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Intravenous regional anesthesia using lidocaine and neostigmine for upper limb surgery
Journal of Clinical Anesthesia (2010) 22, 324–328
Original contribution
Intravenous regional anesthesia using lidocaine and neostigmine for upper limb surgery☆ Divya Sethi MD, DNB (Resident Anesthesiologist)⁎, Rama Wason MD (Professor of Anesthesia) Department of Anesthesia and Intensive Care, Safdarjang Hospital and Vardhman Mahavir Medical College (V.M.M.C), University of Delhi, New Delhi - 110029, India Received 19 April 2008; revised 24 September 2009; accepted 26 September 2009
Keywords: Intravenous regional anesthesia; Lidocaine; Neostigmine; Upper extremity surgery
Abstract Study Objective: To evaluate the effect of adding neostigmine to lidocaine in intravenous regional anesthesia (IVRA). Design: Randomized, double-blinded study. Setting: Tertiary-care academic medical institution. Patients: 40 ASA physical status I and II patients scheduled for elective or emergency forearm and hand surgery. Intervention: Patients were randomized to two groups of 20 patients each. In the control group, IVRA was established using 40 mL of 0.5% lidocaine with one mL of isotonic saline, while neostigmine group patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine. Measurements: Hemodynamic parameters, onset and recovery times of sensory and motor blocks, and quality of anesthesia achieved with IVRA were recorded. After tourniquet deflation, visual analog pain scores (VAS) were noted every 30 minutes in the first two hours, as were the time to first analgesic request and total analgesic requirement in the 24-hour postoperative period. Main Results: In the first 24 hours after surgery, the neostigmine group had significantly lower VAS scores, longer time to first analgesic request, and reduced total analgesic requirement. Intraoperatively, the neostigmine group had significantly shorter sensory and motor block onset times and longer recovery times than the control group. No significant frequency of adverse effects was seen in either group. The quality of intraoperative anesthesia and frequency of tourniquet pain were similar in both groups. Conclusions: The addition of neostigmine to lidocaine shortens onset time and improves postoperative analgesia in IVRA for upper limb surgery. © 2010 Elsevier Inc. All rights reserved.
1. Introduction ☆
Supported by the Department of Anesthesia and Intensive Care, Safdarjang Hospital and V.M.M.C, New Delhi – 110029, India, only. ⁎ Corresponding author. A-2B/118-B, Paschim Vihar, New Delhi – 110063, India. E-mail address: [email protected] (D. Sethi). 0952-8180/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2009.09.005
Intravenous regional anesthesia (IVRA) is an option for short procedures of the upper extremities. It is simple to administer, safe, and cost-effective, but is limited by rapid offset of anesthesia after tourniquet deflation and inadequate
IVRA for upper limb surgery postoperative analgesia [1,2]. In clinical practice, anesthesiologists have been experimenting with various adjuncts for IVRA [ie, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), clonidine, and neuromuscular blocking drugs] to enhance quality of anesthesia, extend anesthesia after tourniquet deflation, improve postoperative analgesia, and mitigate adverse effects of local anesthetic agents [3]. Neostigmine, a cholinergic drug, can produce central and peripheral analgesia. Its use has been investigated as an adjunct in central neuraxial (intrathecal, epidural, and caudal) and peripheral blocks (intraarticular, brachial plexus, IVRA) [4]. Intrathecal neostigmine (5 to 100 μg) prolongs postoperative analgesia but produces a dose-dependent increase in nausea and vomiting [5,6]. In investigational studies of epidural administration (one to 10 μg/kg) for labor analgesia, gynecological surgery, orthopedic, and thoracic surgeries, neostigmine yielded prolonged analgesia without an increase in gastrointestinal side effects [7–10]. Caudal neostigmine (two to 4 μg/kg) improves postoperative pain relief in children undergoing genitourinary surgery [11,12]. A synergistic analgesic interaction of neuraxially administered neostigmine and opioid also has been seen [6,13]. The analgesic benefit of peripherally administered 0.5 mg neostigmine has been observed in patients undergoing knee arthroscopy [10,14] and upper limb surgery during axillary block [15]. A later study, by Van Elstraete et al. [16], reported no analgesic benefit of neostigmine in brachial plexus block. Hence, there is some controversy as to the usefulness of neostigmine in peripheral nerve blocks. Turan et al. [17] showed that the addition of 0.5 mg neostigmine to 0.5% prilocaine (three mg/kg) in IVRA for hand surgery provided significant anesthetic and analgesic advantages; McCartney et al. [18] reported no benefit from 1.0 mg neostigmine added to 0.5% lidocaine (three mg/kg) in IVRA. The latter study was limited by a large number of withdrawals (19 of 54 pts) due to failure of the anesthesic technique. The hypothesis of the study was that neostigmine would improve IVRA because of its peripheral analgesic action. The analgesic benefits of adding 0.5 mg neostigmine to lidocaine in IVRA was evaluated as well as its effect, if any, on the onset and recovery times of sensory and motor blocks, quality of intraoperative anesthesia, tourniquet pain, and adverse side effects.
2. Materials and methods After approval of the study protocol by the Ethics committee of Safdarjang Hospital and Vardhman Mahavir Medical College (V.M.M.C), 40 ASA physical status I and II patients, 18 to 65 years of age, and scheduled for elective or emergency forearm and hand surgery, were enrolled in this double-blinded study. Written, informed consent was obtained from each patient. Exclusion criteria included
325 allergy to local anesthetics, Raynaud's disease, and sickle cell anemia. Patients with preoperative pain or with preoperative VAS scores greater than 3 also were excluded from the study. Patients were allocated to either group (n = 20) based on a computer generated randomization list for 40 patients. The anesthesiologist, patient, surgeon, and recovery staff were all blinded to the randomization. An intravenous (IV) catheter was secured on the non-operative hand and patients were premedicated with IV midazolam 0.02 mg/kg. A 20-guage cannula was then inserted on the dorsum of the operative hand for injecting the IVRA solution. After routine monitors (Cardiocap II; Datex Ohmeda, Inc., Madison, WI, USA) were applied to the patient, a double tourniquet was positioned on the upper operative arm, which was then exsanguinated by elevating it and wrapping it with an Esmarch bandage. The proximal tourniquet was inflated to 250 mmHg and the Esmarch bandage was then removed. Circulatory isolation of the operative arm was confirmed by inspection of the hand and absence of a radial pulse. The IVRA solutions were prepared by a laboratory assistant who had no further role in the study. The assistant added one mL of saline (control group) or 0.5 mg of neostigmine methylsulphate (Myostigmin; neostigmine group) to 40 mL of 0.5% lidocaine, which was prepared by diluting 10 mL of 2% lidocaine (Xylocard 2%) with saline. The solution was then handed over to the resident anesthesiologist who was blinded to the randomization. The IVRA was established by injecting the solution over 60 seconds. Sensory block was assessed by a pinprick with a 22-gauge, short bevel needle every 30 seconds. Patient response was evaluated in the sensory dermatomes of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves. Onset time of sensory block was noted as the time from injection of the drug to sensory block achieved in all dermatomes. Motor function was assessed every 30 seconds and consisted of asking the patient to flex and extend his wrist and fingers; complete motor block was noted when no voluntary movement was possible. Onset time of motor block was noted as the time from injection of drug to complete motor block. After onset of sensory and motor block, with the operative tourniquet (distal tourniquet) inflated to 250 mmHg, the proximal tourniquet was released and the surgery started. Patients' systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and oxygen saturation by pulse oximetry (SpO2) were monitored before and after tourniquet application; after injection of the anesthetic drug; every 5 minutes during the surgery; and, finally, after tourniquet release. Frequency of tourniquet pain and its onset time were noted. Patients suffering tourniquet pain were given IV boluses of fentanyl 25 μg for pain relief. Such patients were excluded from analysis for postoperative pain scores and analgesic requirement. At the end of surgery, motor and sensory block recovery times – the time from tourniquet deflation to movement of
326 fingers, and recovery of sensation as determined by pinprick test, respectively – were noted. The anesthesiologist graded the quality of anesthesia achieved on a numeric scale, in which 4 = excellent: no complaint from patient; 3 = good: minor complaint, but with no need for supplemental anesthesia; 2 = moderate: some complaint, which required supplemental anesthesia; and 1 = unsuccessful: patient given general anesthesia and therefore excluded from the study. After the surgery, all patients were followed for 24 hours. In the first two hours, patients assessed their pain using a 10-cm visual analog scale (VAS) at 30-minute intervals. Patients were given one tablet of diclofenac 50 mg (Voveron 50) when their pain exceeded VAS score 3, to be repeated only after 8 hours if needed. The time to first analgesic request after tourniquet release was noted, as was the number of diclofenac tablets required in the 24-hour postoperative period. Occurrence of adverse side effects (increased salivation, abdominal pain, diarrhea, tachycardia, bradycardia, hypotension, hypertension, skin rash, dizziness, tinnitus, and hypoxemia) also was noted.
2.1. Statistical analysis In the study by Yang et al. [14], a 40% reduction in VAS scores was seen in the test group compared with the control group on intra-articular administration of 0.5 mg neostigmine. Based on that study, the same dosage of neostigmine in IVRA would likely yield a 40% reduction in VAS scores. To detect a significant difference in analgesia (α - 0.05 and β 0.2), power analysis indicated the number of patients required in each group to be 17. To compensate for any study drop-outs, 20 patients were enrolled in each group. Data were analyzed using SPSS software, version 11.5 (SPSS Institute, Inc., Chicago, IL, USA). Hemodynamic parameters, VAS scores, and times (block onset and recovery times, total tourniquet time, tourniquet pain onset time, and time to first analgesic request) were compared between the groups using unpaired Student's t-test. The trend of hemodynamic parameters and VAS scores within the groups was analyzed using two-way analysis of variance with post-hoc analysis by Bonferroni's method. Chi-square test with Yates' correction was used for comparing the quality of anesthesia scores. Frequency of tourniquet pain and number of patients requiring diclofenac postoperatively were compared using Fisher's exact test. The Mann-Whitney U test was used to compare the consumption of diclofenac postoperatively. Unless otherwise indicated, data are presented as means ± SD. A P-value b 0.05 was considered statistically significant.
3. Results Forty patients who were scheduled for elective or emergency forearm and hand surgery were enrolled in this
D. Sethi, R. Wason Table 1
Demographic and perioperative data
Age (yrs) Weight (kg) ASA physical status (I/II) Men/Women Total tourniquet time (min)
Group C (n = 20)
Group N (n = 20)
25.9 ± 9.5 53.8 ± 10.2 12/8 15/5 74.6 ± 26.8
26.5 ± 11.7 53.3 ± 9.8 14/6 16/4 75.2 ± 20.9
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of isotonic saline for intravenous regional anesthesia (IVRA; control group) ; Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA.
study. Their demographic profile is shown in Table 1. All patients underwent the scheduled surgeries during IVRA. Fifteen patients underwent contracture release (8 control group pts and 7 neostigmine group pts), 9 underwent tendon transfer (three control group pts and 6 neostigmine group pts), and 7 underwent open reduction and internal fixation (4 control group pts and three neostigmine group pts). The remaining 9 patients underwent various other surgeries: nerve exploration and repair, removal of hardware, exostosis excision, capsulotomy, and arthrodesis. No statistically significant differences in hemodynamic parameters were noted between the two groups at any time during the study. Total tourniquet times for the control group (74.6 ± 26.8 min) and neostigmine group (75.2 ± 20.9 min) were statistically similar (Table 1). Seven patients (35%) in the control group and 5 neostigmine group patients (25%) experienced tourniquet pain; the frequency of tourniquet pain was comparable in the two groups. There was also no significant difference between the groups in onset time of tourniquet pain (control group: 71.0 ± 21.3 min, neostigmine group: 80.0 ± 7.4 min). The 12 patients who experienced tourniquet pain in the two groups were excluded from analysis for postoperative pain and analgesic requirement. Postoperative VAS scores at 30, 60, 90, and 120 minutes after tourniquet release were significantly lower in the neostigmine group (Table 2). A linearly decreasing trend in VAS scores was seen in both the groups (P b 0.001). In the control group, VAS scores at 120 minutes were significantly lower than VAS scores at 30 and 60 minutes (P = 0.004). However, in the neostigmine group, VAS scores at 120 minutes were significantly lower than those scores at 30, 60, and 90 minutes (P = 0.015, P = 0.042, and P = 0.008, respectively). In the neostigmine group, a significant difference was also observed between VAS scores at 30 and 60 minutes (P = 0.019). The neostigmine group had a significantly longer time to first analgesic request (355.5 ± 198.1 min) than the control group (57.8 ± 75.2 min; P b 0.001; Table 2). Six of the 15 patients (40%) in the neostigmine group
IVRA for upper limb surgery Table 2
327
Postoperative pain scores and analgesic onsumption Group C (n = 13)
VAS 30 min VAS 60 min VAS 90 min VAS 120 min Time to first analgesic request (min) 24-hour total tablet diclofenac consumption
Group N (n = 15)
3.92 ± 1.60 2.20 3.23 ± 1.42 1.53 2.62 ± 1.19 1.47 1.92 ± 0.69 0.93 57.8 ± 75.2 355.5 1.9 ± 1.1
P-value
± 0.78 ± 0.74 ± 1.60 ± 1.44 ± 198.1 b
0.5 ± 0.7
0.003 0.001 0.043 0.026 0.001 0.002
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of isotonic saline for intravenous regional anesthesia (IVRA; control group) ; Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA;VAS = visual analog score.
compared with 11 of 13 control group patients (84.6%) required one or more diclofenac tablets during the 24 hours after tourniquet release (P = 0.043). Total diclofenac tablet consumption over the 24-hour period also was lower in the neostigmine group (0.5 ± 0.7 tablet) than the control group (1.9 ± 1.1 tablets; P = 0.002; Table 2). Intraoperatively, the onset times of sensory and motor blocks were significantly shorter in the neostigmine group (n = 20; P = 0.001). The neostigmine group also had significantly longer sensory block and motor block recovery times (P = 0.005, P = 0.002, respectively; Table 3). The quality of anesthesia was “excellent” (ie, score of 4) in 16 patients (80%) in the control group and 18 patients (90%) in the neostigmine group, whereas it was “good” (ie, score of 3) in 4 patients (20%) in the control group and two patients (10%) in the neostigmine group. No patient required supplemental or general anesthesia (ie, score of 1 or 2) in either group. These data showed no statistical difference in the quality of anesthesia scores (P = 0.66). Except for one patient in the neostigmine group who suffered nausea and vomiting, no patient in either group showed any adverse effects. Table 3 Onset and recovery times of sensory and motor blocks (min) Group C (n = 20)
Group N (n = 20)
Sensory block onset time 7.5 ± 2.1 5.4 ± 1.4 Motor block onset time 15.0 ± 2.4 11.6 ± 3.4 Sensory block recovery time 3.8 ± 2.5 6.2 ± 2.8 Motor block recovery time 2.1 ± 1.6 3.9 ± 1.8
P-value 0.001 0.001 0.005 0.002
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of t1:9 isotonic saline for intravenous regional anesthesia (IVRA; control group); Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA.
4. Discussion Neostigmine as an IVRA agent offered significant postoperative analgesic benefit in terms of reduced VAS scores, longer time to first analgesic request, and lower analgesic consumption, similar to what was noted previously with other IVRA adjuncts such as NSAIDs, clonidine, and meperidine [3]. Turan et al. also observed a longer time to first analgesic request when neostigmine was added to prilocaine in IVRA, though these authors did not analyze its effect on postoperative VAS scores and analgesic consumption [17]. Preclinical studies have shown that acetylcholine receptors exist at peripheral nerve endings [19], enabling cholinergic-mediated antinociception by the activation of the NO-cGMP pathway [20,21]. Neostigmine, due to its chemical structure and pharmacological action, causes protracted inhibition of acetylcholinesterase, enhancing the availability of acetylcholine at peripherally distributed muscarinic receptors, thereby allowing prolonged analgesia [22]. However, when neostigmine is used as an IVRA adjunct, its peripheral action is possibly further aided by the disruption of the blood nerve barrier by tourniquet ischemia [23] and by its injection close to the surgical site. The peripheral analgesic effect of intra-articular neostigmine has been shown in a rat inflamed knee model [24] and in patients undergoing knee arthroscopy [10,14]. Peripherally administered neostigmine also improves postoperative analgesia after upper extremity surgery during axillary brachial plexus block [15]. However, in their study of neostigmine in axillary plexus block for carpal tunnel release, Van Elstraete et al. [16] found no evidence of its analgesic effect. Based on previous studies and the similarity of opioid and cholinergic systems, they suggested that this lack of evidence might be due to the absence of local inflammation and to the intact dense perineurium at the level of a nerve plexus distant from the surgical site [25,26]. Yet Bouaziz et al. [27] noted no peripheral analgesic benefit of intraplantar administration of neostigmine. Neostigmine produced significantly reduced onset times of sensory and motor blocks while prolonging their recovery times. These findings are in agreement with those of Turan et al. [17]. However, McCartney et al. [18] observed merely a reduced motor block onset time in their neostigmine group. Prolongation of the sensory block may be related to the newly discovered acetylcholine-mediated sensory regulatory mechanism controlled by the motor system [28], and the prolonged motor block may be the result of the nicotinic agonistic effect of neostigmine at the neuromuscular junction [29,30]. The addition of neostigmine in IVRA in our study did not affect the quality of anesthesia scores, which were “excellent” or “good” in either group. Turan et al. observed an improvement in quality of anesthesia scores in their neostigmine group [17]. Neostigmine also had no effect on the frequency of tourniquet pain and its onset time, unlike the
328 improved tourniquet tolerance observed previously with clonidine [31,32]. McCartney et al. [18] also reported no effect of neostigmine on tourniquet pain; Turan et al. [17] did not evaluate this aspect. No significant side effects of neostigmine as an IVRA adjunct were noted; however, the limited number of patients prevents firm conclusion. As neostigmine does not cross the blood brain barrier, the analgesia achieved by its peripheral delivery is less likely to be limited by adverse effects (particularly nausea and vomiting) associated with its use in neuraxial blocks [5,6]. Although neostigmine may produce side effects such as increased salivation, diarrhea, and abdominal cramps, these were not seen. In addition, though Turan et al. observed a significant frequency of bradycardia attributable to systemic absorption of neostigmine or its escape during tourniquet inflation [17], we did not observe this side effect in our study. In conclusion, adding 0.5 mg neostigmine to 0.5% lidocaine in IVRA for upper limb surgery resulted in significant analgesic benefits, as seen in lower postoperative VAS scores and analgesic consumption. It also yielded significant anesthetic benefits such as shortened onset times and prolonged recovery times of sensory and motor block; however, it had no effect on quality of anesthesia scores, frequency of tourniquet pain, or adverse effects.
References [1] Brown EM, McGriff JT, Malinowski RW. Intravenous regional anaesthesia (Bier block): review of 20 years' experience. Can J Anaesth 1989;36(3 Pt 1):307-10. [2] Chan VW, Peng PW, Kaszas Z, et al. A comparative study of general anesthesia, intravenous regional anesthesia, and axillary block for outpatient hand surgery: clinical outcome and cost analysis. Anesth Analg 2001;93:1181-4. [3] Choyce A, Peng P. A systematic review of adjuncts for intravenous regional anesthesia for surgical procedures. Can J Anaesth 2002;49:32-45. [4] Habib AS, Gan TJ. Use of neostigmine in the management of acute postoperative pain and labour pain: a review. CNS Drugs 2006;20:821-39. [5] Lauretti GR, Reis MP. Postoperative analgesia and antiemetic efficacy after subarachnoid neostigmine in orthopedic surgery. Reg Anesth 1997;22:337-42. [6] Klamt JG, Slullitel A, Garcia IV, Prado WA. Postoperative analgesic effect of intrathecal neostigmine and its influence on spinal anaesthesia. Anaesthesia 1997;52:547-51. [7] Roelants F. The use of neuraxial adjuvant drugs (neostigmine, clonidine) in obstetrics. Curr Opin Anaesthesiol 2006;19:233-7. [8] Nakayama M, Ichinose H, Nakabayashi K, Satoh O, Yamamoto S, Namiki A. Analgesic effect of epidural neostigmine after abdominal hysterectomy. J Clin Anesth 2001;13:86-9. [9] Chia YY, Chang TH, Liu K, Chang HC, Ko NH, Wang YM. The efficacy of thoracic epidural neostigmine infusion after thoracotomy. Anesth Analg 2006;102:201-8. [10] Lauretti GR, de Oliveira R, Perez MV, Paccola CJ. Postoperative analgesia by intraarticular and epidural neostigmine following knee surgery. J Clin Anesth 2000;12:444-8. [11] Abdulatif M, El-Sanabary M. Caudal neostigmine, bupivacaine, and their combination for postoperative pain management after hypospadias surgery in children. Anesth Analg 2002;95:1215-8.
D. Sethi, R. Wason [12] Mahajan R, Grover VK, Chari P. Caudal neostigmine with bupivacaine produces a dose-independent analgesic effect in children. Can J Anaesth 2004;51:702-6. [13] Omais M, Lauretti GR, Paccola CA. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Anesth Analg 2002;95:1698-701. [14] Yang LC, Chen LM, Wang CJ, Buerkle H. Postoperative analgesia by intra-articular neostigmine in patients undergoing knee arthroscopy. Anesthesiology 1998;88:334-9. [15] Bone HG, Van Aken H, Booke M, Bürkle H. Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine. Reg Anesth Pain Med 1999;24:405-10. [16] Van Elstraete AC, Pastureau F, Lebrun T, Mehdaoui H. Neostigmine added to lidocaine axillary plexus block for postoperative analgesia. Eur J Anaesthesiol 2001;18:257-60. [17] Turan A, Karamanlyoglu B, Memis D, Kaya G, Pamukçu Z. Intravenous regional anesthesia using prilocaine and neostigmine. Anesth Analg 2002;95:1419-22. [18] McCartney CJ, Brill S, Rawson R, Sanandaji K, Iagounova A, Chan VW. No anesthetic or analgesic benefit of neostigmine 1 mg added to intravenous regional anesthesia with lidocaine 0.5% for hand surgery. Reg Anaesth Pain Med 2003;28:414-7. [19] Day NS, Berti-Mattera LN, Eichberg J. Muscarinic cholinergic receptor-mediated phosphoinositide metabolism in peripheral nerve. J Neurochem 1991;56:1905-13. [20] Duarte ID, Lorenzetti BB, Ferreira SH. Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol 1990;186:289-93. [21] Ferreira SH, Nakamura M. I - Prostaglandin hyperalgesia, a cAMP/ Ca2+ dependent process. Prostaglandins 1979;18:179-90. [22] Dollery CT. Neostigmine. In: Dollery CT, editor. Therapeutic drugs, Vol. 2. London: Churchill Livingstone; 1999. p. N53-6. [23] Saray A, Can B, Akbiyik F, Askar I. Ischaemia-reperfusion injury of the peripheral nerve: an experimental study. Microsurgery 1999;19: 374-80. [24] Buerkle H, Boschin M, Marcus MA, Brodner G, Wusten R, Van Aken H. Central and peripheral analgesia mediated by the acetylcholinesterase-inhibitor neostigmine in the rat inflamed knee joint model. Anesth Analg 1998;86:1027-32. [25] Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993;55: 185-95. [26] Antonijevic I, Mousa SA, Schäafer M, Stein C. Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci 1995;15 (1 Pt 1):165-72. [27] Bouaziz H, Gentili ME, Girard F, et al. Lack of peripheral analgesia mediated by intraplantar administration of neostigmine in carrageenaninjected rats. Eur J Anaesthesiol 2001;18:303-5. [28] Chiou-Tan FY, Chiou GC. Contribution of circulating acetylcholine to sensory nerve conduction augmentation. Life Sci 2000;66: 1509-18. [29] Stoelting RK. Anticholinesterase drugs and cholinergic agonists. In: Stoelting RK, editor. Pharmacology and physiology in anesthetic practice. 2nd ed. Philadelphia: J.B. Lippincott Co; 1991. p. 226-41. [30] Yost CS, Maestrone E. Clinical concentrations of edrophonium enhance desensitization of the nicotinic acetylcholine receptor. Anesth Analg 1994;78:520-6. [31] Gentili M, Bernard JM, Bonnet F. Adding clonidine to lidocaine for intravenous regional anesthesia prevents tourniquet pain. Anesth Analg 1999;88:1327-30. [32] Lurie SD, Reuben SS, Gibson CS, DeLuca PA, Maciolek HA. Effect of clonidine on upper extremity tourniquet pain in healthy volunteers. Reg Anesth Pain Med 2000;25:502-5.
Original contribution
Intravenous regional anesthesia using lidocaine and neostigmine for upper limb surgery☆ Divya Sethi MD, DNB (Resident Anesthesiologist)⁎, Rama Wason MD (Professor of Anesthesia) Department of Anesthesia and Intensive Care, Safdarjang Hospital and Vardhman Mahavir Medical College (V.M.M.C), University of Delhi, New Delhi - 110029, India Received 19 April 2008; revised 24 September 2009; accepted 26 September 2009
Keywords: Intravenous regional anesthesia; Lidocaine; Neostigmine; Upper extremity surgery
Abstract Study Objective: To evaluate the effect of adding neostigmine to lidocaine in intravenous regional anesthesia (IVRA). Design: Randomized, double-blinded study. Setting: Tertiary-care academic medical institution. Patients: 40 ASA physical status I and II patients scheduled for elective or emergency forearm and hand surgery. Intervention: Patients were randomized to two groups of 20 patients each. In the control group, IVRA was established using 40 mL of 0.5% lidocaine with one mL of isotonic saline, while neostigmine group patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine. Measurements: Hemodynamic parameters, onset and recovery times of sensory and motor blocks, and quality of anesthesia achieved with IVRA were recorded. After tourniquet deflation, visual analog pain scores (VAS) were noted every 30 minutes in the first two hours, as were the time to first analgesic request and total analgesic requirement in the 24-hour postoperative period. Main Results: In the first 24 hours after surgery, the neostigmine group had significantly lower VAS scores, longer time to first analgesic request, and reduced total analgesic requirement. Intraoperatively, the neostigmine group had significantly shorter sensory and motor block onset times and longer recovery times than the control group. No significant frequency of adverse effects was seen in either group. The quality of intraoperative anesthesia and frequency of tourniquet pain were similar in both groups. Conclusions: The addition of neostigmine to lidocaine shortens onset time and improves postoperative analgesia in IVRA for upper limb surgery. © 2010 Elsevier Inc. All rights reserved.
1. Introduction ☆
Supported by the Department of Anesthesia and Intensive Care, Safdarjang Hospital and V.M.M.C, New Delhi – 110029, India, only. ⁎ Corresponding author. A-2B/118-B, Paschim Vihar, New Delhi – 110063, India. E-mail address: [email protected] (D. Sethi). 0952-8180/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2009.09.005
Intravenous regional anesthesia (IVRA) is an option for short procedures of the upper extremities. It is simple to administer, safe, and cost-effective, but is limited by rapid offset of anesthesia after tourniquet deflation and inadequate
IVRA for upper limb surgery postoperative analgesia [1,2]. In clinical practice, anesthesiologists have been experimenting with various adjuncts for IVRA [ie, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), clonidine, and neuromuscular blocking drugs] to enhance quality of anesthesia, extend anesthesia after tourniquet deflation, improve postoperative analgesia, and mitigate adverse effects of local anesthetic agents [3]. Neostigmine, a cholinergic drug, can produce central and peripheral analgesia. Its use has been investigated as an adjunct in central neuraxial (intrathecal, epidural, and caudal) and peripheral blocks (intraarticular, brachial plexus, IVRA) [4]. Intrathecal neostigmine (5 to 100 μg) prolongs postoperative analgesia but produces a dose-dependent increase in nausea and vomiting [5,6]. In investigational studies of epidural administration (one to 10 μg/kg) for labor analgesia, gynecological surgery, orthopedic, and thoracic surgeries, neostigmine yielded prolonged analgesia without an increase in gastrointestinal side effects [7–10]. Caudal neostigmine (two to 4 μg/kg) improves postoperative pain relief in children undergoing genitourinary surgery [11,12]. A synergistic analgesic interaction of neuraxially administered neostigmine and opioid also has been seen [6,13]. The analgesic benefit of peripherally administered 0.5 mg neostigmine has been observed in patients undergoing knee arthroscopy [10,14] and upper limb surgery during axillary block [15]. A later study, by Van Elstraete et al. [16], reported no analgesic benefit of neostigmine in brachial plexus block. Hence, there is some controversy as to the usefulness of neostigmine in peripheral nerve blocks. Turan et al. [17] showed that the addition of 0.5 mg neostigmine to 0.5% prilocaine (three mg/kg) in IVRA for hand surgery provided significant anesthetic and analgesic advantages; McCartney et al. [18] reported no benefit from 1.0 mg neostigmine added to 0.5% lidocaine (three mg/kg) in IVRA. The latter study was limited by a large number of withdrawals (19 of 54 pts) due to failure of the anesthesic technique. The hypothesis of the study was that neostigmine would improve IVRA because of its peripheral analgesic action. The analgesic benefits of adding 0.5 mg neostigmine to lidocaine in IVRA was evaluated as well as its effect, if any, on the onset and recovery times of sensory and motor blocks, quality of intraoperative anesthesia, tourniquet pain, and adverse side effects.
2. Materials and methods After approval of the study protocol by the Ethics committee of Safdarjang Hospital and Vardhman Mahavir Medical College (V.M.M.C), 40 ASA physical status I and II patients, 18 to 65 years of age, and scheduled for elective or emergency forearm and hand surgery, were enrolled in this double-blinded study. Written, informed consent was obtained from each patient. Exclusion criteria included
325 allergy to local anesthetics, Raynaud's disease, and sickle cell anemia. Patients with preoperative pain or with preoperative VAS scores greater than 3 also were excluded from the study. Patients were allocated to either group (n = 20) based on a computer generated randomization list for 40 patients. The anesthesiologist, patient, surgeon, and recovery staff were all blinded to the randomization. An intravenous (IV) catheter was secured on the non-operative hand and patients were premedicated with IV midazolam 0.02 mg/kg. A 20-guage cannula was then inserted on the dorsum of the operative hand for injecting the IVRA solution. After routine monitors (Cardiocap II; Datex Ohmeda, Inc., Madison, WI, USA) were applied to the patient, a double tourniquet was positioned on the upper operative arm, which was then exsanguinated by elevating it and wrapping it with an Esmarch bandage. The proximal tourniquet was inflated to 250 mmHg and the Esmarch bandage was then removed. Circulatory isolation of the operative arm was confirmed by inspection of the hand and absence of a radial pulse. The IVRA solutions were prepared by a laboratory assistant who had no further role in the study. The assistant added one mL of saline (control group) or 0.5 mg of neostigmine methylsulphate (Myostigmin; neostigmine group) to 40 mL of 0.5% lidocaine, which was prepared by diluting 10 mL of 2% lidocaine (Xylocard 2%) with saline. The solution was then handed over to the resident anesthesiologist who was blinded to the randomization. The IVRA was established by injecting the solution over 60 seconds. Sensory block was assessed by a pinprick with a 22-gauge, short bevel needle every 30 seconds. Patient response was evaluated in the sensory dermatomes of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves. Onset time of sensory block was noted as the time from injection of the drug to sensory block achieved in all dermatomes. Motor function was assessed every 30 seconds and consisted of asking the patient to flex and extend his wrist and fingers; complete motor block was noted when no voluntary movement was possible. Onset time of motor block was noted as the time from injection of drug to complete motor block. After onset of sensory and motor block, with the operative tourniquet (distal tourniquet) inflated to 250 mmHg, the proximal tourniquet was released and the surgery started. Patients' systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and oxygen saturation by pulse oximetry (SpO2) were monitored before and after tourniquet application; after injection of the anesthetic drug; every 5 minutes during the surgery; and, finally, after tourniquet release. Frequency of tourniquet pain and its onset time were noted. Patients suffering tourniquet pain were given IV boluses of fentanyl 25 μg for pain relief. Such patients were excluded from analysis for postoperative pain scores and analgesic requirement. At the end of surgery, motor and sensory block recovery times – the time from tourniquet deflation to movement of
326 fingers, and recovery of sensation as determined by pinprick test, respectively – were noted. The anesthesiologist graded the quality of anesthesia achieved on a numeric scale, in which 4 = excellent: no complaint from patient; 3 = good: minor complaint, but with no need for supplemental anesthesia; 2 = moderate: some complaint, which required supplemental anesthesia; and 1 = unsuccessful: patient given general anesthesia and therefore excluded from the study. After the surgery, all patients were followed for 24 hours. In the first two hours, patients assessed their pain using a 10-cm visual analog scale (VAS) at 30-minute intervals. Patients were given one tablet of diclofenac 50 mg (Voveron 50) when their pain exceeded VAS score 3, to be repeated only after 8 hours if needed. The time to first analgesic request after tourniquet release was noted, as was the number of diclofenac tablets required in the 24-hour postoperative period. Occurrence of adverse side effects (increased salivation, abdominal pain, diarrhea, tachycardia, bradycardia, hypotension, hypertension, skin rash, dizziness, tinnitus, and hypoxemia) also was noted.
2.1. Statistical analysis In the study by Yang et al. [14], a 40% reduction in VAS scores was seen in the test group compared with the control group on intra-articular administration of 0.5 mg neostigmine. Based on that study, the same dosage of neostigmine in IVRA would likely yield a 40% reduction in VAS scores. To detect a significant difference in analgesia (α - 0.05 and β 0.2), power analysis indicated the number of patients required in each group to be 17. To compensate for any study drop-outs, 20 patients were enrolled in each group. Data were analyzed using SPSS software, version 11.5 (SPSS Institute, Inc., Chicago, IL, USA). Hemodynamic parameters, VAS scores, and times (block onset and recovery times, total tourniquet time, tourniquet pain onset time, and time to first analgesic request) were compared between the groups using unpaired Student's t-test. The trend of hemodynamic parameters and VAS scores within the groups was analyzed using two-way analysis of variance with post-hoc analysis by Bonferroni's method. Chi-square test with Yates' correction was used for comparing the quality of anesthesia scores. Frequency of tourniquet pain and number of patients requiring diclofenac postoperatively were compared using Fisher's exact test. The Mann-Whitney U test was used to compare the consumption of diclofenac postoperatively. Unless otherwise indicated, data are presented as means ± SD. A P-value b 0.05 was considered statistically significant.
3. Results Forty patients who were scheduled for elective or emergency forearm and hand surgery were enrolled in this
D. Sethi, R. Wason Table 1
Demographic and perioperative data
Age (yrs) Weight (kg) ASA physical status (I/II) Men/Women Total tourniquet time (min)
Group C (n = 20)
Group N (n = 20)
25.9 ± 9.5 53.8 ± 10.2 12/8 15/5 74.6 ± 26.8
26.5 ± 11.7 53.3 ± 9.8 14/6 16/4 75.2 ± 20.9
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of isotonic saline for intravenous regional anesthesia (IVRA; control group) ; Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA.
study. Their demographic profile is shown in Table 1. All patients underwent the scheduled surgeries during IVRA. Fifteen patients underwent contracture release (8 control group pts and 7 neostigmine group pts), 9 underwent tendon transfer (three control group pts and 6 neostigmine group pts), and 7 underwent open reduction and internal fixation (4 control group pts and three neostigmine group pts). The remaining 9 patients underwent various other surgeries: nerve exploration and repair, removal of hardware, exostosis excision, capsulotomy, and arthrodesis. No statistically significant differences in hemodynamic parameters were noted between the two groups at any time during the study. Total tourniquet times for the control group (74.6 ± 26.8 min) and neostigmine group (75.2 ± 20.9 min) were statistically similar (Table 1). Seven patients (35%) in the control group and 5 neostigmine group patients (25%) experienced tourniquet pain; the frequency of tourniquet pain was comparable in the two groups. There was also no significant difference between the groups in onset time of tourniquet pain (control group: 71.0 ± 21.3 min, neostigmine group: 80.0 ± 7.4 min). The 12 patients who experienced tourniquet pain in the two groups were excluded from analysis for postoperative pain and analgesic requirement. Postoperative VAS scores at 30, 60, 90, and 120 minutes after tourniquet release were significantly lower in the neostigmine group (Table 2). A linearly decreasing trend in VAS scores was seen in both the groups (P b 0.001). In the control group, VAS scores at 120 minutes were significantly lower than VAS scores at 30 and 60 minutes (P = 0.004). However, in the neostigmine group, VAS scores at 120 minutes were significantly lower than those scores at 30, 60, and 90 minutes (P = 0.015, P = 0.042, and P = 0.008, respectively). In the neostigmine group, a significant difference was also observed between VAS scores at 30 and 60 minutes (P = 0.019). The neostigmine group had a significantly longer time to first analgesic request (355.5 ± 198.1 min) than the control group (57.8 ± 75.2 min; P b 0.001; Table 2). Six of the 15 patients (40%) in the neostigmine group
IVRA for upper limb surgery Table 2
327
Postoperative pain scores and analgesic onsumption Group C (n = 13)
VAS 30 min VAS 60 min VAS 90 min VAS 120 min Time to first analgesic request (min) 24-hour total tablet diclofenac consumption
Group N (n = 15)
3.92 ± 1.60 2.20 3.23 ± 1.42 1.53 2.62 ± 1.19 1.47 1.92 ± 0.69 0.93 57.8 ± 75.2 355.5 1.9 ± 1.1
P-value
± 0.78 ± 0.74 ± 1.60 ± 1.44 ± 198.1 b
0.5 ± 0.7
0.003 0.001 0.043 0.026 0.001 0.002
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of isotonic saline for intravenous regional anesthesia (IVRA; control group) ; Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA;VAS = visual analog score.
compared with 11 of 13 control group patients (84.6%) required one or more diclofenac tablets during the 24 hours after tourniquet release (P = 0.043). Total diclofenac tablet consumption over the 24-hour period also was lower in the neostigmine group (0.5 ± 0.7 tablet) than the control group (1.9 ± 1.1 tablets; P = 0.002; Table 2). Intraoperatively, the onset times of sensory and motor blocks were significantly shorter in the neostigmine group (n = 20; P = 0.001). The neostigmine group also had significantly longer sensory block and motor block recovery times (P = 0.005, P = 0.002, respectively; Table 3). The quality of anesthesia was “excellent” (ie, score of 4) in 16 patients (80%) in the control group and 18 patients (90%) in the neostigmine group, whereas it was “good” (ie, score of 3) in 4 patients (20%) in the control group and two patients (10%) in the neostigmine group. No patient required supplemental or general anesthesia (ie, score of 1 or 2) in either group. These data showed no statistical difference in the quality of anesthesia scores (P = 0.66). Except for one patient in the neostigmine group who suffered nausea and vomiting, no patient in either group showed any adverse effects. Table 3 Onset and recovery times of sensory and motor blocks (min) Group C (n = 20)
Group N (n = 20)
Sensory block onset time 7.5 ± 2.1 5.4 ± 1.4 Motor block onset time 15.0 ± 2.4 11.6 ± 3.4 Sensory block recovery time 3.8 ± 2.5 6.2 ± 2.8 Motor block recovery time 2.1 ± 1.6 3.9 ± 1.8
P-value 0.001 0.001 0.005 0.002
Data are means ± SD. Group C patients received 40 mL of 0.5% lidocaine with one mL of t1:9 isotonic saline for intravenous regional anesthesia (IVRA; control group); Group N patients received 40 mL of 0.5% lidocaine with 0.5 mg neostigmine for IVRA.
4. Discussion Neostigmine as an IVRA agent offered significant postoperative analgesic benefit in terms of reduced VAS scores, longer time to first analgesic request, and lower analgesic consumption, similar to what was noted previously with other IVRA adjuncts such as NSAIDs, clonidine, and meperidine [3]. Turan et al. also observed a longer time to first analgesic request when neostigmine was added to prilocaine in IVRA, though these authors did not analyze its effect on postoperative VAS scores and analgesic consumption [17]. Preclinical studies have shown that acetylcholine receptors exist at peripheral nerve endings [19], enabling cholinergic-mediated antinociception by the activation of the NO-cGMP pathway [20,21]. Neostigmine, due to its chemical structure and pharmacological action, causes protracted inhibition of acetylcholinesterase, enhancing the availability of acetylcholine at peripherally distributed muscarinic receptors, thereby allowing prolonged analgesia [22]. However, when neostigmine is used as an IVRA adjunct, its peripheral action is possibly further aided by the disruption of the blood nerve barrier by tourniquet ischemia [23] and by its injection close to the surgical site. The peripheral analgesic effect of intra-articular neostigmine has been shown in a rat inflamed knee model [24] and in patients undergoing knee arthroscopy [10,14]. Peripherally administered neostigmine also improves postoperative analgesia after upper extremity surgery during axillary brachial plexus block [15]. However, in their study of neostigmine in axillary plexus block for carpal tunnel release, Van Elstraete et al. [16] found no evidence of its analgesic effect. Based on previous studies and the similarity of opioid and cholinergic systems, they suggested that this lack of evidence might be due to the absence of local inflammation and to the intact dense perineurium at the level of a nerve plexus distant from the surgical site [25,26]. Yet Bouaziz et al. [27] noted no peripheral analgesic benefit of intraplantar administration of neostigmine. Neostigmine produced significantly reduced onset times of sensory and motor blocks while prolonging their recovery times. These findings are in agreement with those of Turan et al. [17]. However, McCartney et al. [18] observed merely a reduced motor block onset time in their neostigmine group. Prolongation of the sensory block may be related to the newly discovered acetylcholine-mediated sensory regulatory mechanism controlled by the motor system [28], and the prolonged motor block may be the result of the nicotinic agonistic effect of neostigmine at the neuromuscular junction [29,30]. The addition of neostigmine in IVRA in our study did not affect the quality of anesthesia scores, which were “excellent” or “good” in either group. Turan et al. observed an improvement in quality of anesthesia scores in their neostigmine group [17]. Neostigmine also had no effect on the frequency of tourniquet pain and its onset time, unlike the
328 improved tourniquet tolerance observed previously with clonidine [31,32]. McCartney et al. [18] also reported no effect of neostigmine on tourniquet pain; Turan et al. [17] did not evaluate this aspect. No significant side effects of neostigmine as an IVRA adjunct were noted; however, the limited number of patients prevents firm conclusion. As neostigmine does not cross the blood brain barrier, the analgesia achieved by its peripheral delivery is less likely to be limited by adverse effects (particularly nausea and vomiting) associated with its use in neuraxial blocks [5,6]. Although neostigmine may produce side effects such as increased salivation, diarrhea, and abdominal cramps, these were not seen. In addition, though Turan et al. observed a significant frequency of bradycardia attributable to systemic absorption of neostigmine or its escape during tourniquet inflation [17], we did not observe this side effect in our study. In conclusion, adding 0.5 mg neostigmine to 0.5% lidocaine in IVRA for upper limb surgery resulted in significant analgesic benefits, as seen in lower postoperative VAS scores and analgesic consumption. It also yielded significant anesthetic benefits such as shortened onset times and prolonged recovery times of sensory and motor block; however, it had no effect on quality of anesthesia scores, frequency of tourniquet pain, or adverse effects.
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