MULTIMODAL ANALGESIA AFTER TOTAL KNEE ARTHROPLASTY: ROLE OF PERIPHERAL NERVE BLOCKS AND SMALL DOSE KETAMINE

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1 1. 4. MULTIMODAL ANALGESIA AFTER TOTAL KNEE ARTHROPLASTY: ROLE OF PERIPHERAL NERVE BLOCKS AND SMALL DOSE KETAMINE Maher A. Doghiem, MD and Doaa Aboalia MD. Anaesthesia Department, Faculty of Medicine, Alexandria University ABSTRACT This work was carried out on 45 patients ASA physical status I-III scheduled for elective unilateral total knee arthroplasty (TKA) under general anaesthesia. Patients were randomly allocated into three equal groups: femoral group, sciatic femoral group and ketamine femoral group. Continuous femoral nerve block was performed in the three studied groups before induction of general anaesthesia. In sciatic femoral group, sciatic nerve was also blocked. Dose of 0.3 mg/kg ropivacaine 0.5 % was used for both femoral and sciatic nerve block. In ketamine group, ketamine 0.5 mg/kg was given i.v. over 2 minutes just after orotracheal intubation followed by a maintenance i.v. infusion of 3 μg/kg/min ketamine till the patient emerged from anaesthesia. In the post-anaesthesia care unit, continuous femoral and sciatic nerve blocks were maintained by infusion of 0.1 ml/kg/h of 0.2 % ropivacaine. In ketamine group, ketamine infusion of 1.5 μg/kg/min was given. Continuous nerve blocks and ketamine infusion were maintained for 48 hours postoperatively. The three groups were comparable as regards age, sex, weight, physical status and duration of surgery. All pain scores at 4, 8 and 12 hours were significantly lower in sciatic femoral and ketamine femoral groups than in the femoral group. The time elapsed between the end of surgery and first request for analgesic were similar in the three groups. Morphine consumption was significantly higher in femoral group than the other two groups. Significantly better knee flexion was obtained in the sciatic femoral and ketamine femoral groups from day-1 to day-4 postoperatively. Significantly shorter time to reach 90% knee flexion was noted in sciatic and ketamine as compared to the femoral group. In conclusion, addition of continuous sciatic nerve block or i.v. infusion of small dose ketamine to continuous femoral block up to 48 hours after TKA decreases opioid consumption and improves early rehabilitation without increasing the incidence of adverse effects. Key words: Total knee arthroplasty-sciatic block-femoral block-ketamine. INTRODUCTION The concept of multimodal analgesia refers to the use of multiple analgesic methods or drugs. Because acute pain is an integrated process that is mediated by activation of numerous biochemical and anatomical pathways, administration of analgesics acting on different targets is a rational postoperative analgesic strategy (1). Postoperative pain after total knee arthroplasty (TKA) is a major concern. It is severe in 60% of patients and moderate in 30% and it hinders early intense physical therapy, the most influential factor for good post operative knee rehabilitation (2). After TKA, postoperative pain relief can be achieved by a variety of techniques such as intravenous patient controlled analgesia, epidural analgesia, lumbar plexus block or peripheral nerve block (3,4). The N-methyl - D- Aspartate (NMDA) receptors are activated by C fibers inputs triggered by surgical tissue trauma. NMDA receptors play a critical role in neuronal plasticity leading to central sensitization and therefore, in the intensity of perceived postoperative pain (5). Ketamine is a NMDA antagonist with analgesic properties that may be important in the modulation of central sensitization to nociceptive stimulation. This class of drugs may be useful for prevention and treatment of acute postoperative pain. Ketamine is the only NMDA antagonist approved by food and drugs administration (6).

2 1. 5. The aim of this work is to compare the effect of small dose i.v. ketamine infusion and continuous sciatic nerve block supplementing continuous femoral nerve block on postoperative pain and speed of rehabilitation after total knee arthroplasty. PATIENTS AND METHODS This study was carried out at Alexandria University Hospitals. After approval of the local ethics committee, an informed written consent was obtained from 45 patients ASA physical status I III scheduled for elective unilateral total knee arthroplasty under general anaesthesia. All patients underwent thorough preoperative evaluation including history, physical examination and relevant laboratory investigations. Exclusion criteria included age younger than 18 years or older than 80 years, contraindications to continuous femoral nerve block (e.g. coagulation defect, infection at puncture site, pre existing neurological deficit in the lower extremities and allergy to local anaesthetics), chronic opioid use, diabetes and chronic pain syndromes. Patients were randomly allocated into three equal groups (15 patients each) femoral group, sciatic femoral group and ketamine femoral group. Continuous femoral nerve block was performed in the three studied groups before induction of general anaesthesia. With the patient in the supine position, the location of the femoral artery was marked on the skin, the inguinal area was prepared by antiseptic solution and draped. The femoral artery was palpated in the inguinal area and a stimulator needle was placed lateral to pulsations. The femoral nerve was identified by eliciting quadriceps contraction with nerve stimulator (Stimuplex HNS11, B Braun Melsungen, Munchen, Germany) settings at 2 Hz frequency and current between 0.2 and 0.8 ma and 18 gauge tuohy needle was inserted just lateral to the artery. This was followed by a 20-gauge catheter being threaded cm into the psoas compartment, the catheter was taped into position with steristrips and covered with adhesive dressing. After negative aspiration 30 ml 0.5% ropivacaine was injected. Absence sensory response to cold in the area of the femoral nerve confirms the correct position of the catheter (7). In sciatic femoral group, the patient was turned lateral and land marks for sciatic nerve block (greater trochanter, posterior superior iliac spine and sacral hiatus) were identified (8). A line was drawn to connect the posterior superior iliac spine to the greater trochanter of the femur. A perpendicular line was drawn bisecting this line and extending five cm cauded. Another line was drawn from the greater trochanter to the sacral hiatus, along this line, the needle could be redirected medially or laterally until the sciatic nerve could be reached (8). The sciatic nerve was identified by eliciting foot movement with nerve stimulator settings at 2 Hz frequency and current between 0.2 and 0.8 ma. A catheter was positioned and taped with steristrips. To minimize postoperative sciatic nerve evaluation, a small dose and concentration of ropivacaine 20 ml 0.2% was injected. In ketamine group, ketamine 0.5 mg/ kg was given i.v over 2 minutes after orotracheal intubation and before skin incision. The initial bolus was followed by a maintenance i.v infusion of 3 μg/kg/min of ketamine that was continued until the patient emerged from anaesthesia (9). All patients were premedicated by mg/kg i.v midazolam before nerve block and vital signs were monitored. In all groups general anaesthesia was induced with 1 µg/kg fentanyl, 3-5 mg/kg thiopentone and 0.6 mg /kg rocuronium. Trachea was intubated and controlled ventilation was started. Anaesthesia was maintained with isofluorane (0.5-1%) in a mixture of nitrous oxide 50% with oxygen. After tracheal extubation, in the post anaesthesia care unit, the continuous femoral and sciatic nerve blocks were maintained by a continuous infusion of 0.1 ml/kg/h of 0.2% ropivacaine (7). Adequacy of the nerve block was assessed by evaluating sensory response to cold in the distribution of femoral and sciatic nerves. During continuous sciatic nerve block, weakness of planter and/or dorsi flexion of the foot required temporary cessation of the infusion. After recovery of motor

3 1. 6. function, the infusion was reinstated at slower rate. In ketamine group, ketamine infusion was maintained at a rate of 1.5 μg/kg/min (9). Continuous nerve blocks and ketamine infusion were maintained for 48 hours postoperatively. Supplemental postoperative analgesia was standardized, all patients received 30 mg ketorolac iv every 6 hours, the first dose was given on arrival to postanaesthesia care unit. Titration of 3 mg morphine i.v every 5 minutes was given until the visual analog scale (VAS) 30 mm, titration was stopped if sedation score is > 2 (1=awake, 2=drowsy but respond to verbal stimuli, 3=drowsy but arousable to physical stimuli, 4=unarousable) (7) or respiratory rate 12 breaths/min. A bolus dose of morphine 3 mg was given on patient request if VAS 30 mm. After 48 hours, oral analgesic was given in the form of 600 mg ibuprofen every 8 hours. Measurements: 1. Pain intensity at rest and on movement was assessed by the patient using visual analog scale (VAS) (0: No pain, 100: worst possible pain) at 4, 8, 12, 24, 36 and 48 hours. 2. Post operative pain score (PPS) (0=no pain, 1=moderate pain only on movement, 2=moderate pain at rest severe pain on movement, 3=constant severe pain) at 4, 8, 12, 24, 36, and 48 hours. 3. Total dose of supplemental morphine analgesia was recorded. 4. Time that elapsed between the end of surgery and patient's first request for analgesia was recorded. 5. Degree of knee flexion tolerated by each patient was recorded twice daily. 6. Number of postoperative days required to obtain 90 of knee flexion. 7. Side effects of ketamine and opioids including nausea, vomiting, pruritis, dysphoria, hallucination and vivid dreams. 8. After 48 hours, patients rated their global satisfaction of 5 point verbal rating scale (0=very dissatisfied, 1=dissatisfied, 2=neutral, 3=satisfied, 4=very satisfied). Data from the three groups were compared by using analysis of variance and least significant difference test. X 2 test was used to compare the incidence of side effects and global satisfaction. Results are expressed as mean ± SD or numbers and percentage. A p value 0.05 was considered significant. RESULTS Patients' demographic data (age, weight, and gender), physical status, and duration of surgery were comparable in the three studied groups, (table 1). The VAS score at rest and on movement and the PPS 4, 8, 12, 24, 36, and 48 hours are presented in table 2. Compared with the femoral group all pain scores at 4,8, and12 hours were significantly lower in sciatic femoral group and in ketamine femoral group. There were no statistically significant differences between the three groups at 24, 36, and 48 hours. There were no statistically significant differences in all pain scores between the sciatic femoral and the ketamine femoral groups. The time elapsed between the end of surgery and patients' first request for morphine analgesia was similar in the groups (femoral group 11±8 min, sciatic femoral group 10±7 minute, and ketamine femoral group 9±7min). Morphine consumption was significantly more in the femoral group than those in the sciatic femoral and the ketamine femoral groups (Fig. 1). All patients were able to cooperate well with physical therapy. The degree of knee flexion obtained daily in all groups were presented in table 3. compared with the femoral group, significantly better knee flexion was obtained in sciatic femoral and ketamine femoral from day 1 until day 4 then from day 5 till discharge there was no significant difference between the three studied groups. The time required to reach 90 o of active knee flexion was significantly shorter in the sciatic femoral (8±5 days) and ketamine femoral (7±4days) than in the femoral group (12±6 days).

4 1. 7. Nausea and vomiting requiring treatment occurred in 5 patients in femoral group, 2 patients in femoral sciatic group and 2 patients in femoral ketamine group. No patients in the three groups suffered from sedation, hallucination, nightmares, or diplopia. There were no complications observed from the peripheral nerve blocks or continuous infusion. Patients' satisfaction with postoperative analgesia was presented in table 4. Eighty percent of the patients in the sciatic femoral and ketamine femoral groups and 73.3% of the femoral group were satisfied or very satisfied with analgesia. Table 1. Demographic data, physical status, and duration of surgery in the three studied groups. Values are mean ±SD or numbers. Femoral group Sciatic femoral Ketamine femoral N= 15 group N= 15 group N=15 P Sex F/M 9/6 8/7 7/ Age (years) 62±7 59±6 63± Weight (kg) 84±12 81±14 88± ASA physical status (I, II, III) 5/7/3 4/7/4 5/8/ Duration of surgery (hours) 3.4± ± ± * Statistically significant at P Table 2. Pain scores (VAS & PPS) at 4, 8, 12, 24, 36 and 48 hours in the three studied groups. Values are mean ± SD. Femoral group N= 15 Sciatic femoral group Ketamine femoral N= 15 group N=15 P VAS at rest 4h 34±17 14±12 16± * 8h 31±14 16±13 18± * 12h 27±14 14±10 14± * 24h 19±10 18±12 16± h 16±8 14±9 12± h 13±6 11±10 10± VAS at movement 4h 50±18 23±18 26± * 8h 46±12 30±16 33± * 12h 40±14 32±12 31± * 24h 38±21 36±10 32± h 32±16 30±14 28± h 30±10 27±12 25± PPS 4h 1.4± ± ± * 8h 1.3± ± ± * 12h 1.2± ± ± * 24h 0.8± ± ± h 0.8± ± ± h 0.6± ± ± *Statistically significant at P 0.05.

5 Morphine use {mg} Femoral Sciatic femoral Ketamine femoral Day of surgery postoperative day 1 postoperative day 2 Figure 1: Morphine use throughout each measurement period of the three studied groups Table 3. Degree of knee flexion obtained daily in the three studied groups. Values are mean ± SD. Femoral group N= Sciatic femoral group Ketamine femoral 15 N= 15 group N=15 P Day 1 34±12 58±18 52± * Day 2 46±15 66±14 61± * Day 3 52±14 73±12 71± * Day 4 63±17 82±8 78± * Day 5 76±19 85±7 86± Day 6 86±5 88±5 90± Day 7 88±7 92±6 91± Discharge 90±19 95±6 94± *Statistically significant at P Table 4. Patient satisfaction with postoperative analgesia in the three studied groups. Values are numbers and percent. Femoral group N= 15 Sciatic femoral group N= 15 Ketamine femoral group N=15 Very dissatisfied Dissatisfied 1 (6.7%) - - Neutral 3 (20%) 3 (20%) 3 (20%) Satisfied 8 (53.3%) 6 (40%) 5 (33.3%) Very satisfied 3 (20%) 6 (40%) 7 (46.7%)

6 1. 9. DISCUSSION Postoperative pain is a major concern after TKR. When inadequately treated, it intensifies reflex responses, which can cause serious complications, such as pulmonary or urinary problems, thromboembolism, hyperdynamic circulation and increased oxygen consumption (10). Moreover, it hinders early intense physical therapy. Systemic opioids are a popular postoperative analgesic regimen for TKR, because they are relatively simple to administer. Despite the use of i.v opioids by patient controlled analgesia, postoperative pain after TKR remains severe, and side effects as sedation, nausea and pruritis are common (11). Continuous femoral nerve block provides better pain relief than systemic opioids, and induces fewer side effects. It is thus considered the analgesic technique of choice after open knee surgery (12). Isolated femoral nerve block provides incomplete postoperative analgesia because the sensory innervation of the knee is also derived from the obturator, lateral femoral cutaneous and the sciatic nerves (9). In this study sciatic femoral and ketamine femoral groups showed better analgesia for 12 hours postoperatively as compared to the isolated femoral group. Also morphine consumption was significantly higher in the femoral group than the other two groups, during the first 48 hours postoperatively. David et al (13), demonstrated that the sciatic block is usually important for successful analgesia after TKR to block the posterior sensation of the knee joint. Also weber et al (14), reported that 67% of patients who had preoperative femoral block required the addition of sciatic block postoperatively. The possible explanation for the beneficial analgesic effect of small dose of ketamine, is attributed to its effect as a non competitive antagonist of NMDA ion channel receptor that does not interact with opioid receptors (15). Like other NMDA antagonists, ketamine reduces the temporal summation of pain that underlies the induction of central sensitization (16). Experimental studies demonstrate a significant contribution of NMDA receptors to the inflammation induced hyperexcitability in an acute model of arthritis; this suggests that NMDA processes are more involved in dynamic than in static mechanical hyperalgesia (17). Another hypothesis to explain the analgesic effect of small doses of ketamine may be the synergistic or additive interaction to opioids, which elicit the activation of NMDA receptors and NMDA antagonists. Also there is an interaction between ketamine and femoral block peripherally. Peripheral ionotropic glutamate receptors such as NMDA receptors have been identified on peripheral nerve fibers and their number may increase during inflammation (19). After knee surgery, poorly managed pain may inhibit the early ability to mobilize the knee joint. This in turn may result in adhesions, capsular contracture, and muscle atrophy, all of which may delay or permanently impair the ultimate functional outcome (20). after open knee surgery, pain can be associated with severe reflex spasm of the quadriceps muscle causing further pain and impaired muscle function. These spasms begin as soon as the patient begins to ambulate, and their mechanisms are unknown. Animal data suggests that the massive nociceptive input from stimulation of nociceptive afferents produces sensitization not only of the peripheral nociceptors but also of the dorsal horn neurons. This increased excitability in the spinal cord is strong and prolonged; consequently, non-nociceptive input triggers increased reflex excitability with consequent spasm of the muscles supplied by the same and adjacent spinal segments (21). With regional analgesia, the massive afferent nociceptive input is blocked, consequently, this reflex responses do not occur (21).

7 In the present study, sciatic nerve block and continuous i.v ketamine allowed improvement in active knee flexion during the first 4 postoperative days and a shorter recovery to 90 knee flexion. These results are consistent with the results obtained during the studies of Frederic et al (9), Menigaux et al (22) and Guingnard et al (16), who found that continuous i.v ketamine allowed better active knee movement during the first week after surgery, and early recovery to 90 knee flexion. David et al (13) found that sciatic block is not only required for successful analgesia after TKA, but also continuous sciatic infusion is typically needed to maintain the level of analgesia provided by the initial block which allow better active knee flexion and early recovery to 90 o knee flexion in the early postoperative days. As the development of motor blockade would interfere with one of the surgeon's main concern about early rehabilitation, temporary cessation of continuous sciatic infusion is mandatory whenever weakness or paralysis in the tibial (planter flexion) or common peroneal (dorsiflexion) distribution is noticed. Evaluation of global patients' satisfaction 48 hours postoperatively revealed that 73.3% of patients were rated between satisfied and very satisfied using the femoral nerve block alone. Supplementation with either sciatic nerve block or ketamine infusion raised this value to 80%. In conclusion, adding continuous sciatic nerve block or i.v infusion of small dose ketamine to continuous femoral block for 48 hours after TKA decreased morphine consumption and improved early rehabilitation without increasing incidence of adverse effects. Continuous femoral block have all the quality necessary to become the primary choice for regional analgesia after major knee surgery especially when combined with continuous sciatic nerve block or continuous small doses i.v ketamine. References 1. Carr DB, Goudas LC. Acute pain. Lancet 1999; 353: Shoji H, Solomonow M, Yoshino S. Factors affecting postoperative flexion in total knee arthroplasty. Orthopedics 1990; 13: Ilahi OA, Davidson JP, Tullos HS. Continuous epidural analgesia using fentanyl and bupivacaine after total knee arthroplasty. Clin Orthop 1994, 299: Schultz P, Anker E, Dahl JB. Postoperative pain treatment after open knee surgery: Continuous lumbar plexus block with bupivacaine versus epidural morphine. Reg Anesth 1991; 16: McQuay HJ. Preemptive analgesia. Br J Anaesth 1992; 69: Wolf CJ, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth, Analg 1993; 77: Hugh W, Spencer S, Paul D. Peripheral nerve blocks improve analgesia after total knee replacement surgery. Anesth, Analg 1998; 87, Brown DL. Sciatic block. In: Brown DL, ed. Atlas of regional anesthesia. Philadelphia: WB Saunders,1992: Frederic A, Marcel C, Bertrand M. Small dose ketamine infusion improves postoperative analgesia and rehabilitation after total knee arthroplasty. Anesth Analg 2005; 100 : Kehlet H. surgical stress : the role of pain and analgesia. Br J Anaesth 1989; 63: Etches RC, Warriner CB, Bander N. continuous intravenous administration of ketorolac reduces pain and morphine consumption after total hip and knee arthroplasty. Anesth Analg 1995; 81:

8 Capdevila X, Barhelet Y, Biboulet P. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999; 91: 8-15., 13. David B, Kevin S, Chelly J. Analgesia after total knee arthroplasty, is continuous sciatic blockade needed in addition to continuous femoral blockade. Anesth Analg 2004,98: Weber A, Fournier R, Van Gessel E. Sciatic nerve block and the improvement of femoral nerve block analgesia after total knee replacement. Eur J Anaesthesiol 2002; 19: Wong CS, Liaw WJ, Tung CS. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth 1996; 21: Carlton SM, Coggeshull RE. Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res1999;820: Akeson W, Amiel D, Abel M. effects of immobilization on joints. Clin Orthop 1987; 219: Kohrs R, Durieux M. Ketamine: teaching old drug new tricks. Anesth Analg 1998; 87: Guirimand F, Dupont X, Brasseur L. The effect of ketamine on the temporal summation (wind-up) of the "R III" nociceptive flexion reflex and pain in humans. Anesth Analg 2000; 90: Schaible HG, Grubb BD, Nengebauer V. the effect of NMDA antagonists on neuronal activity in cat spinal cord evoked by acute inflammation in the knee joint. Eur J Neurosci 1991; 3: Francois J, Deyaert M, Jorist D. Effects of intravenous patient controlled analgesia with morphine, continuous epidural analgesia and continuous three in one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 1998; 87: Menigaux C, Fletcher D, Dupont X. the benefits of intraoperative small dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000; 90: