Shivering is a common and distressing postoperative phenomenon that affects between 6% and 65% of patients undergoing surgery. It is characterized by involuntary muscle contractions and can be attributed to multiple factors, including pain, reduced sympathetic activity, uncontrolled spinal reflexes, pyrogen release, postoperative cytokine activity, and adrenal suppression. However, the most widely accepted cause is thermoregulatory dysfunction due to hypothermia, typically resulting in a 0.5–1°C decrease in core body temperature [1,2].

Shivering presents several challenges in the perioperative setting, as it can interfere with monitoring parameters such as pulse oximetry, blood pressure, and electrocardiography (ECG). Additionally, it increases oxygen consumption by up to 500%, which can be particularly concerning in elderly patients and those with cardiopulmonary conditions requiring stable cardiac output and ventilation. The physiological strain of shivering may also contribute to muscle fatigue, lactic acidosis, increased carbon dioxide production, elevated intraocular pressure (IOP), and raised intracranial pressure (ICP) [3]. While the incidence of shivering under regional anaesthesia is comparable to that seen with general anaesthesia, the effects can be more prolonged due to impaired thermoregulation and reduced heat production from paralysed lower limb muscles. This ultimately results in a longer recovery period following regional anaesthesia compared to general anaesthesia [4].

Various pharmacological and non-pharmacological approaches have been developed to prevent and manage perioperative hypothermia and shivering. Non-pharmacological methods include preoperative patient warming, maintaining optimal ambient temperatures in the operating room, using heated blankets, and administering warm, humidified air. Skin warming has also been suggested as an effective strategy since peripheral thermal input can help sustain central body temperature regulation. However, this method is only effective when core body temperature remains above 35°C [5].

Pharmacological interventions primarily work by lowering the shivering threshold. Several medications, including midazolam, ketamine, meperidine, clonidine, ketanserin, and magnesium sulfate, have been used to manage intraoperative shivering. However, many of these agents are associated with adverse effects such as sedation, respiratory depression, nausea, vomiting, and pruritus, which may compromise patient comfort and safety [6].

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to influence thermoregulation through central sympathetic stimulation and inhibition of norepinephrine reuptake, thereby reducing heat redistribution. Midazolam, a benzodiazepine, causes minimal impairment of thermoregulatory control. Given their distinct mechanisms of action, a combination of ketamine and midazolam has been proposed as a potential strategy to reduce the incidence of shivering during spinal anaesthesia [7]. This study aims to evaluate the efficacy of this drug combination in preventing shivering and to assess any associated adverse effects.

Study Design, Setting, and Population

This prospective observational study was conducted in the Department of Anaesthesiology at Medical College Hospital, Thiruvananthapuram. The study was undertaken after obtaining approval from the Institutional Ethical Committee, and informed written consent was obtained from all participating patients. The study population included patients undergoing elective lower limb surgeries under spinal anaesthesia, belonging to the American Society of Anaesthesiologists (ASA) Physical Status Class I and II, aged between 18 and 60 years.

Inclusion and Exclusion Criteria

Patients included in the study were those aged between 18 and 60 years undergoing elective lower limb surgeries under spinal anaesthesia and classified as ASA Physical Status Class I and II. Patients with extensive fractures, hypothyroidism or hyperthyroidism, cardiovascular diseases, psychiatric disorders, a history of alcohol or substance abuse, a history of multiple drug allergies, or an initial body temperature of more than 38°C or less than 36°C were excluded. Additionally, patients with a body mass index (BMI) greater than 35 kg/m² were not considered for the study.

Study Duration and Sample Size Calculation

The study was conducted over a period of one year following Ethical Committee clearance. The sample size was calculated using the formula:

N = [(Zα + Z(1-β)2{(P1Q1+P2Q2)}2

(P1-P2)2

where Zα = 1.96 (for an alpha error of 5%), β = 0.84 (for a beta error of 20%), and P1 and P2 represent the incidence of shivering in the two study groups from a previous study. Based on these parameters, the required sample size was determined to be 186 patients.

Sampling Technique

A consecutive sampling method was used, where all eligible patients meeting the inclusion criteria were recruited for the study.

Study Variables

The study included various exposure and outcome variables. Exposure variables included patient age, BMI, and ASA Physical Status classification. The outcome variables assessed were the incidence and degree of shivering, effectiveness of different drug dosages in preventing shivering, side effects of the drugs, mean arterial pressure (MAP), temperature, and heart rate (HR).

Study Procedure

A total of 186 patients undergoing elective lower limb surgeries were recruited and allocated into three groups: low-dose midazolam plus ketamine (Group A), high-dose midazolam plus ketamine (Group B), and the control group (Group C). All patients were required to fast for at least six hours before surgery, and no premedication was administered. Routine investigations were reviewed before the procedure.

Upon arrival at the operating theatre, patients underwent standard monitoring, including non-invasive blood pressure monitoring, three-lead electrocardiography (ECG), and pulse oximetry. Baseline MAP, HR, and SpO₂ were recorded prior to spinal anaesthesia. The baseline core body temperature was measured using an infrared ear thermometer. Spinal anaesthesia was administered at the L3/L4 interspace via a midline approach using a 23G spinal needle under aseptic conditions. The local anaesthetic used was 0.5% hyperbaric bupivacaine (12.5–15 mg) without opioids.

Following the administration of spinal anaesthesia, patients received study drugs according to their assigned group. Patients in Group A received intravenous midazolam 0.02 mg/kg and ketamine 0.25 mg/kg, while those in Group B received midazolam 0.04 mg/kg and ketamine 0.25 mg/kg. Patients in Group C (control group) received normal saline. Only preheated intravenous fluids were used. MAP, HR, SpO₂, and core body temperature were recorded at 5, 10, 20, and 30 minutes after spinal anaesthesia.

The incidence and severity of shivering were assessed at these time intervals using a grading scale:

• 0 = No shivering
• 1 = Piloerection or peripheral vasoconstriction without visible shivering
• 2 = Muscular activity in one muscle group only
• 3 = Muscular activity in more than one muscle group without generalization
• 4 = Shivering affecting the whole body

Additionally, side effects such as MAP and HR alterations, nausea, vomiting, sweating, nystagmus, and hallucinations were documented. Sedation levels were assessed using a five-point scale, where:

• 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 and unarousable to mild physical stimulation

Statistical Analysis

Collected data were entered into Microsoft Excel and analyzed using SPSS software version 27. Qualitative variables were expressed as percentages, while quantitative variables were presented as means. A chi-square test was performed to assess associations between variables. A p-value of <0.05 was considered statistically significant.

Ethical Considerations

Ethical Committee clearance was obtained before data collection. Informed written consent was taken from all participants, ensuring their voluntary involvement. All collected data were kept confidential, and there was no financial burden on the study participants.

The study included 186 patients undergoing elective lower limb surgeries under spinal anaesthesia, divided into three equal groups (A, B, and C). The majority of patients in all three groups were aged ≤ 45 years, with Group A having the highest proportion (69.4%). Group B had the largest proportion of patients in the 46-54 age range (30.6%), while Group C had the lowest percentage of patients aged ≥ 55 years (9.7%). In terms of gender distribution, Group A had a nearly equal male-to-female ratio, whereas Groups B and C had a higher proportion of males, 62.9% and 67.7%, respectively.

Table 1: Distribution of Age and Gender among Study Groups

Graph 1 illustrate significant changes in core body temperature during the first 30 minutes of surgery across all three groups. While there was a statistically significant decrease in temperature over time within each group (p < 0.001 at all-time points), the overall trend of temperature reduction was similar across groups. This indicates that, despite the interventions used, there was no pronounced difference in temperature changes when comparing the groups. The results suggest that the administered drugs did not significantly alter the rate of temperature decline during spinal anesthesia in lower limb surgeries.

Table 2: Degree of Shivering at Different Time Points in the Three Treatment Groups

The table shows the incidence of shivering at different time intervals following spinal anesthesia. At T0 (baseline), there was no statistically significant difference in shivering among groups (p = 0.197). However, at T10, a significant difference emerged (p = 0.004), with Group B (optimum-dose midazolam and ketamine) having the lowest incidence of shivering. This trend continued at T20 and T30, with Group C (control) showing the highest rates of shivering, including higher-grade shivering (grade 3: 11.3% and grade 4: 9.7% at T30). In contrast, 91.9% of patients in Group B did not develop shivering at T30, indicating that the optimum-dose combination was the most effective in preventing shivering.

Shivering is a common and discomforting side effect of spinal and epidural anesthesia, which can have adverse consequences, particularly in individuals with underlying cardiorespiratory conditions. These effects include increased oxygen consumption, elevated carbon dioxide production, hypoxemia, and lactic acidosis.

The vasodilation induced by regional anesthesia contributes to heat redistribution from the core to the periphery, leading to increased heat loss and impaired thermoregulatory vasoconstriction below the level of the block. Several pharmacological agents have been investigated for their effectiveness in preventing shivering during neuraxial anesthesia, including pethidine, a combination of ketamine and midazolam, neostigmine, and ketanserin [8]. A meta-analysis conducted by Crowley and Buggy reported that 55% of individuals in the control group experienced shivering associated with neuraxial anesthesia [9].

This study aimed to compare the hemodynamic effects of two different doses of midazolam combined with ketamine for preventing shivering in patients undergoing elective lower limb surgeries under spinal anesthesia. Participants were divided into three groups (A, B, and C), each consisting of 62 individuals. Observations were recorded at different time intervals: upon arrival in the operating theatre (T0), 10 minutes after spinal anesthesia (T10), 20 minutes after spinal anesthesia (T20), and 30 minutes after spinal anesthesia (T30).

The study findings indicated that mean arterial pressure, heart rate, and temperature were significantly maintained across all three groups (P<0.0001). However, a decline in mean core body temperature was observed in all groups during the initial 30 minutes post-anesthesia.

Honarmand and Safavi previously reported a 60% incidence of shivering due to regional anesthesia and evaluated the efficacy of various interventions, including midazolam, ketamine, their combination, and a placebo [10]. In comparison, the incidence of shivering in the control group in our study was found to be 71%, whereas it was lower in those who received midazolam with ketamine. Among the 62 patients in the control group who experienced shivering (47/62), 24 individuals (38.7%) exhibited a shivering grade of at least 2.

Ketamine, an NMDA (N-methyl-D-aspartic acid) receptor antagonist, plays a significant role in thermoregulation. It modulates non-shivering thermogenesis by acting on the hypothalamus or through the adrenergic effect of norepinephrine, thereby inhibiting shivering. Additionally, NMDA receptors regulate nociceptive transmission in the spinal cord and modulate noradrenergic and serotonergic neurons within the locus coeruleus [11].

Benzodiazepines, including midazolam, influence thermoregulation by reducing neuronal excitability in the spinal cord. Diazepam has been identified as one of the most effective benzodiazepines in preventing post-spinal shivering [12]. Unlike other agents, it does not significantly impair thermoregulatory control [13]. Midazolam, however, reduces core body temperature by inhibiting tonic vasoconstriction related to thermoregulation. The combined use of midazolam and ketamine appears to counterbalance each other's thermoregulatory effects, resulting in more stable core temperature maintenance.

Honarmand and Safavi demonstrated that intravenous midazolam (37.5 μg/kg) combined with ketamine (0.25 mg/kg) was more effective in preventing shivering during regional anesthesia than ketamine (0.5 mg/kg) or midazolam alone (75 μg/kg). Similarly, Kamal and Hussein evaluated the efficacy of nefopam against ketamine with midazolam and a placebo for preventing post-spinal shivering. Their study reported a 16% prevalence of shivering in patients receiving ketamine with midazolam. Among them, only 3% had a shivering score of 2, while 13% showed signs of piloerection, with no cases exceeding a shivering score of 2.

Midazolam has also been widely recognized for its preoperative sedative effects [14]. In our study, patients in both ketamine-midazolam groups exhibited significantly greater sedation levels compared to the control group. Furthermore, no substantial difference in shivering severity among the three groups was noted within the first 10 minutes post-anesthesia. However, at 20 and 30 minutes post-spinal anesthesia, Groups A and B experienced significantly lower shivering incidence and severity compared to Group C (p<0.05). There was no statistically significant difference between Groups A and B (p>0.05) regarding shivering severity.

The study found that both combinations—midazolam 0.02 mg/kg plus ketamine 0.25 mg/kg and the optimum dose of midazolam alone—were effective in preventing shivering during spinal anaesthesia for elective lower limb surgeries.

Conflict of Interest: Nil

1. Kurz A, Sessler DI, Schroeder M, Kurz M. Thermoregulatory response thresholds during spinal anesthesia. Anesth Analg. 1993;77(4):721–6.
2. Ronald DM. Textbook of Anesthesia. USA: Churchill living ton ; 2005.
3. Kirby RR, Gravenstein JS, Gravenstein N, Lobato EB. Clinical anesthesia practice. Saunders; 2002.
4. Chan AM, Ng KF, Tong EW, Jan GS. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth. 1999;46(3):253– 8.
5. De Witte J, Sessler DI. Perioperative shivering: physiology and pharmacology. Anesthesiology. 2002;96(2):467–84.
6. Faiz SH, Rahimzadeh P, Imani F, Bakhtiari A. Intrathecal injection of magnesium sulfate: shivering prevention during cesarean section: a randomized, double-blinded, controlled study. Korean J Anesthesiol. 2013;65(4):293–8. doi: 10.4097/kjae.2013.65.4.293.
7. Misiran K, Aziz F. Effectiveness of low-dose midazolam plus ketamine in the prevention of shivering during spinal anaesthesia for emergency lower limb surgery. Southern African Journal of Anaesthesia and Analgesia. 2013;19(3):164-170.
8. Kamal MM, Hussein NS. Prevention of post-spinal shivering by using ketamine plus midazolam in comparison with nefopam. Egyptian J Anaesthesia. 2011;27:1-5.
9. Crowley LJ, Buggy DJ. Shivering and neuraxial anaesthesia. Reg Anaesth Pain Med. 2008;33(3):241-252.
10. Honarmand A, Safavi MR. Comparison of prophylactic use of midazolam, ketamine and ketamine plus midazolam for prevention of shivering during regional anaesthesia: a randomized doubleblind placebo controlled trial. Br J Anaesth. 2008;101(4):55 -562.
11. Dal D, Kose A, Honca M, et al. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J Anaesth. 2005;95(2):189-192
12. Kamal MM, Hussein NS. Prevention of post-spinal shivering by using ketamine plus midazolam in comparison with nefopam. Egyptian J Anaesthesia. 2011;27:1-5.
13. Kurz A, Sessler DI, Annadata R, et al. Midazolam minimally impairs thermoregulatory control. Anesth Analg. 1995;81(2):393-398.
14. Fredman B, Lahav M, Zohar E, et al. The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. Anesth Analg. 1999;89(5):1161-1166.