Int J Anesthetic Anesthesiol ISSN: 2377-4630

• Abstract
• Keywords
• Introduction
• Material and Methods
• Results
• Discussion
• Table1
• Table2
• Table3
• Figure1
• Figure2
• References

Download PDF
    

International Journal of Anesthetics and Anesthesiology

Intensive care and pain medicine, Medical research institute, Alexandria university, Egypt

Abstract

Background: Shivering occurs frequently during the perioperative period. A prospective, randomized, double-blind study was done to compare between intrathecal dexmedetomidine (5mcg) and intrathecal meperidine (0.2mg/kg) for decreasing the incidence and intensity of shivering after spinal anesthesia for lower abdominal operations.

Methods: Seventy five patients scheduled for lower abdominal operations under spinal anesthesia were randomly allocated to three groups. Spinal anesthesia consisted of 12.5 mg hyperbaric bupivacaine 0.5% in addition to dexmedetomidine (5mcg) (group D) or meperidine (0.2 mg/kg) (group M) or, normal saline (group S). Different parameters, including sublingual temperature, sensory block, motor block, incidence and intensity of shivering, sedation score, blood pressure, heart rate, pruritus, nausea, and vomiting was performed at 10 minute intervals. Statistical analysis was carried out using statistical package for social sciences (SPSS) version 15.0 for windows and employing ANOVA and chi-square test with post-hoc comparisons with Bonferroni's correction.

Results: Hypothermia was recorded in 17 patients (68%) in group D, 16 patients (64%) in group M and 18 patients (72%) in group S, while shivering developed in 5 patients (20%) in group D, 6 patients (24%) in group M and 23 patients (92%) in group S, however, pruritus, nausea and vomiting was more common in the meperidine group compared to the other two groups.

Conclusion: Intrathecal dexmedetomidine and meperidine lowered the incidence of shivering and increased duration of sensory and motor block during lower abdominal operations. Intrathecal meperidine caused more pruritus, nausea and vomiting than intrathecal dexmedetomidine.

Keywords

Anesthesia, Dexmedetomidine, Meperidine, Shivering, Spinal

Introduction

Shivering is a protective mechanism by which heat production occurs, by vigorous involuntary muscle activity, to compensate for the decreased core temperature in a normal healthy living body. The main mechanisms of shivering in patients undergoing surgery are mainly intraoperative heat loss, increased sympathetic tone, pain, and systemic release of pyrogens [1]. Spinal anesthesia impairs the thermoregulation system, it inhibits the tonic vasoconstriction, which plays a significant role in temperature regulation [2]. Spinal anesthesia also causes redistribution of core heat from the trunk (below the block level) to the peripheral tissues. These two effects predispose patients to hypothermia and shivering [3]. Shivering increases oxygen consumption, carbon dioxide production, lactic acidosis and metabolic rate by up to 400% [4,5]. Dexmedetomidine is a highly selective alpha-2-adrenoceptor agonist with potent effects on the central nervous system and it was used for prevention and treatment of shivering associated with general or spinal anesthesia [6-8]. Many other drugs have been used to treat perianesthetic shivering, including meperidine, clonidine, ketanserin, and doxapram; and most studies have concluded that meperidine is considerably more effective in treating shivering than others [9-11]. Adding a small dose of meperidine to the intrathecal mixture during spinal anesthesia reduces the incidence and severity of shivering. and is known to retain characteristics of the sensory block [12-14]. The aim of this study was to compare between intrathecal dexmedetomidine and intrathecal meperidine on the incidence and severity of shivering following spinal anesthesia.

Material and Methods

After approval of the local ethical committee, seventy five patients (American Society of Anesthesiologists physical status I or II, aged 20-50 years) scheduled for elective minor lower abdominal operations under spinal anesthesia, were enrolled in the study. Exclusion criteria include patients with thyroid disease, Parkinson's disease, dysautonomia, Raynaud's syndrome, cardiopulmonary disease, a history of allergy to the agents to be used, a need for blood transfusion during surgery, an initial core temperature above 37.5⁰C or below 36.5⁰C, use of vasodilators, or having contraindications to spinal anesthesia. All patients gave written informed consent to participate in this study. The temperature of the operating room was maintained at 21⁰C to 22⁰C (measured by a wall thermometer). Intravenous fluids were administered at room temperature and given without warming. One layer of surgical drapes over the chest, thighs, and calves were placed during the operation and then one cotton blanket over the entire body postoperatively. No other warming device was used. A core temperature below 36⁰C was considered hypothermia. Preloading with 10 ml/kg of Ringer acetate solution was given to each patient. Spinal anesthesia was induced in the semi-sitting position at either the L3-4 or L4-5 interspaces. Patients were allocated into three equal groups, a dexmedetomidine (Group D, n=25), meperidine group (Group M, n = 25) or a saline control group (Group S, n = 25) by a computer-generated randomization method. To detect a 50% reduction of shivering incidence, a sample size of 18 patients per group was required (with an α = 0.05, β = 0.2, and a power of 80%). It was determined that 25 patients would be included in each group with a power of 90%. The drug mixture was prepared by an investigator who was not otherwise involved in the study, he prepared syringes containing hyperbaric bupivacaine plus dexmedetomidine, meperidine or saline.; thus, the study was double-blinded. The drug mixture was 12.5 mg hyperbaric bupivacaine 0.5% plus 5 mcg dexmedetomidine in 0.5 ml normal saline (Group D), 12.5 mg hyperbaric bupivacaine 0.5% plus 0.2 mg/Kg meperidine hydrochloride 5% in 0.5 normal saline (Group M), and 12.5 mg hyperbaric bupivacaine plus 0.5 ml of normal saline (Group S). A total volume of 3 ml of drug mixture (2.5 ml of hyperbaric bupivacaine 0.5% plus 0.5 ml of the study drugs (dexmedetomidine, meperidine or normal saline) was injected using a 27 G Quincke spinal needle. Supplemental oxygen (4 L/min) was delivered via a facemask during the operation.

The incidence and intensity of shivering, blood pressure (BP), heart rate, SpO₂ and sublingual temperature were evaluated each 10 minutes for 180 minutes. Side effects like pruritus, nausea or vomiting were recorded. Shivering was graded using the scale described by Crossley and Mahajan [15] (0 = no shivering; 1 = piloerection or peripheral vasoconstriction but no visible shivering; 2 = muscular activity in only one muscle group; 3 = muscular activity in more than one muscle group but not generalized shivering; 4 = shivering involving the whole body). Sublingual temperature was monitored using an oral temperature probe with a monitor (Infinity Delta Monitor En, Draeger Medical S Sensory block was assessed by pinprick test with a 22 G hypothermic needle every minute during the first 10 minutes, and then every 10 minutes, the motor block was assessed by modified bromage scale (0, no motor block; 1, hip blocked; 2, hip and knee blocked; 3, hip, knee, and, ankle blocked). The presence of shivering was assessed by a blinded observer after the completion of subarachnoid drug injection. Sublingual temperature, sensory block, motor block, incidence and severity of shivering were recorded at 10-min intervals during the operation and in the recovery room. Side effects, such as hypotension, bradycardia, pruritus, nausea and vomiting were recorded. If the patient's heart rate fell below 50 bpm, 0.5 mg intravenous atropine was administered. Hypotension was defined as a decrease in the mean arterial pressure (MAP) of more than 20 % from baseline (baseline MAP was calculated from three measurements taken in the ward before surgery). Hypotension was treated with 6 mg ephedrine boluses. If patients developed nausea and vomiting, 10 mg metoclopramide was administered intravenously. Postoperatively, all patients were monitored, given oxygen via a facemask and were covered with one layer of drapes and one cotton blanket. The post-anesthesia care unit temperature was maintained at 25⁰C to 26 ⁰C and constant humidity.

Statistical analyses were performed using statistical package for social sciences (SPSS) version 15.0 for windows. Quantitative variables were compared between groups using Student's t-test or a Mann-Whitney U-test where appropriate. Within-group data for core temperature were analyzed by using repeated-measures analysis of variance followed by Bonferroni's post-hoc testing. Within-group data for heart rate and mean arterial pressure were analyzed using a Friedman test. Chi-square analysis was used for comparison of categorical variables. The results are shown as median (range), mean (í^SD), exact numbers or proportions are expressed as a percentage. p,0.05 was considered statistically significant.

Results

All patients completed the study. There were no cases of apnea or oversedation in any group.

Regarding demographic data (age, height, weight, gender) and surgery duration, there were insignificant differences between the three studied groups (Table 1 and Table 2).

Regarding hypothermia, it was recorded in 17 patients in dexmedetomidine group (68%), in 16 patients in meperidine group (64%), and in 18 patients in the control group (72%), with no significant differences between the three studied groups (Table 2).

Regarding motor and sensory block duration, patients of group D and M had longer duration than patients of group S, with significant statistical difference (Table 2).

Regarding shivering, patients of group D and M had less shivering than patients of group S, with significant statistical difference (Table 2).

Regarding the degree of shivering, patients of group D & M had lower degree of shivering than control group, but this difference did not reach statistical significance (Table 2).

Regarding bradycardia and hypotension, there were insignificant differences between the three studied groups (Table 3).

Regarding pruritus, pruritus developed in 5 patients in group M, 1 patient in group D, and none in group S, with significant difference between group M and the other 2 groups (Table 3).

Regarding nausea and vomiting, 3 patients in group D and S, while 5 patients in group M developed nausea and vomiting with significant difference between group M and the other 2 groups (Table 3).

P1 is comparison between group D and group M, P2 is comparison between group M and group S, P3 is comparison between group M and group S, P is significant if less than 0.05.

Table 2: Hypothrtmia, sensory-motor block duration, incidence and degree of shivering and surgery time among the three studied groups

P1 is comparison between group D and group M, P2 is comparison between group M and group S, P3 is comparison between group M and group S, P is significant if less than 0.05.

Table 3: Bradycardia, hypotension, pruritus, nausea and vomiting among the three studied groups

P1 is comparison between group D and group M, P2 is comparison between group M and group S, P3 is comparison between group M and group S, P is significant if less than 0.05.

Hypothermia was recorded in 17 patients (68%) in group D, 16 patients (64%) in group M and 18 patients (72%) in group S, while shivering developed in 5 patients (20%) in group D, 6 patients (24%) in group M and 23 patients (92%) in group S. Intrathecal dexmedetomidine and intathecal meperidine decreased the incidence of shivering and increased the sensory and motor block duration. Intrathecal meperidine caused more pruritus, nausea and vomiting than intrathecal dexmedetomidine (Table 3).

The mean values of mean arterial blood pressure and heart rate were comparable among the 3 groups. (figures 1 and 2) Increments of atropine sulphate were given for bradycardia (4 patients in group D, 3 patients in group M and group S) and increments of ephedrine were given for hypotension (6 patients in group D, 4 patients in group M and 6 patients in group S).

There were no cases of apnea or oversedation in any group.

Discussion

Shivering profoundly increases oxygen consumption (by 200- 500%) and carbon dioxide production and decreases mixed venous oxygen saturation [5,16]. Three major factors contribute to core hypothermia during regional anesthesia: heat loss to the environment, inhibition of central thermoregulatory control, and redistribution of body heat [3,17,18,19]. When the body is exposed to a cold environment, the body temperature drops, and it worsens when cold IV fluid or blood is administered without warming [20-22]. Although one limitation of this study was measuring sublingual temperature instead of core temperature of tympanic membrane, sublingual and axillary temperatures are thought to reflect core temperature with reasonable accuracy [23,24]. It has been reported, though, that axillary temperature does not correlate well with perioperative shivering and that the sublingual temperature reflects changes in body temperature better than the axillary temperature [15]. The autonomic thermoregulatory responses to cold are shivering and vasoconstriction. Normally, upon exposure to cold stress, the cutaneous vasculature constricts to reduce heat loss, metabolic heat production increases, and shivering begins in an effort to maintain core body temperature. Spinal anesthesia alters autonomic thermoregulatory responses by significantly decreasing the thresholds for vasoconstriction and shivering [18]. Shivering during spinal anesthesia is thought to occur due to a loss of thermoregulatory vasoconstriction and a loss of heat by heat redistribution from core to peripheral parts of the body. However, the decrease in core body temperature is not remarkable when compared with general anesthesia because spinal anesthesia causes only redistribution of heat in the lower half of the body [3,18]. Regardless of its cause, shivering has the undesirable effects of markedly increasing oxygen consumption and carbon dioxide production and decreasing mixed venous oxygen saturation [16]. Cardiac output and minute ventilation, as well as mean BP, increase to compensate for this [25]. If these compensatory mechanisms fail, then hypoxemia may occur. These effects are often poorly tolerated by patients with limited cardiac or pulmonary reserve. Therefore, shivering prevention is more important than its treatment in these patients. Adding a small amount of meperidine during spinal anesthesia may aid high risk patients from developing shivering. In treating shivering, meperidine is much more effective than equipotent doses of other μ-opioid agonists, such as fentanyl, alfentanil, sufentanil, or morphine [26,27]. The anti-shivering property of meperidine is not fully understood. Several studies have suggested that the anti-shivering effect of meperidine is mediated by ?-opioid receptor agonist activity [10,28,29]. Also meperidine suppresses the shivering threshold almost twice as much as the vasconstriction threshold and this suppression in the shivering threshold appears to underlie the antishivering effect of meperidine [30]. Potential side effects of meperidine such as nausea, vomiting, pruritus and hypotension must also be considered when administering meperidine [31].

Alpha-2 adrenergic agonists are widely used nowadays in clinical practice of anesthesiology and intensive care. The Alpha-2 receptor agonists are known to prevent shivering to a moderate extent without any associated respiratory depression as with other antishivering drugs like meperidine [30,32]. Dexmedetomidine reduces shivering by suppressing vasoconstriction and shivering thresholds [32.33]. Alpha-2 adrenergic agonists decrease the central thermo-sensitivity by suppressing the neuronal conductance [34]. This is mediated by the increased potassium conductance through G-coupled proteins which causes hyperpolarization of neurons [35-38]. Augmentation of neural suppression response is further mediated by restriction of calcium entry into nerve cells which causes inhibition of neurotransmitter release [38,39]. The increased accumulation of calcium ions on the neuron's surface in the posterior hypothalamus lowers the firing rate of heat gain units by stabilizing the cell membrane [40]. α-2 adrenergic agonists suppress the spontaneous firing rate of neurons in the locus coeruleus and neurotransmitter mediated firing of neurons in the dorsal raphe nucleus when administered intravenously [41]. All these central actions of α-2 agonists are possible due to a high density of α-2 adrenoceptors in the hypothalamus and activation of these receptors produces hypothermia by reduction of heat generated by metabolic activity [42].Intrathecal DXM when combined with spinal bupivacaine prolongs the sensory block by depressing the release of C-fibers transmitters and by hyperpolarization of post-synaptic dorsal horn neurons [43-47]. Motor block prolongation by 2- adrenoreceptor agonists may result from binding these agonists to motor neurons in the dorsal horn of the spinal cord [48,49].

The median incidence of shivering related to neuraxial anesthesia in the control groups of 21 studies is 55 % (interquartile range of 40-64%) [1], which is much less than reported in this study(92%). In this study, intrathecal meperidine decreased the incidence and severity of shivering compared with the control group, this was in agreement with the study done by Chun DH et al. [50] who added intrathecal meperidine (0.2 mg/kg) to bupivacaine for spinal anesthesia during TURP in elderly patients, they concluded that intrathecal meperidine reduces the incidence and intensity of shivering associated with spinal anesthesia. In our study, intrathecal dexmedetomidine reduced shivering and increased the sensory and motor block duration. In agreement with this, Abdelhamid et al. [51] concluded that intrathecal dexmedetomidine at a dose of 5 μg provided less shivering and less postoperative analgesic requirements for patients undergoing lower abdominal surgery with no sedation.

In this study, pruritus developed in 5 patients in group M, which was significantly higher than the other 2 groups. This result coincided with the result of Chun DH et al study [50]. The mean arterial pressure and heart rate showed insignificant differences between groups. There was minimal hypotension and bradycardia, which were easily controlled with ephedrine and atropine boluses. In agreement with our results, Kanazi et al. [52] showed insignificant effect of dexmedetomidine on mean blood pressure when added to intrathecal bupivacaine. Al-Mustafa and colleagues [53], using 5 μg, and 10 μg dexmedetomidine, found a dose dependent, but still insignificant, decrease on the mean blood pressure when compared to the bupivacaine (control) group.

References

1. Crowley LJ, Buggy DJ (2008) Shivering and neuraxial anesthesia. Reg Anesth Pain Med 33: 241-252.
   


2. Glosten B, Sessler DI, Faure EA, Karl L, Thisted RA (1992) Central temperature changes are poorly perceived during epidural anesthesia. Anesthesiology 77: 10-16.
   


3. Ozaki M, Kurz A, Sessler DI, Lenhardt R, Schroeder M, et al. (1994) Thermoregulatory thresholds during epidural and spinal anesthesia. Anesthesiology 81: 282-288.
   


4. Tsai YC, Chu KS (2001) A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. Anesth Analg 93: 1288-1292.
   


5. Macintyre PE, Pavlin EG, Dwersteg JF (1987) Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering. Anesth Analg 66: 751-755.
   


6. Doze VA, Chen BX, Maze M (1989) Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology 71: 75-79.
   


7. Virtanen R, Savola JM, Saano V, Nyman L (1988) Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. Eur J Pharmacol 150: 9-14.
   


8. Elvan EG, Oc B, Uzun S, Karabulut E, CoÅŸkun F, et al. (2008) Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 25: 357-364.
   


9. Kranke P, Eberhart LH, Roewer N, Tramèr MR (2002) Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg 94: 453-460.
   


10. Alfonsi P, Hongnat JM, Lebrault C, Chauvin M (1995) The effects of pethidine, fentanyl and lignocaine on postanaesthetic shivering. Anaesthesia 50: 214-217.
    


11. Wang JJ, Ho ST, Lee SC, Liu YC (1999) A comparison among nalbuphine, meperidine, and placebo for treating postanesthetic shivering. Anesth Analg 88: 686-689.
    


12. Roy JD, Girard M, Drolet P (2004) Intrathecal meperidine decreases shivering during cesarean delivery under spinal anesthesia. Anesth Analg 98: 230-234, table of contents.
    


13. Chen JC, Hsu SW, Hu LH, Hong YJ, Tsai PS, et al. (1993) [Intrathecal meperidine attenuates shivering induced by spinal anesthesia]. Ma Zui Xue Za Zhi 31: 19-24.
    


14. Hong JY, Lee IH (2005) Comparison of the effects of intrathecal morphine and pethidine on shivering after Caesarean delivery under combined-spinal epidural anaesthesia. Anaesthesia 60: 1168-1172.
    


15. Crossley AW, Mahajan RP (1994) The intensity of postoperative shivering is unrelated to axillary temperature. Anaesthesia 49: 205-207.
    


16. De Witte J, Sessler DI (2002) Perioperative shivering: physiology and pharmacology. Anesthesiology 96: 467-484.
    


17. Matsukawa T, Sessler DI, Christensen R, Ozaki M, Schroeder M (1995) Heat flow and distribution during epidural anesthesia. Anesthesiology 83: 961-967.
    


18. Kurz A, Sessler DI, Schroeder M, Kurz M (1993) Thermoregulatory response thresholds during spinal anesthesia. Anesth Analg 77: 721-726.
    


19. Leslie K, Sessler DI (1996) Reduction in the shivering threshold is proportional to spinal block height. Anesthesiology 84: 1327-1331.
    


20. Ahn SW, Kim TH (1999) The effects of warming intravenous fluids, sensory block level, and skin temperature on postanesthetic shivering during spinal anesthesia. Korean J Anesthesiol 37: 787-792.
    


21. Jaffe JS, McCullough TC, Harkaway RC, Ginsberg PC (2001) Effects of irrigation fluid temperature on core body temperature during transurethral resection of the prostate. Urology 57: 1078-1081.
    


22. Moore SS, Green CR, Wang FL, Pandit SK, Hurd WW (1997) The role of irrigation in the development of hypothermia during laparoscopic surgery. Am J Obstet Gynecol 176: 598-602.
    


23. Bissonnette B, Sessler DI, LaFlamme P (1989) Intraoperative temperature monitoring sites in infants and children and the effect of inspired gas warming on esophageal temperature. Anesth Analg 69: 192-196.
    


24. Cork RC, Vaughan RW, Humphrey LS (1983) Precision and accuracy of intraoperative temperature monitoring. Anesth Analg 62: 211-214.
    


25. Eberhart LH, Döderlein F, Eisenhardt G, Kranke P, Sessler DI, et al. (2005) Independent risk factors for postoperative shivering. Anesth Analg 101: 1849-1857.
    


26. Degroot DW, Kenney WL (2007) Impaired defense of core temperature in aged humans during mild cold stress. Am J Physiol Regul Integr Comp Physiol 292: R103-108.
    


27. Alfonsi P, Sessler DI, Du Manoir B, Levron JC, Le Moing JP, et al. (1998) The effects of meperidine and sufentanil on the shivering threshold in postoperative patients. pascal.alfonsi@apr.ap-hop-paris.fr. Anesthesiology 89: 43-48.
    


28. Wang JJ, Ho ST, Lee SC, Liu YC (1999) A comparison among nalbuphine, meperidine, and placebo for treating postanesthetic shivering. Anesth Analg 88: 686-689.
    


29. Kurz M, Belani KG, Sessler DI, Kurz A, Larson MD, et al. (1993) Naloxone, meperidine, and shivering. Anesthesiology 79: 1193-1201.
    


30. Kurz A, Ikeda T, Sessler DI, Larson MD, Bjorksten AR, et al. (1997) Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology 86: 1046-1054.
    


31. Booth JV, Lindsay DR, Olufolabi AJ, El-Moalem HE, Penning DH, et al. (2000) Subarachnoid meperidine (Pethidine) causes significant nausea and vomiting during labor. The Duke Women's Anesthesia Research Group. Anesthesiology 93: 418-421.
    


32. Talke P, Tayefeh F, Sessler DI, Jeffrey R, Noursalehi M, et al. (1997) Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology 87: 835-841.
    


33. Takada K, Clark DJ, Davies MF, Tonner PH, Krause TK, et al. (2002) Meperidine exerts agonist activity at the alpha(2B)-adrenoceptor subtype. Anesthesiology 96: 1420-1426.
    


34. Boulant JA (1974) The effect of firing rate on preoptic neuronal thermosensitivity. J Physiol 240: 661-669.
    


35. Maze M, Tranquilli W (1991) Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology 74: 581-605.
    


36. Surprenant A, North RA (1988) Mechanism of synaptic inhibition by noradrenaline acting at alpha 2-adrenoceptors. Proc R Soc Lond B Biol Sci 234: 85-114.
    


37. Evans RJ, Surprenant A (1993) Effects of phospholipase A2 inhibitors on coupling of alpha 2-adrenoceptors to inwardly rectifying potassium currents in guinea-pig submucosal neurones. Br J Pharmacol 110: 591-596.
    


38. Maze M (1995) Clinical uses of alpha-2 agonists, 46th Annual Refresher Course Lectures. Atlanta: American Society of Anesthesiologists: 125.
    


39. Lipscombe D, Kongsamut S, Tsien RW (1989) Alpha-adrenergic inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating. Nature 340: 639-642.
    


40. Myers RD, Simpson CW, Higgins D, Nattermann RA, Rice JC, et al. (1976) Hypothalamic Na+ and Ca++ ions and temperature set-point: new mechanisms of action of a central or peripheral thermal challenge and intrahypothalamic 5-HT, NE, PGEi and pyrogen. Brain Res Bull 1: 301-327.
    


41. Alojado ME, Ohta Y, Kemmotsu O (1994) The effect of clonidine on the activity of neurons in the rat dorsal raphe nucleus in vitro. Anesth Analg 79: 257-260.
    


42. Quan N, Xin L, Ungar AL, Blatteis CM (1992) Preoptic norepinephrine-induced hypothermia is mediated by alpha 2-adrenoceptors. Am J Physiol 262: R407-411.
    


43. Lawhead RG, Blaxall HS, Bylund DB (1992) Alpha-2A is the predominant alpha-2 adrenergic receptor subtype in human spinal cord. Anesthesiology 77: 983-991.
    


44. Smith MS, Schumbra UB, Wilson KH, Page SO, Hulette C, et al. (1995) Alpha 2-Adrenergic receptor in human spinal cord: specific localized expression of mRNA encoding alpha-2 adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res 34: 109-117.
    


45. Fairbanks CA, Wilcox GL (1999) Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 288: 1107-1116.
    


46. Yaksh TL (1985) Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav 22: 845-858.
    


47. Smith C, Birnbaum G, Carter JL, Greenstein J, Lublin FD (1994) Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. US Tizanidine Study Group. Neurology 44: S34-42.
    


48. Harada Y, Nishioka K, Kitahata LM, Kishikawa K, Collins JG (1995) Visceral antinociceptive effects of spinal clonidine combined with morphine, [D-Pen2, D-Pen5] enkephalin, or U50,488H. Anesthesiology 83: 344-352.
    


49. Yaksh TL, Reddy SV (1981) Studies in primate on the analgesic effects associated with intrathecal actions of opiates, -adrenergic agonists, and baclofen. Anesthesiology 54: 451-467.
    


50. Chun DH, Kil HK, KimHJ, Park C, Chung KH (2010) Intrathecal meperidine reduces intraoperative shivering during transurethral prostatectomy in elderly patients. Korean J Anesthesiol 59: 389-393.
    


51. Abdelhamid SA, El-lakany MH (2013) Intrathecal dexmedetomidine: Useful or not? J Anesth Clin Res 4: 351. [doi:10.4172/2155-6148.1000351]
    


52. Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, et al. (2006) Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand 50: 222-227.
    


53. Al-Mustafa MM, Abu-Halaweh SA, Aloweidi AS, Murshidi MM, Ammari BA, et al. (2009) Effect of dexmedetomidine added to spinal bupivacaine for urological procedures. Saudi Med J 30: 365-370.