The Analgesic Effect of Intravenous Neostigmine and Transdermal...

[Full title: The Analgesic Effect of Intravenous Neostigmine and Transdermal Nitroglycerine Added to Lidocaine on Intravenous Regional Anesthesia (Bier`s Block): A Randomized, Controlled Study in Hand Surgery]

Life International Journal of Pharmacology ISSN 1811-7775 Life science alert ansinet Asian Network for Scientific Information

International Journal of Pharmacology 4 (3): 218-222, 2008 ISSN 1811-7775 2008 Asian Network for Scientific Information The Analgesic Effect of Intravenous Neostigmine and Transdermal Nitroglycerine Added to Lidocaine on Intravenous Regional Anesthesia (Bier's Block): A Randomized, Controlled Study in Hand Surgery Seyed Mojtaba Marashi, 'Arash Yazdanifard, 'Gita Shoeibi, Hooman Bakhshandch and Parin Yazdanilard 'Department of Anesthesiology and Intensive Care, Shariati Hospital, Medical Sciences/University of Tehran, Iran Department of Epidemiology and Biostatistics, School of Public Health, Medical Sciences/University of Tehran, Iran Department of Clinical Research, Medical Sciences/University of Tehran, Iran Abstract: This study was conducted to determine whether intravenous neostigmine, Transdermal Nitroglycerine (NTG) and combination of them enhance analgesia from lidocaine in Bier's block. Fighly patients with American Society of Anesthesiologist (ASA) physical statuses 1. 2 scheduled for elective hand surgery were included in the study. Participants were computer randomized to four groups with 20 patients in each group. All patients received Intravenous Regional Anesthesia (TVRA) with 3 mg kg¯¯ 0.5% lidocaine. Neostigmine group (group 1) received IVRA with 0.5 mg neostigmine added to lidocaine. Nitroglycerine (NTG) group (group 2) received transdermal patch comprise of 5 mg NTG (was applied at the proximal forearm) added to lidocaine. NTG-neostigmine group (group 3) received simultaneously neostigmine and transdermal NTG patch in addition to lidocaine. The control group (group 1) received IVRA with 2 mL saline added to lidocaine. A repeated measure analysis of variance (ANOVA) model was used for statistical analysis. Tourniquet pain onset was not significantly different between groups (p = 0.158). However there was significant differences in surgical pain onset (p<0.001). ANOVA analysis revealed that surgical pain onset was significantly longer in neostigmine group and neostigmine- NTG group in contrast with control group (p 0.001, p<0.001, respectively). Severity of pain between groups was not significant before injection, at the time of injection, as well as at 30, 60, 90 and 120 min after injection (p = 0.123). Prolonged surgical pain onset in group 1 (neostigmine) and group 3 (NTG and neostigmine) revealed that only neostigmine besides lidocaine in Bier's block have an influencing role to lengthen surgical pain onset however it could not be able to decrease severity of surgical pain in the bier's block. Key words: Bier's block, intravenous regional anesthesia, lidocaine, nitroglycerin, neostigmine INTRODUCTION Bier's block or Intravenous Regional Anesthesia (IVRA) is a safe and effective technique involving administration of a local anesthetic into a region where venous return is mechanically impeded. It is particularly considered as an alternative to general anesthesia in upper and lower extremities surgery (Mohr, 2006; Robert. and Hedges, 1991; Blyth et al., 1995). However, IVRA is a well-proven method with most frequent success it has been limited by some disadvantages comprise of slow onset, poor muscle relaxation, tourniquet pain and minimal postoperative relief (Sen et al., 2006; Choyce and Peng. 2002; Estebe et al., 2003; Turan et al., 2005; Johnson 2000). Since, 1908 that IVRA was first described by the Karl Alfred Bier, professor of surgery (Bier, 1908), several studies were performed for improving quality of this method by adding different additives including opioids, tramadol, non-steroidal anti-inflammatory drugs, dexmedetomidine, muscle relaxants, alkalinization with sodium bicarbonate and potassium to lidocaine (Son et al., 2006; Choyce and Peng, 2002; Estebe et al., 2003; Turan et al., 2002, Memis et al., 2004). Recent studies are focused on evaluation of transdermal nitroglycerin and intrathecal neostigmine to lidocaine in Bier's block (Sen et al., 2006; McCartney et al., 2003). This study was conducted to evaluate the effect of transdermal nitroglycerin (NTG), intravenous neostigmine Corresponding Author: Arash Yazdanifard, Department of Anesthesiology and Intensive Care, Shariati Hospital. North Kargar Street, 1411713135, Tehran, Iran Tel: +98 2188026017 Fax: +98 2188026010 218

Int. J. Pharmacol., 4 (3): 218-222, 2008 and combination of them on tourniquet pain onset. surgical pain onset, severity of tourniquet pain when adding to lidocaine in Bier's block. MATERIALS AND METHODS After obtaining institutional ethics committee approval and written informed consent, 80 patients with American Society of Anesthesiologist (ASA) physical statuses I, II scheduled for hand surgery and were included in this randomized, placebo controlled slukly. Patients with sickle cell anemia, Raynaud disease, or a history of allergy to local anesthetic, neostigmine or NTG were excluded from the study. Participants were computer randomized to four groups with 20 patients in each for prospectively evaluation of regional anesthesia by adding transdermal NTG and intravenous neostigmine to lidocaine in Bier's block. Standard monitors including continuous electrocardiography, noninvasive blood pressure measurement and pulse oximetry were used. Two intravenous cannulae were inserted, one in the dorsum of operative hand and the other in the contralateral hand for crystalloid infusion. A double tourniquet was placed on the upper 071 the operative side and was exsanguinated by 2 min elevation and wrapping with an Esmarch bandage. The proximal tourniquet was then inflated to 100 mmllg above systolic blood pressure or to a minimum of 250 mmIIg. Immediately after tourniquet inflation, all patients received IVRA with 3 mg kg -0.5% lidocaine (Lignoxic 2%; Caspian Tamin Pharmaceutical Co., Rasht, Iran) up to 40 mL injected over 1 minute into operative arm. Neostigmine group (group 1) received IVRA with 0.5 mg neostigmine (0.5 mg mL IPDIC, Rasht Iran) added to lidocaine to a total dose of 10 mL. NTG group (group 2) received transdermal patch comprise of 5 mg NTG (2%. Parallin base. Cadila Pharmaceutical Lid... Dholka, India) added to lidocaine that was applied at the proximal forearm (ventral, above surgical site). NTGneostigmine group (group 3) received simultaneously 0.5 mg neostigmine and transdermal patch comprise of 5 mg NTC in addition to lidocaine. The control group (group 4) received IVRA with 2 mL saline added to lidocaine to a total dose of 40 ml. The groups are shown in Table 1. Ten minules was allowed after injection of local anesthetic for block onset. After 15 min of injection in all patients, distal tourniquet was inflated to 250 mmHg and the proximal tourniquet was deflated. Patients who had pain at tourniquet or surgical site and intraoperative anesthetic or analgesic agents were administered for them. excluded from analysis and replaced with another matched Table 1: Definition of study groups classification Neostigmine Transdermal Kind of anesthetic agent use Nitroglycerine- Control neostigmine usc (group 3) n = 20 group (group 4) n = 20 (group 1) n = 20 nitroglycerine usc (group 2) n = 20 Lidocaine 0.5% 3 mg kg 1 Nitroglycerine 3 mg kg 5 mg 3 mg kg 5 mg 3 mg kg 1 patch Neostigmine Saline 0.5 mg 0.5 mg 2 mL patients. In each group tourniquel pain onsel, severity of tourniquet pain, surgical duration time, kinds of surgery (bone or soft tissue), surgical pain onset (painless. duration time) were recorded. Assessment of tourniquet pain score was made on the basis of the Visual Analog Scale (VAS) (0 no pain and 10 worst imaginable pain for the patient) and measured 30, 60, 90 and 120 min after injection of lidocaine. Severity of pain before tourniquet. application was measured on the basis of VSA for assessment of its correlation with kinds of surgery (bone or soft tissue). Also, dosage of morphine that was administered in patients with VAS more than three in the first 24 h of operation was recorded and compared between groups. Statistical analysis: Data was represented as mean standard deviation. and for interval count (relative frequency) for categorical variables. Baseline data were compared among study groups by one-way Analysis of Variance (ANOVA) for interval and Chi-square (and Fisher's exact test for categorical data. Repeated measure ANOVA model was used to compare variations of severity of pain in different time intervals and among study groups. Statistical analysis was performed using SPSS 15 for Windows (SPSS Inc., Chicago, Illinois). RESULTS Eighty patients with ASA physical statuses 1, 2 scheduled for hand surgery and were evaluated for tourniquet pain onset, severity of tourniquet pain surgical duration time, kinds of surgery (bone or soft. tissue), surgical pain onset (painless duration time) and dosage of administered morphine in first 24 h of surgery. The study population comprised of 43 women (53.7%) and 37 men (46.3%) with mean age of 39.3±14.17. They were divided to four groups with 20 cases per group. Mean time for onset of tourniquet pain was 39.3111.2 min for group 1, 34+8.1 min for group 2, 35.6±6.4 min for group 3 and 33.6-6.4 min for group 4 and no significant difference 219

Scoring according to Group 1 (Neostigmine) Int. J. Pharmacol., 4 (3): 218-222, 2008 Table 2: Result of visual analog scale scoring according to time of injection between the groups Group 2 (Transdermal NTG) Group 3 (Transdermal NTGGroup 4 (control group) time of injection (20) (n 20) neostigmine) (20) (0 201 p-value Before injection 1.85±2.10 2.00 1.65 2.10±2.02 2.10±1.95 0.810 At the time of injection 3.75±1.11 2.60=1.50 2.30±1.03 3.15±1.19 0.001 30 min after injection 0.00+0.00 0.05-0.22 0.00+0.00 0.00+0.00 0.400 60 min atter injection 1.20+1.70 2.15=1.92 0.60±1.50 2.65±1.75 0.001 90 min atter injection 3.25±1.97 2.05=2.06 1.85±1.46 1.80±1.28 0.030 120 min after injection 2.2011.76 1.55 1.95 1.1511.22 0.751 0.91 0.030 NTG: Nitroglycerine Table 3: Analysis of continues variables between groups (control group) 33.6046.41 51.60±10.37 Total 35.82-8.35 60.62-12.17 p-value 0.1.58 <0.001 54.65+8.77 55.00-14.77 0.192 Scoring according to time of injection Group 1 (Neostigmine) Group 2 Group 3 Group 4 (Transdermal NTG) Toumiquet pain onset. (min) (n = 20) 39.30-11.18 (n = 20) (Transdermal NTGneostigmine) (n = 20) (n = 20) 34.8018.03 Surgical pain onset 65.30-11.39 58.55 10.23 (painless duration time) (min) Surgical duration time (min) 59.85-17.60 40.75+14.17 35.6046.35 67.0516.29 55.75+16.27 NTG: Nitroglycerine Table 1: Kind of surgery between four groups Kinds of surgery Vale soft tissuc NTG: Nitroglycerine Group 3 Group 1 Group 2 (Transdermal NTGGroup 4 (Neostigmine) 10(0.50) 10(0.50) (Transdermal NTG) 12(0.60) 8(0.40) ncostignine) (control group) 11(0.55) 8(0.40) 9(0.45) 12(0.60) Total 410.51 39(0.49) p-value 0.487 Table 5: Dosage of administered morphine in first 24 h after surgery Dose (mg) Group 1 Neostigmine NTG) Group 2 Group 3 (Transdermal (Transdermal 4.0Group 4 NTG-ncostigminc) (control group) 3.5- 0 9(45) 7(35) 12(60) 12(60) 1 mg 1(5) 0 0 0 2 me 4(20) 4(20) 2(10) 0 3 me 2(10) 1(20) 1(20) 3(15) 1 me 1(5) 2(10) 0 0 S me 3(15) 3(15) 2(10) 3015 8 me 0 0 0 1(5) 10 mg 0 0 0 1(5) Severity of pain (VAS score) 3.0- 2.5- 2.0- 1.5- 1.0Group 1---- Group 2 Group 3 ----- Group 4 VAS: Visual Analog Scale, NTG: Nitroglycerine, p-value, based on Fisher's exact test (two-sided)=0.17 was observed among them (p = 0.158). However there was significant differences in surgical pain orised between four groups (p<0.001). Statistical analysis revealed that. surgical pain onset was significantly longer in neostigmine group (group 1) and neostigmine-NTG group (group 3) in contrast with control group. There was not significant differences in severity of pain between four groups before injection, at the time of injection and 30, 60, 90 and 120 min after injection (p 0.123) (Fig. 1). Distribution of bone and soft tissue surgery was similar between groups (p = 0.487) (Table 4). Postoperative morphine use in first 24 h of surgery was not significant (p = 0.17). Dosage of administered morphine in first 24 h after surgery is shown in Table 5. Details of data in each group are shown in Table 2-4. 0.5- 0.0Before At the 30 min 60 min 90 min 120 min injection time of e after after injection injection injection injection injection after Fig. 1 Trends of the severity of pain among different study groups DISCUSSION Bier's block or IVRA is a practical method for short lasting procedures (about 60 min) involving extremities (Mohr, 2006). For achieving ideal IVRA, its solution. 220

Int. J. Pharmacol., 4 (3): 218-222, 2008 should have the following features: rapid onset, reduced dose of LA, reduced tourniquet pain and prolonged post. deflation analgesia (Lauretti et al., 2001). Several studies were performed for improving quality of this method by adding different additives including opioids, tramadol, non-steroidal anti-inflammatory drugs, dexmedetomidine. muscle relaxants, alkalinization with sodium bicarbonate, potassium, neostigmine and NTG to lidocaine (Sen et al., 2006, Choyce and Peng, 2002; Estebe et al., 2003; Turan et al., 2002; Mcmis et al., 2004; McCartney et al.. 2003). Nowadays Analgesic effect of neostigmine and NTG in varying feature (intrathecal neostigmine, peripherally applying neostigmine, intravenous NTC and transdermal NTG) and their synergistic effect with lidocaine have been established (Laurelli et al., 1996; Krukowski et al., 1997; Lauretti et al., 1998; Bone et al., 1999; Yang et al., 1998, Lauretti et al., 1999a). Regarding to interaction of neostigmine and NTG. the data on acute pain suggest that the antinociception of sufentanil or neostigmine, both linked to the descending inhibitory pathways of pain modulation, have been influenced by a nitric oxide donator and transdermal application of the nitric oxide generator, nitroglycerin, enhances this antinociception from spinal administration of either sufentanil or neostigmine (Lauretti et al., 2001, 1999b, 2000). In the other hand nitric oxide synthesis in the spinal cord is stimulated by acetylcholine that is necessary for the expression of analgesia secondary to the cholinomimetic agents, such as spinal neostigmine (Lauretti et al., 2000, Xu et al., 1996; Bouaziz et al., 1995). According these data, we added transdermal NTG and intravenous neostigmine to lidocaine in Bier's block to evaluate any possible additive or supra additive analgesic action of these agent in the peripheral nerve system. Present data showed there were no significant differences between 4 groups in severity of tourniquet pain. tourniquet pain onset and post surgical morphine use that it is in agree with McCartney. C and disagree wit Selda and their colleagues (Sen et al., 2006; McCartney et al.. 2003). However, painless period or surgical pain onsel. was significantly different between 1 groups (p<0.001) and ANOVA analysis revealed that surgical pain onset was significantly longer in neostigmine group (group 1) and neostigmine- NTG group (group 3) in contrast with control group (p = 0.001, p<0.001, respectively). Only prolonged surgical pain onset in group 1 (neostigmine) and group-3 (transdermal NTG and neostigmine) revealed that neostigmine besides lidocaine in Bier's block have an influencing role to lengthen surgical pain onset. However, we only assessed specific dosage of neostigmine and further studies are needed to clarify which dose of neostigmine will effectively prolong surgical pain onset, or relief severity of it. REFERENCES Bier, A., 1908. A new method for anaesthesia in the extremities. Ann. Surg, 48: 780-780. Blyth, M.LG., A.W.G. Kinnirmonth and D.K. Asante, 1995. Bier's block: A change of injection site. J. Trauma, 39: 726-728. Bone, H.G., H. Van Aken, M. Booke and H. Burkle, 1999. Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine. Reg. Anesth. Pain Med., 21: 105-110. Bouaziz, H., C. Hewitt and IC. Eisenach, 1995. Subarachnoid neostigmine potentiation of alpha 2-adrenergic agonist analgesia. Reg. Anesth.. 20: 121-127. Choyce, A. and P. Peng, 2002. A systematic review of adjuncts for intravenous regional anesthesia for surgical procedure. Can. J. Anaesth., 49: 32-45. Estebe, P., M.E. Gentili, G. Langlois, P. Mouilleron, F. Bernard and C. Hooffey, 2003. Lidocaine priming reduces tourniquet pain during intravenous regional anesthesia: A preliminary study. Reg. Anesth. Pain Mel, 28: 120-123. Johnson, C.N., 2000. Intravenous regional anesthesia: New approaches to old technique. CRNA, 11: 57-61. Krukowski, J.A., D.D. Hood, J.C. Eisenach, K.A. Mallak and R.L. Parker, 1997. Intrathecal neostigmine for post-cesarean section analgesia: Dose response. Anesth Analg., 84: 1269-1275. Lauretti, G.R., MP. Reis, W.A. Prado and J.G. Klamt, 1996. Dose response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg.. 82: 1182-1187. Lauretti, G.R., D.D. Ilood, J.C. Eisenach and B.L. Pfeifer, 1998. A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. Anesthesiology, 89: 913-918. Lauretti, G.R, R. De Oliveira, M.P. Reis, A.L. Mattos and N.L. Pereira, 1999a. Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery. Anesthesiology: 90: 734-739. Laurelli, G.R., LC. Lima, M.P. Reis, W.A. Prado and N.L. Pereira, 1999h. Oral kelamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology, 90: 1528-1533. Lauretti, G.R., A.P. Oliveira, M.C. Juliao, M.P. Reis and N.L. Pereira, 2000. Transdermal nitroglycerine enhances spinal neostigmine postoperative analgesia following gynecological surgery. Anesthesiology, 93: 943-946. 221

Int. J. Pharmacol., 4 (3): 218-222, 2008 Lauretti, G.R., A. Oliveira, A. Rodrigues and C. Paccola, 2001. The effect of transdermal nitroglycerin on spinal 5 (+) ketamine antinociception following orthopedic surgery. J. Clin. Anesth., 13: 576-581. McCartney, C., S. Brill, R. Rawson, K. Sanandaji. A. lagounova and V. Chan, 2003. No anesthetic or analgesic benefit of neostigmine 1 mg added to intravenous regional anesthesia with lidocaine 0.5% for hand surgery. Reg. Anesth. Pain Med., 28: 414-417. Memis, D., A. Turan, B. Karamanlioglu, Z. Pamukcu and 1. Kurt, 2004. Adding dexmedetomidine to lidocaine for intravenous regional anesthesia. Anesth Analg... 98: 835-840. Mohr, B., 2006. Safety and effectiveness of intravenous regional anesthesia (Bier block) for outpatient management of forearm trauma. Can. J. Emerg. Med.. 8: 217-250. Roberts, J.R. and J.R. Hedges, 1991. Clinical Procedures in Emergency Medicine. 2nd Edn., Philadelphia: Saunders, ISBN: 0721676111, pp: 199-503. Sen, S., B. Ugur, O. Aydin, M. Ogurlu, F. Gursoy and 0. Savk, 2006. The analgesic effect of nitroglycerin added to lidocaine 011 intravenous regional anesthesia. Anesth Analg., 102: 916-920. Turan, A., B. Karamanlioglu, D. Memis, G. Kaya and Z. Pamukcu, 2002. Intravenous regional anesthesia using prilocaine and neostigmine. Anesth Analg.. 95: 1119-1122. Turan, A., D. Memis, B. Karamanlioglu, T. Guler and Z. Pamukcu, 2005. Intravenous regional anesthesia using lidocaine and magnesium. Anesth. Analg.. 100: 1189-1192. 222