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1.  Doxapram Only Slightly Reduces the Shivering Threshold in Healthy Volunteers 
Anesthesia and analgesia  2005;101(5):1368-1373.
We determined the effects of doxapram on the major autonomic thermoregulatory responses in humans. Nine healthy volunteers were studied on two days: Control and Doxapram (intravenous infusion to a plasma concentration of 2.4 ±0.8 μg/mL, 2.5 ±0.9 μg/mL, and 2.6 ±1.1 μg/mL at the sweating, vasoconstriction, and shivering thresholds, respectively). Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the sweating, vasoconstriction, and shivering thresholds with compensation for changes in skin temperature. Data were analyzed with paired t tests and presented as means ± SDs; P < 0.05 was considered statistically significant. Doxapram did not change the sweating (Control: 37.5±0.4°C, Doxapram: 37.3±0.4°C, P=0.290) or the vasoconstriction threshold (36.8±0.7 vs. 36.4±0.5°C; P=0.110). However, it significantly reduced the shivering threshold from 36.2±0.5 to 35.7±0.7°C (P=0.012). No sedation or symptoms of panic were observed on either study day. The observed reduction in the shivering threshold explains the drug's efficacy for treatment of postoperative shivering; however, a reduction of only 0.5°C is unlikely to markedly facilitate induction of therapeutic hypothermia as a sole agent.
PMCID: PMC1552102  PMID: 16243996
Anesthesia; Hypothermia; Temperature; Thermoregulation
2.  Nefopam, a Non-sedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold 
Anesthesiology  2004;100(1):37-43.
The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. We evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.
Nine volunteers were studied on three randomly assigned days: 1) control (Saline), 2) nefopam at a target plasma concentration of 35 ng/ml (Small Dose), and 3) nefopam at a target concentration of 70 ng/ml (Large Dose, ≈20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. We determined the thresholds (triggering core temperature at a designated skin temperature of 34°C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.
Nefopam did not significantly modify the slopes for sweating (0.0 ± 4.9°C·μg−1·ml; r2 = 0.73 ± 0.32) or vasoconstriction (−3.6 ± 5.0°C·μg−1·ml; r2=−0.47± 0.41). In contrast, nefopam significantly reduced the slope of shivering (−16.8 ± 9.3°C·μg−1·ml; r2 = 0.92 ± 0.06). Large-Dose nefopam thus reduced the shivering threshold by 0.9 ± 0.4°C (P<0.001) without any discernable effect on the sweating or vasoconstriction thresholds.
Most drugs with thermoregulatory actions — including anesthetics, sedatives, and opioids — synchronously reduce the vasoconstriction and shivering thresholds. Nefopam however reduced only the shivering threshold. This pattern has not previously been reported for a centrally acting drug. That pharmacologic modulation of vasoconstriction and shivering can be separated is of clinical and physiologic interest.
PMCID: PMC1283107  PMID: 14695722
Temperature; Thermoregulation; Nefopam; Shivering; Vasoconstriction; Threshold; Hypothermia
3.  Dantrolene Reduces the Threshold and Gain for Shivering 
Anesthesia and analgesia  2004;98(5):1318-contents.
Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. With IRB approval and informed consent, healthy volunteers were evaluated on two random days: control and dantrolene (≈2.5 mg/kg plus a continuous infusion). In study 1, 9 men were warmed until sweating was provoked and then cooled until arterio-venous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In study 2, 9 men were given cold Ringer's solution IV to reduce core temperature ≈2°C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption vs. core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3±0.3°C, P=0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7±0.2 to 36.3±0.3°C, P=0.01 and systemic gain from 353±144 to 211±93 ml·min−1·°C−1, P=0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition.
PMCID: PMC1454474  PMID: 15105208
Temperature: hyperthermia, fever; Pharmacology: dantrolene; Complications: shivering
4.  Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study 
Critical Care  2007;11(1):R29.
Mild therapeutic hypothermia has been shown to improve outcome for patients after cardiac arrest and may be beneficial for ischaemic stroke and myocardial ischaemia patients. However, in the awake patient, even a small decrease of core temperature provokes vigorous autonomic reactions–vasoconstriction and shivering–which both inhibit efficient core cooling. Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. We tested whether a combination of skin warming and a medium dose of meperidine additively would reduce the shivering threshold to below 34°C without producing significant sedation or respiratory depression.
Eight healthy volunteers participated on four study days: (1) control, (2) skin warming (with forced air and warming mattress), (3) meperidine (target plasma level: 0.9 μg/ml), and (4) skin warming plus meperidine (target plasma level: 0.9 μg/ml). Volunteers were cooled with 4°C cold Ringer lactate infused over a central venous catheter (rate ≈ 2.4°C/hour core temperature drop). Shivering threshold was identified by an increase of oxygen consumption (+20% of baseline). Sedation was assessed with the Observer's Assessment of Alertness/Sedation scale.
Control shivering threshold was 35.5°C ± 0.2°C. Skin warming reduced the shivering threshold to 34.9°C ± 0.5°C (p = 0.01). Meperidine reduced the shivering threshold to 34.2°C ± 0.3°C (p < 0.01). The combination of meperidine and skin warming reduced the shivering threshold to 33.8°C ± 0.2°C (p < 0.01). There were no synergistic or antagonistic effects of meperidine and skin warming (p = 0.59). Only very mild sedation occurred on meperidine days.
A combination of meperidine and skin surface warming reduced the shivering threshold to 33.8°C ± 0.2°C via an additive interaction and produced only very mild sedation and no respiratory toxicity.
PMCID: PMC2151895  PMID: 17316456
5.  Magnesium Sulfate Only Slightly Reduces the Shivering Threshold in Humans 
British journal of anaesthesia  2005;94(6):756-762.
Background: Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous hemodynamic responses and prevents further hypothermia. Magnesium is an attractive antishivering agent because it is used for treatment of postoperative shivering and provides protection against ischemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness.
Methods: We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: 1) Control and 2) Magnesium (80 mg·kg-1 followed by infusion at 2 g·h-1). Lactated Ringer's solution (4°C) was infused via a central venous catheter over a period of approximately 2 hours to decrease tympanic membrane temperature ≈1.5°C·h-1. A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs. core temperature regression. Sedation was evaluated using verbal rating score (VRS, 0-10) and bispectral index of the EEG (BIS). Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analyzed using repeated-measures ANOVA; P<0.05 was statistically significant.
Results: Magnesium reduced the shivering threshold (36.3±0.4 [mean±SD] vs. 36.6±0.3°C, P=0.040). It did not affect the gain of shivering (Control: 437±289, Magnesium: 573±370 ml·min-1·°C-1, P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.
Conclusions: Magnesium significantly reduced the shivering threshold; however, due to the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.
PMCID: PMC1361806  PMID: 15749735
Magnesium; Temperature; Thermoregulation; Therapeutic hypothermia; Brain protection; Cardiac protection; Shivering
6.  Prophylactic Granisetron Vs Pethidine for the Prevention of Postoperative Shivering: A Randomized Control Trial 
Indian Journal of Anaesthesia  2009;53(3):330-334.
Shivering-the “Big Little Problem” has an incidence of 60% in early recovery phase following general anaesthesia. A number of techniques have been tried to prevent postoperative shivering. Previous study showed that, ondansetron in higher doses reduces postoperative shivering. Therefore, this study was done to compare the efficacy of prophylactic granisetron, pethidine and placebo in preventing postoperative shivering.
Ninety patients aged 20-60yrs, ASA physical status I and II, scheduled for laparoscopic surgery under general anaesthesia were randomly allocated to receive either normal saline (Group S, n=30) as negative control, pethidine 25mg (Group P, n=30) as positive control or granisetron−1 (Group G, n=30) intravenously before induction. The anaesthesia was induced with fentanyl−1, propofol−1 and atracurium−1 and maintained with sevoflurane 1 - 1.5%. Nasopharyngeal temperature was measured throughout the procedure. An investigator, blinded to the treatment group, graded postoperative shivering in a scale of 0 to 4. (0= no shivering, 1= piloerection or peripheral vasoconstriction but no visible shivering, 2= muscle activity in only one muscle group 3= muscle activity in more than one muscle group, 4= shivering involving the whole body). Prophylaxis was regarded as ineffective if shivering was greater than grade 3 and intravenous pethidine 25 mg was administered as rescue medication.
The three groups did not differ significantly regarding patient characteristics. The numbers of patients shivering on arrival in the recovery room at 15 minutes after operation were significantly less in Group P (7%) and Group G (17%) than in Group S (60%). Groups P and G differ significantly than in Group S (p<0.05). However, the difference between Groups P and G was not statistically significant (p>0.05). The prophylactic use of granisetron (−1) and pethidine(25mg) intravenous were found to be effective in preventing postoperative shivering.
PMCID: PMC2900125  PMID: 20640142
Shivering; Postoperative; Granisetron; Pethidine
7.  Role of butorphanol and ondansetron premedication in reducing postoperative shivering after general and spinal anesthesia: A randomized comparative study from North India 
Anesthesia, Essays and Researches  2016;10(2):319-323.
Postoperative shivering (PAS) is a common problem following general and spinal anesthesia and may lead to multiple complications. This placebo-controlled, randomized study was performed to evaluate the efficacy of Ondansetron and butorphanol premedication reduces shivering after general and spinal anaesthesia.
The aim of this study to highlight the efficacy of Butorphenol and ondosteron in controlling postoperative shivering.
Materials and Methods:
This clinical trial included 180 patients scheduled for elective general surgery, E.N.T., Ophthamological operations, randomly divided to six groups. Three groups in which General Anaesthesia was used i.e. Group 1-ondansetron 8 mg intravenously(IV).Group 2 butorphanol 2 mg IV and Group 3 – saline 4 ml IV. And three groups where spinal Anaesthesia was used i.e. Group 4-Ondosteron 8 mg IV, Group 5 butorphanol 2 mg IV and Group 6 – saline 4 ml IV 3-5 minutes before anaesthesia. Patients were observed in terms of vital signs, side effects and shivering.
Settings and Design:
The type of the study was double blind randomized trial.
Statistical Analysis Used:
Statistical Package for Social Sciences version 13.0 statistical analysis software.
Postoperative shivering was observed in 15.5%, 22.2% and 60% in general anaesthesia groups I II and III respectively. The reduction of core and dermal temperature during the anaesthesia and recovery, changes in systolic and diastolic blood pressure and heart rate were similar in all three groups (i.e. Group I,II,III). In spinal anaesthesia groups, PAS occurred 10%, 13.3% and 43.3% in group IV, V, VI respectively. The reduction of core temperature is similar in all three groups of spinal anaesthesia. But heart rate and mean arterial pressure increase were significant in control saline group in post operative recovery time. No complication seen in any of the six groups.
This study suggested that use of Butorphanol and Ondansteron both are effective in reducing the incidence of PAS after general and spinal anaesthesia.
PMCID: PMC4864699  PMID: 27212768
General anesthesia; ondansetron; postoperative shivering; spinal anesthesia
8.  Nonpharmacologic Approach to Minimizing Shivering During Surface Cooling: A Proof of Principle Study1  
Journal of critical care  2012;27(6):746.e1-746.e8.
This study had two objectives: (1) to quantify the metabolic response to physical cooling in febrile patients with Systemic Inflammatory Response Syndrome (SIRS); and (2) to provide proof for the hypothesis that the efficiency of external cooling and the subsequent shivering response are influenced by site and temperature of surface cooling pads.
To quantify shivering thermogenesis during surface cooling for fever, we monitored oxygen consumption (VO2) in six febrile patients with SIRS during conventional cooling with cooling blankets and ice packs. To begin to determine how location and temperature of surface cooling influences shivering, we compared 5 cooling protocols for inducing mild hypothermia in six healthy volunteers.
In the SIRS patients, core temperature decreased 0.67°C per hour, all patients shivered, VO2 increased 57.6% and blood pressure increased 15% during cooling. In healthy subjects, cooling with the 10°C vest was most comfortable and removed heat most efficiently without shivering or VO2 increase. Cooling with combined vest and thigh pads stimulated the most shivering and highest VO2, and increased core temperature. Reducing vest temperature from 10°C to 5°C failed to increase heat removal secondary to cutaneous vasoconstriction. Capsaicin, an agonist for TRPV1 warm-sensing channels, partially reversed this effect in 5 subjects.
Our results identify the hazards of surface cooling in febrile critically ill patients and support the concept that optimization of cooling pad temperature and position may improve cooling efficiency and reduce shivering.
PMCID: PMC3494806  PMID: 22762936
Fever; Hypothermia; Surface Cooling; Shivering
9.  Comparison of Ondansetron and Meperidine for Treatment of Postoperative Shivering: A Randomized Controlled Clinical Trial 
The involved neurotransmitter pathways in the postoperative shivering (POS) are poorly understood. Recently, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists have been reported to prevent POS. We investigated the effect of ondansetron, a 5-HT3 antagonist that is used to treat postoperative nausea and vomiting, on shivering.
This study aimed to compare the efficacy of ondansetron and meperidine in the treatment of shivering after general anesthesia.
Patients and Methods:
In this double-blinded randomized clinical trial, 83 patients (age range, 18-60 years) who had shivering after general anesthesia were randomly allocated to any of these three groups: Group A, (number = 27) received 4 mg of intravenous ondansetron, Group B, (number = 27) received 8 mg of intravenous ondansetron, and Group C, (number = 29) received 0.4 mg/kg of intravenous meperidine at recovery room. The surface temperatures and the incidence as well as intensity of shivering were recorded.
Shivering was controlled in 16 patients (59%) in Group A, 22 (81%) in Group B, and 25 (86%) in Group C (P = 0.01). Within each group, there were no significant differences among the surface temperature in recovery room. Patients in groups A and B had significantly lower incidence of nausea and vomiting than group C (P = 0.01).
Ondansetron and meperidine have similar effects on shivering. We concluded that 8 mg of intravenous ondansetron can control shivering and this is the dose of choice, especially in patients with POS with nausea and vomiting.
PMCID: PMC4221999  PMID: 25389473
Anesthetics; Adverse Effects; Meperidine; Therapeutics; Ondansetron; Shivering
10.  Prophylactic effects of intrathecal Meperidine and intravenous Ondansetron on shivering in patients undergoing lower extremity orthopedic surgery under spinal anesthesia 
Intraoperative hypothermia is a common problem with anesthesia. Spinal anesthesia, the same as general anesthesia, affects the process of temperature regulation. The aim of this study was to compare the prophylactic effect of intravenous (IV) ondansetron with intrathecal (IT) meperidine on prevention of shivering during spinal anesthesia in patients underwent orthopedic surgery of the lower limb.
In this study, 120 patients with American Society of Anesthesiologists physical status I to II, between the ages 16 and 65 were randomized into three groups. Group O and Group M were given IV ondansetron 8 mg and IT meperidine 0.2 mg/kg, before spinal anesthesia, respectively. Group C received IV saline 0.9%. The core and ambient temperatures, the incidence and intensity of shivering, blood pressure, heart rate, and maximum level of sensory block were recorded.
Shivering was observed in 15%, 2.5%, and 37.5% of patients in Groups O, M, and C, respectively. There was a significant difference between Group O and M compared to Group C (P = 0.023 for Group O vs. Group C, P < 0.001 for Group M vs. Group C, P = 0.049 for Group M vs. Group O). Shivering incidence and intensity in Group M was significantly lower than Group O (P = 0.049 and P = 0.047, respectively). Twenty-two patients required additional IV meperidine among which 15 patients were from Group C (37.5%), six patients from Group O (15%) and one patient from Group M (2.5%).
We concluded that IT meperidine and IV ondansetron comparably can decrease intensity and incidence of shivering compared to control group as well as decreasing the requirement to additional doses of meperidine for shivering the control without any hemodynamic side effect.
PMCID: PMC4199198  PMID: 25328899
Hypothermia; Meperidine; Ondansetron; orthopedic surgery; shivering; spinal anesthesia
11.  Dexmedetomidine Reduces Shivering during Mild Hypothermia in Waking Subjects 
PLoS ONE  2015;10(8):e0129709.
Background and Purpose
Reducing body temperature can prolong tolerance to ischemic injury such as stroke or myocardial infarction, but is difficult and uncomfortable in awake patients because of shivering. We tested the efficacy and safety of the alpha-2-adrenergic agonist dexmedetomidine for suppressing shivering induced by a rapid infusion of cold intravenous fluids.
Ten subjects received a rapid intravenous infusion of two liters of cold (4°C) isotonic saline on two separate test days, and we measured their core body temperature, shivering, hemodynamics and sedation for two hours. On one test day, fluid infusion was preceded by placebo infusion. On the other test day, fluid infusion was preceded by 1.0 μg/kg bolus of dexmedetomidine over 10 minutes.
All ten subjects experienced shivering on placebo days, with shivering beginning at a mean (SD) temperature of 36.6 (0.3)°C. The mean lowest temperature after placebo was 36.0 (0.3)°C (range 35.7-36.5°C). Only 3/10 subjects shivered on dexmedetomidine days, and the mean lowest temperature was 35.7 (0.4)°C (range 35.0-36.3°C). Temperature remained below 36°C for the full two hours in 6/10 subjects. After dexmedetomidine, subjects had moderate sedation and a mean 26 (13) mmHg reduction in blood pressure that resolved within 90 minutes. Heart rate declined a mean 23 (11) bpm after both placebo and dexmedetomidine. Dexmedetomidine produced no respiratory depression.
Dexmedetomidine decreases shivering in normal volunteers. This effect is associated with decreased systolic blood pressure and sedation, but no respiratory depression.
PMCID: PMC4523180  PMID: 26237219
12.  The Effect of Postoperative Skin-Surface Warming on Oxygen Consumption and the Shivering Threshold 
Anaesthesia  2003;58(12):1228-1234.
Cutaneous warming is reportedly an effective treatment for shivering during epidural and after general anaesthesia. We quantified the efficacy of cutaneous warming as a treatment for shivering. Unwarmed surgical patients (final intraoperative core temperatures ≈35°C) were randomly assigned to be covered with a blanket (n=9) or full-body forced-air cover (n=9). Shivering was evaluated clinically and by oxygen consumption. Forced-air heating increased mean-skin temperature (35.7±0.4 °C vs. 33.2±0.8°C, P< 0.0001) and lowered core temperature at the shivering threshold (35.7±0.2 °C vs. 36.4±0.2°C, P< 0.0001). Active warming improved thermal comfort and significantly reduced oxygen consumption from 9.7±4.4 to 5.6±1.9 mL·min−1·kg−1(P=0.038). However, duration of shivering was similar in the two groups (37±11 min [warming] and 36±10 min [control]). Core temperature thus contributed about four times as much as skin temperature to control of shivering. Cutaneous warming improved thermal comfort and reduced metabolic stress in postoperative patients, but did not quickly obliterate shivering.
PMCID: PMC1314985  PMID: 14705689
shivering; body temperature; thermoregulatory control
13.  Induction of a Prolonged Hypothermic State by Drug-induced Reduction in the Thermoregulatory Set-Point 
The marked improvement in outcome following induction of hypothermia after cardiac arrest has spurred the search for better methods to induce cooling. A regulated decrease in core temperature mediated by a drug-induced reduction in the set point for thermoregulation may be an ideal means of inducing hypothermia. To this end, the exploratory drug HBN-1 was assessed as a means to induce mild and prolonged hypothermia.
Free moving rats were infused i.v. for 12 hours with: a vehicle at room temperature (normothermia), a vehicle chilled to 4°C (forced hypothermia), or HBN-1 (mixture of ethanol, lidocaine, and vasopressin) at room temperature. Core (intra-abdominal) temperature (Tc) was measured telemetrically, tail skin temperature (Ttail) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually.
HBN-1 elicited a reduction in Tc from 37.5°C to 34°C within 80 minutes after initiation of the infusion; Tc was maintained between 33°C and 34°C for more than 13 hours. HBN-1 infusion was associated with a reduction in MR (p=0.0006), a slight reduction in Ttail, and no evidence of shivering (p<0.001). The forced hypothermia group displayed shivering (p<0.001), a significant increase in MR, and a decrease in Ttail, indicative of peripheral vasoconstriction to reduce heat loss.
HBN-1 infusion induced a mild and prolonged hypothermia in free moving, unanesthetized rats characterized by modulation of thermoeffectors to reduce heat gain and increase heat loss. HBN-1 thus appears to elicit regulated hypothermia and may provide a new method for achieving a prolonged state of therapeutic hypothermia.
PMCID: PMC3621333  PMID: 23667774
14.  Pre-induction low dose pethidine does not decrease incidence of postoperative shivering in laparoscopic gynecological surgeries 
The incidence of shivering in patients undergoing a laparoscopic procedure is stated to be about 40%. A majority of laparoscopic gynecological procedures are taken up on an outpatient basis. Postoperative shivering may delay hospital discharge and is a common cause of discomfort in patients recovering from anesthesia.
To determine the effect of pre-induction, low-dose pethidine on postoperative shivering in patients undergoing laparoscopic gynecological surgeries.
Setting and Design:
Sixty females between 25 and 35 years of age, of American Society of Anesthesiologists (ASA) class 1 and 2, were randomly divided into three groups of 20 patients each. Group I and II patients received i.v. pethidine 0.3 mg/kg and 0.5 mg/kg, respectively, while Group III received i.v. 0.9% normal saline just before induction of general anesthesia. Temperature of the Operating Room and the Post Anesthesia Care Unit was standardized and all fluids given during the study period were warmed to 37°C.
Materials and Methods:
Temperature, measured with a tympanic membrane probe, was recorded preoperatively, after induction of anesthesia, on arrival at the Post Anesthesia Care Unit, and postoperatively at 15 minutes and 30 minutes. Shivering was graded (0 – 4 scale) at arrival of the patients to the PACU and every five minutes thereafter, up to 30 minutes.
Statistical Analysis:
ANOVA, Chi-square test, Kruskal-Wallis ANOVA and Mann-Whitney U tests were used. A P-value of less than 0.05 was considered significant.
Core body temperatures were statistically insignificant between groups at pre-induction, post-induction, and in the PACU (P > 0.05). At the end of surgery, shivering was present in 18 patients (30%). In groups I, II, and III, six (30%), three (15%), and nine (45%) patients shivered, respectively. The differences in incidence and grading of shivering among groups was found to be statistically insignificant (P > 0.05). The core body temperature of shiverers and non-shiverers were compared. In the PACU at 0, 15, and 30 minutes, the temperature among shiverers was significantly lower than that in the non-shiverers. Rescue drug i.v. pethidine 20 mg was given to patients with shivering grade ≥2. None of the patients had shivering after 10 minutes.
Prophylactic pre-induction, low-dose pethidine does not have major role in preventing postoperative shivering.
PMCID: PMC3161460  PMID: 21897506
Laparoscopy; pethidine; postoperative shivering
15.  Effect of preoperative warming during cesarean section under spinal anesthesia 
Korean Journal of Anesthesiology  2012;62(5):454-460.
Postoperative hypothermia and shivering is a frequent event in patients during cesarean section under spinal anesthesia. We assessed the effect of preoperative warming during cesarean delivery under spinal anesthesia for prevention of hypothermia and shivering.
Forty five patients undergoing elective cesarean section were randomly assigned to three groups. Group F received warmed intravenous fluid (40℃). Group A patients were actively warmed by forced air-warming. Group C was the control group. Forced air-warming and warmed fluid was maintained for the 15 min preceding spinal anesthesia. Core temperature (tympanic membrane) and the skin temperature of arm and thigh were measured and shivering was graded simultaneously.
The core temperature at 45 min decreased less in Groups F and A than Group C (-0.5℃ ± 0.3℃ vs -0.6℃ ± 0.4℃ vs -0.9℃ ± 0.4℃, respectively; P = 0.004). The arm temperature at 15 min and 30 min exhibited a greater increase in Group A than Group F and Group C (P = 0.001 and P = 0.012, respectively). Leg temperature increased similarly among the three groups. The incidence of shivering was significantly less in Group A and Group F than Group C (20%, 13.3%, and 53.3%, respectively; P = 0.035).
Preoperative forced air-warming and warmed fluid prevents hypothermia and shivering in patients undergoing elective cesarean delivery with spinal anesthesia.
PMCID: PMC3366313  PMID: 22679543
Cesarean section; Shivering; Spinal anesthesia; Warming
16.  Comparison of effect of electroacupuncture and nefopam for prevention of postanesthetic shivering in patients undergoing urologic operation under spinal anesthesia 
Korean Journal of Anesthesiology  2016;69(6):579-586.
Shivering during spinal anesthesia is a frequent complication and is induced by the core-to-peripheral redistribution of heat. Nefopam has minimal side effects and prevents shivering by reducing the shivering threshold. Electroacupuncture is known to prevent shivering by preserving the core body temperature. We compared the efficacies of electroacupuncture and nefopam for the prevention of shivering during spinal anesthesia.
Ninety patients scheduled for elective urological surgery under spinal anesthesia were enrolled in the study. Patients were randomly divided into the control group (Group C, n = 30), the electroacupuncture group (Group A, n = 30), and the nefopam group (Group N, n = 30). Groups C and A received 100 ml of isotonic saline intravenously for 30 minutes before spinal anesthesia, while Group N received nefopam (0.15 mg/kg) mixed in 100 ml of isotonic saline. Group A received 30 minutes of electroacupuncture before receiving anesthesia. Shivering scores, mean arterial pressure, heart rate, body temperature and side effects were recorded before, and at 5, 15, 30, and 60 minutes after spinal anesthesia.
The incidence of postanesthetic shivering was significantly lower in Group N (10 of 30) and Group A (4 of 30) compared with that in Group C (18 of 30)(P < 0.017). Body temperature was higher in Group N and Group A than in Group C (P < 0.05). Hemodynamic parameters were not different among the groups.
By maintaining body temperature during spinal anesthesia, electroacupuncture is as effective as nefopam in preventing postanesthetic shivering.
PMCID: PMC5133229  PMID: 27924198
Electroacupuncture; Nefopam; Shivering; Spinal anesthesia
17.  Prophylactic Low Dose Ketamine and Ondansetron for Prevention of Shivering During Spinal Anaesthesia 
Perioperative shivering is a common problem during anaesthesia. Apart from physical warming many drugs have also been used for prevention of shivering. Ketamine has been used for preventing shivering during anaesthesia in doses of 0.5 to 0.75mg kg-1, but even these doses causes too much sedation and hallucination. Ondansetron (8 mg) has been recently evaluated for its perioperative antishivering effect in patients under anaethesia. Present study was conducted to evaluate the efficacy and safety of low dose Ketamine (0.25mg kg-1) and Ondansetron (4 mg) for prevention of shivering during spinal anaesthesia.
Patients & Methods:
Total 120 patients undergoing lower abdominal surgery under spinal anaesthesia were included. 3ml of hyperbaric bupivacaine 0.5% was used for spinal anaesthesia. After intrathecal injection, the patients were randomly divided in 3 groups of 40 each who received Ketamine 0.25mg kg-1or Ondansetron 4mg IV or Saline. Vitals, temperature and shivering scores were recorded every 5 minutes. Side effects i.e. hypotension, nausea and vomiting, sedation and hallucinations were also recorded.
Fall in temperature was more significant in saline and ondansetron group (gp) than in ketamine group at all time interval. Out of 40 patients, shivering was maximum & seen in 17 patients (42.50%) in saline gp, 4 patients (10%) in ondansetron gp and in only 1patient (2.5%) in ketamine gp. Odd ratio of ketamine, ondansetron and saline are 1, 4.33 and 28.33 respectively which means that shivering in saline gp was 28.83 times higher than ketamine gp and 6.65 times higher than in ondansetron .Shivering rate was 4.33 times higher in ondansetron gp than in ketamine gp. Hypotension was lowest in ketamine gp (10%) in comparison to ondansetron gp (22.5%) and saline gp. (20%). Mild sedation was seen in almost all (95%) patients in ketamine gp,
Prophylactic low dose ketamine (0.25mg kg-1) and Ondansetron (4mg) significantly decreased shivering in patients undergoing spinal anaesthesia without significant side effects.
PMCID: PMC3087257  PMID: 21547171
Shivering; Spinal anaesthesia; Ketamine; Ondansetron
18.  The Effect of an Amino Acid Infusion on Central Thermoregulatory Control in Humans 
Anesthesiology  2004;100(3):634-639.
Administration of protein or amino acids enhances thermogenesis, presumably by stimulating oxidative metabolism. However, hyperthermia results even when thermoregulatory responses are intact, suggesting that amino acids also alter central thermoregulatory control. We thus tested the hypothesis that amino acid infusion increases the thermoregulatory setpoint.
Nine male volunteers each participated on four study days in randomized order: 1) intravenous amino acids infused at 4 kJ·kg−1·hr−1 for 2.5 h combined with skin-surface warming; 2) amino acid infusion combined with cutaneous cooling; 3) a saline infusion combined with skin-surface warming; and, 4) saline infusion combined with cutaneous cooling.
Amino acid infusion increased resting core temperature by 0.3 ± 0.1°C (mean ± SD) and oxygen consumption by 18 ± 12%. Furthermore, amino acid infusion increased the calculated core temperature threshold (triggering core temperature at a designated mean-skin temperature of 34°C) for active cutaneous vasodilation by 0.3 ± 0.3°C, for sweating by 0.2 ± 0.2°C, for thermoregulatory vasoconstriction by 0.3 ± 0.3°C, and for thermogenesis by 0.4 ± 0.5°C. Amino acid infusion did not alter the incremental response intensity (i.e., gain) of thermoregulatory defenses.
Amino acid infusion increased the metabolic rate and resting core temperature. However, amino acids also produced a synchronous increase in all major autonomic thermoregulatory defense thresholds; the increase in core temperature was identical to the setpoint increase — even in a cold environment with amble potential to dissipate heat. In subjects with intact thermoregulatory defenses, amino acid-induced hyperthermia appears to result from an elevated setpoint increase rather than increased metabolic rate per se.
PMCID: PMC1249472  PMID: 15108979
19.  Translating Drug-Induced Hibernation to Therapeutic Hypothermia 
ACS chemical neuroscience  2015;6(6):899-904.
Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 °C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist 6N-cyclohexyladenosine (CHA) with 8-(p-sulfophenyl) theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood–brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 °C, induce and maintain the Tb between 29 and 31 °C for 24 h in both naïve rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management.
Graphical abstract
PMCID: PMC4939144  PMID: 25812681
Adenosine; hibernation; cardiac arrest; targeted temperature management; A1AR and global cerebral ischemia; CHA; 8-SPT
20.  Efficiency and safety of ondansetron in preventing postanaesthesia shivering 
Shivering is one of the most frequent complications of operation during the postanaesthesia period. Ondansetron has been proved to be valid in preventing postanaesthesia shivering (PAS) in several studies. However, its efficiency and safety are still disputable. We therefore performed an updated meta-analysis of randomised controlled trials (RCTs) for evaluation and to clarify this issue.
A literature search using the PubMed, Embase™ and Cochrane Library databases was performed (from inception to January 2015). RCTs that evaluated the efficiency and safety of ondansetron in the prevention of PAS were included in the meta-analysis. The primary outcome measure was incidence of PAS, and secondary outcomes included subgroup analysis and the side effects of ondansetron.
A total of 8 RCTs containing 905 subjects were identified as suitable for this review. Compared with placebo, ondansetron was associated with a significant reduction of PAS (relative risk [RR]: 0.33, 95% confidence interval [CI]: 0.19–0.58, p=0.0001) while no difference was detected between ondansetron and pethidine (RR: 0.89, 95% CI: 0.41–1.94, p=0.78). There was no significant difference between ondansetron and placebo or pethidine in terms of risk of bradycardia but ondansetron was associated with a lower risk of hypotension (RR: 0.26, 95% CI: 0.08–0.79, p=0.020) than placebo. There was no difference in hypotension when ondansetron was compared with pethidine.
Ondansetron can prevent PAS effectively and reduce the risk of hypotension.
PMCID: PMC5209977  PMID: 27138855
Ondansetron; Pethidine; Shivering; Meta-analysis
21.  Active core rewarming avoids bioelectrical impedance changes in postanesthetic patients 
BMC Anesthesiology  2011;11:2.
Postoperative hypothermia is a common cause of complications in patients who underwent laparoscopic cholecystectomy. Hypothermia is known to elicit electrophysiological, biochemical, and cellular alterations thus leading to changes in the active and passive membrane properties. These changes might influence the bioelectrical impedance (BI). Our aim was to determine whether the BI depends on the core temperature.
We studied 60 patients (52 female and 8 male) age 40 to 80 years with an ASA I-II classification that had undergone laparoscopic cholecystectomy under balanced inhalation anesthesia. The experimental group (n = 30) received active core rewarming during the transanesthetic and postanesthesic periods. The control group (n = 30) received passive external rewarming. The BI was recorded by using a 4-contact electrode system to collect dual sets of measurements in the deltoid muscle. The body temperature, hemodynamic variables, respiratory rate, blood-gas levels, biochemical parameters, and shivering were also measured. The Mann-Whitney unpaired t-test was used to determine the differences in shivering between each group at each measurement period. Measurements of body temperature, hemodynamics variables, respiratory rate, and BI were analyzed using the two-way repeated-measures ANOVA.
The gradual decrease in the body temperature was followed by the BI increase over time. The highest BI values (95 ± 11 Ω) appeared when the lowest values of the temperature (35.5 ± 0.5°C) were reached. The active core rewarming kept the body temperature within the physiological range (over 36.5°C). This effect was accompanied by low stable values (68 ± 3 Ω) of BI. A significant decrease over time in the hemodynamic values, respiratory rate, and shivering was seen in the active core-rewarming group when compared with the controls. The temporal course of shivering was different from those of body temperatue and BI. The control patients showed a significant increase in the serum-potassium levels, which were not seen in the active-core rewarming group.
The BI analysis changed as a function of the changes of core temperature and independently of the shivering. In addition, our results support the beneficial use of active core rewarming to prevent accidental hypothermia.
PMCID: PMC3053227  PMID: 21324200
22.  Comparing Two Different Doses of Intravenous Ondansetron With Placebo on Attenuation of Spinal-induced Hypotension and Shivering 
Side effects of spinal anesthesia are hypotension, bradycardia and shivering. Five-hydroxytriptamine (5-HT), a serotonergic receptor, may be an important factor associated with inducing the Bezold Jarish reflex (BJR) that may lead to the bradycardia and hypotension in the setting of decreased blood volume.
This study aimed to investigate the effect of intravenous administration of ondansetron, a 5-HT3 receptor antagonist, which could attenuate spinal-induced hypotension, bradycardia and shivering.
Patients and Methods:
Two hundred and ten patients aged 20-50 years old were scheduled for spinal anesthesia and were divided randomly into three equal groups. The control group received normal saline and intervention groups received 6 mg or 12 mg of intravenous ondansetron 5 minutes before spinal anesthesia. Mean arterial pressure (MAP), heart rate (HR), and shivering were recorded before and after spinal anesthesia every 5 minutes during first 20 minutes of surgery.
Demographic data were not statistically different among groups. HR was statistically different between the experimental groups and the control group. Ten patients (14%) in the control group had HR < 50 bpm, that required intravenous atropine compared to experimental groups (P =0.02). In the control group 12 (17%) patients had MAP < 80 mm Hg and required vasopressors compared to experimental groups (P = 0.04). There were no significant differences in MAP and HR between the experimental groups (P =0.06). Incidence of shivering in the control group was 45% (32.70) that was statistically more than experimental groups (P = 0.02).
Administration of two different doses of intravenous ondansetron, 6 mg and 12 mg, significantly attenuates spinal induced hypotension, bradycardia and shivering compared to the control saline group. However, the hemodynamic profiles and shivering in experimental groups were not statistically different.
PMCID: PMC3997945  PMID: 24790900
Serotonin; Heart Rate; Hypotension; Arterial Pressure; Ondansetron; Anesthesia, Spinal
23.  Effect of irrigation fluid temperature on core temperature and hemodynamic changes in transurethral resection of prostate under spinal anesthesia 
Hypothermia is a frequent observation in elderly males undergoing transurethral resection of prostate (TURP) under spinal anesthesia. The use of irrigating fluids at room temperature results in a decrease body temperature. Warmed irrigating solutions have shown to reduce heat loss and the resultant shivering. Such investigation was not much tried in low resource settings.
To compare the resultant change in core temperature and hemodynamic changes among patients undergoing TURP surgery under spinal anesthesia using warm and room temperature irrigation fluids.
Settings and Design:
Randomized prospective study at a tertiary care center.
This study was conducted on 40 male patients aged 50-85 years undergoing TURP under spinal anesthesia. Of which, 20 patients received irrigation fluid at room temperature 21°C and 20 patients received irrigation fluid at 37°C after random allocation. Core temperatures and hemodynamic parameters were assessed in all patients at preoperative, intra-operative, and postoperative periods. Intra-operative shivering was also noted in both groups.
Statistical Analysis:
Unpaired and Paired Student's t-test.
For patients who underwent irrigation with fluid at room temperature Core temperature drop from 36.97°C in preoperative to 34.54°C in postoperative period with an effective difference of 2.38°C. Among patients who received warmed irrigation fluid at 37°C had core temperature drop from 36.97°C to 36.17°C and the effect of fall was 0.8°C. This difference was statistically significant (P < 0.001). Shivering of Grades 1 and 2 was observed in nine patients, of Group 1 while only three patients had Grades 1 and 2 shivering in Group 2. The hemodynamic parameters were similar in the two groups and did not reach significant difference.
Use of warm irrigation fluid during TURP reduces the risk of perioperative hypothermia and shivering.
PMCID: PMC4173604  PMID: 25886228
Core temperature; hypothermia; irrigating fluid; spinal anesthesia; transurethral resection of prostate
24.  Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis 
PLoS Medicine  2010;7(10):e1000350.
Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit.
The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada.
Methods and Findings
A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1–US$81.1) and health care payers US$61.1 million (US$46.2–US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15–CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88–CDN$1.41).
In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy.
Please see later in the article for the Editors' Summary
Editors' Summary
Although many episodes of gastroenteritis in children are mild and can be managed with oral fluids, including oral rehydration therapy (ORT), some cases are severe enough to require hospital admission for intravenous fluids. Administration of an antiemetic (a drug that reduces nausea and sickness) can be clinically effective, especially ondansetron, (a drug that belongs to a class of drugs known as selective serotonin receptor antagonists), which is safer than other antiemetics, such as promethazine and prochlorperazine, and in which there is good evidence to support its effectiveness in improving the success of ORT in children with gastroenteritis. Furthermore, studies have shown that administration of ondansetron decreases the risk of further vomiting, and hence the need for intravenous rehydration, and immediate hospital admission. However, despite the proven clinical benefits of ondansetron, clinical practice guidelines continue to recommend against the use of antiemetics in gastroenteritis because the evidence of cost savings is not yet clear. Last year, the UK's National Institute for Health and Clinical Excellence recommended that such a cost analysis should be a key research priority in pediatric gastroenteritis.
Why Was This Study Done?
This study—which is an economic analysis—was conducted in response to the various calls for the need to demonstrate the cost effectiveness of ondansetron in the management of pediatric gastroenteritis.
What Did the Researchers Do and Find?
The researchers analysed the costs of the administration of oral ondansetron in both the US and Canada, if routinely given to children with gastroenteritis-induced vomiting and dehydration in the emergency department setting. In addition, the researchers calculated the incremental cost of ondansetron per quality-adjusted life-year (QALY) gained from a health care perspective, compared to a regimen without ondansetron administration. The authors conducted a particular type of statistical analysis, known as decision tree analysis, to compare the two treatment options—administering ondansetron and not administering ondansetron in addition to ORT, with the clinical outcomes (further vomiting, intravenous rehydration, and hospitalization) determined on the basis of the documented efficacy of ondansetron. In addition, the researchers conducted their analyses from both the societal perspective (which included all costs, both direct—the resources required to produce a service; and indirect—productivity costs) and the health care payer's perspective. The US and Canada use similar medical resources, management programs, and treatment guidelines, but as prices differ dramatically (for example, the cost of hospitalization in the US is 8-fold higher than that in Canada), the researchers conducted a separate analysis for each country.
On the basis of data from the US, the researchers found that the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations every year with an annual saving of US$65.6 million to society and US$61.1 million to payers of health care costs if this drug was given routinely. When using Canadian data, the researchers found that the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations every year, with an annual saving of CDN$1.72 million to society and CDN$1.18 million to payers of health care costs if this drug was given routinely.
What Do These Findings Mean?
The results of this study show that the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings from both societal and health care perspectives compared to a policy that does not include ondansetron administration. Furthermore, the societal savings are probably an underestimate because in their model, the researchers assumed that only 10% of children with gastroenteritis presenting to an emergency department would meet eligibility criteria (in reality, this proportion would likely be higher). In addition, the researchers did not include estimates for ondansetron administration in the clinic or private office setting, as although such use is common, no estimates of eligibility and efficacy were available.
Therefore, in addition to being clinically beneficial, the administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis is also economically advantageous.
Additional Information
Please access these Web sites via the online version of this summary at
Patient UK and the US National Institutes of Health provide information for patients on ondansetron
Patient UK provides information on gastroenteritis in children
BBC Health also provides general information on gastroenteritis
The Centers for Disease Control and Prevention contains a report on managing acute gastroenteritis among children
PMCID: PMC2953527  PMID: 20967234
25.  The efficacy of ginger added to ondansetron for preventing postoperative nausea and vomiting in ambulatory surgery 
Pharmacognosy Research  2014;6(1):52-57.
Post-operative nausea and vomiting (PONV) frequently hampers implementation of ambulatory surgery in spite of so many costly antiemetic drugs and regimens.
The study was carried out to compare the efficacy of ginger (Zingiber officinale) added to Ondansetron in preventing PONV after ambulatory surgery.
Materials and Methods:
It was a prospective, double blinded, and randomized controlled study. From March 2008 to July 2010, 100 adult patients of either sex, aged 20-45, of ASA physical status I and II, scheduled for day care surgery, were randomly allocated into Group A[(n = 50) receiving (IV) Ondansetron (4 mg) and two capsules of placebo] and Group B[(n = 50) receiving IV Ondansetron (4 mg) and two capsules of ginger] simultaneously one hour prior to induction of general anaesthesia (GA) in a double-blind manner. One ginger capsule contains 0.5 gm of ginger powder. Episodes of PONV were noted at 0.5h, 1h, 2h, 4h, 6h, 12h and 18h post- operatively.
Statistical Analysis and Results:
Statistically significant difference between groups A and B (P < 0.05), was found showing that ginger ondansetron combination was superior to plain Ondansetron as antiemetic regimen for both regarding frequency and severity.
Prophylactic administration of ginger and ondansetron significantly reduced the incidence of postoperative nausea and vomiting compared to ondansetron alone in patients undergoing day care surgery under general anaesthesia.
PMCID: PMC3897009  PMID: 24497743
Ambulatory (day care) surgery; American Society of Anaesthesiologists; Ginger (Zingiber officinale); Post-operative nausea and vomiting; Visual Analogue Score

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