|Year : 2016 | Volume
| Issue : 4 | Page : 517-523
Dexmedetomidine versus granisetron for the management of postspinal shivering
Usama I Abotaleb1, Abdalla M Abdalla1, Ahmad S Abdelrahman1, Gad S Gad2, Abdalla M Elsayed1
1 Anaesthesia and Intensive Care Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Anaesthesia, Intensive Care and Pain Management Department, Faculty of Medicine, South Valley University, Cairo, Egypt
|Date of Submission||21-Feb-2016|
|Date of Acceptance||24-May-2016|
|Date of Web Publication||12-Jan-2017|
Usama I Abotaleb
214 Faisal St., Alharam, Giza, 11111
Source of Support: None, Conflict of Interest: None
Shivering is one of the most stressful complications for patients and surgeons during spinal anesthesia. In this prospective, randomized, double-blinded study, we compared the efficacy of dexmedetomidine versus granisetron for control of postspinal shivering.
This study was conducted on 120 patients, ASA I–III, of either sex, aged 18–60 years, who were scheduled for elective lower limb and lower abdominal surgeries under spinal anesthesia. The response rate, time taken to control shivering, recurrence rate, and adverse effects were recorded.
Incidence of shivering in 1127 patients was 52.7% (594 patients): we studied 120 patients; 28 patients (2.5%) developed grade 4 and 92 patients (8.2%) developed grade 3 shivering. There were no statistically significant differences regarding the time for onset of shivering, severity, response rate, need for a second dose, or pethidine between the two groups. However, time to control shivering was shorter in the dexmedetomidine group, with a higher recurrence rate. Incidences of hypotension, bradycardia, and sedation were higher in the dexmedetomidine group. However, there was no incidence of severe bradycardia or respiratory depression in our study.
Both dexmedetomidine and granisetron effectively reduce postspinal shivering without any major adverse effects. However, dexmedetomidine has rapid onset and short duration, whereas granisetron has less hemodynamic alterations.
Keywords: dexmedetomidine, granisetron, shivering, spinal anesthesia
|How to cite this article:|
Abotaleb UI, Abdalla AM, Abdelrahman AS, Gad GS, Elsayed AM. Dexmedetomidine versus granisetron for the management of postspinal shivering. Ain-Shams J Anaesthesiol 2016;9:517-23
|How to cite this URL:|
Abotaleb UI, Abdalla AM, Abdelrahman AS, Gad GS, Elsayed AM. Dexmedetomidine versus granisetron for the management of postspinal shivering. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2018 Jul 17];9:517-23. Available from: http://www.asja.eg.net/text.asp?2016/9/4/517/198259
The study was presented at a meeting at Al-Azhar University Hospitals in Cairo, Egypt from March 2014 till October 2015.
| Introduction|| |
Spinal anesthesia is known to significantly impair thermoregulation by inhibiting shivering and vasomotor responses and by heat redistribution from the core body to the peripheral tissues with subsequent rapid hypothermia during anesthesia . Multiple sequelae are caused by shivering: it can increase the metabolic rate up to four-fold; it can double or even triple oxygen consumption and carbon dioxide production; it can cause lactic acidosis and arterial hypoxemia; it can trigger myocardial ischemia; it causes increased intracranial and intraocular pressures; and it can interfere with heart rate, blood pressure, and ECG monitoring .
General and spinal anesthesia are usually associated with shivering and prevention of postanesthesia shivering mainly entails the prevention of perioperative heat loss by increasing operative room ambient temperature, using warmed intravenous fluids, or using conventional warm air blankets .
Shivering is considered as an attempt to raise the metabolic heat production as a physiological response to core temperature, but the exact mechanism of shivering during regional anesthesia has not been fully established .
Although the mechanisms are complex and still unclear, there are various pharmacological drugs available for shivering such as pethidine, clonidine, ketamine, tramadol, physostigmine, and magnesium ; however, every drug has its own adverse effect, and research continues to find the best antishivering agent, and the ideal drug is still not found ,.
Dexmedetomidine is a highly selective α2 agonist that has been used as a sedative. It decreases vasoconstriction and it can reduce the shivering threshold. Intraoperative dexmedetomidine reduces postanesthetic shivering .
Granisetron is a potent and highly selective 5-hydroxytyptamine 3 (5-HT3) receptor antagonist, but it has little or no affinity for other 5-HT receptors, or adrenergic, dopaminergic, histaminic, benzodiazepine, or opioid receptors . There are also four other antagonists of 5-HT3 receptor (ondansetron, dolasetron, palonosetron, and tropisetron) . In contrast, other 5-HT3 receptor antagonists have affinities for various receptor-binding sites. For example, ondansetron has detectable binding to 5-HT1C, 5-HT1B, α1 adrenergic, and µ-opioid receptor sites. Although it has not been proven, the binding of these agents to additional receptor subtypes other than their target receptor may underlie the higher adverse events seen with ondansetron compared with granisetron .
The safety of intravenous granisetron has been evaluated in clinical trials in more than 7000 patients, which have shown the drug to be well tolerated, with mild and transient side effects. The most common adverse events occurring in clinical trials were diarrhea, constipation, and headache .
It is used mainly as an antiemetic, but it has also been reported to prevent postanesthesia shivering; as serotonin (5-HT3) is involved in the regulation of body temperature and as it is responsible for adjustment of thermoregulatory set range in the anterior hypothalamus, administration of 5-HT3 antagonists would decrease the set range and prevent postanesthetic shivering . To our knowledge, no study assessed the granisetron effect in the management of postspinal shivering, and thus we planned this study.
| Aim|| |
The aim of this study was to compare the efficacy and safety of granisetron with that of dexmedetomidine for control of shivering following spinal anesthesia. The null hypothesis of this study was the supposition that there was no difference in the response rate between granisetron and dexmedetomidine when it was used to control postspinal shivering.
| Methods|| |
After approval of the local ethics committee, this prospective, randomized, double-blinded trial was conducted in Al-Azhar University Hospitals. Patients of American Society of Anesthesiologists (ASA) physical status I, II, and III, of either sex, aged between 18 and 60 years, who were scheduled for elective lower limb and lower abdominal surgeries under spinal anesthesia were included, after obtaining informed patient consent. A total of 120 patients who fulfilled the inclusion criteria and developed postspinal shivering of either grade 4 or grade 3 were enrolled. Using a computer-generated randomization schedule, they were randomly assigned into two equal groups.
Patients younger than 18 years or older than 60 years, obese (>35 BMI), ASA physical status above III, allergic and/or contraindicated to one or more of the drugs studied; patients with cardiovascular, renal, or hepatic diseases; patients with a contraindication to spinal anesthesia (e.g. local or general infection, coagulation disorders, or progressive neurological disorders); or those who did not agree to participate in the study were excluded from our study.
Patients were randomly allocated into two groups: group D (n=60), in which dexmedetomidine was administered at a dose of 40 μg intravenously, and group G (n=60), in which granisetron was administered at a dose of 2 mg intravenously. The study drug was diluted to 10 ml with isotonic saline, and it was given slowly intravenously (more than 1 min) at the start of shivering. The study solution was prepared by a resident who was not involved in the anesthesia team. Neither the anesthesiologist nor the patients was aware of the kind of drug used.
Upon arrival into the operative room, an 18-G venous cannula was inserted and a preload of 10 ml/kg Ringer’s lactate solution was infused and maintained at 6 ml/kg/h after spinal anesthesia.
Standard monitors were applied and all baseline parameters such as heart rate, noninvasive blood pressure, oxygen saturation (SpO2), ECG, and axillary temperature were recorded before anesthesia, 5 and 10 min after anesthesia, before administration of the study drug, 5, 10, and 15 min after administration of the study drug, and thereafter every 15 min for 1 h and every 30 min for the rest of observation period.
Under complete aseptic precautions, spinal anesthesia was given in the sitting position at the level of L3–L4 interspace, using a 25-G spinal needle, and after confirming clear and free flow of cerebrospinal fluid, all patients in the two groups received a drug volume of 3 ml of 0.5% hyperbaric bupivacaine containing 15 mg. When a block of T10 level was achieved, patients were prepared for operation.
The operative room was maintained at an ambient temperature of around 22–24°C, intravenous fluids were administered at room temperature, and no other warming devices were used in this study.
Oxygen was administered to all patients at a rate of 4 l/min with a facemask, and the patients were covered with drapes.
Shivering was graded using a four-point scale, as described by Wrench et al. :
Grade 0: No shivering.
Grade 1: One or more of the following − piloerection, peripheral vasoconstriction, peripheral cyanosis but without visible muscle activity.
Grade 2: Visible muscle activity confined to one muscle group.
Grade 3: Visible muscle activity in more than one muscle group.
Grade 4: Gross muscle activity involving the whole body.
Onset of shivering (the time at which shivering started after spinal anesthesia), severity of shivering, time to disappearance of shivering, and response rate were recorded.
If there was no response for 10 min or if shivering recurred, patients were treated with an additional dose of the same solution by the same way mentioned previously and recorded. 10 min after the second dose if the patient still had shivering (grade 3 or 4) that was not controlled by two doses of the study drug, or if shivering recurred for the second time, incremental doses of intravenous pethidine (20 mg) were given; the number of patients who received pethidine and total doses were recorded for each group.
Monitoring was continued until 2 h after spinal block. Adverse effects such as nausea, vomiting, hypotension (>20% of baseline), bradycardia (>20% of baseline), severe bradycardia (<50/min), sedation (Numeric Sedation Score>1), and respiratory changes (airway patency, SpO2<94%, and/or respiratory rate<10/min) were recorded, and the number of patients were compared.
The degree of sedation was evaluated with Numeric Sedation Scores (1=completely awake, 2=awake but drowsy, 3=asleep but responsive to verbal commands, 4=asleep but responsive to tactile stimulus, 5=asleep and not responsive to any stimuli) .
Severe bradycardia was treated with administration of intravenous 0.5 mg atropine boluses, and hypotension was treated with rapid administration of intravenous fluids (300–400 ml) and ephedrine boluses of 10 mg.
Sample size was calculated using G*Power 184.108.40.206 program, Kiel, Germany; depending on our primary outcome (response rate). In a previous study, the response rate in dexmedetomidine-treated patients was 96%; we planned our study to detect 20% difference in the response rate, and a power of 80% (1−β), at 5% significance level (α). The minimum sample size was to study 55 patients in each group [and increase 10% (approximately five patients) for dropout] to be able to reject the null hypothesis.
SPSS version 17 programs, Chicago, USA; were used to enter data and statistical analysis. Data were presented as mean±SD, range, number, and percent. Comparison between the two groups was performed using unpaired Student’s t-tests for parametric data and Mann–Whitney test for nonparametric ordinal data. For data collected as proportions, χ2-test was performed. A P-value less than 0.05 was considered statistically significant.
| Results|| |
The incidence of shivering in 1127 patients was 52.7% (594 patients): only 28 patients (2.5%) developed grade 4 shivering, 92 patients (8.2%) developed grade 3 shivering, 275 patients (24.4%) developed grade 2 shivering, and 199 patients (17.7%) developed grade 1 shivering, whereas 533 (47.3%) did not develop shivering at all. In all, 120 patients who developed grade 3 (92 patients) or 4 (28 patients) shivering were included in the study.
Axillary temperature was comparable between patients who developed shivering and those who did not, and it was also comparable between patients who developed different grades of shivering ([Table 1]).
Both groups were comparable with respect to age, sex, weight, ASA, and duration of surgery ([Table 2]).
There were no statistically significant differences regarding the time for onset of shivering, severity, response rate, need for a second dose, or pethidine between the two groups. However, the interval between the administration of drug and disappearance of shivering was shorter in the dexmedetomidine group; in addition, the recurrence rate was higher in the dexmedetomidine group compared with the granisetron group ([Table 3]).
Rescue doses were given for incomplete response and recurrence; in the granisetron group, shivering was still observed in five patients (of total seven) after the second dose, and in the dexmedetomidine group shivering was still observed in one patient and recurrence for the second time occurred in one patient. These patients (who did not respond) received incremental doses of pethidine (20–40 mg).
Incidences of hypotension, bradycardia, and sedation were higher in the dexmedetomidine group. However, there was no incidence of severe bradycardia or respiratory changes in any of our patients ([Table 4]).
| Discussion|| |
Spinal anesthesia is one of the regional techniques that are commonly used to avoid most of the risks that are associated with general anesthesia. Unfortunately, it carries some complications as well: the most common intraoperative complications are hypotension and shivering ,.
Shivering represents a body response to the decreased body temperature, which should be maintained within the range of 36.5–37.5°C. Multiple risk factors such as age, high level of the sensory block, and temperature of the operation room and fluids are contributing to shivering in neuraxial anesthesia .
Although the room temperature was maintained in our study within 22–24°C, keeping the patients normothermic was not applicable, and also shivering was observed in some patients with normal temperature.
The median incidence of shivering related to neuraxial anesthesia in the control groups of 21 studies was 55% (range of 40–64%) , which was nearly similar to that in our study (52.7%), but only 10.7% were of clinical relevance (grades 3 and 4).
In our study, we recorded axillary temperature because core temperature assessment was not applicable in awake patients, and no relationship has been shown between axillary temperature and occurrence of shivering; this was in agreement with the study by Dal et al. . Usta et al.  and Elvan et al.  in which core temperature was assessed through tympanic temperatures and no relationship was found.
Postspinal shivering can be treated by skin surface warming, radiant heat application, or pharmacological agents . Various drugs have been used to treat or prevent postspinal shivering , but the ideal treatment has not yet been found . The ideal drug is the one that is not only effective but also with rapid onset, minor adverse effects, and inexpensive; in addition, the best drug is the one that can reduce the temperature threshold for shivering near the patient’s body temperature.
Dexmedetomidine has been used for prevention or management  of postoperative shivering after general  and spinal anesthesia ,, but it was associated with delayed orientation time after general anesthesia and increased sedation after spinal anesthesia, which may be related to the higher doses used (1 μg/kg) − double the dose that we usually use (about 0.5 μg/kg); we used 40 μg for all patients for easy blindness (average weight was 83.5±10 kg and average dose/kg was 0.486–0.067 μg/kg).
The action of dexmedetomidine appears to be because of central thermoregulatory inhibition; it increases the range of temperature that did not stimulate the thermoregulatory defense mechanism and can decrease the shivering threshold temperature .
Although dexmedetomidine may be a good choice because of its dual effects of antishivering and sedation, on the other hand, it is short-acting (high recurrence in our study) and has a hypotensive effect . The search continues for drugs that sufficiently improve the tolerance of thermoregulation without simultaneously producing hemodynamic instability, excessive sedation, or respiratory depression.
Serotonin antagonists (granisetron) also have been used for the prevention of postoperative shivering associated with general  or spinal anesthesia .
Our study showed that each of granisetron 2 mg and dexmedetomidine 40 μg effectively control shivering in patients undergoing elective operations under spinal anesthesia. This antishivering effect was not associated with major side effects.
Although both drugs were nearly equally effective in controlling shivering, the time until control of shivering was higher in the granisetron group, but recurrence of shivering was higher in the dexmedetomidine group; Mittal et al.  also reported that it took less time to control shivering with dexmedetomidine.
One of the main objectives in using sedative agents is that the drug should not cause respiratory depression . In our study, the incidence of sedation, nausea, and vomiting was low, and no incidence of excessive sedation, severe bradycardia, or respiratory depression was observed, despite using dexmedetomidine, which may be related to the low dose used.
This was in agreement with previous studies , although Karaman et al.  reported negligible sedation during intraoperative dexmedetomidine infusion despite using a loading dose of 1 μg/kg followed by a maintenance infusion of 0.5 μg/kg/h.
Sedation more than grade 2 occurred only in three patients (5%) in the dexmedetomidine group, which was in accordance with the previous studies .
In our study, the incidences of hypotension and bradycardia were higher after dexmedetomidine administration; this was in agreement with the study by Usta et al. . Bradycardia is secondary to a relative parasympathetic dominance, increased baroreceptor activity, or induction of the Bezold–Jarisch reflex (BJR). This reflex is elicited by stimulation of peripheral serotonin receptors (5-HT3) .
BJR triggered by heart mechanoreceptors results in the systemic response to hypervolemia and hypovolemia. Therefore, serotonin-induced BJR participates in the systemic response to spinal anesthesia by vasodilatation, hypotension, and bradycardia .
These findings are in agreement with those of Tsikouris et al. , who observed that infusion of granisetron diminished heart rate fluctuations and decreased systolic blood pressure changes during head-up tilt table tests, which are likely to be related to the BJR.
In contrast to our study, Mowafi et al.  and Rashad and Farmawy  found that granisetron administration had no effect on hemodynamic variables, but at least granisetron has no hypotensive effect.
Limitations of our study were that we did not assess a lower dose of granisetron (1 mg), we did not use dexmedetomidine infusion, and also in our study five patients (of total seven) did not respond to the second dose of granisetron, but we cannot conclude that 4 mg has no more effect, and thus further studies are needed to evaluate their effects with various doses .
| Conclusion|| |
Both dexmedetomidine 40 μg and granisetron 2 mg effectively reduce postspinal shivering without any major adverse effects. However, dexmedetomidine has rapid onset and also short duration, whereas granisetron is better as regards less hemodynamic alterations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Crowley LJ, Buggy DJ. Shivering and neuraxial anesthesia. Reg Anesth Pain Med 2008; 33:241–252.
Dal D, Kose A, Honca M, Akinci SB, Basgul E, Aypar U. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J Anaesth 2005; 95:189–192.
Alfonsi P. Postanesthetic shivering epidemiology, pathophysiology and approaches to prevention and management. Drugs 2001; 61:2193–2205.
Usta B, Gozdemir M, Demircioglu RI, Muslu B, Sert H, Yaldiz A. Dexmedetomidine for the prevention of shivering during spinal anesthesia. Clinics (Sao Paulo) 2011; 66:1187–1191.
Shakya S, Chaturvedi A, Sah BP. Prophylactic low dose ketamine and ondansetron for prevention of shivering during spinal anaesthesia. J Anaesthesiol Clin Pharmacol 2010; 26:465–469.
Shukla U, Malhotra K, Prabhakar T. A comparative study of the effect of clonidine and tramadol on post-spinal anaesthesia shivering. Indian J Anaesth 2011; 55:242–246.
Elvan EG, Oç B, Uzun S, Karabulut E, Coşkun F, Aypar U. Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 2008; 25:357–364.
Aapro M. Granisetron: an update on its clinical use in the management of nausea and vomiting. Oncologist 2004; 9:673–686.
Hsu ES. A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. Am J Ther 2010; 17:476–486.
Bock M, Sinner B, Gottlicher M, Simon E, Martin E, Motsch J. Involvement of serotonergic pathways in postanesthetic cold defense: dolasetron prevents shivering. J Therm Biol 2002; 27:159–166.
Wrench IJ, Singh P, Dennis AR, Mahajan RP, Crossley AW. The minimum effective doses of pethidine and doxapram in the treatment of postanaesthetic shivering. Anaesthesia 1997; 52:32–36.
Ozgencil E, Yalcin S, Tuna H, Yorukoglu D, Kecik Y. Perioperative administration of gabapentin 1,200 mg day-1 and pregabalin 300 mg day-1 for pain following lumbar laminectomy and discectomy: a randomised, double-blinded, placebo-controlled study. Singapore Med J 2011; 52:883–889.
Rashad MM, Farmawy MS. Effects of intravenous ondansetron and granisetron on hemodynamic changes and motor and sensory blockade induced by spinal anesthesia in parturients undergoing cesarean section. Egypt J Anaesth 2013; 29:369–374.
Powell RM, Buggy DJ. Ondansetron given before induction of anesthesia reduces shivering after general anesthesia. Anesth Analg 2000; 90:1423–1427.
Mittal G, Gupta K, Katyal S, Kaushal S. Randomized double-blind comparative study of dexmedetomidine and tramadol for postspinal anaesthesia shivering. Indian J Anaesth 2014; 58:257–262.
Mohamed HS. Dexmedetomidine versus Nefopam for the management of post-spinal anesthesia shivering: a randomized double-blind controlled study. Egypt J Anaesth 2015; 31:315–320.
Iqbal A, Ahmed A, Rudra A, Wankhede RG, Sengupta S, Das T, Roy D. Prophylactic granisetron vs pethidine for the prevention of postoperative shivering: a randomized control trial. Indian J Anaesth 2009; 53:330–334.
Karaman S, Gunusen I, Ceylan MA, Karaman Y, Cetin EN, Derbent A, Ergenoğlu AM. Dexmedetomidine infusion prevents postoperative shivering in patients undergoing gynaecologic laparoscopic surgery. Turk J Med Sci 2013; 43:232–237.
Eldaba AA, Amr YM. Intravenous granisetron attenuates hypotension during spinal anesthesia in cesarean delivery: a double-blind, prospective randomized controlled study. J Anaesthesiol Clin Pharmacol 2015; 31:329–332.
Khalifa OM. A comparative study of prophylactic intravenous granisetron, ondansetron, and ephedrine in attenuating hypotension and its effect on motor and sensory block in elective cesarean section under spinal anesthesia. Ain-Shams J Anaesthesiol 2015; 8:166–172.
Tsikouris JP, Kluger J, Chow MS, White CM. Usefulness of intravenous granisetron for prevention of neurally mediated hypotension upon head upright tilt testing. Am J Cardiol 2000; 85:1262–1264.
Mowafi HA, Arab SA, Ismail SA, Al-Ghamdi A. The effects of intravenous granisetron on the sensory and motor blockade produced by intrathecal bupivacaine. Anesth Analg 2008; 106:1322–1325.
[Table 1], [Table 2], [Table 3], [Table 4]