1. Introduction
ostoperative shivering is unpleasant and annoying for the patient and occurs in up to 65% of patients undergoing general anesthesia [1, 2]. The causes of chills include heat loss, decreased sympathetic tone, and systemic released foreign febrile substances [1, 3]. Various mechanisms were suggested for postoperative shivering. Postoperative shivering is usually but not always associated with hypothermia; thus, a mechanism of postoperative shivering is thermoregulatory [4]. Surgery-Induced hypothermia is caused by the dysfunction of the thermoregulatory system due to anesthesia medications and the patient’s contact with the cold environment of the operating room [5]. However, postoperative shivering cannot be prevented by warming during and after surgery [5, 6]. Another proposed mechanism is based on the observation that the brain and spinal cord do not concurrently recover from general anesthesia. The faster return of spinal functions leads to the emergence of non-repressed reflexes that appear as clonic activities [4].
Other suggested mechanisms include the following: receptor mechanisms, including a- the activity of kappa receptors; the activity of NMDA receptor c; the activity of 5-hydroxytryptamine receptor [4]. Factors, such as uncontrolled spinal reflexes, pain, decreased sympathetic system activity, adrenal gland inhibition, the release of febrile mediators during surgery, the use of inhaled anesthetics, drug deprivation, blood loss, and the duration of surgery may be involved in the development of thermoregulatory shivering in response to hypothermia [5]. Post-anesthesia shivering can cause cardiovascular complications, bleeding, and infection [5]. Shivering increases oxygen consumption (100% increase in oxygen consumption), elevates CO2 production and enhances sympathetic tone [4]. Postoperative shivering can cause complications, such as discomfort in the patient, as well as increased cardiac output, blood pressure, intraocular pressure, intracranial pressure, minute ventilation, and pain at the operation site by skin incision [4].
There exist pharmacological and non-pharmacological methods to reduce chills. Non-pharmacological methods include preventing hypothermia with warm blankets and inhaling warm, moist oxygen. Various drugs, such as meperidine, clonidine, or ketamine are used to control postoperative shivering [5]. The medication method mainly has the effect of reducing the chill temperature threshold [1]. Intravenous pethidine is among the most common drugs used to treat shivering after anesthesia [4]. Using pethidine has adverse effects for the patient; the prevention of these adverse effects becomes more important immediately after anesthesia. Impaired breathing, nausea and vomiting, drowsiness and prolonged recovery time and confusion, especially in the elderly, urinary retention, pruritus, and constipation, (each of which alone) can prolong the length of hospital stay and impose additional costs on the patient and the community are among these complications [4]. Dexamethasone can reduce the difference between core body temperature and skin temperature through its anti-inflammatory function and the inhibition of the release of vasoconstrictors and febrile cytokines [7]. Modulating immune responses by dexamethasone can reduce chills [8]. Ketamine is an anesthetic drug and a non-competitive NMDA receptor antagonist; in doses below anesthesia, it has the property of suppressing pain. Besides, in several stages, it regulates the temperature and prevents the occurrence of chills. The NMDA receptor modulates noradrenergic and serotonergic neurons in the locus coeruleus [1]. Therefore, considering the anti-tremor (treatment) effects of all 3 drugs, this study aimed to compare the effects of preoperative dexamethasone, ketamine, and pethidine injections on the prevention of postoperative shivering.
2. Materials and Methods
 After the approval of the present study by the University Research Council and obtaining the necessary permissions and the consent of patient candidates for orthopedic surgery, urology, and general surgery referring to 15 Khordad Hospital and Allameh Behlool Gonabadi Hospital, 164 patients with ASA class one and two in the age range of 20-60 years were entered into the study. The inclusion criteria were the range of 20-60 years, anesthesia classes 1 and 2, willingness to participate in the intervention and providing informed consent forms, no heart disease, no lung disease, no thyroid disorders, no allergy to drugs, no Parkinson’s disease, the lack of autonomy, no Raynaud’s syndrome, no alcohol abuse, no use of vasodilators, and no neuropsychological disorders. The exclusion criteria were transfusion during surgery, malignant hyperthermia, drop-in central temperature to <36.5°C and increase to >38°C, and any clinical conditions that prevented the patient from being evaluated after surgery.
The study patients were then divided into 4 groups of ketamine, pethidine, dexamethasone, and placebo. The first group received dexamethasone at a dose of 0.15 mg per kg body weight in a volume of 2 ccs; the second group received ketamine at a dose of 0.5 mg per kg and a volume of 2 ccs; the third group received pethidine at a dose of 0.5 mg per kg and volume 2 cc, and the fourth group received normal saline with a volume of 2 ccs after induction of anesthesia and before surgery. After surgery, the study patients were monitored for visible shivering by the researcher.
To facilitate the double-blind study, the drugs were prepared and injected by an anesthesiologist who was not involved in the study. Thus, the patient and the evaluator were blinded to the patient groups. After the patient entered the operating room and was provided a suitable peripheral intravenous line, 5 cc/kg Ringer serum was first infused. The patient was monitored by heart rate, non-invasive blood pressure, pulse oximeter, and ECG, before anesthesia and during surgery, and in recovery. Operating room temperature 123 was maintained centrally. The induction of anesthesia was performed with midazolam 2 mg, fentanyl 2 mg/kg and Nesdonal 5 mg/kg, and atracurium 0.5 mg/kg; the maintenance of anesthesia was conducted with propofol 200-100 mg/kg/min plus N₂O 60% + O₂40 %. At the end of the operation, after reversing the muscle relaxant with neostigmine and atropine, the patient became ecstatic when attempting to breathe adequately and obediently to the instructions. The patient’s central temperature was recorded on the tympanic membrane before inducing anesthesia and every 15 to 60 minutes after surgery. The difference between the first and the lowest recorded temperatures was calculated as the patient’s temperature change. In the recovery room, all study patients were dressed and received oxygen through a simple face mask.
Postoperative shivering was graded as follows:
Grade 0 = No chills;
Grade 1 = Mild fasciculation of the face and neck;
Grade 2 = Visible muscle activity in a muscle group;
Grade 3 = Visible muscle activity in more than one muscle group;
Grade 4 = Intense muscle activity that involved the whole body.
Any patient with a postoperative chills score of >2 was treated with 20 mg of pethidine. Postoperative pain was rated on a scale of 0 to 10 with visual acuity, and pain ≥4 was treated with morphine 3 mg. Adverse effects, such as nausea and vomiting, hallucinations, hypotension, bradycardia, or tachycardia were recorded during anesthesia for one hour in the recovery room.
The collected data were analyzed in SPSS v. 22. The Kolmogorov-Smirnov test was used to determine the normal distribution of the data. P<0.05 was considered significant.
3. Results
In total, 164 patients were studied and no disease was excluded (Table 1).


In this study, there was no significant relationship between gender and shivering (P=0.463). Only grade 4 severe shivering was observed in the placebo group.
The frequency and severity of shivering in the dexamethasone group were less than that in the control group; there was a significant difference between these groups (P=0.009). Therefore, dexamethasone was effective in preventing postoperative shivering. Furthermore, the frequency and severity of shivering in the pethidine group were less than those in the control group; there was a significant difference between these groups (P=0.004). Therefore, pethidine effectively prevented shivering. Additionally, the frequency and severity of shivering in the ketamine group were less than those in the control group; there was a significant difference between these groups (P=0.000). Thus, ketamine was effective in preventing chills (Table 2).


The frequency and severity of shivering in the dexamethasone group were not significantly different from those in the pethidine group (P=0.565). Besides, the frequency and severity of shivering in the dexamethasone and ketamine groups were not statistically significant (P=0.071). Similar to the previous two groups, the frequency and severity of shivering in the pethidine group with ketamine were not statistically significant (P=0.063) (Table 2). Therefore, there was no significant difference between dexamethasone, pethidine, and ketamine in the prevention of shivering; accordingly, these drugs are equally recommended for the prevention of postoperative shivering.
4. Discussion
In this study, the prevalence and severity of shivering were reduced in the groups of dexamethasone, pethidine, and ketamine. Asl et al. examined the effects of ondansetron and meperidine (pethidine) on preventing postoperative shivering after general anesthesia among 90 patients with gynecological surgery; there was a group of ondansetron 4 mg and the second group of meperidine 0.4 mg/kg and the normal saline control group received anesthesia immediately before induction. Postoperative shivering was observed in 13.3% of the study subjects in the ondansetron group and 20% of the explored participants in the meperidine group [9]. The effects of pethidine on reducing chills were consistent with our study findings.
Khosravi et al. investigated the effects of dexamethasone for preventing postoperative shivering on 200 elective surgical patients. Accordingly, dexamethasone 0.15 mg/kg was injected in the first group and placebo in the control group immediately after inducing anesthesia and before incision. The incidence of postoperative shivering equaled 12% in the dexamethasone group and 31% in the control group. Dexamethasone was found to reduce postoperative shivering (P<0.001) [7]. In our study, dexamethasone also reduced the incidence and severity of postoperative shivering.
Bahman Hasannasab et al. explored the prophylactic effects of doxapram, ketamine, and meperidine on postoperative shivering in 120 patients aged 20 to 45 years under general anesthesia. The first group received meperidine 20 mg, the second group, ketamine 0.25 mg/kg, and the third group received doxapram 0.25 mg/kg intravenously immediately before wound closure. In the meperidine group, one (2.5%) patient, in the ketamine group, 3(7.5%) subjects, and the doxapram group, 4(10%) individuals developed postoperative shivering. This study highlighted that meperidine, ketamine, and doxapram were equally effective in preventing postoperative shivering. In our study, ketamine also reduced the prevalence and severity of postoperative shivering, i.e., consistent with this study.
 Ishwar Bhukal et al. examined the effect of pethidine on preventing postoperative shivering in 60 women aged 25 to 35 years with laparoscopic gynecological surgery. In the first group, pethidine dose was 0.3 mg/kg, in the second group, pethidine equaled 0.5 mg/kg, and in the third group, normal saline was intravenously injected just before the induction of anesthesia. In the first group, 6(30%), in the second group, 3(15%), and the third group, 9(45%) patients developed postoperative shivering. This study reflected that a low dose of pethidine does not insignificantly impact the prevention of postoperative shivering [10]. In our study, pethidine was used at a dose of 0.5 mg/kg, which reduced the incidence of postoperative shivering. 
Masood Entezariasl et al. explored the effects of dexamethasone and pethidine on the prevention of postoperative shivering among 120 general surgery patients. The first group received normal saline 10 ccs, the second group dexamethasone 0.1 mg/kg with a volume of 10 ccs, and the third group received pethidine 25 mg with a volume of 10 ccs after the induction of anesthesia. In the placebo group, 19(47.5%) patients, in the dexamethasone group 4(10%) patients, and the pethidine group 15(37.5%) subjects presented postoperative shivering. The difference between dexamethasone and placebo groups as well as between pethidine and placebo groups was significant (P=0.001).
This study suggested that pethidine and dexamethasone were effective in preventing postoperative shivering; however, dexamethasone was more effective in preventing postoperative shivering than pethidine. However, our study data revealed that pethidine at a dose of 0.5 mg/kg and dexamethasone at a dose of 0.15 mg/kg were equally effective in reducing the incidence of postoperative shivering. This was due to the dose we used in the study.
Vida Ayatollahi et al. compared the prophylactic use of pethidine and ketamine to prevent post-anesthesia shivering in 120 patients aged 20 to 50 years undergoing general anesthesia for sinus endoscopic surgery. The first group received meperidine 0.4 mg/kg, the second group ketamine 0.3 mg/kg, the third group ketamine 0.5 mg/kg, and the fourth group meperidine normal saline 20 minutes before the end of surgery. In the first group (pethidine) no patient encountered shivering after anesthesia; in the second group (ketamine 0.3) 3 subjects, in the third group (ketamine 0.5) one individual, and the placebo group, 9 patients generated shiver after anesthesia. The difference between the first 3 groups and the normal saline group was significant; however, the difference between the first 3 groups was not significant. The level of hallucination was lower in the ketamine group with a lower dose than in the ketamine group with a higher dose [11]. These results were consistent with those of the present study.
Shakya et al. compared the prophylactic effects of ketamine and ondansetron on chills after spinal anesthesia among 120 lower abdominal surgery patients. In the first group, ketamine 0.25 mg/kg, in the second group ondansetron 4 mg, and in the third group normal saline was provided after spinal anesthesia. In the normal saline group 17(42.50%), in the ondansetron group 4(10%), and the ketamine group only one (2.5%) patients manifested postoperative shivering. This study indicated that epitestosterone and low doses of ketamine reduce chills without spinal side effects after spinal anesthesia [12].
Ayatollahi et al. explored the application of triangular sequence analysis to evaluate the efficacy of low-dose dexamethasone in reducing postoperative shivering performed on 140 patients in elective urology, gynecology, orthopedics, and general surgery. In the case group, 70 subjects received a low dose of dexamethasone 0.15 mg/kg and the second group consisted of a placebo group of 70 individuals. Clinically, it was observed that using low-dose dexamethasone significantly reduced the incidence of postoperative shivering, compared to placebo (11.4% vs. 28.6%) [13]. The results were consistent with those of our study.
Mahouri et al. examined the effects of low-dose intravenous ketamine on the prevention of shivering after inguinal hernia repair in 60 patients with ASA I and II candidates for inguinal hernia surgery. The study patients were randomly assigned to receive intravenous ketamine 0.5 mg/kg or a normal volume of saline 5 minutes before surgery. The frequency of shivering in patients at the beginning of recovery and 10 and 20 minutes after the surgery was the same in both research groups; however, the severity of shivering was significantly lower in the test group, compared to the control group (P=0.007) [14]. However, in our study, the frequency and severity of chills were significantly reduced with this dose of ketamine.
 In a comparative study by Jebel Ameli et al., the prophylactic effect of intravenous injection of dexamethasone and pethidine on postoperative elective cesarean section shivering under spinal anesthesia was explored in 99 pregnant women who were pregnant for the first time and were in ASA class one and two. The study participants were randomly assigned to one of three groups of 33 individuals based on the type of shivering medication: group D: 0.15 mg/kg dexamethasone + normal saline up to 4cc, group P: 0.5 mg/kg pethidine + normal saline up to 4 ccs, group C (Control group): normal saline up to 4 ccs after umbilical cord clamping and drugs were injected intravenously within 10-15 seconds. The incidence and severity of postoperative shivering were lower in the groups receiving pethidine and dexamethasone, compared to the control group, with a mean score of shivering of 0.03, 0.15, and -0.27, respectively; the difference between them was significant (P=0.005) [15].
Seyed Morteza Heidari et al. used pethidine, ketamine, and dexamethasone half an hour before the end of surgery to prevent chills. They concluded that pethidine was more effective than the others. The reason for the discrepancy with our study is the time of use of these drugs. Dexamethasone presents a delayed onset of action; thus, it is recommended to be used at the beginning of surgery [16].
5. Conclusion
 The current study data indicated that dexamethasone, pethidine, and ketamine were effective in preventing postoperative shivering.

Ethical Considerations
Compliance with ethical guidelines
This research was approved by the ethics committee of the Gonabad University of Medical Sciences (Code: IRCT2017012432099N3) and registered in the Regional Research Ethics Council of Gonabad University of Medical Sciences (Code: IR.GMU.REC.1395.35).

Funding
This article was supported by the Research Council of Gonabad University of Medical Sciences.

Authors' contributions
All authors equally contributed to preparing this article.

Conflicts of interest
The authors declared no conflict of interest.

Acknowledgements
We would like to thank the Staff, Officials, and Doctors working in the operating room of 15 Khordad Baydokht Hospital in Gonabad and Allameh Behlool Gonabadi who helped us.


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