Granisetron Reduces Shivering after General Anesthesia

Med. J. Cairo Univ., Vol. 81, No. 2, December: 127-131, 213 www.medicaljournalofcairouniversity.net Granisetron Reduces Shivering after General Anesthesia MOHAMED ABD EL MONEIM MAHMOUD, M.D.* and AHMED M. ZAKI, M.D.** The Department of Anesthesiology, National Hepatology & Tropical Medicine, Research Institute*, Al Sahel Teaching Hospital** Abstract Background: The neurotransmitter pathways involved in the mechanism of postanesthetic shivering (PAS) are poorly understood. Meperidine, clonidine, and physostigmine are all effective treatments, indicating that opioid, α 2 -adrenergic, and anticholinergic systems are probably involved. We investigated the effect of Granisetron, a [5-hydroxytryptamine (5- HT 3 )] antagonist used to treat postoperative nausea and vomiting, on intraoperative core and peripheral temperatures and PAS. Methods: Forty five patients (age, 18-6yr) undergoing orthopedic, general, or urological surgery were randomly assigned to receive an intravenous bolus of Granisetron 15µg/kg, isotonic saline, or.5mg/kg meperidine, immediately before the anesthetic induction. Core (tympanic) and fingertip temperature (dorsum of middle finger) were recorded. Anesthesia was induced with IV fentanyl 1µg/kg and propofol 2.- 2.5mg/kg and maintained with 1 minimum alveolar anesthetic concentration isoflurane in oxygen. Heart rate, mean arterial blood pressure, oxygen saturation, visual analog pain score, temperature, and postanesthetic shivering were measured during recovery by anesthesiologist, who was unaware of the group assignment. Results: Postanesthetic shivering occurred in 6 of 15 (4%) patients given saline. In contrast, postanesthetic shivering was significantly reduced in Granisetron treated patients (1 of 15, or 6%) and peripheral temperature increased significantly, but there were no significant differences among the groups at any time interval. Granisetron 15µg/kg IV given during the induction of anesthesia prevents PAS without affecting the core-to-peripheral redistribution of heat during general anesthesia. Conclusions: Granisetron inhibited shivering as well as did established treatment, meperidine. These data suggest that serotonergic pathways have a role in the regulation of PAS. Implications: In a randomized, double-blinded, placebocontrolled, clinical study, Granisetron 15µg/kg IV, given just before the induction, reduced the incidence of postanesthetic shivering compared with saline. The anticipated core-toperipheral redistribution of body temperature during general anesthesia was not affected. This implies that Granisetron probably acts by a central inhibitory mechanism, and that 5- hydroxytryptaminergic pathways have a role in regulating postanesthetic shivering. Correspondence to: Dr. Mohamed Abd El Moneim Mahmoud, The Departments of Anesthesiology, National Hepatology & Tropical Medicine, Research Institute Key Words: Postanesthetic shivering Granisetron- (5-HT3) antagonist. Introduction POSTANESTHETIC shivering (PAS) occurs frequently postoperatively and may be very distressing for patients [1,2]. Although there is general agreement that it is a thermoregulatory phenomenon, i.e., a physiological response to anesthesia-induced core hypothermia [3], there is some evidence that it may also have a nonthermoregulatory component [4]. The neurotransmitter pathways conveying signals from central nervous system control centers, such as the hypothalamus, to skeletal muscle are not clearly understood, but probably involve multiple levels of information integration and numerous neurotransmitters. IV administration of the opioids, meperidine, alfentanil, and nalbuphine [5,6], the nonopioid analgesic tramadol [7], the α 2 -adrenergic agonist clonidine [8], the respiratory stimulant doxapram [9], and the cholinomimetic agent physostigmine [1] have all reduced the incidence of shivering or suppressed established shivering. Serotonin, [5-hydroxytryptamine (5-HT)], a biological amine found in the brain and spinal cord, has a role in neurotransmission [11]. Indeed, tramadol, which inhibits 5-HT reuptake [7], and ketanserin, a 5-HT 2 antagonist, inhibit established PAS [12]. In animal models, direct intraventricular injections of 5-HT influence body temperature and shivering [13]. All these observations suggest that the serotonergic system has a role in the control of postanesthetic shivering. Granisetron is a specific 5-HT 3 antagonist [14,15] that may affect perioperative thermoregulation and PAS. Therefore, we evaluated the effect of Granisetron, given just before the induction of anesthesia, on the typical core-to-peripheral temperature redistribution evoked by general anesthesia and on the incidence of PAS, in a randomized, placebo-controlled, double-blinded study. 127

128 Granisetron Reduces Shivering after General Anesthesia Material and Methods This study was perfomed in Maadi charity hospital (Ministry of health) in the period from 5/212 to 3/213. The ethical committee of the hospital approved the study with written informed consent. 45 patients (ASA physical status I or II), scheduled for elective minor general surgery (i.e., herniorrhaphy, hemorrhoidectomy, varicose veins or varicosellectomy), urological, or knee arthroscopic surgery, were enrolled into the study. Exclusion criteria were a pyrexial illness, allergy to Granisetron, a surgery anticipated to be longer than 9min or to require mechanical ventilation, age less than 18 or more than 6yr, or if use of vasoconstrictors or vasodilators was planned. No patient received premedication. Patients were randomized, by using a sealed envelope technique, to one of three groups before the induction of anesthesia: Patients were randomly assigned to receive an intravenous bolus of Granisetron 15gg/kg, isotonic saline, or.5mg/kg meperidine immediately before the anesthetic induction. These trial preparations were prepared freshly by operating department technologists who were not involved in the study and who recorded the group randomization separately, such that the anesthesiologist recording the data and caring for the patient was unaware of what the preparation contained. All patients received a 4-mL injection, the volume of Granisetron being made up with normal saline to 4mL when necessary. This injection of trial medication was given immediately after placement of the IV cannula and 3-5min before the induction of anesthesia. Baseline core and fingertip temperatures were recorded by using a tympanic thermometer. Core temperature was recorded at the tympanic membrane and after switching the thermometer to skin temperature mode, fingertip temperature was recorded at the dorsum of the middle finger, on the contralateral hand to the IV infusion. These recordings were repeated at 1-min intervals during surgery and in recovery. Baseline noninvasive mean arterial pressure (MAP) was also recorded before the induction as the mean of two recordings at 3-min intervals and repeated at 1-min intervals thereafter. General anesthesia was induced with fentanyl 1gg/kg followed by propofol 2.-2.5mg/kg. After placement of a laryngeal mask airway, anesthesia was maintained with 1 minimum alveolar anesthetic concentration isoflurane in oxygen. Patients had standard cotton surgical drapes and were not actively heated. Ambient temperature was maintained at 2' -22' C with constant humidity. Shivering was defined as readily detectable fasciculations or tremors of the face, trunk, or limbs of a minimum of 15-s duration. PAS was graded visually by an anesthesiologist blinded to the drug administration and core temperature using a three point scale (none, moderate, or severe). Arousal state was assessed by patients' responses to the verbal command Open your eyes and lift your arms. Absent or incomplete responses were graded as arousal state zero, and prompt and appropriate responses were graded as arousal state one. Postoperative pain was assessed using a visual analog scale, in which a score of indicated no pain and 1 identified maximal pain. Statistical analysis: Continuous variables, including demographic data and temperature values over time within groups were analyzed by using repeated measures analysis of variance. One-way analysis of variance was used to analyze differences among the groups. Incidence of shivering was analyzed by using X 2 test with Yates correction. Data were expressed as Mean_+SD, with p<.5 being considered significant. Results Demographic data, sex, and duration of anesthesia were similar among the groups (Table 1). PAS was significantly reduced in patients receiving Granisetron compared with saline control (6% vs 4%, respectively, p<.5). No patient given meperidine shivered (Table 2). Visual analog scale pain scores were low in all groups at 15min after arousal (Table 2). Mean arterial pressure (MAP) and heart rate (HR) are shown in (Table 3). This predictably indicates a significant reduction in MAP and HR compared with baseline after the induction of anesthesia, with MAP values remaining lower than baseline for the duration of the administration of anesthesia, but HR values tending to recover to preinduction values once surgery had commenced. However, there were no significant differences among the groups at any time. MAP and HR values in recovery room also did not indicate any significant differences among the groups (Table 3). Table (4) shows core and fingertip temperature changes with the duration of the administration of anesthesia, respectively. Although core temperature decreased and fingertip temperature increased significantly in all groups with respect to baseline, there were no significant temperature differences among the groups at any time interval.

Mohamed A.E. Mahmoud & Ahmed M. Zaki 129 Table (1): Demographic data. Control (n=15) Granisetron (n=15) Meperidine (n=15) Age (yr) 45± 16 48±2 47± 17 Weight (kg) 76± 13 79± 13 75± 14 Duration of anaesthesia 38± 12 39± 12 38± 19 administration (min) Sex (male/female) 13/2 12/3 13/2 Table (2): Incidence of shivering, postoperative pain and nausea/vomiting. Moderate shivering (%) Severe shivering (%) Overall shivering incidence (%) Episodes of nausea/vomiting Pain scores 15min after arousal (VAS) Control 27 13 4 3/1 2.1 ± 1. VAS = Visual analog score. Granisetron 15µg/kg 6 6* / 2.3± 1.1 Meperidine.5mg/kg * 3/3 * p<.5 versus saline (control). Table (3): Hemodynamic parameters. Control Granisetron 15µg/kg Meperidine.5mg/kg MAP HR MAP HR MAP HR Baseline 12± 13 73±9 13± 16 73±9 97± 17 74± 13 1 min 74± 1 62± 1 79± 16 64± 17 77± 17 64± 11 2 min 73± 1 6± 1 79± 14 65± 17 78± 14 63± 1 3 min 73± 12 63±9 82± 14 69± 18 81 ± 16 63± 11 4 min 8± 16 65±8 85± 13 79± 18 82± 17 65± 1 6 min 92±23 66± 11 93±22 76± 17 94± 14 72±9 9 min 94± 13 76± 16 18± 19 75±27 16± 16 76± 14 Recovery 97± 8 68± 12 98± 14 72± 16 11± 13 71± 14 HR = Heart rate (bpm). MAP = Mean arterial pressure (mm Hg). There were no significant differences. Table (4): Change in core & peripheral temperature with time. Control Granisetron 15µg/kg Meperidine.5mg/kg Tc Tp Tc Tp Tc Tp min 36.7±.5 31.±.6 36.8±.6 3.2±.4 36.7±.5 3.±.8 1 min 36.4±.6 33.±.4 36.6±.5 32.4±.7 36.3±.4 33.±.3 2 min 36.±.4 33.5±.7 36.3±.4 33.4±.6 36.1±.3 33.2±.5 3 min 35.9±.3 33.5±.6 36.3±.4 33.5±.7 36.4±.5 33.4±.6 4 min 35.8±.7 33.±.5 35.8±.6 33.5±.5 36.8±.4 33.5±.5 6 min 35.8±.8 33.8±.6 36.±.7 32.8±.6 35.8±.8 32.4±.6 9 min 35.5±.6 32.4±.3 35.9±.9 31.5±.4 35.9±.6 32.2±.7 Tc= Core temperature C. Tp= Peripheral temperature C. There were no significant differences. Discussion Prevention and treatment of PAS is an important aspect of patient care, as it may be associated with a number of deleterious sequelae, including sympathoadrenal stimulation, increased oxygen consumption, and carbon dioxide production. In the present study, the incidence of PAS was 4% in the saline group compared with 6% in the group receiving Granisetron 15µg/kg. We decided to grade shivering into moderate and severe categories as previous authors have done [4,6,9,1,16]. Specific inhibition of the 5-HT 3 system, therefore, produced reduction in shivering, being statistically significant. Perhaps 5-HT 3 inhibition has a

13 Granisetron Reduces Shivering after General Anesthesia specific antishivering effect, but given the variety of neurotransmitter systems known to be also involved in regulating shivering, an inhibitory effect at the 5-HT 3 receptor probably results from a generalized thermoregulatory inhibition at the level of the hypothalamus, where the bulk of thermoregulatory control occurs [15,17]. This explanation is supported by our data on perioperative temperature. The anticipated core-to-peripheral redistribution of body temperature after the administration of general anesthesia is characterized by an approximate 1 C decrease in core temperature within the first 2-3 minutes after the induction, followed by an increase in fingertip temperature, measured at the skin [18,19]. This was unchanged in our patients who received Granisetron. Thus, the PAS effect of Granisetron is independent of intraoperative core hypothermia, suggesting that it inhibits thermoregulatory responses by a central mechanism. The extent of core hypothermia seems to be related to the degree of vasodilation induced during anesthesia administration, because a recent study demonstrated greater core hypothermia after propofol induction compared with sevoflurane induction, even when anesthesia was maintained with sevoflurane [18]. Granisetron is notable for its lack of hemodynamic side effects [14] ; hence, its lack of effect on redistribution hypothermia is unsurprising. Granisetron did not alter the hemodynamic profile of either group intraoperatively, and although our study did not specifically examine postoperative hemodynamic profiles, it is highly unlikely that this is central to its antishivering effect. In contrast to some other drugs used to treat PAS, we found that Granisetron has innocuous effects on the cardiovascular system. Clonidine may be associated with significant hypotension and sedation [8], but this has not been consistently shown, with other studies indicating no significant hypotensive or sedative effect [1]. Tramadol, a nonopioid analgesic which inhibits 5-HT re-uptake and enhances synaptosomal concentration of 5-HT and noradrenaline, also inhibits shivering after the administration of general anesthesia [6]. It also reduces the sweating, vasoconstriction, and shivering thresholds [2]. Physostigmine increases heart rate and blood pressure [1], which may be detrimental to myocardial oxygen demand in some patients with coronary artery insufficiency. It is also commonly associated with postoperative nausea and vomiting [1]. In contrast, Granisetron effectively relieves postoperative nausea and vomiting. Although meperidine in the doses effective in treating postanesthetic shivering (.33-.4mg/kg) rarely produces untoward cardiovascular effects [6,9,1], it may potentially cause respiratory depression, especially if it or other opioids have been given intraoperatively. However, Granisetron is more expensive than any of the other drugs effective against PAS. Granisetron could very plausibly be an attractive and alternative preventive treatment for PAS, especially as it has powerful antiemetic effects [15,21] and a favorable cardiorespiratory side effect profile. The efficacy of Granisetron in treating established PAS and shivering after epidural anesthesia administration also warrants investigation. In conclusion, we have demonstrated that Granisetron 15 gg/kg given before the induction of anesthesia, reduces the incidence of PAS in adults, without effecting the core-to-peripheral redistribution of temperature normally observed during the administration of general anesthesia. 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