Tourniquet inflation is often used in orthopedic

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1 Preoperative Oral Dextromethorphan Attenuated Tourniquet- Induced Arterial Blood Pressure and Heart Rate Increases in Knee Cruciate Ligament Reconstruction Patients Under General Anesthesia Soichiro Yamashita, MD*, Hiroshi Yamaguchi, MD, Yu Hisajima, MD*, Kazuhiro Ijima, MD*, Kaori Saito, MD*, Ai Chiba, MD*, and Toru Yasunaga, MD Departments of *Anesthesia and Critical Care Medicine and Orthopedics, Iwaki Kyoritsu General Hospital, Iwaki, Fukushima, Japan; and Department of Anesthesia, Ryugasaki Saiseikai Hospital, Ryugasaki, Ibaraki, Japan The precise mechanism of tourniquet-induced arterial blood pressure increase is unknown. We determined the effect of preoperative oral dextromethorphan (DM) on arterial blood pressure and heart rate changes during tourniquet inflation in knee cruciate ligament reconstruction patients under general anesthesia. Patients in the DM group (n 38) received oral DM 30 mg, and patients in the control group (n 38) received oral placebo 2 h before the induction of anesthesia. Anesthesia was maintained with sevoflurane 2.0% and N 2 Oin 33% oxygen, and the trachea was intubated until the end of surgery. Arterial blood pressure and heart rate were measured at 0, 30, and 60 min after the start of tourniquet inflation. Systolic arterial blood pressure and heart rate at 60 min in the control group were significantly more than those in the DM group ( mm Hg versus mm Hg [P 0.05] and bpm versus bpm [P 0.01], respectively). The percentage increase in systolic arterial blood pressure and heart rate in the DM group was also attenuated when compared with that in the control group (P 0.05). In conclusion, preoperative oral DM 30 mg significantly attenuated arterial blood pressure and heart rate increases during tourniquet inflation under general anesthesia. (Anesth Analg 2004;98:994 8) Tourniquet inflation is often used in orthopedic surgery of the upper and lower limbs to reduce blood loss and provide good surgical conditions. However, tourniquet inflation is sometimes accompanied by severe pain and a continuous increase in systemic arterial blood pressure (1 4). Tourniquetinduced arterial blood pressure increases may develop after tourniquet inflation for min despite adequate anesthesia for the surgical procedure, and these changes are often resistant to analgesic drugs and profound anesthesia depth (3 5). The precise mechanism of tourniquet-induced arterial blood pressure increase is unknown, although several possible explanations have been proposed (4,6 9). Satsumae et al. (10) reported that preoperative Accepted for publication October 15, Address correspondence and reprint requests to Soichiro Yamashita, MD, Acute Care Neurology, Division of Brain Injury Outcomes, The Johns Hopkins Medical Institutions, 600 N. Wolfe St., Jefferson 1-109, Baltimore, MD Address to soichi2003@aol.com. DOI: /01.ANE IV ketamine 0.25 mg/kg, an N-methyl-d-aspartate (NMDA) receptor antagonist, significantly prevented tourniquet-induced arterial blood pressure increase in patients undergoing knee surgery under general anesthesia. They hypothesized that the tourniquetinduced arterial blood pressure increase might be related to NMDA receptor activation by peripheral noxious stimuli from the extremities. However, their study may be insufficient to argue the hypothesis because ketamine itself has an antinociceptive effect. Dextromethorphan (DM) is a noncompetitive NMDA receptor antagonist that can suppress central sensitization of the dorsal horn neurons in the spinal cord triggered by nociceptive afferent input from the periphery (11,12). Several studies have shown that DM pretreatment may prevent the sensitization of nociceptive neurons (13 15). Investigating the effect of DM, which is not a direct antinociceptive drug, on tourniquet-induced arterial blood pressure increase will be helpful to argue the hypothesis. Therefore, we investigated the effect of preoperative oral DM on arterial blood pressure and heart rate changes during 2004 by the International Anesthesia Research Society 994 Anesth Analg 2004;98: /04

2 ANESTH ANALG ANESTHETIC PHARMACOLOGY YAMASHITA ET AL ;98:994 8 ORAL DEXTROMETHORPHAN AND TOURNIQUET tourniquet inflation in patients undergoing knee cruciate ligament reconstruction under general anesthesia. Methods This study protocol was approved by the local ethical committee, Iwaki Kyoritsu General Hospital, Fukushima, Japan, and was performed in a randomized, double-blinded, prospective fashion. Written, informed consent was obtained from each patient. Seventy-six patients, ASA physical status I II, undergoing knee cruciate ligament reconstruction with tourniquet inflation under general anesthesia, were included in this study. Patients with hypertension, ischemic heart disease, cardiac arrhythmias, and diabetes mellitus were excluded from the study. The patients were randomly assigned to either the DM group (n 38) or the control group (n 38) by using a random numbering card. A sample-size estimate indicated that 38 patients per group would give a power of 80% at a level of 0.05 for detecting a difference of 6.5% (approximately 6.5% in preliminary data) in the percentage increase of the baseline arterial blood pressure at 60 min after the start of tourniquet inflation. All patients received oral diazepam 5 mg and ranitidine 150 mg 2 h before the induction of anesthesia. At the same time, patients in the DM group received oral DM 30 mg, and patients in the control group received oral placebo. After IV infusion of acetated Ringer s solution 10 ml/kg, anesthesia was induced with thiamylal 5 mg/kg IV, and the trachea was intubated after the administration of vecuronium 0.1 mg/kg IV. Anesthesia was maintained with sevoflurane and N 2 O in 33% oxygen. Ventilation was controlled mechanically to maintain end-tidal CO 2 in the mm Hg range. The usual monitoring was used. The end-tidal sevoflurane concentration was kept at 2.0% during the study period regardless of arterial blood pressure. When systolic arterial blood pressure increased to more than 170 mm Hg, fentanyl 100 g was given IV, and these patients data were excluded from further analysis. After skin incision, tourniquet inflation was performed at the thigh level by using 300 mm Hg of pressure. Arterial blood pressure and heart rate were recorded at 0, 30, and 60 min after the start of tourniquet inflation. After surgery, the anesthetics were terminated, and the patient s trachea was extubated after neuromuscular blockade was antagonized by using atropine 0.02 mg/kg IV and neostigmine 0.05 mg/kg IV. Statistical comparison was made between the DM group and the control group. Categorical data were compared by using the 2 test, and continuous data were compared by using the two-tailed Student s t-test. Hemodynamic changes were analyzed by twoway repeated-measures analysis of variance followed by Bonferroni s multiple comparison test. A statistical application, StatView Version 5 (SAS Institute, Cary, NC), was used for statistical analysis. P 0.05 was considered statistically significant. Results One patient in the DM group and one patient in the control group were excluded from the study because their systolic arterial blood pressure increased to more than 170 mm Hg after skin incision, and fentanyl 100 g was given IV. The statistical analysis was performed with the remaining patients data. There were no significant demographic differences between the groups (Table 1). No patient complained of symptoms related to the side effects of DM, such as dizziness, before anesthesia. Table 2 shows the hemodynamic changes during tourniquet inflation. Hemodynamic values at the start of tourniquet inflation (baseline) were not significantly different between the groups. Systolic, diastolic, and mean arterial blood pressure at 60 min were significantly increased when compared with that at baseline in both the control and DM groups (P ), but systolic arterial blood pressure at 60 min in the control group was significantly more than that in the DM group ( mm Hg versus mm Hg; P 0.05). Heart rate at 60 min significantly increased when compared with that at baseline in the control group (P ), but heart rate did not significantly change during the study period in the DM group. Heart rate at 60 min in the control group was significantly faster than that in the DM group ( bpm versus bpm; P 0.01). Figure 1 demonstrates the percentage increase of systolic arterial blood pressure and heart rate during tourniquet inflation. In both the control and DM groups, systolic arterial blood pressure significantly increased at 60 min after the start of tourniquet inflation (P ), but the percentage increase in systolic arterial blood pressure in the DM group was significantly attenuated when compared with that in the control group (P 0.05). Heart rate in the control group significantly increased at 60 min after the start of tourniquet inflation (P ), but heart rate in the DM group did not significantly change during the study period. The percentage increase in heart rate in the DM group was significantly reduced when compared with that in the control group (P 0.05). Discussion We demonstrated that preoperative oral DM significantly attenuated arterial blood pressure and heart

3 996 ANESTHETIC PHARMACOLOGY YAMASHITA ET AL. ANESTH ANALG ORAL DEXTROMETHORPHAN AND TOURNIQUET 2004;98:994 8 Table 1. Patients Demographic Data Variable DM group (n 37) Control group (n 37) Male/female 25/12 26/11 Age (yr) Height (cm) Weight (kg) Duration of tourniquet inflation (min) Data are presented as mean sd unless otherwise noted. DM dextromethorphan. rate increases during prolonged tourniquet inflation in patients undergoing knee cruciate ligament reconstruction under general anesthesia. Satsumae et al. (10) reported that a preoperative small dose of IV ketamine significantly prevented tourniquet-induced arterial blood pressure increases in patients undergoing knee surgery under general anesthesia, and they argued that tourniquet-induced arterial blood pressure increases might be related to NMDA receptor activation by peripheral noxious stimuli from the extremities. Our results may more strongly suggest the relationship between tourniquet-induced arterial blood pressure increases and NMDA receptor activation. DM is not a direct antinociceptive drug, but a noncompetitive NMDA receptor antagonist that may suppress central sensitization of the dorsal horn neurons in the spinal cord triggered by nociceptive afferent input from the periphery. Experimental animal studies have shown that DM can reduce the windup phenomenon (11), formalin-induced increases in spinal cord c-fos messenger RNA expression, and pain behavior (12). Clinically, several studies have suggested that oral DM treatment might prevent the sensitization of nociceptive neurons (13 15). Although its duration of action as an NMDA receptor antagonist is unknown, the elimination half-life of orally administered DM is approximately eight hours (16). Accordingly, we supposed that preoperative oral DM, as an NMDA receptor antagonist, attenuated tourniquetinduced arterial blood pressure increases by modulating a windup process of nerve transmission of peripheral noxious stimuli from the extremities toward high brain centers. We should also consider the relationship between tourniquet-induced arterial blood pressure increases and sympathetic nervous system changes. It has been demonstrated that tourniquet-induced arterial blood pressure increases are correlated with activation of the sympathetic nervous system (8,9). A possible interaction between catecholamines and NMDA receptor activation in the control of blood pressure at the level of the spinal cord has been investigated in animals (17 19). However, it is not clear whether oral DM directly blunted the increase of sympathetic outflow during tourniquet inflation through NMDA receptor antagonism in this study. The findings of this study are concerned with the effects of DM on other parts of the central nervous system, because DM is not a specific NMDA antagonist. DM possesses affinity for serotonin receptors at relatively large concentrations compared with its affinity for NMDA receptors (20,21). Moreover, it has been suggested that DM indirectly modulates serotoninergic transmission at serotonin receptors through attenuation of the glutamatergic receptors (22). A result conflicting with our hypothesis has been reported. Kauppila et al. (23) found that DM 100 mg given orally to 8 healthy volunteers did not attenuate pain intensity induced by tourniquet ischemia to the hand. However, pain intensity evaluated every 2 minutes for 6 minutes after submaximal exercise with the ischemic hand after tourniquet inflation was not induced by noxious stimulation which persisted for a relatively long time, such as that induced by tourniquet pain. Our findings are significant, but the effect of DM may not be strong enough to use clinically in orthopedic surgery involving a tourniquet. A larger dose of DM may be more effective to attenuate the hemodynamic changes related to tourniquet inflation. DM may also affect postoperative pain and recovery, although we did not investigate it in this study. Weinbroum et al. (24) reported that oral DM 60 or 90 mg given once before surgery and once daily for two days after surgery helped to reduce pain intensity, minimized sedation, and spared IV patient-controlled analgesia morphine after orthopedic oncology surgery. Wadhwa et al. (25) demonstrated that oral DM 200 mg every eight hours led to a modest reduction in morphine requirements but no reduction in pain levels in knee surgical patients undergoing postoperative passive knee movement. Further study to investigate the appropriate dose of DM for use in orthopedic surgery involving a tourniquet is needed. There are two limitations in this study. First, we could not show the effect of DM on tourniquetinduced pain itself or the relationship between tourniquet-induced pain and arterial blood pressure increase because this study was performed with patients under general anesthesia. Second, anesthetic depth might not be identical among the patients, because we did not use a bispectral index or auditory evoked potential index to ensure similar anesthetic depth. However, the end-tidal sevoflurane concentration was maintained at 2.0% during the study period. Moreover, the intensity of noxious stimuli that the patients received during surgery might be relatively homogeneous because of the uniform surgery. Therefore, we believe that there may have been only a small

4 ANESTH ANALG ANESTHETIC PHARMACOLOGY YAMASHITA ET AL ;98:994 8 ORAL DEXTROMETHORPHAN AND TOURNIQUET Table 2. Patients Hemodynamic Data Variable Group Before induction Baseline 30 min 60 min Systolic AP (mm Hg) DM * * Control * * Diastolic AP (mm Hg) DM * Control * * Mean AP (mm Hg) DM * Control * * HR (bpm) DM Control * Data are presented as mean sd. DM dextromethorphan; AP arterial blood pressure; HR heart rate. * P compared with baseline. P 0.05; P 0.01 compared with the control group. in patients undergoing knee cruciate ligament reconstruction under general anesthesia. Figure 1. The percentage increase of baseline hemodynamic data during tourniquet inflation. The percentage increase in systolic arterial blood pressure in the DM group was significantly attenuated when compared with that in the control group (P 0.05). The percentage increase in heart rate in the DM group was also reduced when compared with that in the control group (P 0.05). DM dextromethorphan. Values are expressed as mean sd.*p ; ** P when compared with baseline. #P 0.05 when compared with 30 min. difference in anesthetic depth between the groups during the study period. In conclusion, preoperative oral DM 30 mg significantly attenuated arterial blood pressure and heart rate increases during prolonged tourniquet inflation References 1. Kaufman RD, Walts LF. Tourniquet-induced hypertension. Br J Anaesth 1982;54: Hagenouw RR, Bridenbaugh PO, van Egmond J, Stuebing R. Tourniquet pain: a volunteer study. Anesth Analg 1986;65: Valli H, Rosenberg PH, Kytta J, Nurminen M. Arterial hypertension associated with the use of a tourniquet with either general or regional anaesthesia. Acta Anaesthesiol Scand 1987; 31: Kam PC, Kavanaugh R, Yoong FF. The arterial tourniquet: pathophysiological consequences and anaesthetic implications. Anaesthesia 2001;56: Valli H, Rosenberg PH. Effects of three anaesthesia methods on haemodynamic responses connected with the use of thigh tourniquet in orthopaedic patients. Acta Anaesthesiol Scand 1985; 29: Chabel C, Russell LC, Lee R. Tourniquet-induced limb ischemia: a neurophysiologic animal model. Anesthesiology 1990;72: Maclver MB, Tanelian DL. Activation of C fibers by metabolic perturbations associated with tourniquet ischemia. Anesthesiology 1992;76: Tetzlaff JE, O Hara J, Yoon HJ, Schubert A. Tourniquet-induced hypertension correlates with autonomic nervous system changes detected by power spectral heart rate analysis. J Clin Anesth 1997;9: Heropoulos M, Schieren H, Seltzer JL, et al. Intraoperative hemodynamic, renin, and catecholamine responses after prophylactic and intraoperative administration of intravenous enalaprilat. Anesth Analg 1995;80: Satsumae T, Yamaguchi H, Sakaguchi M, et al. Preoperative small-dose ketamine prevented tourniquet-induced arterial pressure increase in orthopedic patients under general anesthesia. Anesth Analg 2001;92: Dickenson AH, Sullivan AF, Stanfa LC, Mcquay HJ. Dextromethorphan and levorphanol on dorsal horn nociceptive neurones in the rat. Neuropharmacology 1991;30: Elliott KJ, Brodsky M, Hynansky AD, et al. Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mrna. Pain 1995;61: Weinbroum AA, Rudick V, Paret G, Ben-Abraham R. The role of dextromethorphan in pain control. Can J Anaesth 2000;47: Price DD, Mao J, Frenk H, Mayer DJ. The N-methyl-d-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 1994;59:

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