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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 16  |  Issue : 2  |  Page : 176-183

Studying the effects of granisetron, ketamine, and pethidine on prevention of shivering induced by spinal anesthesia


Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al Azhar University, Cairo, Egypt

Date of Submission06-Aug-2017
Date of Acceptance12-Sep-2017
Date of Web Publication27-Feb-2019

Correspondence Address:
Alaa El-Deen M Sayed
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al Azhar University, Cairo, 71121
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_38_17

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  Abstract 

Background Spinal anesthesia avoids the hazards of airway management during general anesthesia. Shivering is a frequent risk factor in patients undergoing lower half operations under spinal anesthesia. Premedication with intravenous serotonin receptor antagonists such as granisetron has been used to overcome this problem. Ketamine increases arterial pressure and heart rate and may decrease core-to-peripheral redistribution of heat. Moreover, pethidine which is considered as a time-tested drug for control of shivering can be of value for shivering prophylaxis.
Objective This study evaluates the efficacy of granisetron, ketamine, and pethidine on shivering in patients undergoing lower half operation under spinal anesthesia.
Patients and methods A total of 60 patients were assigned to three equal groups: group G received 3 mg granisetron, group K received 25 mg ketamine, and group P received 25 mg pethidine 5 min before spinal anesthesia. The incidence of shivering episodes was recorded at baseline monitoring, intraoperatively, and postoperatively. Moreover, propagation and regression of motor and sensory block were assessed.
Results Regarding mean arterial blood pressure, there was significant decrease in group P in comparison with groups G and K. Regarding decreased incidence of shivering, there was no significant difference between the study groups. Regarding incidence of nausea and vomiting, there was significant decrease incidence in group G compared with groups K and P. Moreover, there was significant difference regarding faster time to regression of sensory block in group G in comparison with groups K and P.
Conclusion In patients undergoing lower half surgery under spinal anesthesia, prophylactic intravenous administration of 3 mg granisetron, 25 mg ketamine, or 25 mg pethidine 5 min before induction of spinal anesthesia significantly reduced the severity of shivering. Regression of sensory block was faster with granisetron than ketamine and pethidine. Moreover, prophylactic granisetron also reduces nausea and vomiting and the need of antiemetics.

Keywords: 5-hydroxytryptamine 3, granisetron, ketamine, pethidine, shivering, spinal anesthesia


How to cite this article:
Sayed ADM. Studying the effects of granisetron, ketamine, and pethidine on prevention of shivering induced by spinal anesthesia. Al-Azhar Assiut Med J 2018;16:176-83

How to cite this URL:
Sayed ADM. Studying the effects of granisetron, ketamine, and pethidine on prevention of shivering induced by spinal anesthesia. Al-Azhar Assiut Med J [serial online] 2018 [cited 2020 Jul 6];16:176-83. Available from: http://www.azmj.eg.net/text.asp?2018/16/2/176/253087




  Introduction Top


Shivering is distressing for the patients undergoing surgery both under regional and after general anesthesia. The main causes for shivering intraoperatively/postoperatively are temperature loss, decreased sympathetic tone, and systemic release of pyrogens [1].

Shivering is unpleasant and causes several undesirable physiologic consequences such as increase in oxygen consumption, carbon dioxide production, chances of myocardial ischemia, infection, bleeding, and minute ventilation. It also induces hypoxemia and lactic acidosis, increased intraocular pressure and intracranial pressure, and interferes with patient monitoring such as ECG, noninvasive blood pressure, and oxygen saturation (SaO2). Spinal anesthesia is known to decrease the shivering threshold, preceded by core hypothermia and vasoconstriction above the level of block [2].

Regional anaesthesia may impair thermoregulatory control, and up to a 57% incidence of shivering during regional anaesthesia has been reported. Shivering during neuraxial anesthesia could have potentially detrimental effects. Regional anesthesia produces vasodilatation, which facilitates core-to-peripheral redistribution of heat [3].

Various methods are available for the control of shivering such as nonpharmacological or pharmacological. Nonpharmacological preventing measures such as fluid warmers, maintaining ambient operating room temperature, space blankets, surgical drapes, and active circulating water mattress have been used. Pharmacological methods including various drugs such as opioids (pethidine, pentazocine, and tramadol), α2 agonists (clonidine), and others such as doxapram, neofam, neostigmine, and magnesium sulfate have been tried [4].

Recently, studies on serotonin (5-hydroxytryptamine), a biological amine found in the brain and the spinal cord, which has a role in neurotransmission and thermoregulation, suggest the involvement of serotonergic system in the control of postanesthetic shivering. Serotonin antagonism seems to lower the human thermal set range, thereby reducing metabolic cold defenses and discomfort associated with postoperative hypothermia. These 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, used as antiemetics routinely, are easily available and cost-effective [5].

Ketamine, a competitive N-methyl-d-aspartate receptor antagonist, is an agent used to decrease postanesthetic shivering [6]. It increases arterial pressure, heart rate, and cardiac output because of direct central sympathetic stimulation and inhibition of norepinephrine uptake into postganglionic sympathetic nerve endings, and may decrease core-to-peripheral redistribution of heat [7]. Thus, it may be logical to use ketamine in patients who are at risk of hypothermia.

Pethidine decreases the shivering threshold and is effective in controlling shivering [8]. Pethidine, which is considered as a time-tested drug for control of shivering, can have adverse effects such as respiratory depression, nausea, and vomiting. This begs to investigate the efficacy of other drugs.

Thus, in search of an ideal antishivering agent, we compared the effect of prophylactic granisetron, ketamine, or pethidine for the prevention of intraoperative and postoperative shivering in patients undergoing elective lower half surgeries under spinal anesthesia.


  Patients and methods Top


For this prospective, randomized, controlled, parallel-group, effectiveness study, patients of both sexes, aged between 20 and 50 years, with an ASA physical status of I–II, with Glasgow coma scale 15, were eligible if they were scheduled to undergo lower half surgery under spinal anesthesia such as lower limb orthopedic surgeries, lower limb plastic surgeries, or lower abdominal surgeries. Patients were excluded if have any of the following exclusion criteria:
  1. Who refused to participate.
  2. Had any contraindications to subarachnoid block.
  3. Had a history of hypersensitivity to studied drugs.


After approval of the departmental ethical committee, this study was conducted from 15 June 2016 to 22 February 2017, at Al Azhar University Hospitals on 60 patients undergoing lower half surgeries after signing a written informed consent.

Patients were randomly assigned to receive granisetron 3 mg (group G), ketamine 25 mg (group K), or pethidine 25 mg (group P). Each group contains 20 patients. Study medications were prepared and presented as identical 10-ml filled syringes and injected 5 min before spinal anesthesia.

For eligible patients, demographic information was collected, and physical examination was performed. A standardized anesthesia regimen was followed. Age, weight, height, duration of surgery, and ASA I/II were recorded and analyzed.

In the preoperative preparation room, nearly 500-ml crystalloid (lactated ringer’s or normal saline 0.9%) was given intravenously (i.v.) after insertion of i.v. 18 G cannula in nondominant hand.

On arrival in the operating room, patients were monitored for mean arterial blood pressure (MAP), ECG, and pulse oximeter, and this becomes baseline monitoring.

After sterilization of the back, spinal anesthesia was induced at L3–L4, with the patient in the sitting position, with 3.5 ml (17.5 mg) of 0.5% hyperbaric bupivacaine after confirmation of free flow of cerebrospinal fluid through a 25-G Quincke spinal needle. The patients were then placed in the supine position.

Supplemental oxygen was administered through facemask at 5 l/min. Maintenance fluids (10 ml/kg in the first 1 h and 5 ml/kg in the subsequent hours) were given at room temperature. Hemodynamic data (MAP, heart rate, SaO2 and ECG changes), sensory block, motor block, nausea, vomiting, and shivering were recorded at 5 min interval in the first 15 min and then every 15 min until the end of procedure and then every 1 h for 6 h postoperatively.

Shivering was graded using the following scale [9]: 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; and 4, shivering involving the whole body.

During surgery, a shivering score was recorded at 5-min intervals. Just 15 min after spinal anesthesia, and concomitant administration of a prophylactic dose of one of the study drugs, if grade 3 or 4 shivering was noted, the prophylaxis was regarded as ineffective, and i.v. meperidine 25 mg was administered.

Hallucination as an adverse effect was defined as a false sensory experience where the patients reported they saw, heard, smelled, tasted, and felt something that was nonexistent. The attending anesthetist also assessed the degree of sedation on a five-point scale: 1, fully awake and oriented; 2, drowsy; 3, eyes closed but arousable to command; 4, eyes closed but arousable to mild physical stimulation; 5, eyes closed but unarousable to mild physical stimulation [10].

Rescue i.v. bolus doses of 9-mg ephedrine were given if the patient became hypotensive (hypotension was defined as a decrease in MAP of >20% from the baseline). Decrease in HR to less than 50 beat/min was treated with i.v. 0.5 mg atropine. Rescue i.v. 10 mg metoclopramide was given for vomiting episodes. Persistent pain sensation or movement of lower half was considered a failed spinal anesthesia treatment, and the patients underwent general anesthesia and were excluded from the study.

The height of sensory blockade was assessed as the highest dermatome with loss of fine pinprick sensation at two consecutive times. The time to two-segment regression and sensory regression to T10 and S1 were recorded and analyzed. The Bromage scale ([Table 1]) was used to evaluate motor block [11].
Table 1 Bromage scale for grading of motor block

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Statistical analysis

The statistical program (SPSS; SPSS Inc., Chicago, Illinois, USA) for Windows, version 20, was used for data entry and analysis. Quantitative data were presented as mean and SD, whereas qualitative data were presented as frequency distribution. Analysis of variance was used to compare the means between groups, followed by post-hoc analysis. The χ2-test and Fisher’s exact test were used to compare between proportions.


  Results Top


A total of 60 patients were selected and divided into three groups of 20 each. Regarding demographic data (age, weight, height, procedure duration, and ASA I/II), there were no significant differences between the three groups, and regarding the basal monitoring (MAP, HR, SaO2, ECG, sensory block, motor block, nausea, vomiting, and shivering), there were nonsignificant differences among the three groups.

However, regarding intraoperative MAP, there were significant decreases in group P compared with both groups G and K at 5, 10, 15, and 60 min, with P values of 0.035, 0.003, 0.006 and 0.042, respectively ([Table 2]), whereas there were nonsignificant differences between groups G and K regarding MAP.
Table 2 Comparison between study groups regarding mean arterial blood pressure intraoperative at 5, 10, 15, and 60 min

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Regarding postoperative MAP, there were nonsignificant differences among the three groups.

Regarding heart rate, oxygen saturation, and ECG, there were no significant differences among the three groups.

For shivering, there was no significant difference regarding the total number of patients who had episodes of shivering between the three groups, where three (15%) of 20 patients in group G stated having shivering: one patient had grade 2 shivering, one patient had grade 3 shivering, and 1 patient had grade 4 shivering; in group K, three (15%) of 20 patients, one patient had grade 2 shivering and two patients had grade 3 shivering; and lastly in group P 3/20 (15%): 2 patients had grade 2 shivering and one patient had grade 3 shivering. No patients in any of the three groups had grade 4 shivering ([Table 3] and [Figure 1]).
Table 3 Number of patients who had shivering episodes at 15, 30, 45, and 60 min

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Figure 1 Number of patients who had shivering episodes at 15, 30, 45, and 60 min.

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Regarding sedation, all patients of group G had grade one on sedation scale, whereas all patients of group P had grade 2 on sedation scale, but in group K, 50% of patient had grade 3 and 50% had grade 4.

Regarding the maximum cephalad spread of sensory block, there were no significant differences.

At 60 min intraoperatively, there was significant regression in sensory block in group G, which was faster than both groups K and P, with P value of less than 0.001 ([Table 4]).
Table 4 Level of sensory block at 60 min intraoperatively regarding study groups

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At 2:00 and 4:00 h postoperatively, there was significant regression in sensory block in group G, which was faster than both groups K and P, with P value of less than 0.001 ([Table 5]).
Table 5 Sensory block among study groups at 2:00 and 4:00 h postoperatively

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Also, regression to T10, and S1 were faster in group G than groups K and P, P value between groups K and P ([Table 6]).
Table 6 Comparison between times of regression of sensory block among study groups.

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However, there was no significant difference between groups K and P regarding sensory regression.

Regarding motor block, there were no significant differences among the three groups in the time to maximum motor block and the time to complete motor recovery.

Regarding nausea, there were significant decrease of incidence of nausea in group G compared with both groups K and P at 15 min and 30 min intraoperatively and 2:00 h postoperative, with P values of 0.046, 0.042, and 0.017, respectively ([Table 7]). However, there was no significant difference between groups K and P regarding nausea. Moreover, the total number of patients in group G having nausea episodes is 3/20 (15%) but in group K is 17/20 (85%) and group P is 16/20 (80%).
Table 7 Nausea at 15 and 30 min (intraoperatively) and 2:00 h (postoperatively) among study groups

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Regarding vomiting, there was significant decrease in incidence of vomiting in group G compared with both groups K and P at 30 min and 45 min intraoperatively, and 2:00 h postoperatively, with P values of 0.003, 0.020, and 0.002, respectively ([Table 8]). However, there was no significant difference between groups K and P regarding vomiting. Moreover, the total number of patient in group G having vomiting episodes is 3/20 (15%) but in group K is 17/20 (85%) and group P is 16/20 (80%).
Table 8 Vomiting at 30 and 45 min (intraoperatively) and 2:00 h (postoperatively) among study groups

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  Discussion Top


Postoperative shivering reportedly complicates emergence from anesthesia in 5–60% of cases [12]. A number of factors, including age, duration of surgery, temperature of the operating room, type of regional anesthesia (spinal or epidural), and infusion solution, are risk factors for hypothermia and shivering [13]. Opioid and nonopioid drugs are often used to treat postoperative shivering, but they have potential adverse effects, including hypotension, hypertension, sedation, respiratory depression, nausea, and vomiting [14].

Granisetron, which is 5-HT3 receptor antagonists, have been used effectively to decrease postanesthetic shivering. The mechanism for 5-HT3 receptor antagonists is still unclear but is thought to be related to inhibition of serotonin reuptake on the preoptic anterior hypothalamic region [15].

Ketamine probably controls shivering by nonshivering thermogenesis either influencing the hypothalamus or by the beta adrenergic effect of norepinephrine [16].

Pethidine has been shown to be one of the most effective treatments to prevent postoperative shivering. The antishivering effect of pethidine is because of stimulation of kappa receptors and drug-induced decrease in the shivering threshold [17].

On evaluating the occurrence of shivering, it was found that prophylactic use of granisetron, ketamine, and pethidine was effective in preventing shivering during neuraxial anesthesia without causing any untoward adverse effects.

These results are supported by the findings of Iqbal et al. [18] in which prophylactic use of granisetron (40 µg/kg) and pethidine (25 mg) i.v. was effective in preventing postoperative shivering.

In present study, results were also similar to the findings of Shakya et al. [19] who suggested that the prophylactic administration of low-dose ketamine 0.25 mg/kg and ondansetron 4 mg produces significant antishivering effect in comparison with placebo in patients undergoing spinal anesthesia and that ketamine 0.25 mg/kg is significantly more effective than ondansetron (4 mg).

Abotaleb et al. [20] in a study compared between dexmedetomidine and granisetron for the management of postspinal shivering and found that granisetron 2 mg effectively reduces postspinal shivering without any major adverse effects. Moreover, Kabade et al. [21] obtained that prophylactic granisetron 40 μg/kg i.v. is as effective as pethidine 0.4 mg/kg i.v. in preventing perioperative shivering following spinal anesthesia and also reduces the need of antiemetics. Gangopadhyay et al. [22] concluded that ketamine 0.5 mg/kg, i.v. was effective in preventing shivering under spinal anaesthesia.

Mahmood and Zweifler [23] reported that ketamine i.v. 0.5 mg/kg was effective in the treatment of shivering after general and regional anesthesia. Moreover, it provided sedation and analgesia. Although two (2/20) patients in their study had hallucinations, none of the patients in our study reported hallucinations. Adam et al. [24] demonstrated that a 3-mg/kg ketamine infusion after a 0.5-mg/kg bolus dose did not cause hallucinations.

This finding corroborates well with the finding of Park et al. [25] who reported incidence of postoperative shivering was decreased with pethidine pretreatment group.

In a similar study, no case of shivering was reported in the pethidine group. In addition, the use of prophylactic low-dose ketamine in shivering control after anesthesia for tonsillectomy in children was more effective than pethidine [16].

In another study, it was found that 0.5 mg/kg ketamine was better than 0.3 mg ketamine; however, pethidine is still the first and best choice [26].

Regarding hemodynamics, the important finding in this study is that there is decrease in reduction in mean blood pressure in the granisetron and ketamine groups but there is a reduction in MAP in pethidine group, with significant difference recorded. Although nonsignificant differences in heart rate were observed between the groups at any time of study duration.

Eldaba and Amr [27] showed that administration of 1 mg of granisetron at 5 min before spinal anesthesia can reduce significantly the incidence of hypotension in these patients in comparison with placebo (normal saline). Moreover, they also reported that the dosages of ephedrine and atropine in the granisetron group were significantly lower than those of the placebo group.

Shrestha et al. [28] concluded that granisetron given i.v. does not decrease the incidence of hypotension and bradycardia following subarachnoid block in patients undergoing lower abdominal surgery. However, it attenuates the fall of diastolic and MAP spinal anesthesia.

In contrast, Jabalameli et al. [29] concluded that the most effective method for prevention of hypotension was administration of crystalloid preload plus ephedrine, but there was no significant effect on the severity of nausea.

Regarding motor and sensory block, one of the most important finding in this study is that i.v. granisetron administration before spinal bupivacaine results in a faster recovery of the sensory blockade. On the contrary, the offset of motor blockade was similar in all groups.

Granisetron strongly and selectively binds to the 5-HT3 receptors with minimal or no affinity for other 5-HT receptors, or dopaminergic, adrenergic, histaminic, and opioid receptors [30]. Additionally, it has minimal adverse effects and possible drug interactions [31].These findings are in agreement with prior studies by Khalifa [32], Mowafi et al. [33], and Rashad and Farmawy [34], who concluded that i.v. granisetron facilitated the recovery of sensory block after bupivacaine subarachnoid anesthesia.

Kasem [35] found that administration of 1 mg of granisetron before spinal anesthesia in ambulatory surgeries resulted in a statistically faster sensory regression and earlier home discharge from the day-surgery unit.

Nausea and vomiting are common and sometimes dangerous adverse effects following surgery. Most of the incidences of nausea and vomiting occur during the first 2 h of recovery from anesthesia. The etiology of postoperative nausea and vomiting is multifactorial [36].

Janelsins et al. [37] in their study to prevent nausea and vomiting following cancer chemotherapy concluded that both ondansetron and granisetron have similar antiemetic efficacy, but dose of granisetron is much less than ondansetron.

Makker et al. [38] concluded that in the early postoperative period both ondansetron and granisetron are equally effective in preventing postoperative nausea and vomiting in patients undergoing gynecological surgery under spinal anesthesia.


  Conclusion Top


In patients undergoing lower half surgery under spinal anesthesia, prophylactic i.v. administration of 3 mg granisetron, 25 mg ketamine or 25 mg pethidine 5 min before induction of spinal anesthesia significantly reduces the severity of postanesthetic shivering without significant difference between the three drugs.

Granisetron reduces the incidence of nausea and vomiting and because of its hemodynamic stability, lack of significant adverse effects, and better patient satisfaction, it is preferred over other antiemetic and antishivering drugs.

Another finding regarding sensory block showed a significant faster recovery of sensory block with granisetron compared with both ketamine and pethidine groups, with no significant differences between the latter two groups, so granisetron may be useful in day case surgery and faster departure of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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  In this article
   Abstract
  Introduction
  Patients and methods
  Results
  Discussion
  Conclusion
   References
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