European Journal of Cardiovascular Medicine

Intraoperative shivering is a common side effect observed in patients undergoing caesarean section under spinal anaesthesia, with an incidence ranging from 30% to 55%.^1,2 Shivering is a physiological response to core hypothermia and presents as spontaneous, involuntary, and repetitive muscle activity. Although not life-threatening, it is distressing and uncomfortable for awake patients. Shivering can lead to increased heart rate, oxygen consumption, carbon dioxide production, and may cause lactic acidosis. Additionally, it can raise intracranial and intraocular pressures and exacerbate wound pain due to excessive muscle activity. These effects can pose serious risks, especially in patients with underlying cardiorespiratory conditions.³ Both pharmacological and non-pharmacological strategies are used to manage shivering. Among pharmacological options, drugs such as pethidine, tramadol, ketamine, clonidine, ondansetron, and dexmedetomidine have shown efficacy.^4,5

Tramadol, a synthetic opioid analgesic with both central and peripheral actions, has demonstrated effective anti-shivering properties. Its mechanism involves modulation of central monoaminergic pathways by inhibiting the neuronal reuptake of noradrenaline and serotonin within the spinal cord, thereby increasing serotonin (5-HT) levels and resetting the body’s thermoregulatory centre. Intravenous tramadol is known for its reliable anti-shivering effects, characterized by a rapid onset of action, low recurrence rates, minimal side effects, affordability, and ready availability in the operating room. Prophylactic administration of intravenous tramadol at a dose of 0.5 mg/kg has shown promising results in the prevention of shivering in several clinical studies.⁶

Ketamine hydrochloride, a rapidly acting phencyclidine derivative, produces sedation, bronchodilation, decreased intraoperative awareness, and profound somatic analgesia, while minimally affecting protective laryngeal and pharyngeal reflexes. It helps prevent perioperative shivering by modulating thermoregulatory pathways at multiple levels.⁷

Several studies have evaluated the use of ketamine at doses of 0.25 mg/kg and 0.5 mg/kg for the prevention of shivering, reporting favourable outcomes. However, despite an extensive review of the literature, we found no direct comparative study assessing these two doses specifically within the Indian population. Furthermore, the optimal dose of ketamine for this indication remains unclear. Therefore, we designed this study to compare the efficacy of intravenous tramadol with two different doses of ketamine in preventing shivering in patients undergoing caesarean section under spinal anaesthesia.

Aim and objectives:  Aim To compare the efficacy of two different doses of intravenous ketamine with tramadol for prevention of shivering in patients undergoing caesarean section under spinal anaesthesia. Secondary objective was to asses any side effects due to study drugs in terms of nausea, vomiting, sedation, hypotension, bradycardia.

Material and methods: This prospective, randomized, and double-blinded study was conducted at a tertiary care hospital in India, after obtaining approval from the institutional ethical committee and registry of trials under the Clinical Trials Registry of India (CTRI) with the CTRI number: CTRI/2024/05/085377 during the period of November 2023 to March 2025. One hundred and twenty pregnant women, 20-40 years of age, without any comorbid conditions requiring caesarean section under spinal anaesthesia were enrolled for the study. Patients having history of Hypersensitivity to study drugs, any cardiovascular diseases, patients who developed shivering prior to administration of study drugs, patients who required general anaesthesia or sedation or any other major intraoperative complications were excluded from the study.

Sample size calculation: Sample size was calculated on basis of study done by Faraz et al⁸, In this study, Type I error (Alpha, Significance), Zα was 1.96, Z1-β was 0.84, power was 80%, percentages of effect (▲) was 55% (based on Shivering in ketamine group) and standard deviation (σ) was 0.88. Minimum of 40 patients were taken in each group.

All patients were subjected to complete general physical as well as systemic examination including spine examination prior to surgery. Routine investigations like complete hemogram, bleeding time, clotting time and urine routine examination was carried out. The purpose and protocol of the study was explained to all the patients and informed written consent was obtained for participation in the study. Patients were randomly allocated to one of the three groups according to computer generated randomisation list. Group 1 (n=40) received 0.25mgkg-1 ketamine in 10ml normal saline IV infusion over 10 minutes. Group 2 (n=40) received 0.5 mgkg-1 ketamine in 10ml normal saline IV infusion over 10 minutes. Group 3(n=40) received 0.5mgkg-1 Tramadol in 10ml normal saline IV infusion over 10 minutes. The study drugs were prepared and administered by fellow anaesthesiologist not involved in the study.

After arrival in operating room, standard monitoring comprising of Pulse oximetry (SpO2), Electrocardiography (ECG), Non-invasive blood pressure (NIBP) was established. Baseline readings of vital parameters and body temperature were recorded using digital thermometer. Intravenous line was secured with appropriate size intravenous cannula and 10mlkg-1 ringer lactate was administered. All patients were given spinal anaesthesia as per standard technique. Then the patients were repositioned to supine position with left uterine displacement. Modified Bromage Scale was used for the assessment of spinal anaesthetic block for intended sensory and motor block around T6.  After delivery of baby and placenta, study drugs as per group allocations were administered by fellow anaesthesiologist who is not involved in the study. Patient’s heart rate, blood pressure and oxygen saturation was measured and recorded, every 5 minutes intraoperatively and every 10 minutes postoperatively over an hour.   

Shivering was graded using a five-point scale as outlined by Crossley and Mahajan.⁹

Grade 0: No shivering

Grade 1: One or more of the following: Piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscle activity.

Grade 2: Visible muscle activity confined to one muscle group.

Grade 3: Visible muscle activity in more than one muscle group.

Grade 4: Gross muscle activity involving the whole body.

Grade 3 and 4 were considered as presence of shivering.

The degree of sedation will, be graded on a four-point scale described by Filos et al.¹⁰

Grade 1: Awake and alert

Grade 2: Drowsy, responsive to verbal stimuli

Grade 3: Drowsy, arousable to physical stimuli

Grade 4: Unarousable

Grade 2 and 3 were considered as presence of sedation.

Complications such as nausea, vomiting, sedation, bradycardia, or hypotension were recorded and treated accordingly. Pulse rate of less than 50 per minute was considered as Bradycardia and was treated with Injection Atropine 0.6 mg IV. Blood pressure of less than 90/60 mmHg was considered as Hypotension and was treated with Injection Mephentermine 3mg IV. Any episode of nausea or vomiting was treated with Injection Ondansetron 4mg IV.

Statistical analysis -The data was coded and entered into Microsoft Excel spreadsheet. Analysis was done using IBM SPSS (SPSS Inc., IBM Corporation, NY, USA) Statistics Version 25 for Windows software program. Descriptive statistics included computation of percentages, means and standard deviations. The data were checked for normality before statistical analysis using Kolmogorov Simonov test. The ANOVA test (for quantitative data to compare two and more than two observations) with Post Hoc Tukey HSD were applied. The chi square test was used for qualitative data comparison of all clinical indicators. Level of significance was set at P≤0.05.

Sociodemographic characteristics (age, weight and height, gestational age, parity, and duration of surgery) were comparable among all the three the groups (Table 1).

Table1

All baseline hemodynamic parameters (HR, SBP, DBP, MAP, SPO2) were comparable among three groups. (Table2)

Table2

Variations in heart rate in intraoperative period and postoperative period were comparable among all three groups. (graph 1)

Graph 1

Changes in the Mean arterial pressure (MAP) among all groups were not statistically significant. (Graph2)

Graph2

Difference in the incidence of sedation among all the three groups was statistically significant. More number of patients had sedation in ketamine group as compared to tramadol group. P value=0.004 (Table3)

Table3

Incidence of nausea and vomiting were more in tramadol group and the difference among three groups was statistically significant.  P value=0.001 (Table4)

Table 4

Shivering was present in more number of patients in tramadol group.  Difference in incidence of shivering among three groups was statistically significant. P =0.028 (Table5)

Table 5

This prospective, randomized, double-blinded study demonstrated that intravenous ketamine at a dose of 0.5 mg/kg was more effective in reducing the incidence and severity of shivering in patients undergoing cesarean section under spinal anesthesia, compared to 0.25 mg/kg ketamine followed by 0.5 mg/kg tramadol. Shivering was most common in the tramadol group, with 28 patients affected—26 of whom experienced grade 3 shivering. In the low-dose ketamine group (Group 1), shivering occurred in 22 patients, including 21 with grade 3 shivering. In the high-dose ketamine group (Group 2), shivering was observed in 17 patients, 15 of whom had grade 3 shivering. The differences in shivering incidence among the three groups were statistically significant (P = 0.028), with the high-dose ketamine group showing the greatest effectiveness in preventing shivering. Sedation was reported in 32 patients in Group 1 and 38 patients in Group 2, while only 2 patients in the tramadol group experienced sedation—a statistically significant difference. Hemodynamic parameters were similar across all three groups. However, nausea and vomiting were notably higher in the tramadol group, affecting 38 patients, compared to fewer cases in the ketamine groups.

A study conducted by Lema et al. involved a prospective, randomized, double-blinded trial on one hundred and twenty three ASA I and II patients aged 18–39 years undergoing cesarean section. Patients were randomly assigned to one of three groups: Group S received saline, Group K received intravenous ketamine 0.2 mg/kg, and Group T received intravenous tramadol 0.5 mg/kg. The incidence of shivering was significantly lower in the ketamine and tramadol groups (41.5% and 53.7%, respectively) compared to the saline group (70.7%; P = 0.028). Grade 3 shivering occurred in 16 patients (39%) in the saline group, 9 patients (22%) in the tramadol group, and 8 patients (19.5%) in the ketamine group. Only two patients in the saline group experienced grade 4 shivering (P < 0.01). Neonatal outcomes and perioperative complications were comparable across all groups. Based on these findings, the authors concluded that prophylactic low-dose IV ketamine or tramadol effectively reduces the incidence and severity of shivering.³In comparison, our study found that a higher dose of ketamine (0.5 mg/kg) was even more effective than tramadol in preventing shivering, suggesting a dose-dependent improvement in ketamine’s anti-shivering efficacy.

In a study conducted by Azam et al. four hundred ASA I and II parturients undergoing cesarean section were randomly assigned to one of two groups: Group K received intravenous ketamine 0.5 mg/kg, and Group T received intravenous tramadol 2 mg/kg. Following spinal anesthesia, shivering occurred in 111 patients (27.75%), while 289 patients (72.25%) did not experience shivering. Shivering was observed in 72 patients (36%) in the tramadol group and in 39 patients (19.5%) in the ketamine group—a statistically significant difference (P = 0.000). The authors concluded that prophylactic low-dose ketamine (0.5 mg/kg IV) is significantly more effective than intravenous tramadol in preventing intraoperative shivering.¹¹ Similarly, our findings also demonstrated that ketamine was more effective than tramadol in the prevention of shivering during cesarean sections under spinal anesthesia.

Our findings contrast with those of a study by Jouryabi et al., who conducted a randomized, double-blind trial involving five hundred and eight term parturient women undergoing cesarean section. Participants were randomly assigned to one of four groups: low-dose ketamine (0.2 mg/kg, Group K), tramadol (0.5 mg/kg, Group T), ondansetron (4 mg, Group O), and placebo with normal saline (Group P). Shivering was observed in 53.5% of patients in the ketamine group (468 patients), 20.5% in the tramadol group (26 patients), 59.1% in the ondansetron group (75 patients), and 64.6% in the placebo group (82 patients). The differences among groups were statistically significant (P = 0.0001). The authors concluded that tramadol was the most effective agent for shivering prevention, followed by low-dose ketamine and ondansetron, with the highest incidence observed in the placebo group.¹² The reduced efficacy of ketamine in their study may be attributed to the use of a lower dose (0.2 mg/kg). In contrast, our study demonstrated that a higher dose of ketamine (0.5 mg/kg) was more effective than tramadol in preventing intraoperative shivering, suggesting a possible dose-dependent effect of ketamine.

Manhas et al. conducted a randomized, double-blinded study involving ninety patients undergoing elective cesarean section under spinal anesthesia. Patients were randomly assigned to one of three groups: Group T received intravenous tramadol 0.5 mg/kg, Group K received ketamine 0.25 mg/kg, and Group D received dexmedetomidine 0.5 mcg/kg. The primary outcome measured was the cessation of shivering within 10 minutes of drug administration. Secondary outcomes included hemodynamic changes, adverse effects, and patient satisfaction. Shivering stopped within 10 minutes in 43.4% of patients. Adverse effects were reported in 31.6% of cases, while 68.4% experienced no side effects. Hemodynamic parameters remained within normal limits in 60% of patients, while 22.5% showed elevated values and 17.5% showed decreased values. The authors concluded that intravenous tramadol, ketamine, and dexmedetomidine are all effective options for managing intraoperative shivering.¹

Faraz et al conducted a randomized, double blinded study in one hundred eighty pregnant women undergoing caesarean with spinal anaesthesia and randomly assigned patients into three groups: Tramadol 0.5 mgkg-1 (T), ketamine 0.2mgkg-1 (K) and placebo with normal saline (P). The incidence of shivering were recorded and the observations were compared among the three groups. Shivering was observed in 33(55.0%) patients in the ketamine (k) group, 12 (20%) in the tramadol (T) group and 39 (65%) in the placebo (P) group (P=0.0001). They concluded that tramadol was more efficacious than ketamine for prevention of post spinal anesthesia shivering.⁸

Kapil et al. conducted a randomized, double-blinded study involving one hundred and twenty patients scheduled for elective cesarean section under spinal anesthesia. Patients were randomly assigned to one of three groups: Group T received intravenous tramadol 1 mg/kg, Group K received intravenous ketamine 0.5 mg/kg, and Group P received normal saline as a placebo. The incidence of intraoperative shivering was significantly lower in Group T (15%) and Group K (20%) compared to the placebo group (70%) (P < 0.001). Both tramadol and ketamine were also effective in reducing the severity of shivering compared to placebo (P < 0.001). Hemodynamic parameters remained stable across all groups. However, adverse effects such as nausea and sedation were more commonly observed in the tramadol group than in the ketamine and placebo groups. The authors concluded that both intravenous tramadol and ketamine are effective in managing intraoperative shivering, but ketamine is a safer alternative due to its lower incidence of side effects.¹³ Similarly, in our study, tramadol was associated with a higher incidence of nausea and vomiting and was less effective in preventing shivering compared to ketamine.

In obstetric patients, ketamine at a dose of 0.5 mg/kg is more effective than tramadol at the same dose for the prevention of post-spinal anaesthesia shivering. Our study also found that higher doses of ketamine were more effective than lower doses. Although both ketamine groups experienced a higher incidence of sedation, ketamine 0.5 mg/kg demonstrated superior efficacy in preventing intraoperative shivering, with fewer occurrences of nausea and vomiting, and improved patient satisfaction compared to tramadol.

Limitation- Fluid and room temperatures were not strictly controlled during the study, which may have influenced the outcomes. Therefore, further research with larger sample sizes and better environmental control is needed to establish more robust evidence.

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