European Journal of Cardiovascular Medicine

Shivering is not only a leading cause of discomfort to patients in perioperative period, but also hinders postoperative recovery significantly. Shivering in perioperative period causes many folds increase in metabolism, oxygen demand, and consumption besides CO2 production at cellular level. In severe cases, resultant lactic acidosis and hypoxemia may adversely affect peri- and postoperative outcome. Shivering is not an uncommon complication of spinal and general anesthesia, being reported with an incidence of 40–60% in various studies.[1,2]

Shivering is termed as an involuntary and repetitive skeletal muscles activity.[1] It occurs as a response to hypothermia in majority of cases; however, it is also reported in normothermic patients. Mechanisms mediated through uninhibited spinal reflexes, postoperative pain, and hyperactive sympathetic activities been hypothesized. Different frequencies and patterns of shivering has been noted in different forms of anesthesia.[1]

Endogenous peptides, biogenic monoamines, choline-mimetic drugs, and possibly N-Methyl-D-aspartic acid(NMDA) antagonists seem to participate in integration and modulation of central thermoregulatory control mechanisms.[1,2,3] Age, type of surgery, duration of surgery, baseline body core temperature, and associated comorbidities independently influence triggering of shivering and its severity as well.[4]

A plethora of opioid and non opioid drugs are often used in prevention and management of postoperative shivering, but are associated with potential side effects, including hypotension, hypertension, sedation, respiratory depression, nausea and vomiting. More recently, 5-HT3 receptor antagonists have emerged as a means of preventing peri- and postoperative shivering. However, their efficacy is yet to be proven conclusively.[5,6]

A double-blind prospective study was conducted to assess and compare the newly available 5-HT3 receptor antagonist “Palonosetron” against the older drug of same class “Ondansetron” in preventing PAS among patients undergoing spinal anesthesia.

This study was done at our hospital from January 1, 2023, to December 31, 24 in a hospital in India. The study adhered to the tenets of the Declaration of Helsinki, and approval from the institutional research ethics board was obtained for the study.

In this study, using computer software 84 patients were enrolled and randomly assigned to the two study groups (Group” O”, the Ondansetron group and Group” P”, the Palonosetron group).

Patients in the age group of 18-35 years with singleton pregnancy belonging to American Society of Anaesthesiologists (ASA) grade I and II undergoing elective lower segment cesarean section (LSCS) under spinal anesthesia were included in the study. Patients with allergy to 5-HT3 receptor antagonist drugs, psychological disorders, initial body temperature >38 °C or <36 °C, those requiring sedation/supplementation with other anesthetic drugs, or blood transfusion during period of observation were excluded from the study. All patients were assessed for anesthesia/surgery fitness in preanesthetic clinic as per protocol and inclusion criteria. Patients were kept nil orally for solids for 8 hours as per standard protocol pre-operatively. Ranitidine in the dose of 50 mg and metoclopramide in the dose of 10 mg were administered intravenously (i/v) prior to sending the patient to operating room. In the operating room, patients were given either 8 mg of ondansetron or 0.075 mg of palonosetron i/v, 30 minutes prior to spinal anesthesia as per their assigned group. Both the drugs were made to 4 ml volume in 5 ml syringes and the operation theater (OT) staff who prepared the drugs was kept unaware of the study. Subarachnoid block was established using 2.8 ml of 0.5% bupivacaine (heavy) with 25/26G Quincke needle and block adequacy was ensured.

Preoperatively, all patients wore a cotton gown and were covered by a single blanket. Intraoperatively, all patients were covered in surgical drapes and were not actively warmed. However, the ambient temperature in the OT suite was maintained between 22 and 24 °C and supplemental oxygen administered at a rate of 3-4 L/min through face mask. All intravenous fluids were at room temperature prior to administration. All patients were coloaded with 500 mL of Ringer lactate solution while establishing spinal anesthesia and no anesthetic supplementation was done intraoperatively. SpO2, electrocardiograph (ECG), and non-invasive blood pressure (NIBP) were monitored as per ASA standards. Sublingual temperature was measured prior to the beginning of surgery and then recorded at every 30 min interval for next 90 min. Perioperatively, bradycardia, hypotension, and vomiting were monitored and treated with atropine, mephenteramine and metoclopramide respectively in appropriate doses. Severe PAS was treated with 5 mg boluses of pethidine i/v titrated to effect as and when required. Grading of shivering was adapted from the study by Wrench et al.[7] [Table 1] All patients were observed for 90 min postoperatively and patients with grade 3 or 4 of shivering were included for the study.

Medical calculator from medicalc.org was used for sample size calculation for testing two-tailed null hypotheses. Based on the previous studies, incidence of postspinal shivering in ondansetron and palonosetron was assumed to be 40% and 15% respectively. A total of 42 patients (n = 42) in each group participated in the study. Observations obtained were analyzed using the Statistical Package for the Social Sciences (SPSS). Results are presented as mean ± standard deviation (SD) and number (%). Chi-square/Fisher's exact test was applied for categorical variables between the two groups. A P value of <0.1 was considered as statistically significant.

The present study enrolled 42 patients in each study group (Group “O” and Group “P”). Patient characteristics are described in Table 2. Mean of the age, height, weight, duration of surgeries, and sublingual temperature was calculated in both the groups, as some of them are independent risk factors for development of postspinal shivering and others determine the extent of distribution of drug in subarachnoid space. No significant intergroup difference was observed in demographic variables (age, height, and weight), duration of surgery, and sublingual temperatures. Major indication in both the study groups was post-LSCS pregnancy; however, few other indications included in the study have been noted in Table 3.

Although 23.8% patients (10 out of 42 patients) experienced shivering in “O” group, it was significantly lower in “P” group (9.5%; 4 out of 42 patients) and P value was 0.07, which in our study was deemed statistically significant.

Table 1 showing grading of shivering (adapted from Wrench et al.)[8]

Table 2: Baseline characteristics of study population

Table 3: Indications of surgery

Peri- and postoperative shivering also referred to as postanesthesia shivering (PAS) is a commonly encountered complication with general as well as spinal anesthesia. Multiple pharmaco-therapeutic agents have been studied for prevention of PAS which include various classes of drugs, e.g., alpha-2 agonists, opioids, benzodiazepines, choline-mimetics, NMDA antagonists, and several other drugs such as magnesium sulfate and lignocaine.[1,3] PAS has various mechanisms and contributory factors both in hypothermic and normothermic patients. Redistribution of body heat from core to the peripheral compartment (secondary to sympathetic block and peripheral vasodilatation), loss of thermoregulatory vasoconstriction below the level of the spinal block, and alteration of thermoregulatory mechanism under central neuraxial block are some of the contributory mechanisms to this response. In addition, rapid administration of cold intravenous fluid also augments the development of shivering in such patients.[8]

5-HT3 antagonists have demonstrated definite beneficial role in prevention of PAS and have an established favorable clinical profile and less side effects, such as dizziness, hypotension, etc., Besides their usefulness as antiemetics, their effectiveness in prevention of PAS is being widely explored. Ondansetron, granisetron, dolasetron, and tropisetron were introduced in 1990s and were found to be beneficial in nausea and vomiting induced by chemotherapy. Palonosetron is a 5-HT3 receptor antagonist, newly introduced as a potent, single stereo-isomeric compound, with a fused tricyclic ring system structure attached to a quinuclidine moiety in contrast to first-generation drugs, which are based on a three-substituted indole structure. Palonosetron has plasma half-life of approximately 40 h, while first generation drugs have half-lives of 5–12 h. The binding affinity of palonosetron to 5-HT3 receptor is also 30 times higher than the older 5-HT3 receptor antagonists.[9,10,11] Antagonists of 5-HT3 receptor inhibit the neurotransmission involved in thermoregulation in the hypothalamus. Owing to its different chemical structure, long plasma half-life and receptor affinity, palonosetron is presumed to interact efficiently at molecular level with 5-HT3 receptors at sites different from or in addition to that of ondansetron and granisetron binding.[10] Various meta-analysis have found definite advantage of administration of 5HT3 antagonists in lowering the incidence of PAS during general and spinal anesthesia.[11,12] Both ondansetron and palonosetron have been widely studied separately but literature is in paucity on their comparative study for efficacy on PAS after subarachnoid block. Lakhe et al.[13] found an incidence of PAS of around 16.7% (5 out of 30 patients) with 4 mg prophylactic intravenous ondansetron in surgeries being performed under spinal anesthesia. In our study, incidence of shivering was noted to be slightly higher with similar dose of intravenous ondansetron. Our study was conducted exclusively in pregnant ladies with peculiar hemodynamic milieu undergoing LSCS, which probably might have contributed to a higher rate of PAS. In another study by Badawy and Mokhtar[14] in obstetric patients undergoing elective LSCS under spinal anesthesia, 51% incidence of PAS was observed in control group (with normal saline) and 26% with 8 mg intravenous ondansetron. Incidence of shivering in our study after administration of prophylactic ondansetron was observed to be 25%, which is comparable with the observation made in this study.

Palonosetron has not yet been extensively studied for its efficacy on PAS after neuraxial blocks. Jo et al.[10] demonstrated the incidence of PAS to be 21% in their study with prophylactic use of 0.075 mg palonosetron intravenously. However, their study was conducted in laparoscopic cholecystectomy surgery with general anesthesia in patients of age group 65-80 years, which might explain higher incidence of PAS compared to our study. Jo et al.[6] observed the incidence to be about 27% when they used prophylactic palonosetron in patients undergoing gynecological laparoscopic surgery with propofol-remifentanil total intravenous anesthesia. However, this increased incidence may again be attributed to general anesthesia with remifentanil which has been considered associated with PAS. Both these studies involved patients undergoing surgery under general anesthesia but have not found any beneficial effect of palonosetron on PAS. Independent risk factors for development of PAS (laparoscopic surgeries, total intravenous anesthesia, general anesthesia, and elderly patients) present in both the groups might have mitigated the effect of palonosetron. Our study was conducted in young patients undergoing similar surgery (elective LSCS) under neuraxial block, which might be one of the important reasons for relatively lower (10%) incidence of PAS with palonosetron. Existing data on effect of palonosetron on PAS after spinal anesthesia are scarce. However, beneficial effects of 5-HT3 receptor antagonists are apparently more obvious with neuraxial blocks.

A limitation of the study is that only shivering of grade-3 and above was included in this study which might have missed some patients who had milder form of PAS. Small sample size was another limitation in our study. The study was done only in elective LSCS surgeries under spinal anesthesia; hence, extrapolation of the results to other major surgeries under general anesthesia needs further studies for generalization.

Palonosetron is more effective than ondansetron in preventing PAS in patients undergoing surgery under spinal anesthesia. However, considering the small sample size and homogenous nature of surgery and anesthesia, the authors believe that further studies with larger sample size need to be undertaken to establish and generalize the beneficial effects of palonosetron on postspinal shivering among other major surgeries.

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