Randomized Double-Blinded Comparative Study of Intravenous Nalbuphine and Tramadol for the Treatment of Postspinal Anesthesia Shivering.

CONTEXT: Shivering is one of the most commonly recognized complications of the central neuraxial blockade. For optimal perioperative care, control of postspinal anesthesia shivering is essential. AIMS: The present study designed to compare the clinical efficacy, hemodynamic parameters, and side effects of nalbuphine and tramadol for control of postspinal anesthesia shivering. SETTINGS AND
DESIGN: This was a prospective, randomized, double-blind study.
MATERIALS AND METHODS: This study was conducted on 90 American Society of Anesthesiologists Physical Status I and II patients of either gender, aged between 18 and 60 years, who subsequently developed shivering grade 3 or 4, scheduled for different surgical procedures under spinal anesthesia. The patients were randomized into two groups of 45 patients each to receive either nalbuphine 0.06 mg.kg-1 (Group N) or tramadol 1 mg.kg-1 (Group T). Grade of shivering, onset of shivering, time interval for cessation of shivering, response rate at 5 and 30 min, rescue dose, hemodynamic parameters, and side effects were observed at scheduled intervals. STATISTICAL ANALYSIS USED: Independent t-test and Chi-square/Fisher's exact test were used to analyze the data.
RESULTS: The time taken for cessation of shivering was significantly less with nalbuphine in comparison with tramadol (P < 0.05). It was observed that the response time at 5 and 30 min and rescue dose requirement for control of shivering were not much difference (P > 0.05).
CONCLUSIONS: Both nalbuphine and tramadol are effective; however, the time taken for cessation of shivering is significantly less with nalbuphine when compared to tramadol. Furthermore, tramadol causes significantly more nausea and vomiting; however, nalbuphine causes significantly more sedation. Copyright:

INTRODUCTION

Spinal anesthesia is a widely used technique for both elective and emergency surgeries. Shivering is one of the most commonly recognized complications of the central neuraxial blockade because of impairment of thermoregulatory control, reported in 40%-70% of the patients undergoing surgery under spinal anaesthesia.[1] Postanesthetic shivering is defined as an involuntary, spontaneous, rhythmic oscillating muscle hyperactivity that increases metabolic heat production up to 600% after anesthesia.[2] Shivering during neuraxial anesthesia is a common issue that could have possibly adverse impacts, for example, increased oxygen consumption, carbon dioxide production, lung ventilation and cardiac work, as well as causing diminished mixed venous oxygen saturation. Spinal anesthesia impedes the thermoregulatory system by restraining tonic vasoconstriction which assumes significant role in the regulation of temperature.[3]

Both nonpharmacological and pharmacological methods using drugs of antishivering properties play a vital role to control shivering during anesthesia. However, nonpharmacological methods using equipment are effective but expensive and lack practicality.[4] The most popular mode of treatment of shivering is still pharmacological agents. Various agents such as meperidine, doxapram, dexamethasone, tramadol, nefopam, ketanserin, clonidine, propofol, physostigmine, magnesium sulfate, and fentanyl have been used to eliminate postoperative shivering.[567]

Tramadol hydrochloride, a μ-opioid receptor agonistic drug, has a modulatory impact on central monoaminergic pathways and in this way represses the neuronal uptake of noradrenaline/serotonin and energizes 5HT3 discharge, which resets the body temperature regulating center. Nalbuphine is a mixed agonist–antagonist opioid which has a high affinity for κ opioid receptor and acts as a competitive opioid antagonist and partial opioid agonist. Theoretically, nalbuphine may have remarkable antishivering effects on postanesthetic shivering.

The present study is designed to compare the efficacy of nalbuphine and tramadol for the treatment of postanesthetic shivering following subarachnoid block.

MATERIALS AND METHODS

After taking the institutional ethics committee approval, this prospective, randomized, double-blinded study was conducted during the period of March 2018 to September 2019 and the trial registration was done with the Clinical Trial Registry India (CTRI/2018/02/012125). Written and informed consent was obtained. The study involved elective surgeries under spinal anesthesia except parturient in 90 American Society of Anesthesiologists (ASA) Physical Status I or II patients of either sex in the age group of 18–60 years, height between 150 and 175 cm, and patients who had grade 3 or 4 shivering. Patients’ refusal to participate in the study, patients with a history of coagulation disorders, history of allergy to agents to be used, thyroid disease, Parkinson's disease, Reynaud's syndrome, cardiopulmonary disease, dysautonomia, need for blood transfusion during surgery, history of alcohol or sedative–hypnotic abuse, use of vasodilators, an initial core temperature >37.5°C or <36.5°C, sepsis, and patients having subarachnoid block failure were excluded from the study.

On arrival to the operation theater, an 18G intravenous (IV) cannula was secured in all the patients before induction of anesthesia. Before giving spinal anesthesia, preloading is done with Ringer's lactate solution of 10 ml.kg − 1 and maintained at 6 ml.kg − 1.h − 1 after spinal anesthesia. Monitoring gadgets comprising 5-lead electrocardiogram (ECG), noninvasive automatic blood pressure (NIBP), and pulse oximeter were applied to all the patients. Baseline heart rate (HR), blood pressure, respiratory rate (RR), and oxygen saturation (SpO2) were recorded. Under aseptic precaution, subarachnoid block was given with 0.5% heavy bupivacaine (15 mg) at L3–4 or L4–5 interspace using 26G Quincke's spinal needle. Operation theaters and recovery room were maintained at an ambient temperature of around 22°C–24°C with humidity of approximately 55%–65%. IV fluids and anesthetic agents were administered at room temperature.

All included patients who developed postspinal anesthesia shivering were enrolled in the study and randomized using random number table dispensed into two groups (n = 45 each), with allocation ratio of 1:1 into both of the two groups and received one of the accompanying treatments via the IV route. Group N (n = 45) received nalbuphine 0.06 mg.kg − 1 in 5 ml normal saline and Group T (n = 45) received tramadol 1 mg.kg − 1 in 5 ml normal saline. The examiner who was surveying the shivering grade before and after treatments was unaware of the patients’ group and treatments. Assessment of shivering grade and response to each treatment were done at 0, 5, 15, and 30 min after treatment. Assessment of shivering that responded to each treatment was as follows: null (intensity of shivering not changed), improvement (decreased shivering intensity), and success (no shivering). Absence of shivering after treatment was considered as successfully treated. The main end point of the present study was to stop postspinal shivering within 30 min after medication. Postanesthetic shivering was graded as 0 = absence of shivering, 1 = peripheral vasoconstriction or piloerection but absence of visible shivering, 2 = only one muscle group showed muscular activity, 3 = more than one muscle group showing muscular activity but not generalized shivering, and 4 = shivering involved in the whole body.[8] The patients with grade 3 or 4 shivering for at least 3 min were studied. When postanesthetic shivering developed, patients were covered with a blanket and oxygen was given at the rate of 5 l/min through a Hudson face mask. Body temperature (axillary temperature) was monitored. Patients were observed for 30 min and vital signs such as NIBP, HR, and RR were monitored at 0 min (T0), 5 min (T1), 10 min (T2), 15 min (T3), 20 min (T4), 25 min (T5), and 30 min (T6). The SpO2 was monitored continuously using pulse oximetry. Side effects such as nausea, vomiting, bradycardia (<50/min), hypotension (>20% of baseline), dizziness, and sedation score were recorded. With atropine, mephentermine, and metoclopramide, bradycardia, hypotension, and vomiting were treated respectively, in titrated doses when required. Level of sedation was assessed by means of Ramsay sedation scale;[9] 1 point = worried, anxious, or unpeaceful; 2 points = interactive, oriented, and calm; 3 points = response to oral command only; 4 points = rapid response to a light glabellar tap or loud auditory stimulus; 5 points = sluggish response to a light glabellar tap or loud auditory stimulus; and 6 points = absence of response to a light glabellar tap or loud auditory stimulus. The presence of nausea or vomiting was measured on a three-point scale,[10] with 0 – none; 1 – nausea; and 2 – vomiting. With injection metoclopramide 10 mg IV, nausea and vomiting were treated.

The sample size was calculated on the basis of a previous study in view of keeping α error less than 0.05%, β error less than 0.05%, and power of study of 80%.[11] Therefore, a total of 90 patients were enrolled in the study with 45 patients in each study group.

Statistical analysis

The statistical software namely SPSS V22 (IBM, Armonk, New York, USA) has been used for the analysis of the data. Continuous measurements are presented as mean ± standard deviation while categorical measurements are presented in number (%). Independent t-test and Chi-square/Fisher's exact test has been used to analyze the study parameters on a continuous and categorical scale between two groups (intergroup analysis), respectively. All statistical tests with P < 0.05 were considered statistically significant.

RESULTS

In the present study, out of 112 patients, a total of 90 patients were met the inclusion criteria, experienced shivering of grades 3 and 4 after spinal anesthesia, completed this study, and none of the patient was lost to follow-up [Figure 1]. Patient's characteristics such as age, gender, height, weight, duration of surgery, amount of fluid given, and blood loss in both groups were comparable [Table 1].

Figure 1

Consort flow diagram

Table 1

Demographic characteristics of patients of both groups

Variables	Group T (n=45)	Group N (n=45)	P
Age (years)	44.5±8.3	41.5±8.6	0.09
Gender (male/female)	24/21	22/23	0.81
Height (cm)	161.2±6.5	159.6±4.6	0.18
Body weight (kg)	60.3±6.9	59.4±5.5	0.50
Duration of surgery (min)	72.38±14.68	76.23±15.36	0.23
Crystalloid fluids (ml)	1822.38±192.64	1784.54±178.96	0.34
Blood loss (ml)	204.46±36.23	198.62±27.46	0.39

Age, height, body weight, and duration of surgery are presented as mean±SD. Test done was independent t-test. n=Number of patients, SD=Standard deviation

Nalbuphine delivered a rapid and potent antishivering effect like that observed with tramadol. Grade 3 shivering observed in Group N and Group T was 31 (68.89%) and 29 patients (64.44%), respectively, and grade 4 shivering observed in Group N and Group T was 14 (31.11%) and 16 patients (35.56%), respectively (P = 0.79). Onset of shivering between the two groups was statistically insignificant; however, the difference in the time interval for cessation of shivering after treatment was significantly shorter in the nalbuphine group compared to tramadol group [Table 2].

Table 2

Parameters for postspinal anesthetic shivering and adverse effects

Parameter	Group T (n=45)	Group N (n=45)	P
Shivering grade 3/4	29/16	31/14	0.79
Onset of shivering (min)	18.62±12.34	17.86±11.65	0.76
Time interval for cessation of shivering (min) after treatment	4.84±1.23	3.84±1.23	0.009
Treatment response at 5 min (%)	84	80	0.62
Overall treatment response (30 min) (%)	95.56	93.33	0.65
Rescue dose requirement, n (%)	2 (4.44)	3 (6.67)	0.65
Sedation score
At T0	1.27±0.45	1.78±0.42	<0.0001
At T1	1.29±0.46	1.87±0.59	<0.0001
At T2	1.18±0.39	2.00±0.52	<0.0001
At T3	1.27±0.45	2.07±0.33	<0.0001
At T4	1.51±0.51	2.18±0.39	<0.0001
At T5	1.53±0.50	2.20±0.40	<0.0001
At T6	1.53±0.50	2.13±0.34	<0.0001

Data were analyzed using independent t-test, Chi-square/Fisher’s exact test. Treatment expressed as percentage. Statistically significant at P<0.05. SD=Standard deviation

Five minutes after nalbuphine and tramadol, postanesthetic shivering was effectively treated with high response rates of 80% and 84%, respectively [Table 2]. There were no significant differences among groups in blood pressure, HR, RR, body temperature, and arterial SpO2 after each treatment (P > 0.05).

There was no shivering in 42 (93.33%) and 43 (95.56%) patients who received nalbuphine patients, respectively. Both the drugs were found to be effective in reducing shivering. However, complete cessation of shivering does not occur in 3 (6.67%) patients in Group N and 2 (4.44%) patients in Group T. Three patients in Group N and two patients in Group T were given rescue doses of nalbuphine or tramadol, respectively. The mean sedation score at time interval T1 in Group N and in Group T was 1.87 ± 0.59 and 1.29 ± 0.46, respectively. There was significant variation in sedation score between the groups (P < 0.0001). Three was the maximum sedation score seen in nalbuphine group [Table 2]. Nalbuphine causes more sedation than tramadol.

Nausea and vomiting were significantly more in Group T in comparison to Group N (P = 0.0008). Tramadol causes more nausea and vomiting than nalbuphine [Figure 2]. We did not observe bradycardia, hypotension, and dizziness in our study.

Figure 2

Incidence of nausea and vomiting between the two groups

DISCUSSION

The present study revealed the clinical efficacy and adverse effects of nalbuphine (0.06 mg.kg−1) and tramadol (1 mg.kg−1) for treating postanesthetic shivering. Although tramadol is an established drug in the treatment of shivering, in this study, we found that nalbuphine is almost equally effective as tramadol with shorter time of cessation in treating postspinal shivering. However, nalbuphine causes more sedation and tramadol causes more nausea and vomiting.

Shivering is an accompanying part of anesthesia, and it prompts different outcomes and inconvenience to the patient; appropriate advances must be taken for its avoidance and treatment. However, the exact mechanism of shivering during spinal anesthesia is still not completely recognized. It is believed that a combination of anesthetic-induced thermoregulatory impairment and exposure to a cool environment makes most unwarmed surgical patients hypothermic.[12] In this study, to exclude confounding factors, intravenous fluids and drugs were maintained at room temperature and operation theaters were kept an ambient temperature of 22°C–24°C. The factors that impact the occurrence of shivering such as amount of IV fluids and duration of spinal anesthesia were not firmly controlled; however, this should not influence the validity of our study on the grounds that the present study is centered around response to treatment used instead of incidence of shivering, and by randomization, both groups were exposed to similar degrees of influence of these factors. Despite various drugs and techniques to prevent shivering, it keeps on staying a progressing issue in the peri- and post-operative period. Temperature monitoring must be precise and consistent. Research demonstrates that when core temperature rapidly changes during the perioperative period, the relationship between the temperatures estimated at different body sites may vary significantly.[13] To reduce the confounding bias, we measured axillary temperature in all the studied patients.

A number of drugs have been attributed to potent antishivering properties.[11415] These drugs belongs to different classes such as biogenic monoamines, endogenous peptides, cholinomimetics, cations, and possibly N-methyl-D-aspartate receptor antagonists. All these drugs seem to modulate central thermoregulatory control mechanisms, and with diverse functions of these drugs, transcendent site of action of most of these drugs is tough to recognize.[12] In view of their different adverse effects, search for an ideal antishivering agent is still going on.

The dose-dependent sedative effect of nalbuphine, without respiratory depression, may eliminate anxiety, especially in patients under spinal anesthesia. By external temperature, stimulation of kappa (κ) receptors may produce a sensation of the skin.[16] The κ receptors are dispersed in the ventral tegmental area of the hypothalamus, substantia nigra, nucleus accumbens, olfactory tubercle, and amygdala.[17] Nalbuphine has a high affinity for κ receptors and assumes an antishivering role by modulating central thermoregulatory control mechanisms at hypothalamus and reduces temperature regulation threshold for shivering. It was reported that intrathecal nalbuphine effectively prevented the event of shivering.[11]

Sun et al. observed that the mean time to cessation of shivering in nalbuphine was 3.5 ± 2.7, when 0.07 mg.kg−1 nalbuphine was used for the treatment of shivering.[11] We used 0.06 mg.kg−1 nalbuphine to analyze the effect.

The role of nalbuphine in the treatment of postanesthetic shivering was assessed previously.[1118] Because of its dual effects of antishivering and sedation, it may be a good choice. Götz et al. reported that nalbuphine reduces postoperative shivering as successfully and timely as meperidine when 10 mg nalbuphine was used to treat shivering and suppression of shivering was achieved within 4.6 ± 4.1 min following the injection of nalbuphine.[19]

Wang et al. revealed that, 5 min and 30 min after treatment, nalbuphine provided a rapid and effective antishivering effect on postanesthetic shivering, with high response rates of 80% and 90%, respectively.[20] In our study, we also observed almost same response rate of 80% and 93.33% after 5 and 30 min of treatment, respectively. Although a dose of 0.08 mg.kg−1 nalbuphine was used to treat shivering, in our study, 0.06 mg.kg−1 nalbuphine was the used.

Tramadol is opioid receptor agonist with the mainly being mediated through μ receptors and with minimal effect on κ and σ (Sigma) receptors. The probable mechanism of antishivering action of tramadol is through its opioid or serotonergic and noradrenergic activity or both.[2122]

Tramadol is the most commonly used drug for postanesthetic shivering; however, vomiting or vomiting tendency is its common side effect. Various studies reported about different response rate of treatment with a dose of 0.5 mg.kg−1 of tramadol,[4222324] and the response rate of treatment in our study was 95.56% which was in accordance with Reddy and Chiruvella; however, in their study, fixed dose of 50 mg of tramadol was used. We compared the incidence of nausea and vomiting among studied drug and found that tramadol causes more nausea and vomiting than nalbuphine. Mittal et al. and Maheshwari et al. found that recurrence rate with tramadol was 8% with a dose of 0.5 and 1 mg.kg − 1, respectively;[2425] however, we observed that 4.44% of patients required rescue doses of tramadol. In our study, we also measured response of treatment at 5 min similar to a previous study[2026] and observed that response rate with tramadol was 84% and with nalbuphine was 80%. The various study showed a different incidence of nausea and vomiting,[427] which could be because of different patient characteristics in different studies. Mittal et al. and Maheshwari et al. observed that the incidence of sedation was higher with tramadol comparing respective drugs.[2425] In our study, we observed that nalbuphine causes more sedation compared to tramadol with maximum sedation score of three and less incidence of nausea and vomiting which provided better surgical conditions as patients were given spinal anesthesia.

The limitations of this study were small sample size, and selection of medium-duration surgeries as the chance of developing core hypothermia are more in long-duration surgeries. Tympanic membrane temperature probe and mid-esophagus temperature probe could not be used to measure core body temperature because it causes patient discomfort who is awake under spinal anesthesia. Rectal temperature monitoring was a possibility however could not be attempted.

CONCLUSION

Both nalbuphine (0.06 mg.kg−1) and tramadol (1 mg.kg−1) are effective in treating patients with postspinal anesthesia shivering. However, time interval for complete cessation of shivering after treatment was significantly shorter with nalbuphine as compared to tramadol. Furthermore, tramadol causes significantly more nausea and vomiting and sedation caused by nalbuphine was significantly high which may provide additional comfort to the patient. More studies of large sample size with different doses are needed to confirm the optimal dose as an efficient antishivering agent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.