at recovery room discharge; pain at rest at 24 hr and total number of oral analgesic tablets used in the first 24 postoperative hours. Duration of stay in the recovery room until discharge criteria were met (pain controlled, ability to tolerate oral fluids, stand unassisted, micturate) was also recorded. The surgeon, anesthesiologists and nurses were all blinded to the study groups.
Statistical analysis
We compared study group variables during recovery room stay and at 24 hr after surgery. Descriptive statistics were used to evaluate the characteristics of treatment groups (e.g., age, weight, height and surgery duration) and study outcomes. The results were examined with both univariate and multivariate analyses. The multivariate analysis adjusted for the putative confounding effects of age, weight, height, and duration of surgery. The difference between group means and the 95% confidence interval (CI) were calculated for each variable. The analysis of each study outcome was performed using the SAS general linear model procedure. Statistical significance was defined as P < 0.05. All tests were performed using the Statistical Applications Software of the SAS Institute, version 8.2 (Cary, NC, USA).
For the sample size calculation, a significant outcome was defined as a difference between groups in mean NRS pain score with movement at 24 hr of 1.6, with a standard deviation of 1.6. These figures were based on results of a previous study.6 Using Power and Sample Size Calculator, version 1.0.15 (Nashville, TN, USA), for an 
of 5% and power of 80%, a sample size of 40 (n = 20/group) was sufficient to find such an outcome difference, if it existed.
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Results |
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. At discharge and 24 hr postoperatively, patients experienced pain that was mild at rest and moderate with movement. The site of ketorolac administration had no significant effect on pain scores. There were no differences between groups with respect to any other outcome variables: TTFA, iv morphine consumption, time in the recovery room or oral analgesic use in the first 24 hr. After multivariate analysis to control for the possible combined confounding effects of age, weight, height, and duration of surgery, the findings were unchanged.
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One patient in the operative site ketorolac group developed a small scrotal hematoma while in the postanesthesia care unit and was admitted to hospital overnight for observation. He was discharged the next morning without requiring further intervention. No wound hematoma was observed in either group.
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Discussion |
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Ben-David et al.5 found ketorolac 30 mg intra-wound as effective as infiltrating 20 mL bupivacaine 0.25%, and more effective than 60 mg im in reducing pain scores during the first 24 hr postoperatively. In that trial, infiltrations were performed at the end of surgery under general anesthesia, and there were only eight patients per treatment group, with no other analgesics administered intraoperatively. The systemic ketorolac was administered by deltoid im injection, without a placebo control. It is possible that this may have unblinded their study to recovery room observers. In a subsequent trial,9 the same investigators found no difference between intrawound, im or iv administration in analgesia 90 min after surgery using combined field block and general anesthesia. In that series, the systemic groups were placebo-controlled, each group contained 14 patients and infiltration was performed preoperatively with 50% more local anesthetic volume.
Connelly et al.6 studied 30 hernia repairs performed under local anesthesia using 1% lidocaine with epinephrine. They found that ketorolac 60 mg infiltrated in the wound significantly decreased analgesic requirements and pain on movement at 24 hr postoperatively compared to the same dose given in a double-blind manner intravenously. However, the group receiving ketorolac injected in the wound also received significantly more supplemental lidocaine infiltration.
Intramuscular ketorolac reaches peak systemic levels almost one hour later than an iv dose.10 This delay in systemic effect may have presented a significant bias to positive results when an iv control group was compared. Although ketorolac absorption kinetics from a surgical wound are unknown, we feel that a control injection in corresponding contralateral tissue provided a reasonable comparison, because of similar tissue vascularity.
The dose of ketorolac (30 mg) evaluated in our study was half that used in one trial reporting effects at 24 hr,6 but similar results were claimed for 30 mg in another.5 Since these reports, the recommended parenteral dose of ketorolac for postoperative analgesia has been lowered to 30 mg in the United States and 10 mg in the United Kingdom.11
It has been suggested that clinical studies of analgesia require a placebo control group to accurately quantitate drug effects.12 However, ketorolac has already been shown to improve analgesia and reduce opioid requirements postoperatively when given by a variety of parenteral routes.3,4,13 Our objective was to test claims of enhanced efficacy of the same ketorolac dose when added to local anesthetic infiltration. We felt it was neither necessary nor ethical to include a placebo group, since NSAIDs are part of our routine postoperative analgesia regimen.
There is concern from the perspective of study design that the combination of spinal bupivacaine-fentanyl and local lidocaine may have produced analgesia of sufficient duration to overwhelm any effect of the ketorolac. However, the mean time to first analgesic request in our patients (315 ± 176 min) was not significantly different from that of patients undergoing hernia surgery with local anesthesia and iv ketorolac (379 ± 177 min) in another trial.6 In that study, as in ours, there were no differences in pain scores in the recovery room. In any case, our primary goal was to examine the effect on movement-associated pain at 24 hr reported by others.5,6 Shorter-term differences which may have existed before surgical analgesia dissipated (median of approximately five hours in both groups) are clinically moot. Only those effects beyond the immediate recovery period would confer a practical advantage to ketorolac infiltration over repeated systemic dosing. Our results are consistent with clinical experience that a single dose of ketorolac by traditional systemic routes does not provide significant analgesia 24 hr later.11
Local ketorolac infiltration has potential disadvantages. One is that the alcohol diluent may be irritating to tissues.6 The occurrence of a scrotal hematoma in the study group raised the concern of a local antiplatelet effect, a well-documented side effect of systemic NSAIDs.14 However, no hematomas at the site of injection were observed.
In summary, the results of our study do not disprove a peripheral mechanism of NSAID analgesia. However, our findings do suggest there is no clinical advantage to adding ketorolac to local anesthetic infiltration compared to systemic administration for postoperative analgesia.
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Acknowledgments |
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Footnotes |
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Accepted for publication December 1, 2004. Revision accepted February 19, 2005.
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References |
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2 Lundell JC, Silverman DG, Brull SJ, et al. Reduction of postburn hyperalgesia after local injection of ketorolac in healthy volunteers. Anesthesiology 1996; 84: 502–9.[Medline]
3 Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular bupivacaine and ketorolac. Anesth Analg 1995; 80: 1154–7.[Abstract]
4 Reuben SS, Steinberg RB, Kreitzer JM, Duprat KM. Intravenous regional anesthesia using lidocaine and ketorolac. Anesth Analg 1995; 81: 110–3.[Abstract]
5 Ben-David B, Katz E, Gaitini L, Goldik Z. Comparison of i.m. and local infiltration of ketorolac with and without local anaesthetic. Br J Anaesth 1995; 75: 409–12.
6 Connelly NR, Reuben SS, Albert M, Page D. Use of preincisional ketorolac in hernia patients: intravenous versus surgical site. Reg Anesth 1997; 22: 229–32.[Medline]
7 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 Anesth 2004; 51: 886–91.
8 Reinhart DJ, Stagg KS, Walker KG, et al. Postoperative analgesia after peripheral nerve block for podiatric surgery: clinical efficacy and chemical stability of lidocaine alone versus lidocaine plus ketorolac. Reg Anesth Pain Med 2000; 25: 506–13.[Medline]
9 Ben-David B, Baune-Goldstein U, Goldik Z, Gaitini L. Is preoperative ketorolac a useful adjunct to regional anesthesia for inguinal herniorraphy? Acta Anaesthesiol Scand 1996; 40: 358–63.[Medline]
10 Jung D, Mroszczak E, Bynum L. Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration. Eur J Clin Pharmacol 1988; 35: 423–5.[Medline]
11 Sweetman SC. Martindale. The Complete Drug Reference, 33rd ed. London: Pharmaceutical Press; 2002: 49.
12 Kalso E. Better standardisation will improve the quality of analgesic studies. Acta Anaesthesiol Scand 1996; 40: 397–8.[Medline]
13 Gillies GW, Kenny GN, Bullingham RE, McArdle CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 42: 727–31.[Medline]
14 Marret E, Flahault A, Samama CM, Bonnet F. Effects of postoperative, nonsteroidal, anti-inflammatory drugs on bleeding risk after tonsillectomy. Meta-analysis of randomized, controlled trials. Anesthesiology 2003; 98: 1497–1502.[Medline]
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