European Journal of Cardiovascular Medicine

Shivering is a common perioperative problem in obstetric patients undergoing cesarean section under regional anaesthesia and its incidence is approximately 30% to 55%.1

Shivering is involuntary hyperactivity of muscles.2 It augments the metabolic heat production leading to hypoxia and hypercarbia, also very distressing to patients 3. Shivering interferes with monitoring of vitals and makes the assessment difficult.2 In obstetrics patients, intra operative amniotic fluid loss also contributes to shivering. Therefore, prevention and control of shivering are necessary.

Regional anaesthesia impairs the thermoregulatory centers by inhibiting tonic vasoconstriction and causing a core-to-peripheral redistribution of heat below the level of block4,5. Hypothermia, pyrogen release6, and loss of body fluids also contribute to this .1

Various drugs have been used like pethidine, meperidine, fentanyl, tramadol, ketamine, clonidine, ondansetron, and dexmedetomidine7,8. All the available drugs are associated with various side effects. Many studies are available in the normal population that compare intravenous dexmedetomidine with intravenous tramadol, and their results showed that intravenous dexmedetomidine was better than intravenous tramadol for controlling post-spinal anaesthesia shivering7,8, but in obstetric patients, only a few studies are available. So, we plan to do this study to compare the efficacy of intravenous dexmedetomidine with intravenous tramadol in the prevention of post-spinal anaesthesia shivering in patients undergoing cesarean section.

Aim And Objectives:

To compare the efficacy of intravenous Dexmedetomidine, intravenous Tramadol with placebo in prevention of post-spinal anaesthesia shivering in obstetric patients undergoing caesarean section. Secondary objective is to observe perioperative complications if any like Nausea, Vomiting, Sedation, Hypotension and Bradycardia.

This prospective, randomized, and double-blinded study was conducted in the Department of Anaesthesiology and critical care, 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/2023/04/05681 during the period of November 2022 to March 2024.

129 Healthy 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 previous study by Lema et al2. In this study, Type I error (Alpha, Significance-α) was 1.96, β was 0.84, power was 80%, percentages of effect (Δ) was 22% (Shivering in group Tramadol), standard deviation (σ) was 0.55.

The minimum of 40 patients in each group. In view of dropouts, 129 patients were enrolled for the study.

After preanaesthetic checkup, written informed consent was taken from the patients. 129 patients were enrolled for the study but a total of 3 patients were excluded, out of which, 2 patients were excluded because of conversion of spinal anaesthesia into general anaesthesia and 1 patient had shivering prior to spinal anaesthesia. So, 126 patients were randomly allocated into one of the three groups according to computer generated randomisation list.

Group A (n=41) received 0.5 mcg/kg Dexmedetomidine in 100ml normal saline IV infusion over 10 minutes.

Group B (n=43) received 0.5 mg/kg Tramadol in 100ml normal saline IVinfusion over 10 minutes.

Group C (n=42) received plain 100 mL normal saline IV infusion over 10 minutes as to standardise the protocol and eliminate any observer bias.

The study drugs were prepared and administered by fellow anaesthesiologist (who was not involved in study) in 100ml normal saline as intravenous infusion over 10 minutes. The anaesthesiologist involved in the data collection and analysis were blinded to the group allocation. Operating room temperature was maintained between 22 °C and 24°C and all patients received blankets and warm fluids.

After arrival in operating room, standard monitors were attached. Intravenous line was secured with appropriate size intravenous cannula and 10ml/kg ringer lactate administered. Spinal anaesthesia given with 2.0ml of 0.5% Heavy Bupivacaine. Spirit swab (cotton ball soaked in ethyl alcohol) and Modified Bromage Scale were used for the assessment of spinal anaesthetic block for intended sensory and motor block around T6. After delivery of baby and placenta, study drugs were administered by the fellow anaesthesiologist who was not involved in the study.

Patient’s heart rate, blood pressure was measured and recorded, every 5 minutes intraoperatively till 15 minutes and thereafter every 15 minutes till the completion of surgery. 0 min is taken as the time- point of administration of study drugs intra operatively.

Shivering was graded using a five-point scale as outlined by Crossley and Mahajan7,9: Grade 0: No shivering

Grade 1: One or more of the following: Piloerection, peripheralvasoconstriction, 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.

All the patients who developed shivering grade 3 or higher were given Injection Ondansetron 4 mg intravenous and Injection Tramadol 0.5 mg/kg intravenous as rescue drug.

The degree of sedation was graded on a four-point scale described by Filos et al7,10: Grade 1: Awake and alert

Grade 2: Drowsy, responsive to verbal stimuli Grade 3: Drowsy, arousable to physical stimuli Grade 4: Unarousable

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

All statistical analyses were performed by using SPSS 26.0 software package (SPSS Inc., Chicago, IL, USA). All data were summarised as mean ± SD for continuous variables, numbers and percentages for categorical variables. The variables were assessed for normality using the Kolmogorov Smirnov test. A p-value < 0.05 was accepted as statistically significant.

All the three groups were comparable in terms of demographic data such as distribution of patients, age, weight, height, BMI, period of gestation, duration of surgery. (Table 1)

Table 1- demographics of three groups

Table 2: Intraoperative comparison of heart rate (bpm) over time

Comparison of Heart rate over time (table 2)

The three groups differed significantly in terms of Heart Rate (bpm) at the following timepoints: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 75 min, 90 min .

In Group A, the mean Heart Rate (bpm) decreased from a maximum of 86.56 at the Baseline timepoint to a minimum of 73.12 at the 30 min timepoint, and then increased to 77.67 at the 90 min timepoint. This change was statistically significant (Friedman Test: χ2 = 46.6, p-value < 0.001).

In Group B, the mean Heart Rate (bpm) increased from a minimum of 86.93 at the Baseline timepoint to a maximum of 93.53 at the 15 min timepoint, and then decreased to 91.92 at the 90 min timepoint. This change was statistically significant (Friedman Test: χ2 = 34.1, p-value < 0.001).

In Group C, the mean Heart Rate change was not statistically significant (Friedman Test: χ2 = 8.9, p- value = 0.446).

Table 3: Intra operative comparison of MAP (mmHg) over time

Comparison of intra operative MAP over time (table 3):

In Group A, the mean MAP (mmHg) decreased from a maximum of 94.60 at the Baseline timepoint to a minimum of 80.37 at the 15 min timepoint, and then increased to 83.92 at the 90 min timepoint. This change was statistically significant (Friedman Test: χ2 = 61.0, p-value < 0.001).

In Group B and Group C change in the mean arterial blood pressure (mmHg) was not statistically significant (Friedman Test: χ2 = 14.6, p-value = 0.103).

The overall change in MAP (mmHg) over time was compared in the three groups using the Generalized Estimating Equations method. There was a significant difference in the trend of MAP (mmHg) over time between the three groups (p-value < 0.001) .

Table 4: Association between Group and Sedation

Association between study Groups and Sedation:

There was a significant difference between the various groups in terms of distribution of incidence of Sedation (χ2 = 52.244, p-value < 0.001) (Table 4).

51.2% (n=21) of the participants in the Group A had Sedation. There was no sedation in 48.8% of the participants in the Group A. None (n=0) of the patients in Group B and Group C had sedation (Table 4). Sedation in group was never above grade 2.

Table 5 : Association between Group and Shivering

Association between study Groups and Shivering:

There was a significant difference between the various groups in terms of distribution ofIncidence of Shivering (χ2 = 48.199, p-value < 0.001) (Table 5).

9.8% (n=4) of the participants in the Group A, 53.5% (n=23) of the participants in the Group B,and 85.7% (n=36) of the participants in the Group C had shivering .

Table 6: Intra operative comparison of Shivering weighted score over time

The overall change in Shivering Weighted Score over time was compared in the three groups using the Generalized Estimating Equations method. There was a significant difference in the trend of Shivering

Weighted Score over time between the three groups (p-value < 0.001) (Table 6). It decreased significantly in dexmedetomidine group as compared to other two groups.

We reported that 14 patients in tramadol group, 6 patients in dexmedetomidine group and 11 patients in placebo group had nausea. 4 patients in tramadol group and 7 patients in NS group had vomiting for which we had given Inj Ondansetron 4 mg IV. None of the patients in dexmedetomidine group had vomiting. But this difference was not statistically significant.

In our study, there was no significant difference between the various groups in terms of distribution of incidence of Bradycardia (p-value = 0.124). 3% (n=3) of the patients in the Group A, 2.3% (n=1) of the patients in the Group B, and none of the patients in the Group C had bradycardia. We reported 3 patients in dexmedetomidine group and 1 patient in tramadol group had bradycardia for which Inj Atropine 0.6 mg IV was given. This incidence of bradycardia was not statistically significant.

We reported hypotension in 9 patients in dexmedetomidine group, 3 patients in tramadol group and 5 patients in placebo group, for which Inj Mephentermine 3 mg IV bolus. This is also not statistically significant.

Shivering is a very common postoperative complication after anaesthesia. Shivering after spinal anaesthesia is due to cessation of central thermoregulation, internal redistribution of body heat, inhibition of spinal reflex, decreased sympathetic activity, and pyrogen release.11 Various pharmacological and nonpharmacological methods have been tried in the past for the prevention and control of shivering. Tramadol is an opioid receptor agonist. Opiods act on thermoregulatory centre via mu or kappa receptors 11. Dexmedetomidine is an alpha 2 agonist, it exerts its anti-shivering effect by binding to alpha-2 receptors that mediates vasoconstriction 12,13,14. Sedative and analsegic effects are via central actions in the locus coeruleus and dorsal horn of spinal cord respectively15. It also decreases the shivering threshold16,17.

In this study, when compared among the study groups statistically significant fall in heart rate and mean arterial blood pressure was observed at all the time-points in dexmedetomidine group which was maximum at 15 min. Dexmedetomidine is an alpha-2 agonist and causes a fall in blood pressure. We also reported a decrease in systolic, diastolic, and mean arterial blood pressure in the dexmedetomidine group after up to 90 min of administration of the drug which was maximum at the 15 min timepoint and statistically significant when compared to the tramadol and placebo groups. This fall in heart rate and blood pressure may be a limiting factor for its use as a preventive effect. In the recovery room, the heart rate and blood pressure returned to their baseline in the dexmedetomidine group after 50 -60 mins.

In the study conducted by Mittal G et al (2014) they compared dexmedetomidine (0.5 µg/kg) with tramadol (0.5 mg/kg) for control of post spinal anaesthesia shivering and they found that hemodynamic parameters remained within normal limits throughout theprocedure. It can be due to their different study population which was non obstetric patients.2 Our study was done in obstetric patients and lot of factors can contribute to this difference. 2 As this study was done in non-obstetric patients so the difference can be attributed to different study population. Obstetric patients are more prone to hypotension and bradycardia after spinal anaesthesia than non-obstetric population because of their increased sensitivity to the local anaesthetic agents. Lamontagne C et al (2019) conducted a randomised controlled trial on dexmedetomidine for the treatment of shivering during caesarean delivery under neuraxial anaesthesia and they found that there was a brief decrease in heart rate after administration of dexmedetomidine.7 In another study conducted by Rao V U et al (2019) they compared dexmedetomidine (0.5 µg/kg), tramadol (0.5 mg/kg) and pethidine for control of shivering during spinal anaesthesia and they found that mean pulse rate and SBP were significantly higher in tramadol group than in dexmedetomidine group which was statistically significant.18 Our study results are similar to above study results as we reported a decrease in heart rate in the dexmedetomidine group compared to tramadol and placebo groups. This decrease was highest after 15 and 30 mins of giving dexmedetomidine.

Sedation score was more in dexmedetomidine group as compared to tramadol and placebo groups. Dexmedetomidine causes awake sedation, the patients can be easily aroused, so it can be advantageous to the patients in post operative room. It makes them calm, comfortable and decreases anxiety and heart rate. The level of sedation was never above grade 2 and all patients were able to maintain their airway and Spo2 at room air. Metanalysis of randomised controlled trials by WangJ et al (2020) of intravenous dexmedetomidine and intravenous tramadol for treatment of shivering after spinal anaesthesia also reported higher incidence of sedation indexmedetomidine group.17 Gandotra M et al (2023) studied low dose intravenous dexmedetomidine (20 µg) for prevention of shivering following LSCS underanaesthesia and they did not report any significant sedation. This can be due to use of lower dose than used in our study.

In our study, there was a significant difference between the various groups in terms of distribution of incidence of shivering (p-value < 0.001). 9.8% (n=4) of the patients in the Group A, 53.5% (n=23) of the patients in the Group B and 50% (n=63) of the patients in the Group C had shivering. There was a significant difference in the trend of Shivering Weighted Score over time between the three groups (p-

value < 0.001). In a study conducted by Mittal G et al (2014), they found that the difference in the time interval between administration of drug after onset of shivering and cessation was significantly shorter inthe Dexmedetomidine group (2.52 ± 0.44min) compared to Tramadol group (5.92

±0.81min) (p-value = 0.002). In another study conducted by Deng L et al (2021), they found that shivering at grade 2 or higher is significantly lower in group Dexmedetomidine (17%, 23/145) than in group NS (30.9%, 39/126), (p-value < 0.01).12 In the meta-analysis of RCTs conducted by Wang J et al (2020), they found that all the RCTs reported the effective rate of shivering control. Dexmedetomidine had higher rate of shiveringcontrol than Tramadol (RR=1.03; 95%CI [1.01, 1.06], p=0.01). They also found that recurrent rate of shivering, time to cease shivering was significantly higher in Tramadol than that of Dexmedetomidine. Sween LK et al (2021) evaluated the role of low dose dexmedetomidine for reducing shivering following caesareandelivery and they concluded that 10 µ/kg IV Dexmedetomidine after delivery reduced shivering without significant side effects. All these study results are similar to the results of our study.

In our study, there was no significant difference between the various groups in terms of distribution of incidence of Nausea (p-value = 0.156) , vomiting , hypotension and bradycardia.

In obstetric patients, the administration of both 0.5 mg/kg of Tramadol and 0.5 mcg/kg of Dexmedetomidine effectively prevents post-spinal anaesthesia shivering. Our study results showed dexmedetomidine as a better drug for the prevention of shivering after spinal anaesthesia in caesarean section as compared to tramadol as it has a low incidence of shivering, benefits of awake sedation and not associated with nauseaand vomiting. Only concern was bradycardia and hypotension which was not statistically significant when compared among groups

Small sample size, more studies with larger sample size will provide strong evidence.

1. J, Zheng Z, Li Y, Zou L, Li G, et al. Nalbuphine versus dexmedetomidine forthe treatment of combined spinal-epidural post-anesthetic shivering in pregnant women undergoing cesarean section. J Int Med Res. 2019;47(9):4442-53.
2. Lema GF, Gebremedhn EG, Gebregzi AH, Desta YT, Kassa AA. Efficacy of intravenous tramadol and low-dose ketamine in the prevention of post-spinal anesthesia shivering following cesarean section: a double-blinded, randomized control trial. Int J Womens Health. 2017;9:681-8.
3. Mittal G, Gupta K, Katyal S, Kaushal S. Randomised double-blind comparative study of dexmedetomidine and tramadol for post-spinal anaesthesia shivering. Indian J Anaesth. 2014;58(3):257-62.
4. Nnacheta TE, Onyekwulu FA, Amucheazi AO. Prevention of postanesthetic shivering under subarachnoid block for cesarean section: A randomized, controlled study comparing tramadol versus ondansetron. Nigerian J Clin Pract. 2020;23(5):619-25.
5. Jan De Witte, Daniel I. Sessler; Perioperative Shivering: Physiology and Pharmacology. Anesthesiology. 2002;96:467–484.
6. Anup N. Chowdhury, Santosh K, Lohar, Arvind K. Ray, Anindya Baruah. Comparison of intravenous ondansetron and tramadol for control of shivering during spinal anaesthesia: A prospective, observer blind study. International Journal of Contemporary Medical Research. 2018;5(12):L7-L11.
7. Lamontagne C, Lessage S, Villeneuve E, Lidzborski E, Derstenfeld A, Crochetière
8. Intravenous dexmedetomidine for the treatment of shivering during Cesarean delivery under neuraxial anesthesia: a randomized-controlled trial. Can J Anesth.
9. 2019;66(7):762-71.
10. Jayaraj A, Balachander H, Kuppusamy SK, Arusamy S, Rai Y, Siddiqui N. Comparison of meperidine, tramadol and fentanyl for post-spinal shiveringprevention during cesarean delivery: A double-blind randomized controlled trial. J Obstet Gynaecol Res. 2019;45(11):2202-8.
11. Crossley AW, Mahajan RP. The intensity of postoperative shivering is unrelated to axillary temperature. Anaesthesia. 1994;49(3):205-7.
12. Subedi M, Bajaj S, Kumar MS, YC M. An overview of tramadol and its usage in pain management and future perspective. Biomedicine & Pharmacotherapy 2019;(111):443-51.
13. Tilahun A, Seifu A, Aregawi A, Abera B, Demsie D. Effectiveness of meperidine versus tramadol on post spinal anesthesia shivering in elective cesarean section: A prospective observational cohort study. International Journal of Surgery Open. 2021;28:22-6.
14. Deng L, Zen B, Ouyang F, Tang L, Kuang H, Zhang Z. Prophecy with dexmetomitidine will decrease the incidence of pre-operative shivering and enhance anti-shivering-effect of tramadol during cesarean Section. Biomedical J Sci & Tech Res. 2021;35(1):27331-6.
15. Arora N. Prophylactic tramadol versus dexmedetomidine for prevention of shivering during spinal anaesthesia. Int J Sci Stud. 2014;2(7):17-20.
16. Fern L and Misiran K. Comparison of dexmedetomidine, pethidine and tramadol in the post-neuraxial anaesthesia shivering. Southern Afr J Anaesth Analg. 2015;21(1):14-18.
17. Kim YS, Kim YI, Seo KH, Kang HR. Optimal dose of prophylactic dexmedetomidine for preventing postoperative shivering. Int J Med Sci. 2013;10(10):1327-32.
18. Usta B, Gozdemir M, Demircioglu RI, Muslu B, Sert H, Yaldiz A. Dexmedetomidine for the prevention of shivering during spinal anesthesia. Clinics (Sao Paulo). 2011;66(7):1187-91.
19. Wang J, Wang Z, Liu J et al. Intravenous dexmedetomidine versus tramadol for treatment of shivering after spinal anesthesia: a meta-analysis of randomized controlled trials. BMC Anesthesiol. 2020;104.
20. Rao VU, Shankar M. Efficacy of dexmedetomidine, tramadol and pethidine in the management of shivering in cased under spinal anaesthesia – a comparative study. Saudi J Med. 2019;4(6):424-8.