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Intraoperative wound infiltration with bupivacaine in patients undergoing lumbar spine surgery
Intraoperative wound infiltration with bupivacaine in patients undergoing lumbar spine surgery
T i m o t h y S t e e p FRACS, R o b e r t Jones 2 FRCS, John C r o s s m a n 3 FRCS, John S h e e h y 1 FRACS, P e t e r B e n t i v o g l i o ~ FRACS, M a l c o l m PelP FRACS 1Department of Neurosurgery, St Vincent's Hospital, Sydney,Australia 2Department of Neurosurgery, Sydney Children's Hospital, Sydney,Australia, 3Department of Surgical Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
We conducted a randomized double-blind trial to evaluate the effect o f intraoperative wound infiltration with bupivacaine 0.25% (1 m l / k g ) c o m p a r e d to placebo (NaCI 0.9% 1 m l / k g ) in patients undergoing lumbar spine surgery. Fifty-two patients were entered in the trial and 50 completed it. Two methods o f wound infiltration were assessed: (a) infiltration after partial wound closure and (b) infiltration prior to wound closure. Postoperatively patients received morphine sulfate o n demand. Visual analog pain scores were r e c o r d e d every 2 h for 12 h after the operation. Analgesia requirements were r e c o r d e d over the duration o f the study for each patient. The patients who received bupivacaine infiltration prior to wound closure had significantly reduced pain scores in the recovery r o o m and used significantly less morphine in the first 2 h following the procedure. They also had r e d u c e d pain scores and r e d u c e d morphine demand in the first 10 h but this did not reach statistical significance. No difference was n o t e d between the placebo group and those receiving infiltration after partial wound closure. It is concluded that infiltration o f bupivacaine is a simple and safe aid in obtaining analgesia in patients undergoing lumbar spine surgery provided that it is infiltrated prior to wound closure. Journal of Clinical Neuroscience 1998, 5(3): 298-303
© Harcourt Brace & Co. Ltd 1998
Keywords: lumbar laminectomy, bupivacaine, wound infiltration, postoperative analgesia
Introduction Perioperative local anesthetic infiltration of surgical wounds as an adjunct to standard postoperative analgesia is a c o m m o n practice employed by many surgeons. Multiple studies have detailed the use of bupivacaine in abdominal procedures such as cholecystectomy>a, hernia repair 4-9 and hysterectomy) °al Orthopedic procedures 12-14 and traumatic lacerations 15 have also been studied. These studies have been conflicting in their findings with some demonstrating benefits to the patient 2,8,10,12,14 while others r e p o r t no significant reduction in postoperative pain levels or in postoperative analgesic c o n s u m p t i o n ) '3,n Postoperative analgesia following lumbar spinal surgery remains a problem which is distressing for the patient and hinders early mobilization. In an effort to reduce this discomfort many spine surgeons infiltrate long acting anaesthetics such as bupivacaine into the subcutaneous tissues and paraspinal musculature prior to or following the surgery. Despite this widespread practice the only trials r e p o r t e d on the use of bupivacaine infiltration and lumbar spine surgery have shown no benefit to the patient. 16,17 Only three reports have been published detailing bupivacaine infiltration (BVI) in spine surgery) 6-18 T h e first description is a technical note which claimed that
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the infiltration of 50 ml of 0.25% bupivacaine into the paravertebral musculature at the conclusion of the operation resulted in a 'marked reduction of postoperative pain following lumbar disc surgery'38 However, a subseq u e n t randomized trial f o u n d no significant difference between BVI and a placebo infiltration of saline. 17A subsequent study on the use of corticosteroids and local anesthetic infiltration also showed no significant benefit for the use of BVI alone. 16 Because of the widespread nature of this practice and its uncertain therapeutic value we decided to evaluate the efficacy of bupivacaine infiltration of the paraspinal musculature in a prospective randomized double-blind study.
Methods All patients undergoing lumbar spine surgery for lumbar disc prolapse or lumbar canal stenosis at St Vincent's public hospital between April 1993 and December 1993 were considered for the study. Any patient who had had previous lumbar spine surgery was excluded, as were patients in whom decompression was planned at more than two levels. Four patients were excluded because of language difficulty. Fifty-two patients were enrolled into the study.
Bupivacaine in lumbar surgery Approval for the study was obtained f r o m the hospital ethics committee. I n f o r m e d consent was obtained for the e x p e r i m e n t a l p r o c e d u r e f r o m each patient on the evening prior to surgery at the time of obtaining the surgical consent. T h e use of the 10 cm visual analogue scale (VAS) was d e m o n s t r a t e d to the patients at the time of obtaining the consent. T h e VAS was of the standard form a t and a separate scale was used for each patient. TM A score of '0' indicated no pain, '1' r e p r e s e n t e d a slight a m o u n t of back pain and '10' was the 'worst pain imaginable'. T h e patient was specifically requested to indicate that the pain r e f e r r e d to was back pain, rather than pain f r o m any other sources postoperatively. Unlabelled, serially n u m b e r e d vials of test solution were allocated to each patient. These were supplied by Astra Pharmaceutical C o m p a n y (Sweden) and contained either Marcain 0.25% (bupivacaine hydrochloride) or sterile normal saline as a placebo. The randomization code was kept by the Pharmacy D e p a r t m e n t of St Vincent's Hospital and at Astra Pharmaceuticals office in Sydney, and was not accessed during the period of the study. All patients received a standard p r e m e d i c a t i o n of narcotic based on the patient's weight ' o n call' to the operating room. Anesthesia was induced with thiopental 3.0 m g / k g and m a i n t a i n e d with nitrous oxide (67%) in oxygen and h a l o g e n a t e d inhalational agents. All patients h a d surgery p e r f o r m e d u n d e r the direction of one of three consultant surgeons. Each patient had a standard exposure of the l u m b a r region involving bilateral subperiosteal muscle dissection. At the conclusion of each operation 1 m l / k g of the test solution was infiltrated widely into the subcutaneous tissues and into the paraspinal musculature. T h e dose of bupivacaine administered for each patient was 2.5 m g / k g . Initially, for the first 28 patients, this infiltration was p e r f o r m e d after closure of the lumbodorsal fascia after the w o u n d drain h a d b e e n placed. However, the drain was noticed to aspirate variable a m o u n t s of the test solution indicating that some infiltrate was not reaching the tissues but rather entering the w o u n d cavity. Subsequently for the r e m a i n i n g 24 patients the infiltration was carried out into the subcutaneous tissues and paraspinal musculature with the w o u n d retractors still in place, prior to the c o m m e n c e m e n t of the w o u n d closure. All patients had a w o u n d drain inserted. A standard layered closure and skin staples were used in all patients. All patients were provided with postoperative analgesia of intramuscular m o r p h i n e at a dose of 1 mg p e r 10 kg of body mass every 3 h on a d e m a n d basis. No patient received any o t h e r f o r m of analgesia in the first 12 h postoperatively. Every patient had their initial pain score r e c o r d e d by the principal investigator (TS) in the recovery r o o m as soon as the patient b e c a m e coherent. This was designated ' T i m e 0'. Pain levels were then r e c o r d e d by the nursing staff of the neurosurgical ward every 2 h for 12 h. Opiate doses and time of administration were also r e c o r d e d for 12 h postoperatively. At the time of the operation the sex, age a n d weight of the patient was recorded. T h e n u m b e r of levels o p e r a t e d upon, a n d whether the patient received a discectomy or
Clinical studies posterior decompression alone was also recorded. T h e size of the w o u n d was designated as small if the incision was less than 5 cm, m e d i u m if it was between 5 and 10 cm and large if it was greater than 10 cm in length. These factors were separately analyzed to ensure h o m o g e n e i t y of each g r o u p and to ensure that these separate factors were not influencing the pain levels r e c o r d e d postoperatively.
Results Fifty-two patients were initially enrolled in the study; there were 29 males and 23 females with a m e a n age of 56.5 years. Twenty-eight patients had a lumbar discectomy while 24 had posterior decompression alone. Seventeen of these were at a single level while seven were p e r f o r m e d at two spinal levels. Two patients were subsequently excluded. O n e patient, an elderly female, was initially confused postoperatively and another had respiratory difficulties in the immediate postoperative period rendering their data invalid. Fifty patients were available for analysis. Twenty-five patients received the placebo (normal saline) and 25 patients received bupivacaine. O f those receiving BVI, 13 were infiltrated after partial wound closure and 12 received infiltration prior to wound closure while the retractors were still in place. Data were analyzed in three groups: Group I received placebo, Group 2 received BVI after partial wound closure and Group 3 received BVI before c o m m e n c i n g the wound closure. Statistical analysis was p e r f o r m e d using multivariate r e p e a t e d measures analysis of variance (ANOVA) and linear progression. A P-value of less than 0.05 was considered statistically significant. Groups 1, 2 and 3 were f o u n d to be well m a t c h e d statistically. T h e r e was also no significant difference between the three groups of patients in the n u m b e r of levels o p e r a t e d on, the size of the incision, or n u m b e r of patients u n d e r g o i n g discectomy versus decompression alone. T h e average age of the placebo g r o u p was 56.2 years. T h e r e was a slight difference in the ages of the two groups who received BVI (Fig. 1). This difference a p p r o a c h e d statistical significance b u t did not attain it (P = 0.08). In the recovery r o o m at time zero the patients who h a d received BVI prior to w o u n d closure (Group 3) r e p o r t e d an average visual analog pain score of 3.1; this is a greater than 50% reduction in pain scores c o m p a r e d to the o t h e r two groups. T h e patients who received BVI after partial w o u n d closure (Group 2) r e p o r t e d an average pain score of 6.3 while the patients who received the placebo infiltration r e p o r t e d an average pain score of 7.1 (Fig. 2). At 2 h following the p r o c e d u r e there was no difference in the pain scores r e c o r d e d for the three test groups. From 4-8 h G r o u p 3 patients showed a significant reduction in aggregate VAS scores (P = 0.01). Beyond 8 h there was no benefit to BVI (Fig. 2). T h e administration of m o r p h i n e sulfate over the 12 h was separately analyzed. In the first 2 h the placebotreated g r o u p required an average of 9.5 mg; the G r o u p 2 patients received an average of 12.3 m g and g r o u p 3 patients required only 7.0 mg. This difference was statistically significant (P< 0.05) (Fig. 3).
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70.
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Mean age of the three groups. Placebo treated with 0.9% NaCl, Groups 2 and 3 treated with bupivacaine infiltration.
• Placebo 7
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~2 1
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Mean pain scores for the three groups over the 12 h of the study.
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Fig. 3
Mean morphine sulfate use over the 12 h of the study with the first 2 h shaded.
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Group 3
Bupivacaine in lumbar surgery Over the total 12 h of the study, the Group 3 patients used less morphine, 17.3 mg, than either of the two other groups; however, this did not quite gain statistical significance (P= 0.06). The placebo treated group used a total average of 24.4 mg m o r p h i n e while the bupivacaine treated Group 2 used 26.5 mg (Fig. 3). Separate analysis of patient age and sex to the pain scores and to m o r p h i n e sulfate administration was performed. T h e r e was no difference in pain scores between males and females; n o r was there a difference based on patient age. Patients with larger body mass used more m o r p h i n e and these t e n d e d to be the younger patients, as one would expect, but there was no significant difference between the patients' pain scores. T h e r e was no difference in either the pain scores or m o r p h i n e sulfate administration when separate analysis of wound size, n u m b e r of levels decompressed, or discectomy versus posterior decompression was performed; the only significant variable was the administration of BVI prior to the wound closure.
Discussion The first description of BVI in the lumbar spine was in 1979 by Mullen and Cook. .8 They described infiltration of 50 ml of 0.25% plain bupivacaine into the paravertebral musculature after closure of the lumbar fascia in an uncontrolled study of 18 consecutive patients undergoing lumbar disc surgery. A 'substantial reduction' in postoperative pain levels was r e p o r t e d but the authors did not quantify their results. Interestingly out of 21 procedures p e r f o r m e d on their 18 patients only two patients requested a single dose of narcotic for 'transient radicular pain'. No other analgesics were used or requested by any other patient in the study. They suggested that a prospective trial should be performed. Teddy and colleagues subsequently r e p o r t e d a blinded trial of 46 patients in which each patient received 40 ml of 0.25% bupivacaine hydrochloride or normal saline into the subcutaneous tissue and paravertebral muscles at the completion of the p r o c e d u r e ) 7 This study f o u n d no significant difference in the pain scores between their two groups for the duration of their study. Although they f o u n d a marked reduction in postoperative analgesic d e m a n d (75%) in the BVI-treated group in the initial 2 h following the surgery, they concluded that bupivacaine was ineffective in reducing postoperative pain and did not r e c o m m e n d it as routine practice. Glaser and colleagues in 1993 reported a study on the use of perioperative corticosteroids and bupivacaine in the m a n a g e m e n t of 32 patients undergoing lumbar microdiscectomy) 6 Patients received either 6 0 m l of 0.25 % bupivacaine with 1:200 000 adrenaline infiltration, or BVI combined with both local and systemic corticosteroids (methylprednisolone sodium succinate and methylprednisolone acetate). A third group, who received preoperative subcutaneous infiltration of 10 ml of 0.5% lidocaine with 1:100 000 adrenaline, served as a control group. Mean hospital stay was reduced to fewer than 2 days in the group receiving local anesthetic and methylprednisolone. This group averaged only 2.6
Clinical studies requests for pain medication in the first 24 postoperative h compared to 4.9 and 5.0 for the other two groups. However, they found no difference between the groups treated with BVI alone and the control group. They concluded that high dose corticosteroids enabled a more rapid discharge from hospital but that the local anesthetic infiltration by itself did not significantly alter the outcome. This study was not double-blinded and the allocation of the adjuvant therapy was made intraoperatively by the operating surgeons. This is not fully explained in the report and we are not informed on what basis the intraoperative decision was made. Unwitting treatment bias at the time of operation or in the methods of obtaining patient discharge may have influenced the results of such a small study. The authors made no attempt to quantify the pain levels experienced by their patients in the early postoperative period. A questionnaire was given to the patients following their discharge from hospital asking them to rate their back pain and radicular pain as being completely relieved, partially relieved or not relieved at 1 day, 1 week and 1 m o n t h following the surgery. Given this m e t h o d of assessment we believe that the authors cannot draw accurate conclusions on the efficacy ofperioperative bupivacaine infiltration. Our study is the first to show a significant difference in postoperative pain scores using intraoperative BVI for lumbar spine surgery. Our protocol leads to a greater than 50% reduction in back pain levels in the immediate postoperative period. We have also shown a reduction in postoperative analgesia requirements in the first 2 h following operation. We have also seen a trend towards lower pain scores and reduced opiate requirements over the first 8 h of the recording; however, our study lacks the statistical power to confirm this as significant. The alteration in our infiltration technique, while reducing the statistical power of our study, has demonstrated that the timing of BVI is important in obtaining its effect. No benefit was found in patients who received their infiltration after the wound was partially closed with the drain in place. Direct infiltration into the musculature and tissues prior to c o m m e n c i n g the wound closure was n e e d e d to attain the benefit to the patient. Some surgeons infiltrate surgical wounds after closure has been completed; however, this study indicates that patients derive little or no benefit from this practice. The previously published studies did not demonstrate any benefit to local anesthetic wound infiltration following lumbar spine surgery. Our protocol used higher doses than in previous studies. At 1 ml per kg body mass, the patients received between 60 and 110 ml of infiltrate (0.25% bupivacaine). In the original description of the technique by Mullen, a total of only 50 ml of bupivacaine 0.25% was used on all patients. TM In the trial reported by Teddy and colleagues only 40 ml was administered. ~7 In the study reported by Glaser and colleagues a total of 60 ml was administered. 16 The doses used in these previous studies may have been insufficient to provide a benefit to the patients. The duration of analgesia for bupivacaine has been r e p o r t e d to be 6-18 h for intercostal blocks, and 8-18 h
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Clinical studies for femoral and brachial plexus nerve blocks; 15yet in our study the majority of the benefit was lost 2 h after the procedure. It is possible that the relatively high blood flow in the paraspinal musculature is responsible for relatively rapid absorption of plain bupivacaine, leading to a shorter duration of action. The addition of adrenaline to bupivacaine prolongs the analgesic effect by causing local vasoconstriction, thereby reducing the speed of systemic absorption) 4 In some studies systemic levels of bupivacaine have been measured to assess the speed of absorption. 5'9 This was not p e r f o r m e d in our study and further studies comparing bupivacaine with adrenaline, and plain bupivacaine alone would n e e d to be p e r f o r m e d to assess if this provides a longer duration of action. The serum level of bupivacaine is also important in light of reports of seizure activity and cardiac arrhythmia in patients receiving epidural and peripheral nerve blocks. 15Bupivacaine may produce toxic effects at plasma concentrations greater than 4 g g / m l although the rate of increase of plasma concentration is also thought to be an important factor. 9 In situations where adverse effects have occurred, it is believed that inadvertent intravascular injection of the bupivacaine has been responsible) 5 This underscores the importance of keeping the tip of the needle moving while infiltrating. In studies where serum levels of bupivacaine have been measured, doses of 1.25 m g / k g administered via subcutaneous infiltration led to peak serum concentrations of only 0.36 g g / m l , well below the toxic threshold of 4 g g / m l . 9 No patients in our study experienced any adverse effects attributable to the infiltration. The use of a double-blind placebo-controlled trial is a valid design for this study; however, it creates potential problems. By using 0.9% NaC1 solution as the placebo we are assuming that it is an inert substance in relation to nociception. However, no prospective randomized study has evaluated the effect of NaC1 infiltration alone on postoperative pain. TM Wound infiltration with normal saline may have an analgesic effect due to the dilution of inflammatory substances released at the site of the incision. This would reduce the apparent benefit of the bupivacaine infiltration. On the other hand the saline infiltration may worsen wound pain in which case any apparent benefit to the bupivacaine infiltration would be misleading. Further studies are n e e d e d to clarify this point. In many reported series of wound infiltration in various surgical disciplines, BVI is p e r f o r m e d at the conclusion of the procedure. TM It has been postulated that local analgesia administered following a surgical p r o c e d u r e will only be effective briefly and that pain levels will rise rapidly in the postoperative period. 2° Recent findings suggest that sensory signals generated by tissue damage during surgery can trigger a prolonged state of increased excitability in the central nervous system, z° This is due to a lowering of the threshold of nociceptor afferents in the periphery, as well as an increase in the excitability of spinal neurons. Central sensitization occurs in response
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Bupivacaine in lumbar surgery to the initial painful stimulus and is then maintained by the inflammatory changes in the tissues postoperatively. Therefore, the optimal form of pain treatment for surgical procedures would be 'pre-emptive' applied both prior to and during the operation itself. 11'2°This has been advocated as the most efficacious m e t h o d of p e r f o r m i n g wound infiltration, z° For this reason many surgeons infiltrate the dermis prior to p e r f o r m i n g the initial skin incision. Some spine surgeons infiltrate the lumbar musculature and proposed d o n o r graft sites as well as the subcutaneous tissues prior to p e r f o r m i n g the skin incision. This was not p e r f o r m e d in this series of patients due to concern over infection risk by the consultant surgeons. One study has demonstrated that pre-incisional w o u n d infiltration with lignocaine is s u p e r i o r to postincisional infiltration. 21 However, other studies examining the pre-emptive effect of wound infiltration with lignocaine have been inconclusive, l°,n Only two studies have specifically looked at the difference between preoperative and postoperative wound infiltration in patients receiving bupivacaine following surgical p r o c e d u r e s ) 1,12 In one study, patients undergoing abdominal hysterectomy received BVI either 15 min prior to the skin incision or at the completion of the procedure. 1~ Neither group demonstrated any significant reduction in pain scores when measured every 4-8 h postoperatively when c o m p a r e d to the untreated control group that did not receive wound infiltration. By looking at the results of our own study it is likely that the majority of any benefit would have been seen in the first 4 h, prior to the first recordings of pain scores. Given the theoretical benefits of pre-incision infiltration and the addition of adrenaline to the infiltrate, further trials are indicated to ascertain how to attain the maximal benefits of bupivacaine wound infiltration.
Conclusion The findings of the study show that perioperative infiltration of the subcutaneous tissues and paraspinal musculature in lumbar spine surgery is a safe and effective m e t h o d of providing postoperative analgesia in the immediate postoperative period. Providing it is infiltrated prior to wound closure bupivacine can reduce patient pain scores by more than 50% in the recovery r o o m and can reduce analgesic requirements in the early postoperative period.
Acknowledgments The authors would like to thank Professor R. Gibberd for assistance with the statistical analysis and Sr Alison Kent for assistance with the data collection and preparation of the manuscript. The blinded trial preparation was produced and delivered by Astra AB, Sodertaje, Sweden. Received11 August 1995; Accepted 17 March 1997
Correspondence and offprint requests: Mr M. Pell, Suite 704, St Vincent's Clinic, 438 Victoria Street, Darlinghurst, Sydney, NSW 2021, Australia, Tel: 61 02, 9332 6754, Fax: 61 02 9332 6761
Bupivacaine in lumbar surgery References 1. Adams WJ, AuramovicJ, Barraclough BH. Wound infiltration with 0.25% bupivacaine not effective for postoperative analgesia after cholecystectomy. Aust NZJ Surg 1991; 61 (8): 626-630. 2. Moss G, Regal ME, Lichtig L. Reducing postoperative pain, narcotics and length of hospitalization. Surgery 1986; 99(2): 206-210. 3. Van Raay~J, RoukemaJA, Lenderink BW. Intraoperative wound infiltration with bupivacaine in patients undergoing elective cholecystectomy. Arch Surg 1992; 127(4): 457-459. 4. Cross GD, Barrett RF. Comparison of two regional techniques for postoperative analgesia in children following herniotomy and orchidopexy. Anesthesia 1987; 42: 845-849. 5. Kastrissios H, Triggs EJ, Sinclair F, Motran P, Smithers M. Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study. EurJ Clin Pharmacol 1993; 44 (6): 555-557. 6. LangerJL, Shandling B, Rosenberg M. Intraoperative bupivacaine during outpatient hernia repair in children. A randomized double blind trial. J Pediatr Surg 1987; 22(3): 267-270. 7. Levack ID, HolmesJD, Robertson GS. Abdominal wound perfusion for the relief of postoperative pain. BrJ Anaesth 1986; 58: 615-619. 8. McLoughlinJ, Kelley CJ. Study of the effectiveness of bupivacaine infiltration of the ilioinguinal nerve at the time of hernia repair for postoperative pain relief. BrJ Clin Pract 1989; 43(8): 281-283. 9. Mobley KA, WandlessJG, Fell D. Serum bupivacaine concentrations following wound infiltration in children undergoing inguinal herniotomy. Anesthesia 1991; 46 (6): 500-501. 10. Hannibal K, Galatius H, Hansen A, Obel E, Ejlersen E. Preoperative wound infiltration with bupivacaine reduces early and late opioid requirements after hysterectomy. Anaesth Analg 1996; 83 (2): 376-381.
Clinical studies 11. Victory RA, Gajraj NM, Van-Elstraete A, Pace NA, Johnson ER, White PE Effect of preincision versus postincision infiltration with bupivacaine on postoperative pain. J Clin Anaesth 1995; 7 (3): 192-196. 12. Bourne MH, Johson KA. Postoperative pain relief using local anesthetic instillation. Foot Ankle 1988; 8: 350-351. 13. Edwards ND, Wright EM. Continuous low-dose 3-in-1 nerve blockade for postoperative pain relief after total knee replacement. Anesth Analg 1992; 75: 265-267. 14. Todd BD, Reed SC. The use of bupivacaine to relieve pain at iliac graft donor sites. Int Orthop 1991; 15: 53-55. 15. Spivey WH, McNamara RM, MacKenzie RS, Bhat S, Burdick WP. A clinical comparison of lidocaine and bupivacaine. Ann Emerg Med 1987; 16: 752-757. 16. Glasser RS, Knego RS, DelashawJB, Fessler RG. The perioperative use of corticosteroids and bupivacaine in the management of lumbar disc disease. J Neurosurg 1993; 78: 383-387. 17. Teddy PJ, Fabinyi GCA, KerrJH, Briggs M. Bupivacaine infiltration after lumbar laminectomy. Anesthesia 1981; 36: 380-383. 18. MullenJB, Cook WA. Reduction of post-operative lumbar hemi-laminectomy pain with Marcain. Technical note. J Neurosurg 1979; 51: 126-127. 19. Revill SI, RobinsonJO, Rosen M, Hogg MIJ. The reliability of a linear analogue for evaluating pain. Anesthesia 1976; 31: 1191-1198. 20. Woolf CJ, Chong MS. Pre-emptive analgesia-treating postoperative pain by preventing the establishment of central sensitization. Anaesth Analg 1993: 77: 362-379. 21. Ejlersen E, Andersen HB, Eliasen K, Mogensen T. A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain. Anesth Analg 1992; 74: 495-498. 22. Orntoft S, Longren A, Moiniche S, DahlJB. A comparison of pre- and postoperative tonsillar infiltration with bupivacaine on pain after tonsillectomy. Anesthesia 1994; 94: 151-154.
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T i m o t h y S t e e p FRACS, R o b e r t Jones 2 FRCS, John C r o s s m a n 3 FRCS, John S h e e h y 1 FRACS, P e t e r B e n t i v o g l i o ~ FRACS, M a l c o l m PelP FRACS 1Department of Neurosurgery, St Vincent's Hospital, Sydney,Australia 2Department of Neurosurgery, Sydney Children's Hospital, Sydney,Australia, 3Department of Surgical Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
We conducted a randomized double-blind trial to evaluate the effect o f intraoperative wound infiltration with bupivacaine 0.25% (1 m l / k g ) c o m p a r e d to placebo (NaCI 0.9% 1 m l / k g ) in patients undergoing lumbar spine surgery. Fifty-two patients were entered in the trial and 50 completed it. Two methods o f wound infiltration were assessed: (a) infiltration after partial wound closure and (b) infiltration prior to wound closure. Postoperatively patients received morphine sulfate o n demand. Visual analog pain scores were r e c o r d e d every 2 h for 12 h after the operation. Analgesia requirements were r e c o r d e d over the duration o f the study for each patient. The patients who received bupivacaine infiltration prior to wound closure had significantly reduced pain scores in the recovery r o o m and used significantly less morphine in the first 2 h following the procedure. They also had r e d u c e d pain scores and r e d u c e d morphine demand in the first 10 h but this did not reach statistical significance. No difference was n o t e d between the placebo group and those receiving infiltration after partial wound closure. It is concluded that infiltration o f bupivacaine is a simple and safe aid in obtaining analgesia in patients undergoing lumbar spine surgery provided that it is infiltrated prior to wound closure. Journal of Clinical Neuroscience 1998, 5(3): 298-303
© Harcourt Brace & Co. Ltd 1998
Keywords: lumbar laminectomy, bupivacaine, wound infiltration, postoperative analgesia
Introduction Perioperative local anesthetic infiltration of surgical wounds as an adjunct to standard postoperative analgesia is a c o m m o n practice employed by many surgeons. Multiple studies have detailed the use of bupivacaine in abdominal procedures such as cholecystectomy>a, hernia repair 4-9 and hysterectomy) °al Orthopedic procedures 12-14 and traumatic lacerations 15 have also been studied. These studies have been conflicting in their findings with some demonstrating benefits to the patient 2,8,10,12,14 while others r e p o r t no significant reduction in postoperative pain levels or in postoperative analgesic c o n s u m p t i o n ) '3,n Postoperative analgesia following lumbar spinal surgery remains a problem which is distressing for the patient and hinders early mobilization. In an effort to reduce this discomfort many spine surgeons infiltrate long acting anaesthetics such as bupivacaine into the subcutaneous tissues and paraspinal musculature prior to or following the surgery. Despite this widespread practice the only trials r e p o r t e d on the use of bupivacaine infiltration and lumbar spine surgery have shown no benefit to the patient. 16,17 Only three reports have been published detailing bupivacaine infiltration (BVI) in spine surgery) 6-18 T h e first description is a technical note which claimed that
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the infiltration of 50 ml of 0.25% bupivacaine into the paravertebral musculature at the conclusion of the operation resulted in a 'marked reduction of postoperative pain following lumbar disc surgery'38 However, a subseq u e n t randomized trial f o u n d no significant difference between BVI and a placebo infiltration of saline. 17A subsequent study on the use of corticosteroids and local anesthetic infiltration also showed no significant benefit for the use of BVI alone. 16 Because of the widespread nature of this practice and its uncertain therapeutic value we decided to evaluate the efficacy of bupivacaine infiltration of the paraspinal musculature in a prospective randomized double-blind study.
Methods All patients undergoing lumbar spine surgery for lumbar disc prolapse or lumbar canal stenosis at St Vincent's public hospital between April 1993 and December 1993 were considered for the study. Any patient who had had previous lumbar spine surgery was excluded, as were patients in whom decompression was planned at more than two levels. Four patients were excluded because of language difficulty. Fifty-two patients were enrolled into the study.
Bupivacaine in lumbar surgery Approval for the study was obtained f r o m the hospital ethics committee. I n f o r m e d consent was obtained for the e x p e r i m e n t a l p r o c e d u r e f r o m each patient on the evening prior to surgery at the time of obtaining the surgical consent. T h e use of the 10 cm visual analogue scale (VAS) was d e m o n s t r a t e d to the patients at the time of obtaining the consent. T h e VAS was of the standard form a t and a separate scale was used for each patient. TM A score of '0' indicated no pain, '1' r e p r e s e n t e d a slight a m o u n t of back pain and '10' was the 'worst pain imaginable'. T h e patient was specifically requested to indicate that the pain r e f e r r e d to was back pain, rather than pain f r o m any other sources postoperatively. Unlabelled, serially n u m b e r e d vials of test solution were allocated to each patient. These were supplied by Astra Pharmaceutical C o m p a n y (Sweden) and contained either Marcain 0.25% (bupivacaine hydrochloride) or sterile normal saline as a placebo. The randomization code was kept by the Pharmacy D e p a r t m e n t of St Vincent's Hospital and at Astra Pharmaceuticals office in Sydney, and was not accessed during the period of the study. All patients received a standard p r e m e d i c a t i o n of narcotic based on the patient's weight ' o n call' to the operating room. Anesthesia was induced with thiopental 3.0 m g / k g and m a i n t a i n e d with nitrous oxide (67%) in oxygen and h a l o g e n a t e d inhalational agents. All patients h a d surgery p e r f o r m e d u n d e r the direction of one of three consultant surgeons. Each patient had a standard exposure of the l u m b a r region involving bilateral subperiosteal muscle dissection. At the conclusion of each operation 1 m l / k g of the test solution was infiltrated widely into the subcutaneous tissues and into the paraspinal musculature. T h e dose of bupivacaine administered for each patient was 2.5 m g / k g . Initially, for the first 28 patients, this infiltration was p e r f o r m e d after closure of the lumbodorsal fascia after the w o u n d drain h a d b e e n placed. However, the drain was noticed to aspirate variable a m o u n t s of the test solution indicating that some infiltrate was not reaching the tissues but rather entering the w o u n d cavity. Subsequently for the r e m a i n i n g 24 patients the infiltration was carried out into the subcutaneous tissues and paraspinal musculature with the w o u n d retractors still in place, prior to the c o m m e n c e m e n t of the w o u n d closure. All patients had a w o u n d drain inserted. A standard layered closure and skin staples were used in all patients. All patients were provided with postoperative analgesia of intramuscular m o r p h i n e at a dose of 1 mg p e r 10 kg of body mass every 3 h on a d e m a n d basis. No patient received any o t h e r f o r m of analgesia in the first 12 h postoperatively. Every patient had their initial pain score r e c o r d e d by the principal investigator (TS) in the recovery r o o m as soon as the patient b e c a m e coherent. This was designated ' T i m e 0'. Pain levels were then r e c o r d e d by the nursing staff of the neurosurgical ward every 2 h for 12 h. Opiate doses and time of administration were also r e c o r d e d for 12 h postoperatively. At the time of the operation the sex, age a n d weight of the patient was recorded. T h e n u m b e r of levels o p e r a t e d upon, a n d whether the patient received a discectomy or
Clinical studies posterior decompression alone was also recorded. T h e size of the w o u n d was designated as small if the incision was less than 5 cm, m e d i u m if it was between 5 and 10 cm and large if it was greater than 10 cm in length. These factors were separately analyzed to ensure h o m o g e n e i t y of each g r o u p and to ensure that these separate factors were not influencing the pain levels r e c o r d e d postoperatively.
Results Fifty-two patients were initially enrolled in the study; there were 29 males and 23 females with a m e a n age of 56.5 years. Twenty-eight patients had a lumbar discectomy while 24 had posterior decompression alone. Seventeen of these were at a single level while seven were p e r f o r m e d at two spinal levels. Two patients were subsequently excluded. O n e patient, an elderly female, was initially confused postoperatively and another had respiratory difficulties in the immediate postoperative period rendering their data invalid. Fifty patients were available for analysis. Twenty-five patients received the placebo (normal saline) and 25 patients received bupivacaine. O f those receiving BVI, 13 were infiltrated after partial wound closure and 12 received infiltration prior to wound closure while the retractors were still in place. Data were analyzed in three groups: Group I received placebo, Group 2 received BVI after partial wound closure and Group 3 received BVI before c o m m e n c i n g the wound closure. Statistical analysis was p e r f o r m e d using multivariate r e p e a t e d measures analysis of variance (ANOVA) and linear progression. A P-value of less than 0.05 was considered statistically significant. Groups 1, 2 and 3 were f o u n d to be well m a t c h e d statistically. T h e r e was also no significant difference between the three groups of patients in the n u m b e r of levels o p e r a t e d on, the size of the incision, or n u m b e r of patients u n d e r g o i n g discectomy versus decompression alone. T h e average age of the placebo g r o u p was 56.2 years. T h e r e was a slight difference in the ages of the two groups who received BVI (Fig. 1). This difference a p p r o a c h e d statistical significance b u t did not attain it (P = 0.08). In the recovery r o o m at time zero the patients who h a d received BVI prior to w o u n d closure (Group 3) r e p o r t e d an average visual analog pain score of 3.1; this is a greater than 50% reduction in pain scores c o m p a r e d to the o t h e r two groups. T h e patients who received BVI after partial w o u n d closure (Group 2) r e p o r t e d an average pain score of 6.3 while the patients who received the placebo infiltration r e p o r t e d an average pain score of 7.1 (Fig. 2). At 2 h following the p r o c e d u r e there was no difference in the pain scores r e c o r d e d for the three test groups. From 4-8 h G r o u p 3 patients showed a significant reduction in aggregate VAS scores (P = 0.01). Beyond 8 h there was no benefit to BVI (Fig. 2). T h e administration of m o r p h i n e sulfate over the 12 h was separately analyzed. In the first 2 h the placebotreated g r o u p required an average of 9.5 mg; the G r o u p 2 patients received an average of 12.3 m g and g r o u p 3 patients required only 7.0 mg. This difference was statistically significant (P< 0.05) (Fig. 3).
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70.
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Mean age of the three groups. Placebo treated with 0.9% NaCl, Groups 2 and 3 treated with bupivacaine infiltration.
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Mean pain scores for the three groups over the 12 h of the study.
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Fig. 3
Mean morphine sulfate use over the 12 h of the study with the first 2 h shaded.
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Group 3
Bupivacaine in lumbar surgery Over the total 12 h of the study, the Group 3 patients used less morphine, 17.3 mg, than either of the two other groups; however, this did not quite gain statistical significance (P= 0.06). The placebo treated group used a total average of 24.4 mg m o r p h i n e while the bupivacaine treated Group 2 used 26.5 mg (Fig. 3). Separate analysis of patient age and sex to the pain scores and to m o r p h i n e sulfate administration was performed. T h e r e was no difference in pain scores between males and females; n o r was there a difference based on patient age. Patients with larger body mass used more m o r p h i n e and these t e n d e d to be the younger patients, as one would expect, but there was no significant difference between the patients' pain scores. T h e r e was no difference in either the pain scores or m o r p h i n e sulfate administration when separate analysis of wound size, n u m b e r of levels decompressed, or discectomy versus posterior decompression was performed; the only significant variable was the administration of BVI prior to the wound closure.
Discussion The first description of BVI in the lumbar spine was in 1979 by Mullen and Cook. .8 They described infiltration of 50 ml of 0.25% plain bupivacaine into the paravertebral musculature after closure of the lumbar fascia in an uncontrolled study of 18 consecutive patients undergoing lumbar disc surgery. A 'substantial reduction' in postoperative pain levels was r e p o r t e d but the authors did not quantify their results. Interestingly out of 21 procedures p e r f o r m e d on their 18 patients only two patients requested a single dose of narcotic for 'transient radicular pain'. No other analgesics were used or requested by any other patient in the study. They suggested that a prospective trial should be performed. Teddy and colleagues subsequently r e p o r t e d a blinded trial of 46 patients in which each patient received 40 ml of 0.25% bupivacaine hydrochloride or normal saline into the subcutaneous tissue and paravertebral muscles at the completion of the p r o c e d u r e ) 7 This study f o u n d no significant difference in the pain scores between their two groups for the duration of their study. Although they f o u n d a marked reduction in postoperative analgesic d e m a n d (75%) in the BVI-treated group in the initial 2 h following the surgery, they concluded that bupivacaine was ineffective in reducing postoperative pain and did not r e c o m m e n d it as routine practice. Glaser and colleagues in 1993 reported a study on the use of perioperative corticosteroids and bupivacaine in the m a n a g e m e n t of 32 patients undergoing lumbar microdiscectomy) 6 Patients received either 6 0 m l of 0.25 % bupivacaine with 1:200 000 adrenaline infiltration, or BVI combined with both local and systemic corticosteroids (methylprednisolone sodium succinate and methylprednisolone acetate). A third group, who received preoperative subcutaneous infiltration of 10 ml of 0.5% lidocaine with 1:100 000 adrenaline, served as a control group. Mean hospital stay was reduced to fewer than 2 days in the group receiving local anesthetic and methylprednisolone. This group averaged only 2.6
Clinical studies requests for pain medication in the first 24 postoperative h compared to 4.9 and 5.0 for the other two groups. However, they found no difference between the groups treated with BVI alone and the control group. They concluded that high dose corticosteroids enabled a more rapid discharge from hospital but that the local anesthetic infiltration by itself did not significantly alter the outcome. This study was not double-blinded and the allocation of the adjuvant therapy was made intraoperatively by the operating surgeons. This is not fully explained in the report and we are not informed on what basis the intraoperative decision was made. Unwitting treatment bias at the time of operation or in the methods of obtaining patient discharge may have influenced the results of such a small study. The authors made no attempt to quantify the pain levels experienced by their patients in the early postoperative period. A questionnaire was given to the patients following their discharge from hospital asking them to rate their back pain and radicular pain as being completely relieved, partially relieved or not relieved at 1 day, 1 week and 1 m o n t h following the surgery. Given this m e t h o d of assessment we believe that the authors cannot draw accurate conclusions on the efficacy ofperioperative bupivacaine infiltration. Our study is the first to show a significant difference in postoperative pain scores using intraoperative BVI for lumbar spine surgery. Our protocol leads to a greater than 50% reduction in back pain levels in the immediate postoperative period. We have also shown a reduction in postoperative analgesia requirements in the first 2 h following operation. We have also seen a trend towards lower pain scores and reduced opiate requirements over the first 8 h of the recording; however, our study lacks the statistical power to confirm this as significant. The alteration in our infiltration technique, while reducing the statistical power of our study, has demonstrated that the timing of BVI is important in obtaining its effect. No benefit was found in patients who received their infiltration after the wound was partially closed with the drain in place. Direct infiltration into the musculature and tissues prior to c o m m e n c i n g the wound closure was n e e d e d to attain the benefit to the patient. Some surgeons infiltrate surgical wounds after closure has been completed; however, this study indicates that patients derive little or no benefit from this practice. The previously published studies did not demonstrate any benefit to local anesthetic wound infiltration following lumbar spine surgery. Our protocol used higher doses than in previous studies. At 1 ml per kg body mass, the patients received between 60 and 110 ml of infiltrate (0.25% bupivacaine). In the original description of the technique by Mullen, a total of only 50 ml of bupivacaine 0.25% was used on all patients. TM In the trial reported by Teddy and colleagues only 40 ml was administered. ~7 In the study reported by Glaser and colleagues a total of 60 ml was administered. 16 The doses used in these previous studies may have been insufficient to provide a benefit to the patients. The duration of analgesia for bupivacaine has been r e p o r t e d to be 6-18 h for intercostal blocks, and 8-18 h
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Clinical studies for femoral and brachial plexus nerve blocks; 15yet in our study the majority of the benefit was lost 2 h after the procedure. It is possible that the relatively high blood flow in the paraspinal musculature is responsible for relatively rapid absorption of plain bupivacaine, leading to a shorter duration of action. The addition of adrenaline to bupivacaine prolongs the analgesic effect by causing local vasoconstriction, thereby reducing the speed of systemic absorption) 4 In some studies systemic levels of bupivacaine have been measured to assess the speed of absorption. 5'9 This was not p e r f o r m e d in our study and further studies comparing bupivacaine with adrenaline, and plain bupivacaine alone would n e e d to be p e r f o r m e d to assess if this provides a longer duration of action. The serum level of bupivacaine is also important in light of reports of seizure activity and cardiac arrhythmia in patients receiving epidural and peripheral nerve blocks. 15Bupivacaine may produce toxic effects at plasma concentrations greater than 4 g g / m l although the rate of increase of plasma concentration is also thought to be an important factor. 9 In situations where adverse effects have occurred, it is believed that inadvertent intravascular injection of the bupivacaine has been responsible) 5 This underscores the importance of keeping the tip of the needle moving while infiltrating. In studies where serum levels of bupivacaine have been measured, doses of 1.25 m g / k g administered via subcutaneous infiltration led to peak serum concentrations of only 0.36 g g / m l , well below the toxic threshold of 4 g g / m l . 9 No patients in our study experienced any adverse effects attributable to the infiltration. The use of a double-blind placebo-controlled trial is a valid design for this study; however, it creates potential problems. By using 0.9% NaC1 solution as the placebo we are assuming that it is an inert substance in relation to nociception. However, no prospective randomized study has evaluated the effect of NaC1 infiltration alone on postoperative pain. TM Wound infiltration with normal saline may have an analgesic effect due to the dilution of inflammatory substances released at the site of the incision. This would reduce the apparent benefit of the bupivacaine infiltration. On the other hand the saline infiltration may worsen wound pain in which case any apparent benefit to the bupivacaine infiltration would be misleading. Further studies are n e e d e d to clarify this point. In many reported series of wound infiltration in various surgical disciplines, BVI is p e r f o r m e d at the conclusion of the procedure. TM It has been postulated that local analgesia administered following a surgical p r o c e d u r e will only be effective briefly and that pain levels will rise rapidly in the postoperative period. 2° Recent findings suggest that sensory signals generated by tissue damage during surgery can trigger a prolonged state of increased excitability in the central nervous system, z° This is due to a lowering of the threshold of nociceptor afferents in the periphery, as well as an increase in the excitability of spinal neurons. Central sensitization occurs in response
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Bupivacaine in lumbar surgery to the initial painful stimulus and is then maintained by the inflammatory changes in the tissues postoperatively. Therefore, the optimal form of pain treatment for surgical procedures would be 'pre-emptive' applied both prior to and during the operation itself. 11'2°This has been advocated as the most efficacious m e t h o d of p e r f o r m i n g wound infiltration, z° For this reason many surgeons infiltrate the dermis prior to p e r f o r m i n g the initial skin incision. Some spine surgeons infiltrate the lumbar musculature and proposed d o n o r graft sites as well as the subcutaneous tissues prior to p e r f o r m i n g the skin incision. This was not p e r f o r m e d in this series of patients due to concern over infection risk by the consultant surgeons. One study has demonstrated that pre-incisional w o u n d infiltration with lignocaine is s u p e r i o r to postincisional infiltration. 21 However, other studies examining the pre-emptive effect of wound infiltration with lignocaine have been inconclusive, l°,n Only two studies have specifically looked at the difference between preoperative and postoperative wound infiltration in patients receiving bupivacaine following surgical p r o c e d u r e s ) 1,12 In one study, patients undergoing abdominal hysterectomy received BVI either 15 min prior to the skin incision or at the completion of the procedure. 1~ Neither group demonstrated any significant reduction in pain scores when measured every 4-8 h postoperatively when c o m p a r e d to the untreated control group that did not receive wound infiltration. By looking at the results of our own study it is likely that the majority of any benefit would have been seen in the first 4 h, prior to the first recordings of pain scores. Given the theoretical benefits of pre-incision infiltration and the addition of adrenaline to the infiltrate, further trials are indicated to ascertain how to attain the maximal benefits of bupivacaine wound infiltration.
Conclusion The findings of the study show that perioperative infiltration of the subcutaneous tissues and paraspinal musculature in lumbar spine surgery is a safe and effective m e t h o d of providing postoperative analgesia in the immediate postoperative period. Providing it is infiltrated prior to wound closure bupivacine can reduce patient pain scores by more than 50% in the recovery r o o m and can reduce analgesic requirements in the early postoperative period.
Acknowledgments The authors would like to thank Professor R. Gibberd for assistance with the statistical analysis and Sr Alison Kent for assistance with the data collection and preparation of the manuscript. The blinded trial preparation was produced and delivered by Astra AB, Sodertaje, Sweden. Received11 August 1995; Accepted 17 March 1997
Correspondence and offprint requests: Mr M. Pell, Suite 704, St Vincent's Clinic, 438 Victoria Street, Darlinghurst, Sydney, NSW 2021, Australia, Tel: 61 02, 9332 6754, Fax: 61 02 9332 6761
Bupivacaine in lumbar surgery References 1. Adams WJ, AuramovicJ, Barraclough BH. Wound infiltration with 0.25% bupivacaine not effective for postoperative analgesia after cholecystectomy. Aust NZJ Surg 1991; 61 (8): 626-630. 2. Moss G, Regal ME, Lichtig L. Reducing postoperative pain, narcotics and length of hospitalization. Surgery 1986; 99(2): 206-210. 3. Van Raay~J, RoukemaJA, Lenderink BW. Intraoperative wound infiltration with bupivacaine in patients undergoing elective cholecystectomy. Arch Surg 1992; 127(4): 457-459. 4. Cross GD, Barrett RF. Comparison of two regional techniques for postoperative analgesia in children following herniotomy and orchidopexy. Anesthesia 1987; 42: 845-849. 5. Kastrissios H, Triggs EJ, Sinclair F, Motran P, Smithers M. Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study. EurJ Clin Pharmacol 1993; 44 (6): 555-557. 6. LangerJL, Shandling B, Rosenberg M. Intraoperative bupivacaine during outpatient hernia repair in children. A randomized double blind trial. J Pediatr Surg 1987; 22(3): 267-270. 7. Levack ID, HolmesJD, Robertson GS. Abdominal wound perfusion for the relief of postoperative pain. BrJ Anaesth 1986; 58: 615-619. 8. McLoughlinJ, Kelley CJ. Study of the effectiveness of bupivacaine infiltration of the ilioinguinal nerve at the time of hernia repair for postoperative pain relief. BrJ Clin Pract 1989; 43(8): 281-283. 9. Mobley KA, WandlessJG, Fell D. Serum bupivacaine concentrations following wound infiltration in children undergoing inguinal herniotomy. Anesthesia 1991; 46 (6): 500-501. 10. Hannibal K, Galatius H, Hansen A, Obel E, Ejlersen E. Preoperative wound infiltration with bupivacaine reduces early and late opioid requirements after hysterectomy. Anaesth Analg 1996; 83 (2): 376-381.
Clinical studies 11. Victory RA, Gajraj NM, Van-Elstraete A, Pace NA, Johnson ER, White PE Effect of preincision versus postincision infiltration with bupivacaine on postoperative pain. J Clin Anaesth 1995; 7 (3): 192-196. 12. Bourne MH, Johson KA. Postoperative pain relief using local anesthetic instillation. Foot Ankle 1988; 8: 350-351. 13. Edwards ND, Wright EM. Continuous low-dose 3-in-1 nerve blockade for postoperative pain relief after total knee replacement. Anesth Analg 1992; 75: 265-267. 14. Todd BD, Reed SC. The use of bupivacaine to relieve pain at iliac graft donor sites. Int Orthop 1991; 15: 53-55. 15. Spivey WH, McNamara RM, MacKenzie RS, Bhat S, Burdick WP. A clinical comparison of lidocaine and bupivacaine. Ann Emerg Med 1987; 16: 752-757. 16. Glasser RS, Knego RS, DelashawJB, Fessler RG. The perioperative use of corticosteroids and bupivacaine in the management of lumbar disc disease. J Neurosurg 1993; 78: 383-387. 17. Teddy PJ, Fabinyi GCA, KerrJH, Briggs M. Bupivacaine infiltration after lumbar laminectomy. Anesthesia 1981; 36: 380-383. 18. MullenJB, Cook WA. Reduction of post-operative lumbar hemi-laminectomy pain with Marcain. Technical note. J Neurosurg 1979; 51: 126-127. 19. Revill SI, RobinsonJO, Rosen M, Hogg MIJ. The reliability of a linear analogue for evaluating pain. Anesthesia 1976; 31: 1191-1198. 20. Woolf CJ, Chong MS. Pre-emptive analgesia-treating postoperative pain by preventing the establishment of central sensitization. Anaesth Analg 1993: 77: 362-379. 21. Ejlersen E, Andersen HB, Eliasen K, Mogensen T. A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain. Anesth Analg 1992; 74: 495-498. 22. Orntoft S, Longren A, Moiniche S, DahlJB. A comparison of pre- and postoperative tonsillar infiltration with bupivacaine on pain after tonsillectomy. Anesthesia 1994; 94: 151-154.
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