Effectiveness of Low Dose Lidocaine With and Without Tramadol for Intravenous Regional Anesthesia: A Randomized Prospective Study

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1 Med. J. Cairo Univ., Vol. 81, No. 1, September: , Effectiveness of Low Dose Lidocaine With and Without Tramadol for Intravenous Regional Anesthesia: A Randomized Prospective Study ENAS M. SAMIR, M.D. The Department of Anesthesia and Intensive Care, Faculty of Medicine, Cairo University Abstract Background: Intravenous regional anesthesia (IVRA) is a simple, reliable and safe anesthesia technique suitable for short procedures of both upper and lower extremities. It does not, however, provide postoperative analgesia. Local anesthesia toxicity is a concern during IVRA. Several techniques have been devised to decrease the dose of lidocaine while improving postoperative pain, including the use of lidocaine with adjuvants such as opioids, alpha-2 agonists, and NSAIDs. The lowest concentration of lidocaine used in most reported studies is 0.5%. Objective: To compare the efficacy of 0.4% lidocaine, alone, or with tramadol 100mg, with lidocaine 0.5% alone for IVRA. Methods: This prospective randomized controlled study was carried out on 90 adult patients ASA I and II undergoing minor hand and forearm surgeries. Patients were randomized into three groups received IVRA: (Group A): Received 40mL Lidocaine 0.5%, (Group B): Received 40mL Lidocaine 0.4% and, (Group C): Received 40mL Lidocaine 0.4% + 100mg tramadol. Sensory block was tested by pinprick method. Visual analogue scale (VAS) was used to assess pain levels. Patients were also assessed for the time to the first analgesic request, the total 24h analgesic consumption, and side effects. Results: Patient demographic and operative data were insignificantly different between groups. The incidence of tourniquet pain and the number of patients requiring GA were significantly higher in group B compared to the other 2 groups. Tramadol group (Group C), was significantly better compared to group A and B with respect to the time to the first analgesia. Patients in group C required less analgesia in 24h compared to the other 2 groups. Conclusion: Lidocaine 0.4% with tramadol provides a superior analgesia than lidocaine 0.5% alone, and may decrease the risk of local anesthetic toxicity. Lidocaine 0.4% alone, did not provide reliable analgesia. Key Words: Intravenous regional anesthesia Tramadol Lidocaine. Correspondence to: Dr. Enas M. Samir, The Department of Anesthesia and Intensive Care, Faculty of Medicine, Cairo University Introduction AUGUST Bier was the first to describe intravenous regional anesthesia (IVRA) in IVRA is suitable for surgeries involving both upper and lower extremities. Being relatively safe, simple, with high success rates (94% to 98%), cost-effective and provides rapid recovery of function with a bloodless operating field are the main advantages which make it ideal for surgeries performed in ambulatory setting. Limitations for its use include, tourniquet time and pain, lack of post-operative analgesia and local anesthetic (LA) toxicity [1,2]. Lidocaine is the most commonly used local anesthetic for IVRA in North America. It has a relatively short duration of action which limits its postoperative analgesic effect [3]. Seizure has been reported with lidocaine anesthesia. The lowest dose associated with a seizure was 1.4mg/kg [4]. Cardiac arrests and deaths were also reported with lidocaine 2.5mg/kg [4] Local anesthetic toxicity during tourniquet inflation was reported, with tourniquet pressure 150mmHg above the initial systolic arterial blood pressure. Seizures could occur after tourniquet deflation even with a tourniquet time more than 60 minutes 141. Bupivacaine, a long-acting LA which is no longer recommended for IVRA because of the risk of causing cardiac arrest [5]. Ropivacaine, is a derivative of bupivacaine causes less depression of cardiac conduction. It has a prolonged and improved analgesia compared to lidocaine, with a lower incidence of toxicity than bupivacaine [6-8]. Prilocaine is the most commonly used LA for IVRA in Europe. It has the least toxic profile among the amino-amide local anesthestics with a relatively short duration of action [5]. 665

2 666 Effectiveness of Low Dose Lidocaine With & Without Tramadol Several adjuncts have been added to LA to improve the quality of IVRA, including muscle relaxants, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), alkalizing agents and alpha 2 agonists. Tramadol is a synthetic opioid selective for pt receptors with dual mechanism of action. It acts as a pt receptor agonist and prevents re-uptake of the neurotransmitter norepinephrine. Some investigators have suggested that tramadol could have a local anesthetic effect on peripheral nerves when used alone [9,10]. Accordingly, this prospective randomized controlled study was designed to investigate the effectiveness of low dose 0.4% lidocaine either alone or combined with 100mg tramadol for IVRA as compared to 0.5% lidocaine. Patients and Methods After Institutional Ethical Committee approval, and informed written consent from each patient, 90 adult patients American Society of Anesthesiologists (ASA) physical status I and II undergoing hand and forearm surgeries (e.g. tendon graft, of contracture, carpal tunnel syndrome, and tendon ) were enrolled in this prospecfive randomized controlled study. Exclusion criteria included patient refusal, hypersensitivity to local anesthetic or opioids, coagulation disorders, and sickle cell disease. The study was conducted at Kasr El Aini Hospitals in the period between May 2011 and April Patients were randomly assigned to one of three groups, 30 patients each, using closed envelops: Group A (control group): Received Lidocaine 0.5% 40m. Group B: Received Lidocaine 0.4% 40mL. Group C (tramadol): Received Lidocaine 0.4% 40mL + 100mg Tramadol. On arrival to the operating theater and without any premedication, standard monitoring including electrocardiography (ECG), pulse oximetry, and non-invasive blood pressure were applied to each patient. After obtaining baseline values of hemodynamic variables and oxygen saturation, two cannulae (20- gauge) were inserted, one at the dorsum of the hand on the operative site and the other on the opposite hand. Esmarch's bandage was used to exsanguinate the arm of the operative side of each patient. A double pneumatic tourniquet was applied around the upper arm. Then, the proximal one was inflated to 250mmHg (or at least 100mmHg above the patient systolic blood pressure). After removal of the bandage, 40mL of solution was injected i.v. slowly on the surgical side according to the group. The sensory block to pinprick was assessed at 60- s intervals after injection of the solution. After anesthesia was confirmed, the distal tourniquet was inflated to 250mmHg and the proximal one was deflated. Oxygen 3L/min was applied to all patients via nasal prongs. Mean arterial pressure (MAP) and heart rate (HR) were monitored every five minutes intra-operatively and every 15min in the post anesthesia care unit (PACU). The level of pain based on visual analogue scale (VAS) (where 0=No pain, and 10=Worst pain) was assessed in the PACU and recorded at the following time intervals (immediately after tourniquet deflation, at 30min, 1 h, 2h, and 24h post deflation). General anesthesia was induced to patients with VAS >4 intraoperatively with fentanyl 1-2mg/kg and propofol 2mg/kg. A laryngeal mask airway was inserted. Anesthesia was then maintained with sevoflurane with 0 2 and air 50%. After surgery, the tourniquet was deflated gradually (but not before 30min after injection of the LA), and patients were transferred to PACU. Diclofenac sodium 75mg i.m was used for postoperative analgesia when VAS >4. The onset of sensory blockade, tourniquet time and incidence of tourniquet pain, the time to the first analgesic request as well as, the total analgesic consumption in the first 24h were all assessed. Side effects including dizziness, headache, blurred vision, lethargy, tinnitus, hypotension, bradycardia, and seizures were also reported. Statistical analysis: Statistical analysis was performed using Prism 6.02 (Graph Pad Software, Inc.). Data were expressed as mean (SD), median and range or ratio, number and percent as indicated. One way analysis of variance (ANOVA) was used for comparisons between groups. Categorical variables were compared using the Chi-square test. Ap-value of <0.05 was considered statistically significant.

3 Enas M. Samir 667 Results There were no significant differences between patients in the three groups with respect to age, body weight, operative and tourniquet time (Table 1). Mean arterial blood pressure, heart rate and, oxygen saturation, remained stable; no significant differences were noted between the groups either during the surgery or in the PACU. The onset of sensory blockade was variable between the three groups, the fastest onset was recorded among patients of group C (tramadol) followed by group A (control), whereas group B had the most delayed onset of the sensory blockade (Table 2). The incidence of tourniquet pain reported in the current study was significantly higher among patients of Group B. Twelve patients in this group (40%) had discomfort from the tourniquet. Whereas, three patients in group A (9.9%) complained of pain at the tourniquet site at 15-20min after tourniquet inflation. Only one patient in Group C (3.3%) developed pain from the tourniquet at 20min after inflation (Table 1). Incomplete analgesia was reported in 10 patients of Group B compared to 2 patients in group A and one patient in group C. Those patients complained of tourniquet pain as well. General anesthesia was initiated in those patients 15-20min after the beginning of surgery (Table 1). Postoperative pain scores (VAS) were significantly higher in Group B compared to the other two groups immediately after tourniquet deflation and at 30min thereafter. Visual analogue Scale scores were significantly lower in group C at one hour following deflation when compared to group A (Table 3). There was significant difference between the three study groups with respect to the time to first analgesic request. Tramadol group (Group C), was significantly better compared to group A and B. In addition, the total postoperative 24h analgesic requirement was significantly higher in group B compared to the other 2 groups (Table 2). As regard the incidence of postoperative complications, one patient in Group C (tramadol) developed postoperative nausea and vomiting which was treated with Ondansteron 4mg. Table (1): Demographic and operative data [mean (SD), number, percent and ratio]. Age (years) Weight (kg) Sex (male/female) Duration of surgery Tourniquet time Group A Group B Group C (5.49) 78.1 (4.3) 14/ (2.29) 77.6 (6.02) 15/ (2.57) 80.2 (4.7) 17/13 39 (12.4) 41 (10.02) 37 (11.7) 46 (12.4) 49 (11.03) 47 (12.6) Incidence of 3 (9.9%) 12 (40%)* 1 (3.3%) Tourniquet pain GA supplementation 2 (6.6%) 10 (33.3%)* 1 (3.3%) Group A (control group): Lidocaine 0.5% 40mL, Group B: Lidocaine 0.4% 40mL, Group C: Lidocaine 0.4% 40mL + 100mg Tramadol, GA= General anesthesia, * statistically significant compared to group A & C, *p<0.05. Table (2): Onset of sensory blockade, time for first analgesic request and total postoperative 24 hours analgesic consumption [mean (SD)]. Onset of sensory blockade Time for 1st. analgesic request Group A Group B Group C 5.2 (1.3) (2.4) 4.5 (1.2)* 110 (24) + 65 (18) 180 (35)* Total postoperative 128 (12.6) (24.9) (27)* 24 hours analgesic consumption (mg) Group A (control group): Lidocaine 0.5% 40mL, Group B: Lidocaine 0.4% 40mL, Group C: Lidocaine 0.4% 40mL + 100mg Tramadol, *statistically significant compared to group A & B, +statistically significant compared to group B, *p<0.05. Table (3): Post-operative VAS at different times of the study [median (rang)]. Group A Group B Group C Immediate after 0 (0-2) 3 (2-4)* 0 (0-1) tourniquet 30 min after tourniquet lh after tourniquet 2h after tourniquet 24h after tourniquet 2 (0-3) 4 (3-5) + 1 (1-3) 5 (4-6)* 1 (1-3) 1 (0-2) 2 (0-2) 3 (2-4)++ VAS = Visual Analogue Scale, Group A (control group): Lidocaine 0.5% 40mL, Group B: Lidocaine 0.4% 40mL, Group C: Lidocaine 0.4% 40mL+100mg Tramadol, * statistically significant compared to group A & C, + statistically significant compared to group B & C, +F statistically significant compared to group A & B *p <0.05.

4 668 Effectiveness of Low Dose Lidocaine With & Without Tramadol Discussion The result of the present study suggests that 100mg Tramadol, as adjuvant to 0.4% Lidocaine for IVRA, improves intraoperative analgesia as well as decreasing postoperative analgesic requirement without significant side effects. Intravenous regional anesthesia (Bier block) is useful for procedures involving the extremities and lasting less than 60 minutes. Several attempts have been made in order to modify and improve IVRA, both technically and pharmacologically, decreasing the risks, enhancing the benefits and minimizing its limitations. Most of these attempts were pharmacological, evaluating different types of local anesthetics and agents which have a local anesthetic properties, as well as testing adjuvant in order to improve analgesia duration, muscle relaxation, tourniquet tolerance um During IVRA, lidocaine in small concentrations acts on the sensory nerve endings and small nerves. A larger concentration of lidocaine was required for nerve trunks. The initial effect of LA during IVRA is a direct block of the nerve endings near the injection site, followed by a profound block of the main nerve trunks [12,13]. Tramadol is a selective pt-receptor agonist structurally related to codeine [14]. In addition, tramadol acts on the monoaminergic system preventing the reuptake of norepinephrine and 5-hydroxytryptamine at a 2 adrenergic receptors [15]. Tramadol has been proved to have a local anesthetic effects on peripheral nerves. The sensory blocking effect of tramadol is mediated through blocking the voltage dependant sodium and potassium channels in a way similar to that of lidocaine [16]. The onset of sensory blockade in the present study was enhanced by the addition of 100mg tramadol to lidocaine 0.4%. This result was in agreement with previous studies which demonstrated a faster onset of sensory block with the addition of tramadol to LA [1 7,1 8]. Siddiqui et al. [1 8] investigated the effects of two different doses of tramadol 50mg and 100mg added to 0.5% lidocaine and revealed a faster onset of sensory block with both doses. Similarly, Alayurt et al. [17] found a faster onset of sensory block when tramadol 100mg was added to lidocaine 0.5%. The incidence of tourniquet pain reported in this study was significantly lower in group C where tramadol was added to LA. Tourniquet pain could be due to, neuropathic pain secondary to nerve compression, stimulation of nerve endings in the connective tissue, or ischemia of the skeletal mus- cles with the of metabolic substances. Tramadol could help in management of tourniquet pain as it has been used for treatment of neuropathic pain. In addition, Tramadol has been proved to be more effective than morphine in relieving ischemic pain in rats [18]. Tan et al. [19] in a previous study found that tramadol 50mg decreased tourniquet pain at 30 minutes and after the change over to the distal tourniquet. Also, Alayurt et al. [1 7] found that tramadol 100mg added to LA decreased intraoperative fentanyl requirements and tourniquet pain at 20 and 40 minutes. On the other hand, Siddiqui et al. [18] found no difference with 50mg tramadol, as regard intraoperative analgesia but reported decrease in intraoperative fentanyl requirements. So far, it has been observed that, adequate analgesia was obtained with lidocaine, 0.5% suggesting that, lower concentrations of lidocaine alone do not appear to provide adequate analgesia. Abdulla and Fadhil [20], in an attempt to reduce the dose of lidocaine during IVRA concluded that, lidocaine, 0.25% alone failed to provide adequate analgesia, successful analgesia was obtained in 13.3% of their patients. The addition of fentanyl 0.05mg improved the quality of analgesia and successful analgesia was obtained in 26.6%. These results are in agreement with the results of the present study, as lidocaine 0.04% alone provided inadequate analgesia whereas, the addition of 100mg tramadol improved intraoperative analgesia. The time to first analgesia observed in the present study was significantly prolonged with the addition of tramadol to lidocaine. Siddiqui et al. [18] reported similar results, they found a significantly longer time to first analgesia with tramadol 100mg but not 50mg added to LA. The total 24 hours analgesia consumption reported in the current study was significantly lower with the addition of tramadol to 0.4% lidocaine. The effect of adding tramadol to lidocaine during IVRA on postoperative analgesia has been investigated in several studies, which revealed contradicting results. Some investigators found no significant advantage with this combination [17]. Whereas, other studies appreciated the addition of tramadol to lidocaine for IVRA [18,21]. Side effects reported with the use of tramadol for IVRA included, skin rash distal to the tourniquet, burning sensation and pain on injection and postoperative nausea and vomiting [18,19,22]. Siddiqui et al. [18] found increased incidence of postoperative nausea and vomiting with tramadol ad-

5 Enas M Samir 669 ministration both 50mg and 100mg. Acalovschi et al. [22] reported a significant increased incidence of skin rash below the tourniquet and pain on injection with tramadol. However, no significant side effects were reported in the current study apart from one patient in Group C (tramadol group) who developed postoperative nausea and vomiting. Pain on injection was not reported with tramadol in the present study, as the local anesthetic effect of lidocain could prevent this side effect. Conclusion: The addition of 100mg tramadol to lidocaine 0.4% during IVRA resulted in better post operative analgesia, and less total analgesic consumption in the first 24h after surgery with a lower chance for LA toxicity compared to Lidocaine 0.5%, larger studies may be needed to confirm these results. References 1- BLACKBURN E.W. and SHAFRITZ A.B.: Why do Bier blocks 15. Ko M.J., Lee J.H., Cheong S.H., Shin C.M., Kim Y.J., Choe Y.K., work for hand surgery. Most of the time? J. Hand Surg. Am., 35 (6): , MOHR B.: Safety and effectiveness of intravenous regional anesthesia (Bier block) for outpatient ma n a g ement of for earm trauma. CJEM, 8 (4): , HENDERSON C.L., WARRINER C.B., MCEWEN J.A. and MERRICK P.M.: A North American survey of intravenous regional anesthesia. Anesth. Analg., 85 (4): , GUAY J.: Adverse events associated with intravenous regional anesthesia (Bier block): A systematic review of complications. J. Clin. Anesth. Dec., 21 (8): , NIEMI T.T., NEUVONEN P.J. and ROSENBERG P.H.: Comparison of ropivacaine 2mg ml (-1) and prilocaine 5mg ml (-1) for i.v. regional anaesthesia in outpatient surgery. Br. J. Anaesth. May. 96 (5): Epub. Mar., 17, BEILIN Y. and HALPERN S.: Focused review: Ropivacaine versus bupivacaine for epidural labor analgesia. Anesth. Analg., 111 (2): , KNUDSEN K., BECKMAN SUURKULA M., BLOMBERG S., SJOVALL J. and EDVARDS SON N.: Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br. J. Anaesth., 78 (5): , REIZ S., HAGGMARK S., JOHANSSON G. and NATH S.: Cardiotoxicity of ropivacaine -a new amide local anaesthetic agent. Acta. Anaesthesiol. Scand, 33 (2): 93-98, PANG W.W., MOK M.S., CHANG D.P. and HUANG M.H.: Local anesthetic effect of tramadol, metoclopromide and lidocaine following intradermal injection. Reg. Anesth. Pain. Med., 23: 580-3, PANG W.W., HUANG P.Y., CHANG D.P. and HUANG M.H.: The peripheral analgesic effect of tramadol in reducing propofol injection pain: A comparison with lidocaine. Reg. Anesth. Pain. Med., 24: 246-9, VLASSAKOV K.V. and BHAVANI K.: The forearm tourniquet Bier block. Logic and authority versus science and experience. Minerva Anesthesiol. Feb., 76 (2): 91-2, LAY Y.Y., CHANG C.L. and YEH F.C.: The site of action of lidocaine in intravenous regional anesthesia. Acta. Anesthesiol. Sin., 31: 31-4, ACALOVSCHI I., CRISTEA T., MARGARIT S. and GAVRUS R.: Tramadol added to lidocaine for intravenous regional anesthesia. Anesth. Analg. Jan., 92 (1): , DAYER P., COLLART L. and DESMENLES J.: The pharmacology of tramadol. Drugs, 47 (Suppl): 3-7, DESMEULES J.A., PIGUET V., COLLART L. and DAY- ER P.: Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br. J. Clin. Pharmacol., 41: 7-12, JOU I.M., CHU K.S., CHEN H.H., et al.: The effects of intrathecal tramadol on spinal somatosensory-evoked potentials and motor evoked responses in rats. Anesth. Analg., 96: 783-8, ALAYURT S., MEMIS D. and PAMUKCU Z.: The addition of sufentanil, tramadol, or clonidine to lignocaine for intravenous regional anaesthesia. Anaesth. Intensive. Care, 32 (1): 22-27, SIDDIQUI A.K., MOWAFI H.A., AL-GHAMDI A., ISMAIL S.A. and ABUZEID H.A.: Tramadol as an adjuvant to intravenous regional anesthesia with lignocaine. Saudi. Med. J., 29 (8): , TAN S.M., PAY L.L. and CHAN S.T.: Intravenous regional anaesthesia using Lignocaine and tramadol. Ann. Acad. Med. Singapore., 30 (5): , ABDULLA W.Y. and FADHIL N.M.: A new approach to intravenous regional anesthesia. Anesth. Analg. Oct., 75 (4): , ASLAN B., IZDE 5 S., KESIMCI E., GOMO5 T., KAN- BAK 0.: Comparison of the effects of lidocaine, lidocaine plus tramadol and lidocaine plusmorphine for intravenous regional anesthesia. Agri. Jan., 21 (1): 22-8, ACALOVSCHI I., CRISTEA T., MARGARIT S. and GAVRUS R.: Tramadol added to lidocaine for intravenous regional anesthesia. Anesth. Analg., 92 (1): , 2001.