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Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 3  |  Page : 663-668  

Comparative efficacy and safety of intravenous clonidine and tramadol for control of postspinal anesthesia shivering


1 Department of Anesthesia, D. Y. Patil School of Medicine and Hospital, Navi Mumbai, Maharashtra, India
2 Department of Anesthesia, VMMC and Safdarjung Hospital, New Delhi, India

Date of Web Publication11-Sep-2018

Correspondence Address:
Dr. Varsha Vyas
Department of Anaesthesia, D. Y. Patil School of Medicine and Hospital, Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.AER_86_18

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   Abstract 

Background: Shivering is a common problem in patients undergoing surgery under spinal anesthesia. Aims: The aim of this study was to compare efficacy and safety of clonidine versus tramadol in postspinal anesthesia shivering. Settings and Design: This prospective, randomized, double-blind controlled clinical trial was conducted in a tertiary care setting. Materials and Methods: A total of 60 American Society of Anesthesiologists physical status Class l and II adult patients (age 18–65 years) undergoing surgery under spinal anesthesia and developed shivering received either clonidine 1 μg/kg or tramadol 1 mg/kg intravenously. The time required for cessation of shivering, control and recurrence rate of shivering, effect on hemodynamics and side effects were compared between two groups. Statistical Analysis: Unpaired t-test and Chi-square test were used for comparison of continuous variables and dichotomous data between two groups, respectively. P < 0.05 was considered as statistically significant. Results: Time for cessation of shivering was less in clonidine group than tramadol group (02.51 vs. 04.82 min; P < 0.001). Complete control of shivering was achieved in 80% of patients in clonidine group versus 70% in tramadol group. There was no significant difference for control (P = 0.5) and rate of recurrence of shivering between clonidine and tramadol group (06.7% vs. 16.7%; P = 0.42). Pulse rate and systolic blood pressure were significantly lower in clonidine group at 5 and 15 min as compared with tramadol. Significantly more number of patients experienced nausea and dizziness (36.7% vs. 0%; P < 0.001 and 20% vs. 0%; P = 0.01) with tramadol while bradycardia and hypotension were numerically more common in patients receiving clonidine (6.7% vs. 0% and 13.3% vs. 0%). Conclusion: Clonidine provides early relief from shivering than tramadol with fewer side effects in patients undergoing surgery under spinal anesthesia.

Keywords: Clonidine, postspinal anesthesia shivering, tramadol


How to cite this article:
Vyas V, Gupta R, Dubey P. Comparative efficacy and safety of intravenous clonidine and tramadol for control of postspinal anesthesia shivering. Anesth Essays Res 2018;12:663-8

How to cite this URL:
Vyas V, Gupta R, Dubey P. Comparative efficacy and safety of intravenous clonidine and tramadol for control of postspinal anesthesia shivering. Anesth Essays Res [serial online] 2018 [cited 2018 Dec 13];12:663-8. Available from: http://www.aeronline.org/text.asp?2018/12/3/663/240878


   Introduction Top


Shivering is one of the most important postoperative complications seen in clinical practice.[1] It is an important concern in patients undergoing surgery under general anesthesia [2] as well as regional anesthesia, i.e. spinal anesthesia [3] or epidural anesthesia.[4] The reported median incidence of shivering related to neuraxial anesthesia from different studies is 55%.[5]

The exact site of origin for the pathogenesis of postoperative shivering is not known. Several mechanisms have been postulated for its pathogenesis.[6] Inhibition of thermoregulation and nonthermoregulatory mechanisms are suggested to be involved in the pathogenesis of postanesthesia shivering. Anesthetic-induced inhibition of thermoregulation resulting in hypothermia is an important cause of postanesthesia shivering.[2] Pain, uncontrolled spinal reflexes,[7] and cutaneous vasodilation are the other suggested mechanisms involved in the pathogenesis of shivering.[2] Opioid receptors, α2 receptors, and serotonergic receptors are involved in the pathogenesis of shivering.[8]

Because of its associated discomfort,[2],[3] distress,[3] aggravation of pain, increased metabolic demands, and increased oxygen consumption [9] prevention and treatment of postanesthesia shivering is an important component of perioperative management of the patient.[2] Nonpharmacological as well as pharmacological measures are useful in prevention of hypothermia and shivering. Nonpharmacological measure, i.e., active rewarming of patient helps to prevent hypothermia, but it is less effective than pharmacotherapy.[2]

Pharmacological agents acting on the pathways discussed above are useful for the treatment of shivering.[8] Different pharmacological agents studied for their potential in prevention of peri- or post-operative shivering include clonidine, tramadol, dexmedetomidine, ondansetron, granisetron, ketamine, and pethidine.[2],[3],[10],[11],[12],[13],[14]

Tramadol is μ receptor agonist and also inhibits the reuptake of norepinephrine and 5-hydroxytryptamine (5-HT) and also improves the release of 5-HT. This pharmacological mechanism of tramadol is postulated to be useful for the control of thermoregulation.[15] Prophylactic use of tramadol is effective in prevention of shivering postspinal anesthesia.[16] Tramadol is commonly used in our clinical practice for prevention of shivering in patients undergoing surgery under regional anesthesia. However, in patients who do not tolerate tramadol or have a contraindication for its use, an alternative option is desired.

The available evidence suggests the usefulness of α2 receptor agonist in effectively reducing shivering through their action on α2 receptors.[17],[18] Clonidine, a α2 receptor agonist is effective in reducing the incidence of shivering and decrease oxygen consumption during recovery from anesthesia Kundra et al.[10] The anti-shivering effect of clonidine is because of the actions at three levels; hypothalamus, locus coeruleus, and spinal cord. The postulated mechanisms include alteration of thermoregulatory threshold for vasoconstriction, activation of α2 receptors at the spinal cord level and release of norepinephrine and other mediators.[19] However, because of no routine use of clonidine is our clinical settings, we wanted to examine through a well-designed study if it can be used as an alternative to tramadol for control of shivering in patients undergoing surgery under general anesthesia.

Objective

The objective of this study was to compare efficacy and safety of intravenous clonidine versus tramadol for control of postspinal anesthesia shivering.


   Materials and Methods Top


In this prospective, double-blind, randomized controlled trial, American Society of Anesthesiologists physical status Class I and II (ASA-I and II) consecutive patients of either sex, aged between 18 and 65 years, scheduled for elective lower abdominal and lower limb surgeries under spinal anesthesia and developed intraoperative shivering postspinal anesthesia lasting for minimum period of 2 min were included in this study. Patients with known hypersensitivity to clonidine and tramadol, known the history of alcohol or substance abuse, hyperthyroidism, cardiovascular diseases, psychological disorder, severe diabetes or autonomic neuropathies, and urinary tract infection were excluded from the study.

Detailed preanesthetic checkup of all the patients was done a day before surgery. All patients were kept nil by mouth for >8 h before surgery. During the surgery, oxygen was given through Hudson's mask at 4–5 L/min. Intravenous fluids were infused at room temperatures and ambient temperature of the operating room 22°C–28°C. Spinal anesthesia was performed in sitting position with a 23- or 25-gauge Quincke spinal needle in the L3–4/4–5 interspace (midline approach) and injection bupivacaine (0.5%, heavy) was given to achieve a desirable level at T5–T6 dermatome, in accordance with the surgical procedure. After induction of spinal anesthesia, patients were observed for the occurrence of shivering until the postoperative period.

The cases were randomly allocated with a table of random numbers technique to one of the two groups by an investigator who prepared study drug solutions. Patients in one group received intravenous tramadol 1 mg/kg diluted till 10 mL by normal saline slowly. Patients in another group received an intravenous clonidine 1 μg/kg diluted till 10 mL normal saline slowly. Two operator techniques were employed to maintain blinding. Further interventions and monitoring were done by an investigator blinded to the group allocation. Time of the onset of shivering after spinal anesthesia was noted. The treatment was started immediately after the onset of shivering. The study drug was given along with injection ondansetron 4 mg. Shivering control was defined as “complete” when posttreatment shivering score declined to “0,” “incomplete” when the scores decreased but did not abolish the shivering completely and “failed” if there was no change in the score.

Sedation was assessed on a 5 point scale; 0 – alert; 1 – arouse to voice; 2 – 1 rouse with gentle tactile stimulation; 3 – arouse with vigorous tactile stimulation; and 4 – no awareness. The time taken for the cessation of rigors and hemodynamic changes were recorded at regular 5 min intervals up to 15 min. Recurring (any rise in shivering scores posttreatment) episodes of rigor with axillary temperatures and core body temperature at two data points (during shivering and 15 min posttreatment) were noted. Side effects were also noted in each group. Episodes of recurrence or incomplete control were treated with active warming measures using convection heaters, infusing moderately warm fluids or multimodal therapy (injection midazolam 0.03 mg/kg). Pulse rate, blood pressure, axillary temperature, core body temperature, and SpO2 were monitored throughout. Fall in the systolic arterial pressure of >20% below the preanesthetic value was considered as significant hypotension and treated with intravenous injection ephedrine 6 mg in increments. The study was conducted from October 2014 to May 2016 after obtaining permission from the Institutional Ethics Committee and written informed consent from the patients.

Statistical analysis

The sample size for mean difference between two groups was calculated using “OpenEPI, Version 3” available on website www.openepi.com/SampleSize/SSMean.htm. The input parameters used for calculation of sample size were 99% confidence interval (two-sided), 90% power and ratio of sample size (Group 2/Group 1) as 1.

All the collected data were entered into Microsoft Excel sheet. The data were then transferred and analyzed using SPSS version 17 (SPSS Inc., Chicago, Illinois, USA). Qualitative data are presented in the form of frequency and percentage while quantitative data are presented using mean and standard deviation. Unpaired t-test and Chi-square test were used for comparison of continuous variables and dichotomous data between two groups, respectively. P < 0.05 was considered as statistically significant.


   Results Top


A total of 60 patients (male n = 29 and female n = 31) enrolled in the present study were randomized into two groups of 30 each [Figure 1]. The mean age, weight, duration surgery, percentage of male and female patients, percentage of patients with different ASA physical status class, and duration of surgery for both groups are given in [Table 1]. There was no significant difference in any of these parameters between two groups [P > 0.05 for all; [Table 1]. There was no significant difference in the time for onset of shivering (P = 0.87) and severity of shivering (P = 1) between two groups [Table 1].
Figure 1: Flow diagram

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Table 1: Baseline characteristics in the tramadol and clonidine group

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Distribution of subjects as per control of shivering

Complete control of shivering was achieved in 80% cases of clonidine group compared to 70% in tramadol group. Incomplete control of shivering was observed in 10% and 20% cases of clonidine and tramadol group, respectively. Both agents failed to achieve either complete or incomplete control in 10% cases each [Figure 2]. There was no significant difference in both groups for control of shivering (P = 0.5).
Figure 2: Control of postspinal anesthesia shivering with clonidine and tramadol

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Meantime required for cessation of shivering was significantly less in clonidine group compared to tramadol group [2.51 ± 0.66 vs. 4.82 ± 0.90 min; P < 0.001; [Figure 3].
Figure 3: Comparative mean time for cessation of postspinal anesthesia shivering in clonidine and tramadol group

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A total of 2 (6.70%) and 5 (16.70%) patients in clonidine and tramadol group had recurrence of shivering whereas 28 (93.30%) and 25 (83.30%) patients in both groups did not have a recurrence, respectively. There was no statistically significant difference for the recurrence of shivering between two groups [P = 0.42; [Figure 4].
Figure 4: Recurrence of shivering in clonidine and tramadol group in patients with spinal anesthesia

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Pulse rate and systolic blood pressure were significantly lower in clonidine group at 5 and 15 min after shivering as compared to tramadol group [Table 2]. No difference was observed between the two groups based on the partial pressure of oxygen (SpO2) during and after shivering [Table 2].
Table 2: Comparative hemodynamic parameters with clonidine versus tramadol when used for control of postspinal anesthesia shivering

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Sedation score of 2 was seen in 80% patients of tramadol group compared to 60% in clonidine group (P = 0.15). Significantly more number of patients experienced nausea (P< 0.001) and dizziness after tramadol (P = 0.01) while incidence of bradycardia and hypotension was numerically more with clonidine treatment than tramadol (6.7% vs. 0% and 13.3% vs. 0%; [Table 3]) however, the difference was not statistically significant.
Table 3: Comparison of the safety profile of clonidine and tramadol for control of postspinal anesthesia shivering

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   Discussion Top


Shivering is a frequent concern of in patients undergoing surgery.[10] Postspinal anesthesia shivering is unpleasant and discomforting problem in many patients.[10],[20] Simple and inexpensive measures are always sought for control of shivering in these patients. Clonidine, a α2 agonist and tramadol are useful for control of shivering. The former acts by reducing the central thermosensitivity and release of noradrenaline from axonal terminals in the hypothalamus whereas later reduces uptake of neuronal uptake of noradrenaline and (5-HT).[3] Tramadol acts at the level of pons. It reduces the uptake of 5-HT, a major neurotransmitter in the raphe nucleus, which plays an important role in the modulation of pain.[21] In a single-center study, we compared efficacy and safety of intravenous clonidine and tramadol given prophylactically for the control of shivering postspinal anesthesia. The age of patients in our study ranged from 18 to 65 years. Age-related changes in the thermoregulatory mechanisms are known De Witte and Sessler.[21] In order to avoid age-related bias, we did not include elderly patients in our study. Ideal dose of clonidine for prevention of postspinal anesthesia shivering is not known.[22] In a previous study,[23] has concluded that preventive intravenous clonidine 1 μg/kg results significant reduction in the incidence of postextradural shivering without clinically significant adverse events. Based on the results of this study, we selected this dose for comparison with tramadol. In another recent study, the same dose of clonidine was used by Venkatraman et al.[3] Tramadol in the dose of 1 mg/kg has been shown to be effective for prevention of postoperative shivering.[24] Dose of clonidine as well as tramadol in our study is similar to another study.[3]

As reported in another study by Guha et al.,[19] tramadol and clonidine both were effective in controlling shivering in our study too. The response rate with clonidine was more and with tramadol, it was less in our study compared to another study from India.[25] In a study conducted by Verma and Kumar,[25] response rate was 100% with tramadol as opposed to complete control observed in 70% patients in our study. The differences might be explained by the dosages of medicines used in the study. We used intravenous tramadol and clonidine in the dose of 1 mg/kg and 1 μg/kg whereas study by Verma and Kumar [25] used it in the dose of 2 mg/kg (max 100 mg) and 0.5 μg/kg, respectively. As compared to our study, in terms of the time required for the cessation of shivering with clonidine was quicker as compared to tramadol. Our observation is similar to a study performed by Shukla et al.[26]

Rate of recurrence of shivering in our study was more with tramadol as compared to clonidine. This observation is in accordance with a study performed by Venkatraman et al.[3] which used same dose of clonidine and tramadol as in our study. In another study, the rate of recurrence of shivering with tramadol was more than dexmedetomidine.[10]

Nausea and vomiting may limit the use of tramadol for control of shivering. In a comparative trial, incidence of vomiting with tramadol has been shown to be more than clonidine.[3] In our study also, rate of vomiting was numerically higher with tramadol. In another study from India, the incidence of nausea and vomiting was higher with tramadol as compared with clonidine.[26] Rates of nausea and vomiting are also higher with tramadol as compared with dexmedetomidine.[10] Surprisingly, despite higher dose of tramadol, incidence of nausea and vomiting in another study [18] was lesser as compared to our study.

Bradycardia and hypotension are the hemodynamics related adverse events with use of clonidine.[3],[26] The rates of bradycardia and hypotension are higher with clonidine than tramadol.[3],[26] In our study, pulse rate and systolic blood pressure were significantly lower with clonidine group at 5 and 15 min after shivering as compared to tramadol group. Incidence of hypotension and bradycardia was numerically more with clonidine than tramadol in our study whereas despite lower dose than our study, incidence of hypotension with clonidine was higher in another study.[25]

The results of our study may help in increased usage of clonidine for control of postanesthesia shivering. Clonidine can also be a good alternative for patients in whom tramadol cannot be administered or not well tolerated. Convenience sampling method, small sample size, and single-center study are the limitations of our study. Larger randomized controlled trials are required to confirm our observations.


   Conclusion Top


Both clonidine and tramadol are effective in controlling postspinal anesthesia shivering. However, clonidine results in early complete cessation of shivering compared with tramadol. Clonidine also offers better thermodynamics with lesser side effects. Side effects such as nausea, vomiting, and dizziness may limit the use of tramadol as an anti-shivering drug.

Acknowledgment

Authors of this study would like to acknowledge the support of Dr. Anant Patil for assistance in writing and editing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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