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Nefopam and tramadol for the prevention of shivering during neuraxial anesthesia
Nefopam and Tramadol for the Prevention of Shivering During Neuraxial Anesthesia Federico Bilotta, M.D., Ph.D., Paolo Pietropaoli, M.D., Raffaele Sanita’, M.D., Gianni Liberatori, M.D., and Giovanni Rosa, M.D. Background and Objectives: In patients undergoing neuraxial anesthesia, heat loss and core-to-peripheral redistribution of body heat causes the core temperature to decrease. The shivering threshold is therefore reached soon, and more shivering is required to prevent further hypothermia. Because shivering has deleterious metabolic and cardiovascular effects, it should ideally be prevented by pharmacologic or other means. We evaluated the usefulness of intravenous (IV) nefopam and tramadol in preventing and reducing the severity of shivering in patients undergoing neuraxial anesthesia for orthopedic surgery. Methods: Ninety patients, scheduled for neuraxial anesthesia (epidural or subarachnoid) for lower limb orthopedic surgery, were prospectively enrolled. Patients were randomly assigned to 1 of 3 groups. Immediately before neuraxial anesthesia, 30 patients received 0.15 mg/kg⫺1 IV nefopam in 10 mL saline, 30 patients received 0.5 mg/kg⫺1 IV tramadol in 10 mL saline, and a control group of 30 patients received 10 mL IV saline. Neuraxial anesthesia was induced at the L3-L4 or L4-L5 interspaces with 1 mg/kg⫺1 mepivacaine for epidural anesthesia and 0.2 mg/kg⫺1 for subarachnoid anesthesia. An investigator blinded to the antishivering drug injected recorded the frequency and degree of shivering. Results: The overall frequency and the intensity of shivering was significantly lower in patients treated with nefopam than in those treated with tramadol or placebo (P ⬍ .05 and P ⬍ .01) and in patients treated with tramadol than in those treated with placebo (P ⬍ .05). Conclusions: As a pharmacologic means of preventing shivering in patients undergoing neuraxial anesthesia, nefopam may hold the greatest promise. Reg Anesth Pain Med 2002;27:380-384. Key Words: Anesthetic techniques, Epidural and subarachnoid, Complications, Shivering, Pharmacology, Nefopam, Tramadol.
B
ecause of the rapid heat loss and core-to-peripheral redistribution of body heat, maintaining core temperature is especially difficult in patients undergoing neuraxial anesthesia.1 The shivering threshold is reached sooner, and more shivering is required to prevent further hypothermia. Shivering, a common side effect of neuraxial
From the Department of Anesthesia and Intensive Care, University of Rome “La Sapienza” (F.B., P.P., G.R.), Rome; and the Department of Anesthesia Policlinico Casilino (R.S., G.L.), Rome, Italy. Accepted for publication February 20, 2002. Supported in part with departmental research funds, without a corporate sponsor. Presented in part at the 9th Annual Meeting of the European Society of Anaesthesiologists, Gothenburg, Sweden, April 7-10, 2001. None of the authors have a financial association with the manufacturer of nefopam or tramadol. Reprint requests: Federico Bilotta, M.D., Ph.D., via dei Tadolini 13, Rome 00196, Italy. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2704-0006$35.00/0 doi:10.1053/rapm.2002.33563
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(spinal and epidural) anesthesia,2 is distressing for the patient. The metabolic and hemodynamic consequences of shivering include increased expenditure of cardiac and systemic energy, increased oxygen consumption and carbon dioxide production, and increased cardiac work.3 The mechanisms chiefly responsible for shivering in patients undergoing surgery are intraoperative temperature loss, increased sympathetic tone, pain, and systemic release of pyrogens.4 The best way to avoid the intraoperative and postoperative shivering-induced increase in hemodynamic and metabolic demands is to prevent shivering.5 Although clonidine prevents shivering after general6 and epidural7 anesthesia, its use is limited by side effects including bradycardia, sedation, and hypotension. Nefopam (3,4,5,6-tetrahydro-5-methyll-phenyl-1H-2.5-benoxazocine hydrochloride) is a nonopioid analgesic drug that is effective in treating8 and preventing5,6 shivering after general anesthesia. Although the mechanisms underlying its analgesic action are unclear, nefopam does not bind to opiate receptors but inhibits synaptosomal uptake
Regional Anesthesia and Pain Medicine, Vol 27, No 4 (July–August), 2002: pp 380 –384
Nefopam and Tramadol
of several neurotransmitters, including dopamine, norepinephrine, and serotonin.9,10 Tramadol is a centrally acting analgesic that has weak opioid agonist properties. It also inhibits serotonin and norepinephrine uptake in the spinal cord and is effective in the treatment of postoperative shivering after general and regional anesthesia.11-14 No studies to date have investigated whether nefopam or tramadol help to prevent, rather than treat, intraoperative shivering after neuraxial anesthesia. The aim of this randomized, double-blind study was to evaluate the usefulness of intravenous (IV) nefopam and tramadol in reducing the frequency and severity of intraoperative shivering in patients undergoing neuraxial anesthesia for orthopedic surgery.
Methods After institutional approval, informed consent was obtained from 90 patients, American Society of Anesthesiologists physical status I or II, scheduled for neuraxial anesthesia for lower limb orthopedic surgery. No premedication was given. Patients were randomly assigned (by a computer-generated randomization sequence) to 1 of 3 groups. Immediately before neuraxial anesthesia, 30 patients received 0.15 mg/kg⫺1 IV nefopam (Oxadol, Kedrion, Italy) in 10 mL saline, 30 patients received 0.5 mg/kg⫺1 IV tramadol in 10 mL saline, and a control group of 30 patients received 10 mL IV saline. Neuraxial anesthesia was induced at the L3-L4 or L4-L5 interspaces with 1 mg/kg⫺1 mepivacaine for epidural anesthesia and 0.2 mg/kg⫺1 for subarachnoid anesthesia. Sensory block height was evaluated by loss of temperature discrimination and by pinprick testing 10 and 30 minutes after the induction of anesthesia. Immediately before the induction of anesthesia, all patients received an IV bolus 5 mL/kg⫺1 crystalloid solution followed intraoperatively by 15 mL 䡠 kg⫺1 䡠 h⫺1 in continuous infusion. The attending anesthesiologist was blinded to the substance injected. Patients wore a light cotton shirt and were covered with a single cotton drape. Operating room temperature was 22°C ⫾ 1°C, with a room humidity of approximately 60%. Laminar flow was not available, and the air turnover rate was 20 cycles per hour. Data from continuous monitoring of heart rate (HR) with 3-lead electrocardiogram (ECG), peripheral arterial oxygen saturation (SpO2) by pulse oximetry, noninvasive mean arterial pressure (MAP), skin temperature measured in the forearm, and core temperature measured in the urinary bladder through Foley catheters with thermistors were recorded at baseline, before anesthesia induction, and at 10-minute intervals thereafter.
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An investigator blinded to the antishivering drug injected recorded the frequency of visible shivering for 90 minutes after anesthesia induction. Shivering was graded on a 5-point scale similar to that validated by Crossley and Mahajan15: 0, absent; 1, piloerection or peripheral vasoconstriction but no visible shivering; 2, muscular activity in one muscle group; 3, muscular activity in more than one muscle group but no generalized shivering; and 4, generalized shivering. The shivering grade was calculated as the mean of patients who exhibited grade 1 to 4 shivering. A study population of 30 patients for each group was needed to produce statistical power ⱖ 90%, with ␣ ⫽ 0.05 (2-tailed) to detect a difference of 30% in the frequency of shivering during neuraxial anesthesia comparing the control group with nefopam and tramadol groups. The efficacy of prevention for shivering was statistically tested with the 2 test. Differences in the means were tested by the Student’s t test for paired values with the Bonferroni correction and analysis of variance (ANOVA) for repeated measures and then checked by the Mann-Whitney U test. Results are expressed as mean ⫾ SD. P values ⱕ .05 were considered statistically significant.
Results Patients’ characteristics, anesthetic (spinal or epidural anesthesia), and surgical variables were similar in the 3 groups (Table 1). In all patients, the sensory block reached the T4 dermatome. No differences were found in the sensory block height in the 3 groups. The overall frequency of intraoperative shivering was significantly lower in patients treated with nefopam than in those treated with tramadol or placebo (P ⬍ .05 and P ⬍ .01) and in patients treated with tramadol than in those treated with placebo (P ⬍ .05; Table 1). The intensity of shivering was also significantly lower in patients treated with nefopam and tramadol than those treated with placebo (P ⬍ .05; Table 1). No significant differences were found for hemodynamic variables (HR, MAP, and SpO2) between the 3 groups (Table 2). When data for HR, MAP, and SpO2 were analyzed in shivering and nonshivering patients, shivering patients had significantly higher HR and MAP, but lower SpO2 (data not shown). Measurement of skin temperature, to validate that heat loss did not alter skin temperature more in the placebo group than in the other groups, showed no differences between the 3 groups (data not shown). After induction of anesthesia the core temperature measured in the bladder decreased in all patients; it decreased slightly, although not significantly, more in patients treated with tramadol (Table 2). In some
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Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 1. Morphometric Data, Anesthetic Variables, and Postanesthetic Shivering Nefopam (n ⫽ 30)
Tramadol (n ⫽ 30)
Placebo (n ⫽ 30)
48 (12) 17/13 65 (10) 22/8 2/30 (6%) 1.5 (2 patients) 1–2 42 (10) 28 (10)
45 (13) 14/16 70 (14) 22/8 7/30 (24%)* 2.1 (7 patients) 1–3 37 (11) 30 (7)
45 (12) 13/17 65 (13) 21/9 17/30 (57%)†‡ 2.6† (17 patients) 1–4 40 (7) 33 (8)
Age mean (yr) Gender (M/F) Duration of surgery No. of patients receiving spinal or epidural anesthesia No. of patients shivering (%) Grade of shivering [mean among shivering patients] Range Time from baseline to onset of shivering (min) Duration of shivering (min)
NOTE. Data are means (SD). *P ⬍ .05 nefopam v tramadol; †P ⬍ .01 nefopam v placebo; ‡P ⬍ .05 tramadol v placebo by Student’s t test.
patients (⬍ 10%) nefopam and tramadol both induced transient, tolerable adverse reactions, including nausea, vomiting, and sweating.
Discussion We found that nefopam significantly lowered the rate and severity of intraoperative shivering in patients undergoing neuraxial anesthesia for orthopedic surgery. The opioid derivative tramadol, at the standard therapeutic doses used for the control of shivering,11-13 had a similar, but apparently less potent effect. We cannot exclude the possibility that we missed more effect from tramadol owing to our dose selection. The frequency of shivering during neuraxial anesthesia in the control group was higher than that reported in similar obstetric series (57% v about 40%).11,12 This difference probably reflects the greater decrease in body core temperature in our patients, possibly related to surgical techniques (ir-
rigation, greater anatomic exposure, and longer duration of orthopedic procedures) or to our anesthetic techniques. Most of our patients had spinal anesthesia, and hypothermia develops faster during spinal anesthesia than during epidural anesthesia.2 Neuraxial anesthesia causes significant vasodilation and thus heat loss, thereby reducing body core temperature.2 Intraoperative shivering during neuraxial anesthesia at a constant ambient temperature (in our study relatively low, 22° ⫾ 1°C) is triggered by various mechanisms including body core hypothermia caused by body heat loss and redistribution, heat loss exceeding metabolic heat production, and anesthetic-induced inhibition of centrally and peripherally mediated thermoregulatory control. A difficult question to answer is why nefopam, at the doses we used for preventing shivering, was more effective than tramadol in preventing intraoperative shivering after neuraxial anesthesia. Although nefopam and tramadol are both
Table 2. MAP, HR, SpO2, and T Recorded at Baseline and at 15, 30, 60, and 90 Minutes After Induction of Neuraxial Anesthesia Minutes
HR (beat/min⫺1) Nefopam Tramadol Placebo MAP (mm Hg) Nefopam Tramadol Placebo SpO2 (%) Nefopam Tramadol Placebo T (°C) Nefopam Tramadol Placebo
Baseline
15
30
60
90
74 (5) 74 (7) 76 (8)
70 (4) 74 (7) 65 (7)
73 (7) 67 (6) 83 (10)
70 (5) 72 (46) 85 (76)
75 (5) 71 (8) 85 (7)
92 (8) 91 (7) 91 (8)
90 (7) 89 (5) 92 (6)
88 (4) 95 (7) 99 (6)
87 (10) 96 (6) 100 (8)
90 (3) 95 (5) 99 (6)
98 (2) 99 (1) 98 (2)
98 (1) 98 (1) 97 (2)
98 (2) 98 (2) 98 (2)
98 (2) 99 (2) 97 (2)
99 (1) 98 (2) 97 (2)
36.9 (0.3) 36.8 (0.3) 36.9 (0.2)
36.4 (0.3) 36.3 (0.4) 36.5 (0.5)
36.3 (0.3) 36.0 (0.8) 36.4 (0.5)
36.0 (0.3) 35.6 (0.4) 36.1 (0.5)
35.6 (0.3) 35.4 (0.4) 35.9 (0.7)
NOTE. Values are expressed as mean and (SD). None of the data showed significant differences between groups by paired Student’s t test for paired values with the Bonferroni correction and ANOVA for repeated measures. Abbreviations: MAP, mean arterial pressure; HR, heart rate; SpO2, arterial oxygen saturation; T, bladder temperature.
Nefopam and Tramadol
analgesic drugs, their pharmacologic properties and mechanisms of action differ in various ways. Nefopam is a nonopioid analgesic drug that inhibits the synaptic uptake of dopamine, noradrenaline, and serotonin in an amphetamine-like fashion.10 Ample evidence confirms the efficacy of nefopam for the treatment8 and prevention5,6 of postanesthetic shivering. Our findings now confirm its efficacy for preventing intraoperative shivering. Tramadol is an atypical opioid analgesic.16 Its opioid action is preferentially mediated via the -receptor, with minimal effects at -, and ⌬-binding sites. Tramadol also activates the monoaminergic receptors of the descending neuraxial inhibitory pain pathway. Like nefopam, tramadol inhibits in vitro synaptosomal noradrenaline and serotonin uptake. This inhibitory action contributes substantially to tramadol’s analgesic action. The antishivering action of opioids is mostly related to the -receptor.17 The antishivering effect of tramadol is probably mediated via its opioid or serotonergic and noradrenergic activity or both. No pharmacologic evidence has yet shown whether the opioid action of tramadol is necessary for the prevention of shivering. These distinct mechanisms of action may partially explain why we found nefopam more effective than tramadol in preventing intraoperative shivering. Current knowledge on the relationship between shivering and the effects of drugs on vasoconstriction makes our results easier to interpret. An important influence on a drug’s effectiveness in preventing shivering is its effect on the patient’s shivering threshold, the body core temperature triggering shivering, and on the vasoconstriction threshold, the body core temperature triggering vasoconstriction. Meperidine, an opioid derivative widely used to treat shivering, with - and -receptor activity similar to that of tramadol, decreases the shivering threshold twice as much as the vasoconstriction threshold.17 Conversely, other antishivering drugs, such as clonidine (a partial ␣2-adrenoceptor agonist), alfentanil (a selective -opioid receptor agonist), propofol, and the volatile anesthetics decrease the vasoconstriction and shivering thresholds to the same extent. We failed to identify significant differences in forearm temperature in the 3 groups, possibly because of the small sample size. In patients undergoing neuraxial anesthesia, nefopam may nonetheless be more effective than tramadol (a - and -opioid receptor agonist) in preventing shivering, because the earlier activation of the vasoconstriction threshold may diminish body heat loss. A limitation of this study is that in our small sample of patients the statistical power was too low to confirm the difference in body core temperature
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in the 3 groups. Nonetheless, body core temperature decreased faster and to a greater extent in patients treated with tramadol, less in patients treated with nefopam, and even less in patients treated with placebo. It may also be that bladder temperature is less accurate than tympanic temperature as a measure of core temperature due to an increase in pelvic blood flow related to central block compensating for temperature redistribution. Nonetheless, in our patients, bladder temperature invariably decreased at a comparable rate to that reported in studies using tympanic temperature.2 The possibility that tramadol was less effective than nefopam in preventing shivering because we used a too low dose seems unlikely to us. The doses of both drugs used in our study (0.15 mg/kg⫺1 IV nefopam, 0.5 mg/kg⫺1 IV tramadol) were equal to those commonly reported as effective for treating shivering with minimal side effects.6,11-13 Chan et al.11 showed that administration of tramadol IV at 0.25 mg/kg effectively controlled shivering during cesarean delivery during regional anesthesia with minimal side effects, while increasing tramadol dose to 0.5 mg/kg did not increase its therapeutic effects. Because the 2 drugs differ in their mechanisms of action, their dose response curves presumably have different slopes. The potency of the 2 drugs in preventing shivering needs confirmation from complete dose-response curves. The distinctive feature of this study is that we assessed the effectiveness of 2 antishivering drugs for the prevention, rather than for the treatment, of shivering during neuraxial anesthesia. Because of the difficulty in physically warming patients undergoing neuraxial anesthesia, an alternative pharmacologic method for preventing shivering would be clinically useful. Among the drugs so far used for this purpose, our findings suggest that nefopam, a drug with few disadvantages, may hold promise. Future studies are needed to compare the effectiveness of nefopam and meperidine in preventing shivering in patients undergoing neuraxial anesthesia.
Acknowledgment The authors thank Prof. Paolo Nencini for his helpful comments on the pharmacologic content of the manuscript.
References 1. Sessler DI, Ponte J. Shivering during epidural anesthesia. Anesthesiology 1990;72:816-821. 2. Saito T, Sessles DI, Fujita K, Ooi Y, Jeffrey K. Thermoregulatory effects of spinal and epidural anesthesia during cesarean delivery. Reg Anesth Pain Med 1998;23:418-423.
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3. Imrie MM, Hall GM. Body temperature and anesthesia. Br J Anaesth 1990;64:346-354. 4. Sessler DI. Perioperative heat balance. Anesthesiology 2000;92:578-596. 5. Bilotta F, Pietropaoli P, La Rosa I, Spinelli F, Rosa G. Effects of shivering prevention on hemodynamic and metabolic demands in hypothermic post operative neurosurgical patients. Anaesthesia 2001;56:514-519. 6. Piper SN, Suttner W, Schmidt C, Maleck WH, Kumle B, Boldt J. Nefopam and clonidine in prevention of postanaesthetic shivering. Anaesthesia 1999;54:683702. 7. Sia S. I.V. clonidine prevents post-extradural shivering. Br J Anaesth 1998;81:145-146. 8. Rosa G, Pinto G, Orsi P, De Blasi A, Conti G, Sanita` R, La Rosa I, Gasparetto A. Control of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery. Acta Anaesthesiol Scand 1995;39:90-95. 9. Fuller RW, Snoddy HD. Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice. Neuropharmacology 1993;32:995-999. 10. Heel RC, Brogden RN, Pakes GE. Nefopam: A review of its pharmacological properties and therapeutic efficacy. Drugs 1980;19:249-267.
11. Chan AM, Ng KF, Tong EW, Kj GS. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth 1999;46:253-258. 12. Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. Anesth Analg 2001;93:12881292. 13. De Witte J, Deloof T, De Veylder J, Housmans PR. Tramadol in the treatment of postanesthetic shivering. Acta Anaesthesiol Scand 1997;41:506-510. 14. Eggers KA, Power I. Editorial: Tramadol. Br J Anaesth 1995;74:247-249. 15. Crossley AWA, Mahajan RP. The intensity of postoperative shivering is unrelated to axillary temperature. Anaesthesia 1994;49:205-207. 16. Raffa RB, Friderichs E, Reinmann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ’atypical’ opioid analgesic. J Pharmacol Exp Ther 1992;260:275-285. 17. Kurz A, Ikeda T, Sessler DI, Larson MD, Bjorksten AR, Dechert M, Christensen R. Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology 1997;86:10461054.
B
ecause of the rapid heat loss and core-to-peripheral redistribution of body heat, maintaining core temperature is especially difficult in patients undergoing neuraxial anesthesia.1 The shivering threshold is reached sooner, and more shivering is required to prevent further hypothermia. Shivering, a common side effect of neuraxial
From the Department of Anesthesia and Intensive Care, University of Rome “La Sapienza” (F.B., P.P., G.R.), Rome; and the Department of Anesthesia Policlinico Casilino (R.S., G.L.), Rome, Italy. Accepted for publication February 20, 2002. Supported in part with departmental research funds, without a corporate sponsor. Presented in part at the 9th Annual Meeting of the European Society of Anaesthesiologists, Gothenburg, Sweden, April 7-10, 2001. None of the authors have a financial association with the manufacturer of nefopam or tramadol. Reprint requests: Federico Bilotta, M.D., Ph.D., via dei Tadolini 13, Rome 00196, Italy. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2704-0006$35.00/0 doi:10.1053/rapm.2002.33563
380
(spinal and epidural) anesthesia,2 is distressing for the patient. The metabolic and hemodynamic consequences of shivering include increased expenditure of cardiac and systemic energy, increased oxygen consumption and carbon dioxide production, and increased cardiac work.3 The mechanisms chiefly responsible for shivering in patients undergoing surgery are intraoperative temperature loss, increased sympathetic tone, pain, and systemic release of pyrogens.4 The best way to avoid the intraoperative and postoperative shivering-induced increase in hemodynamic and metabolic demands is to prevent shivering.5 Although clonidine prevents shivering after general6 and epidural7 anesthesia, its use is limited by side effects including bradycardia, sedation, and hypotension. Nefopam (3,4,5,6-tetrahydro-5-methyll-phenyl-1H-2.5-benoxazocine hydrochloride) is a nonopioid analgesic drug that is effective in treating8 and preventing5,6 shivering after general anesthesia. Although the mechanisms underlying its analgesic action are unclear, nefopam does not bind to opiate receptors but inhibits synaptosomal uptake
Regional Anesthesia and Pain Medicine, Vol 27, No 4 (July–August), 2002: pp 380 –384
Nefopam and Tramadol
of several neurotransmitters, including dopamine, norepinephrine, and serotonin.9,10 Tramadol is a centrally acting analgesic that has weak opioid agonist properties. It also inhibits serotonin and norepinephrine uptake in the spinal cord and is effective in the treatment of postoperative shivering after general and regional anesthesia.11-14 No studies to date have investigated whether nefopam or tramadol help to prevent, rather than treat, intraoperative shivering after neuraxial anesthesia. The aim of this randomized, double-blind study was to evaluate the usefulness of intravenous (IV) nefopam and tramadol in reducing the frequency and severity of intraoperative shivering in patients undergoing neuraxial anesthesia for orthopedic surgery.
Methods After institutional approval, informed consent was obtained from 90 patients, American Society of Anesthesiologists physical status I or II, scheduled for neuraxial anesthesia for lower limb orthopedic surgery. No premedication was given. Patients were randomly assigned (by a computer-generated randomization sequence) to 1 of 3 groups. Immediately before neuraxial anesthesia, 30 patients received 0.15 mg/kg⫺1 IV nefopam (Oxadol, Kedrion, Italy) in 10 mL saline, 30 patients received 0.5 mg/kg⫺1 IV tramadol in 10 mL saline, and a control group of 30 patients received 10 mL IV saline. Neuraxial anesthesia was induced at the L3-L4 or L4-L5 interspaces with 1 mg/kg⫺1 mepivacaine for epidural anesthesia and 0.2 mg/kg⫺1 for subarachnoid anesthesia. Sensory block height was evaluated by loss of temperature discrimination and by pinprick testing 10 and 30 minutes after the induction of anesthesia. Immediately before the induction of anesthesia, all patients received an IV bolus 5 mL/kg⫺1 crystalloid solution followed intraoperatively by 15 mL 䡠 kg⫺1 䡠 h⫺1 in continuous infusion. The attending anesthesiologist was blinded to the substance injected. Patients wore a light cotton shirt and were covered with a single cotton drape. Operating room temperature was 22°C ⫾ 1°C, with a room humidity of approximately 60%. Laminar flow was not available, and the air turnover rate was 20 cycles per hour. Data from continuous monitoring of heart rate (HR) with 3-lead electrocardiogram (ECG), peripheral arterial oxygen saturation (SpO2) by pulse oximetry, noninvasive mean arterial pressure (MAP), skin temperature measured in the forearm, and core temperature measured in the urinary bladder through Foley catheters with thermistors were recorded at baseline, before anesthesia induction, and at 10-minute intervals thereafter.
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An investigator blinded to the antishivering drug injected recorded the frequency of visible shivering for 90 minutes after anesthesia induction. Shivering was graded on a 5-point scale similar to that validated by Crossley and Mahajan15: 0, absent; 1, piloerection or peripheral vasoconstriction but no visible shivering; 2, muscular activity in one muscle group; 3, muscular activity in more than one muscle group but no generalized shivering; and 4, generalized shivering. The shivering grade was calculated as the mean of patients who exhibited grade 1 to 4 shivering. A study population of 30 patients for each group was needed to produce statistical power ⱖ 90%, with ␣ ⫽ 0.05 (2-tailed) to detect a difference of 30% in the frequency of shivering during neuraxial anesthesia comparing the control group with nefopam and tramadol groups. The efficacy of prevention for shivering was statistically tested with the 2 test. Differences in the means were tested by the Student’s t test for paired values with the Bonferroni correction and analysis of variance (ANOVA) for repeated measures and then checked by the Mann-Whitney U test. Results are expressed as mean ⫾ SD. P values ⱕ .05 were considered statistically significant.
Results Patients’ characteristics, anesthetic (spinal or epidural anesthesia), and surgical variables were similar in the 3 groups (Table 1). In all patients, the sensory block reached the T4 dermatome. No differences were found in the sensory block height in the 3 groups. The overall frequency of intraoperative shivering was significantly lower in patients treated with nefopam than in those treated with tramadol or placebo (P ⬍ .05 and P ⬍ .01) and in patients treated with tramadol than in those treated with placebo (P ⬍ .05; Table 1). The intensity of shivering was also significantly lower in patients treated with nefopam and tramadol than those treated with placebo (P ⬍ .05; Table 1). No significant differences were found for hemodynamic variables (HR, MAP, and SpO2) between the 3 groups (Table 2). When data for HR, MAP, and SpO2 were analyzed in shivering and nonshivering patients, shivering patients had significantly higher HR and MAP, but lower SpO2 (data not shown). Measurement of skin temperature, to validate that heat loss did not alter skin temperature more in the placebo group than in the other groups, showed no differences between the 3 groups (data not shown). After induction of anesthesia the core temperature measured in the bladder decreased in all patients; it decreased slightly, although not significantly, more in patients treated with tramadol (Table 2). In some
382
Regional Anesthesia and Pain Medicine Vol. 27 No. 4 July–August 2002 Table 1. Morphometric Data, Anesthetic Variables, and Postanesthetic Shivering Nefopam (n ⫽ 30)
Tramadol (n ⫽ 30)
Placebo (n ⫽ 30)
48 (12) 17/13 65 (10) 22/8 2/30 (6%) 1.5 (2 patients) 1–2 42 (10) 28 (10)
45 (13) 14/16 70 (14) 22/8 7/30 (24%)* 2.1 (7 patients) 1–3 37 (11) 30 (7)
45 (12) 13/17 65 (13) 21/9 17/30 (57%)†‡ 2.6† (17 patients) 1–4 40 (7) 33 (8)
Age mean (yr) Gender (M/F) Duration of surgery No. of patients receiving spinal or epidural anesthesia No. of patients shivering (%) Grade of shivering [mean among shivering patients] Range Time from baseline to onset of shivering (min) Duration of shivering (min)
NOTE. Data are means (SD). *P ⬍ .05 nefopam v tramadol; †P ⬍ .01 nefopam v placebo; ‡P ⬍ .05 tramadol v placebo by Student’s t test.
patients (⬍ 10%) nefopam and tramadol both induced transient, tolerable adverse reactions, including nausea, vomiting, and sweating.
Discussion We found that nefopam significantly lowered the rate and severity of intraoperative shivering in patients undergoing neuraxial anesthesia for orthopedic surgery. The opioid derivative tramadol, at the standard therapeutic doses used for the control of shivering,11-13 had a similar, but apparently less potent effect. We cannot exclude the possibility that we missed more effect from tramadol owing to our dose selection. The frequency of shivering during neuraxial anesthesia in the control group was higher than that reported in similar obstetric series (57% v about 40%).11,12 This difference probably reflects the greater decrease in body core temperature in our patients, possibly related to surgical techniques (ir-
rigation, greater anatomic exposure, and longer duration of orthopedic procedures) or to our anesthetic techniques. Most of our patients had spinal anesthesia, and hypothermia develops faster during spinal anesthesia than during epidural anesthesia.2 Neuraxial anesthesia causes significant vasodilation and thus heat loss, thereby reducing body core temperature.2 Intraoperative shivering during neuraxial anesthesia at a constant ambient temperature (in our study relatively low, 22° ⫾ 1°C) is triggered by various mechanisms including body core hypothermia caused by body heat loss and redistribution, heat loss exceeding metabolic heat production, and anesthetic-induced inhibition of centrally and peripherally mediated thermoregulatory control. A difficult question to answer is why nefopam, at the doses we used for preventing shivering, was more effective than tramadol in preventing intraoperative shivering after neuraxial anesthesia. Although nefopam and tramadol are both
Table 2. MAP, HR, SpO2, and T Recorded at Baseline and at 15, 30, 60, and 90 Minutes After Induction of Neuraxial Anesthesia Minutes
HR (beat/min⫺1) Nefopam Tramadol Placebo MAP (mm Hg) Nefopam Tramadol Placebo SpO2 (%) Nefopam Tramadol Placebo T (°C) Nefopam Tramadol Placebo
Baseline
15
30
60
90
74 (5) 74 (7) 76 (8)
70 (4) 74 (7) 65 (7)
73 (7) 67 (6) 83 (10)
70 (5) 72 (46) 85 (76)
75 (5) 71 (8) 85 (7)
92 (8) 91 (7) 91 (8)
90 (7) 89 (5) 92 (6)
88 (4) 95 (7) 99 (6)
87 (10) 96 (6) 100 (8)
90 (3) 95 (5) 99 (6)
98 (2) 99 (1) 98 (2)
98 (1) 98 (1) 97 (2)
98 (2) 98 (2) 98 (2)
98 (2) 99 (2) 97 (2)
99 (1) 98 (2) 97 (2)
36.9 (0.3) 36.8 (0.3) 36.9 (0.2)
36.4 (0.3) 36.3 (0.4) 36.5 (0.5)
36.3 (0.3) 36.0 (0.8) 36.4 (0.5)
36.0 (0.3) 35.6 (0.4) 36.1 (0.5)
35.6 (0.3) 35.4 (0.4) 35.9 (0.7)
NOTE. Values are expressed as mean and (SD). None of the data showed significant differences between groups by paired Student’s t test for paired values with the Bonferroni correction and ANOVA for repeated measures. Abbreviations: MAP, mean arterial pressure; HR, heart rate; SpO2, arterial oxygen saturation; T, bladder temperature.
Nefopam and Tramadol
analgesic drugs, their pharmacologic properties and mechanisms of action differ in various ways. Nefopam is a nonopioid analgesic drug that inhibits the synaptic uptake of dopamine, noradrenaline, and serotonin in an amphetamine-like fashion.10 Ample evidence confirms the efficacy of nefopam for the treatment8 and prevention5,6 of postanesthetic shivering. Our findings now confirm its efficacy for preventing intraoperative shivering. Tramadol is an atypical opioid analgesic.16 Its opioid action is preferentially mediated via the -receptor, with minimal effects at -, and ⌬-binding sites. Tramadol also activates the monoaminergic receptors of the descending neuraxial inhibitory pain pathway. Like nefopam, tramadol inhibits in vitro synaptosomal noradrenaline and serotonin uptake. This inhibitory action contributes substantially to tramadol’s analgesic action. The antishivering action of opioids is mostly related to the -receptor.17 The antishivering effect of tramadol is probably mediated via its opioid or serotonergic and noradrenergic activity or both. No pharmacologic evidence has yet shown whether the opioid action of tramadol is necessary for the prevention of shivering. These distinct mechanisms of action may partially explain why we found nefopam more effective than tramadol in preventing intraoperative shivering. Current knowledge on the relationship between shivering and the effects of drugs on vasoconstriction makes our results easier to interpret. An important influence on a drug’s effectiveness in preventing shivering is its effect on the patient’s shivering threshold, the body core temperature triggering shivering, and on the vasoconstriction threshold, the body core temperature triggering vasoconstriction. Meperidine, an opioid derivative widely used to treat shivering, with - and -receptor activity similar to that of tramadol, decreases the shivering threshold twice as much as the vasoconstriction threshold.17 Conversely, other antishivering drugs, such as clonidine (a partial ␣2-adrenoceptor agonist), alfentanil (a selective -opioid receptor agonist), propofol, and the volatile anesthetics decrease the vasoconstriction and shivering thresholds to the same extent. We failed to identify significant differences in forearm temperature in the 3 groups, possibly because of the small sample size. In patients undergoing neuraxial anesthesia, nefopam may nonetheless be more effective than tramadol (a - and -opioid receptor agonist) in preventing shivering, because the earlier activation of the vasoconstriction threshold may diminish body heat loss. A limitation of this study is that in our small sample of patients the statistical power was too low to confirm the difference in body core temperature
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in the 3 groups. Nonetheless, body core temperature decreased faster and to a greater extent in patients treated with tramadol, less in patients treated with nefopam, and even less in patients treated with placebo. It may also be that bladder temperature is less accurate than tympanic temperature as a measure of core temperature due to an increase in pelvic blood flow related to central block compensating for temperature redistribution. Nonetheless, in our patients, bladder temperature invariably decreased at a comparable rate to that reported in studies using tympanic temperature.2 The possibility that tramadol was less effective than nefopam in preventing shivering because we used a too low dose seems unlikely to us. The doses of both drugs used in our study (0.15 mg/kg⫺1 IV nefopam, 0.5 mg/kg⫺1 IV tramadol) were equal to those commonly reported as effective for treating shivering with minimal side effects.6,11-13 Chan et al.11 showed that administration of tramadol IV at 0.25 mg/kg effectively controlled shivering during cesarean delivery during regional anesthesia with minimal side effects, while increasing tramadol dose to 0.5 mg/kg did not increase its therapeutic effects. Because the 2 drugs differ in their mechanisms of action, their dose response curves presumably have different slopes. The potency of the 2 drugs in preventing shivering needs confirmation from complete dose-response curves. The distinctive feature of this study is that we assessed the effectiveness of 2 antishivering drugs for the prevention, rather than for the treatment, of shivering during neuraxial anesthesia. Because of the difficulty in physically warming patients undergoing neuraxial anesthesia, an alternative pharmacologic method for preventing shivering would be clinically useful. Among the drugs so far used for this purpose, our findings suggest that nefopam, a drug with few disadvantages, may hold promise. Future studies are needed to compare the effectiveness of nefopam and meperidine in preventing shivering in patients undergoing neuraxial anesthesia.
Acknowledgment The authors thank Prof. Paolo Nencini for his helpful comments on the pharmacologic content of the manuscript.
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