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Dexmedetomidine and clonidine have been used for the prevention and treatment of shivering following spinal blockade. A prospective randomized, double-blinded study was conducted to compare the efficacy and safety of dexmedetomidine and clonidine in controlling postspinal shivering.
A total of sixty participants of equal sex, aged between 18 and 60 years of American Society of Anesthesiologists (ASA) I/II Class, who underwent orthopedic lower limb surgeries under spinal anesthesia with ≥Grade III shivering were randomly divided into two groups, Group D (n = 30) received injection dexmedetomidine 0.5 μg/kg and Group C (n = 30) received injection clonidine 1 μg/kg when they experienced shivering. Time taken to control shivering, response rate, recurrence rate, and side effects such as nausea, vomiting, dry mouth, respiratory depression, and deep sedation were observed.
The demographic profile, ASA Class, duration of surgery, duration of anesthesia, temperature, onset and grade of shivering were all comparable between the two groups. Time taken to control shivering and recurrence rate were significantly lower in Group D when compared with Group C. Level of sedation was adequate with Group D, and the incidence of hypotension and bradycardia were significantly higher in Group C. The other side effects profiles were comparable between the two groups.
Dexmedetomidine 0.5 μg/kg is more efficient than clonidine 1 μg/kg in controlling postspinal blockade shivering. Dexmedetomidine has early onset of effect, high response rate, and less recurrence rate with added advantage of good sedation and stable cardiorespiratory parameters.
Shivering occurs most commonly after central neuraxial blockade due to altered thermoregulatory control.[1,2] It is defined as involuntary, repetitive activity of skeletal muscles. It is caused by temperature loss, increased sympathetic tone, pain, and release of pyrogens. Shivering increases oxygen consumption, carbon dioxide production, and metabolic rate.[4,5] Hence, it is necessary to control shivering for better patient outcome.
The treatment of shivering includes both pharmacological and nonpharmacological methods. Nonpharmacological includes external heating by warming blankets, warm IV fluids. In drugs, pethidine, tramadol, and ondansetron were widely used. However, these drugs had their own demerits such as high sedation, nausea, vomiting, and allergy. Hence, their use is declining now.
Recently, α2 adrenergic agonists, clonidine, and dexmedetomidine were found to have anti-shivering properties.[6,7,8] Clonidine is an α2 adrenergic agonist with antihypertensive, sedative, analgesic, and antishivering property dexmedetomidine has highly selective α2-agonist. It has been used as a sedative agent, and it also has antishivering property.
Since no head to head comparison was done on the antishivering effects of these drugs, we planned a double-blind, prospective, randomized controlled study to compare the efficacy and safety of these drugs in controlling postspinal anesthesia shivering in patients undergoing lower limb orthopedic surgeries.
After getting permission from the Institutional Ethical Committee and written informed consent from sixty American Society of Anesthesiologists (ASA) Classes I and II patients, aged 18–60 years undergoing elective lower limb orthopedic surgeries who developed Grade III and above level of shivering were enrolled for the study. Patients with Grades I and II shivering, patients with cardiac disease (heart blocks, bradyarrhythmias, and left ventricular failure), renal disease, hepatic disease, psychiatric disorder, neuropathies, known history of substance or alcohol abuse were excluded from the study. Since the study confined to the intraoperative period, there is no risk of loss of cases during the study. All patients were given the tablet ranitidine 150 mg a night before and on the morning before surgery. In the operation room (OR), an intravenous (IV) access was secured with a wide bore cannula and all standard ASA monitors were attached and monitored. Under strict aseptic precautions, spinal anesthesia was given through L3–L4 interspinous space with 3.5 ml of 0.5% hyperbaric bupivacaine using a 25-gauge Quincke spinal needle. Only a single layer surgical draping was used to cover all the patients. OR temperature was maintained constant (24–26°C), and the patients were observed for shivering intraoperatively. Presence of shivering was observed by an anesthesiologist who was blinded to the study drug. Based on a shivering grade scale by Tsai and Chu, when the patient was noted to have Grade III or IV shivering, they were randomly allocated to one of the following two groups by drawing sequential numbered, opaque sealed envelopes containing a code based on computer generated number list: Group D received injection dexmedetomidine 0.5 µg/kg IV and Group C received injection clonidine 1 µg/kg IV. Only two groups were selected because we were comparing these two drugs on shivering control. Drugs were diluted to 5 ml in a coded syringe by an anesthesiologist who is not involved in the study. After few minutes of administering the drug, the following parameters were noted by the independent observer. (1) Time taken to stop shivering, (2) response rate (good if shivering stopped within 15 min), (3) recurrence rate (recurrence before the end of surgery), (4) side effects such as hypotension, bradycardia, nausea, vomiting, dry mouth, respiratory depression, and deep sedation (Ramsay sedation scale >3). If the study drug did not relieve the shivering, injection dexamethasone 8 mg IV was given as a rescue drug to control shivering. Hypotension (fall in systolic blood pressure <100 mm Hg) was treated with injection mephentermine 6 mg IV bolus and bradycardia (heart rate <50/min) was treated with 0.01 mg/kg of injection atropine. Nausea and vomiting were treated with 0.1 mg/kg of IV injection Ondansetron.
Sample size was calculated based on the previous studies. They found an incidence of shivering recurrence of the order of 45–60%. We anticipated an incidence of 50%. Hence, >28 patients were required in each group for type I error (α) of 0.05 and power of the study of 0.8. Hence, we selected 30 patients per group. The descriptive statistics such as mean, standard deviation, or percentages were calculated for the variables. Statistical Package for Social Science (IBM Software Group, Chicago, IL 60606, USA) Version 21.0 for Windows was used to compare the continuous variables between the two groups. To test the hypothesis, Student's t-test and Chi-square tests were used at 5% level of significance.
The demographic profile of the patients in both groups was comparable with regards to age, weight, sex, and ASA Class [Table 1]. Duration of surgery, duration of spinal anesthesia, and patient's baseline temperature were similar and comparable in both groups [Table 2].
Grades of shivering (III and IV) were also comparable in both groups [Table 2]. Time taken to control shivering was significantly lower in Group D (2.23 ± 0.43 min) when compared to Group C (5.54 ± 0.58 min). There was no recurrence in Group D whereas in Group C, eight patients (26%) registered for relapse (P < 0.05). Moreover, dexmedetomidine group showed a statistically significant good response rate (100% vs. 80%) when compared to clonidine group [Table 3].
Incidence of bradycardia and hypotension was significantly higher in Group C when compared with Group D. We have given the injection bupivacaine heavy in same dose in all patients. The hypotension and bradycardia developed in Group C only after given the clonidine, which were not seen in other group and other patients. The incidence of other side effects such as dry mouth, nausea and vomiting were similar in both groups and also statistically nonsignificant [Table 4].
Level of sedation was better with dexmedetomidine when compared to clonidine [Figure 1]. Sedation is better in Group D because most of the patients had Grade III sedation compared to Group C they had Grade II level sedation which was statistically significant. None of the patients in either group showed deep sedation (sedation score >3) or respiratory depression.
Shivering during spinal anesthesia is a most common problem encountered in the operation theaters. It causes increase in heart rate, blood pressure, and metabolic demands during the perioperative period. Apart from heat loss and decrease in core body temperature, the other mechanisms contributing to the development of shivering are decrease in sympathetic activity, increase in pyrogen release, anxiety, inhibited spinal reflexes, adrenal suppression, and respiratory alkalosis.[9,10] The other risk factors associated with shivering include the duration of anesthesia and surgery, age, sex, and temperature of OR. Since all these factors are comparable between the two groups and maintaining a constant OR temperature and infusion of warm fluids reduced their contribution to shivering in both groups.
The neurotransmitter pathways involved in the initiation of shivering includes opioids, α2 adrenergic agonists, anticholinergic and serotenergic receptors. Hence, the drugs acting on these pathways (pethidine, clonidine tramadol, ondansetron) have been used in the treatment of shivering.[12,13,14] However, their side effects such a hypotension, hypertension, sedation, nausea, vomiting, and respiratory depression limits their use in the treatment of shivering. Recent studies on α2 agonists showed that these drugs can effectively reduce the shivering by binding to α2 receptor that mediate vasoconstriction and antishivering effects.[15,16] Clonidine and dexmedetomidine are the α2 agonists that have sedative, analgesic, and antishivering properties. Various studies compared the anti-shivering properties of these drugs with opioids. However, there was no literature on comparison between clonidine and dexmedetomidine for their anti-shivering effects. So, we had a thought to compare the effects of these α2 agonists in the control of shivering. We considered major orthopedic surgeries because the duration of surgery should be more than an hour to evaluate the hypothermia and shivering.
In our study, we selected the dose of dexmedetomidine (0.5 µg/kg) as half the clonidine dose (1 µg/kg) because dexmedetomidine has 8 times more affinity to α2 receptors than clonidine. The results of our study showed that dexmedetomidine took less time to control shivering with no recurrence rate. Response rate to shivering was 100% in Group D when compared to Group C, which is only 80%. The level of sedation and hemodynamic parameters was adequate and stable in Group D, which was good for patients and the operating surgeon. Usta et al. found that IV infusion of injection dexmedetomidine 1 µg/kg reduced the shivering during perioperative period.
Reddy and Chiruvella compared IV clonidine (1 µg/kg) and IV tramadol (1 mg/kg) in controlling the shivering in patients undergoing cesarean section. They concluded that response rate was lesser and time to control shivering was higher with clonidine. Response rate in their study with clonidine was 86.6% compared to our study which was 80%. Time taken to stop shivering with Clonidine was 3.17±0.03 mins but in our study it was 5.54 ± 0.58 mins.
Mittal et al. compared injection dexmedetomidine 0.5 µg/kg versus injection tramadol 0.5 mg/kg. They found that injection dexmedetomidine control the shivering with lesser time (2.52 ± 0.44 compared to 2.23 ± 0.43 in our study) and with less side effects. The response rate of injection dexmedetomidine was 100% comparable to our study.
The side effect profile of Group D is quite favorable, as the incidence of bradycardia and hypotension is significantly lower than the Group C. This can be attributed to less selective action of clonidine on α2 receptors. None of the patients in either group had profound deep sedation (sedation score > 3) or respiratory depression. This is due to the α2 agonists properties of sedation with no respiratory depression.
The limitations of our study include the following: (1) Small sample size, (2) not studied about analgesia and its effects on shivering, (3) study was restricted only to the intraoperative period, (4) no postoperative follow-up for monitoring of shivering.
Results of our study provide strength and add evidence to the studies that showed IV dexmedetomidine significantly reduced the time taken to control shivering and also lowers the recurrence rate. The response rate of dexmedetomidine was 100% with a favorable side effect profile.
Research studies on different doses of dexmedetomidine and its comparison with well-established drugs such as pethidine should be carried out in the future. Moreover, the antishivering effects of newer drugs such as granisetron and palonosetron should be evaluated to address the major burden of this perioperative problem.
It can be concluded from our study that IV dexmedetomidine 0.5 µg/kg was better than IV clonidine 1 µg/kg in controlling perioperative shivering following spinal anesthesia with higher response rate, lesser recurrence rate, better sedation, and less side effects.
Financial support was from the department research funds and drugs from the pharmaceutical companies.
There are no conflicts of interest.