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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.
doi:10.1213/01.ANE.0000180198.13467.DF
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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/cc5709
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.
doi:10.1093/bja/aei105
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.
Summary
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 40mcg.kg−1 (Group G, n=30) intravenously before induction. The anaesthesia was induced with fentanyl 2mcg.kg−1, propofol 2mg.kg−1 and atracurium 0.5mg.kg−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 (40mcg.kg−1) and pethidine(25mg) intravenous were found to be effective in preventing postoperative shivering.
PMCID: PMC2900125  PMID: 20640142
Shivering; Postoperative; Granisetron; Pethidine
7.  Comparison of Ondansetron and Meperidine for Treatment of Postoperative Shivering: A Randomized Controlled Clinical Trial 
Background:
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.
Objectives:
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.
Results:
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).
Conclusions:
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.
doi:10.5812/ircmj.13079
PMCID: PMC4221999  PMID: 25389473
Anesthetics; Adverse Effects; Meperidine; Therapeutics; Ondansetron; Shivering
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.
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jcrc.2012.04.016
PMCID: PMC3494806  PMID: 22762936
Fever; Hypothermia; Surface Cooling; Shivering
9.  Prophylactic effects of intrathecal Meperidine and intravenous Ondansetron on shivering in patients undergoing lower extremity orthopedic surgery under spinal anesthesia 
Objective:
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.
Methods:
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.
Findings:
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%).
Conclusion:
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.
doi:10.4103/2279-042X.141105
PMCID: PMC4199198  PMID: 25328899
Hypothermia; Meperidine; Ondansetron; orthopedic surgery; shivering; spinal anesthesia
10.  The Effect of Postoperative Skin-Surface Warming on Oxygen Consumption and the Shivering Threshold 
Anaesthesia  2003;58(12):1228-1234.
Summary
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
11.  Induction of a Prolonged Hypothermic State by Drug-induced Reduction in the Thermoregulatory Set-Point 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1089/ther.2012.0011
PMCID: PMC3621333  PMID: 23667774
12.  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.
Background
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).
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1000350.
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
doi:10.1371/journal.pmed.1000350
PMCID: PMC2953527  PMID: 20967234
13.  Pre-induction low dose pethidine does not decrease incidence of postoperative shivering in laparoscopic gynecological surgeries 
Objectives:
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.
Aims:
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.
Results:
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.
Conclusions:
Prophylactic pre-induction, low-dose pethidine does not have major role in preventing postoperative shivering.
doi:10.4103/0970-9185.83680
PMCID: PMC3161460  PMID: 21897506
Laparoscopy; pethidine; postoperative shivering
14.  Effect of preoperative warming during cesarean section under spinal anesthesia 
Korean Journal of Anesthesiology  2012;62(5):454-460.
Background
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.
Methods
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.
Results
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).
Conclusions
Preoperative forced air-warming and warmed fluid prevents hypothermia and shivering in patients undergoing elective cesarean delivery with spinal anesthesia.
doi:10.4097/kjae.2012.62.5.454
PMCID: PMC3366313  PMID: 22679543
Cesarean section; Shivering; Spinal anesthesia; Warming
15.  Dexamethasone for Prevention of Postoperative Shivering: A Randomized Double-Blind Comparison with Pethidine 
Background:
Postoperative shivering is very common and followed by many problems such as increasing oxygen consumption, blood pressure, intracranial and intraocular pressure, and postoperative pain. Therefore, prevention of shivering is important, especially in elderly and ischemic heart disease patients. The goal of this study was to compare the effect of pethidine (meperidine), dexamethasone, and placebo on prevention of shivering.
Methods:
This double-blind clinical trial study was carried out on 120 patients who were candidates for surgery under general anesthesia. The patients were randomly divided into three groups. Induction and maintenance of anesthesia for all patients were similar. Temperature of patients was measured every 5 min interval. After induction, saline 0.9%, dexamethasone and pethidine were injected to groups a, b, and c, respectively. In recovery, patients were controlled for visible shivering. All data were statistically analyzed by analysis of variance (ANOVA) and Chi-square tests.
Results:
There were no significant differences among three mentioned groups regarding gender, age, duration of surgery and anesthesia, extubation time, duration of recovery, and basic clinical characteristics. Nineteen cases (47.5%) of placebo group had postoperative shivering, whereas in dexamethasone group only four cases (10%) had shivering and the difference between the two groups was significant. Also in pethidine group, 15 cases (37.5%) had shivering and the difference with placebo group was significant (P value = 0.001).
Conclusion:
The present study showed that pethidine and dexamethasone are effective drugs for prevention of postoperative shivering in elective surgery and the effect of dexamethasone in preventing the postoperative shivering is better than pethidine.
PMCID: PMC3775222  PMID: 24049601
Dexamethasone; general anesthesia; shivering; surgery; pethidine
16.  Prophylactic Low Dose Ketamine and Ondansetron for Prevention of Shivering During Spinal Anaesthesia 
Background:
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.
Results:
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,
Conclusion:
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
17.  The Effect of an Amino Acid Infusion on Central Thermoregulatory Control in Humans 
Anesthesiology  2004;100(3):634-639.
Background
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.
Methods
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.
Results
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.
Conclusions
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
18.  Comparing Two Different Doses of Intravenous Ondansetron With Placebo on Attenuation of Spinal-induced Hypotension and Shivering 
Background:
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.
Objectives:
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.
Results:
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).
Conclusions:
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.
doi:10.5812/aapm.12055
PMCID: PMC3997945  PMID: 24790900
Serotonin; Heart Rate; Hypotension; Arterial Pressure; Ondansetron; Anesthesia, Spinal
19.  Active core rewarming avoids bioelectrical impedance changes in postanesthetic patients 
BMC Anesthesiology  2011;11:2.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2253-11-2
PMCID: PMC3053227  PMID: 21324200
20.  The efficacy of ginger added to ondansetron for preventing postoperative nausea and vomiting in ambulatory surgery 
Pharmacognosy Research  2014;6(1):52-57.
Background:
Post-operative nausea and vomiting (PONV) frequently hampers implementation of ambulatory surgery in spite of so many costly antiemetic drugs and regimens.
Objective:
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.
Conclusion:
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.
doi:10.4103/0974-8490.122918
PMCID: PMC3897009  PMID: 24497743
Ambulatory (day care) surgery; American Society of Anaesthesiologists; Ginger (Zingiber officinale); Post-operative nausea and vomiting; Visual Analogue Score
21.  Effect of irrigation fluid temperature on core temperature and hemodynamic changes in transurethral resection of prostate under spinal anesthesia 
Background:
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.
Aim:
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.
Methods:
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.
Results:
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.
Conclusion:
Use of warm irrigation fluid during TURP reduces the risk of perioperative hypothermia and shivering.
doi:10.4103/0259-1162.134508
PMCID: PMC4173604
Core temperature; hypothermia; irrigating fluid; spinal anesthesia; transurethral resection of prostate
22.  Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study 
Gut  2005;54(8):1169-1173.
Background and aims: There are no available effective therapies for fatigue associated with chronic hepatitis C (CHC). The serotonin antagonist ondansetron has been shown to be effective in the chronic fatigue syndrome. In this randomised, placebo controlled, double blind trial, we investigated the effect of orally administered ondansetron on fatigue in CHC.
Methods: Thirty six patients with CHC were included if fatigue was their predominant symptom and they scored more than 4 on a visual analogue scale (0–10). During the study, fatigue and depression were measured on days 0, 15, 30, and 60 using a validated self report questionnaire (fatigue impact scale and Beck depression inventory). Patients were randomised to receive ondansetron tablets 4 mg twice daily or placebo for one month followed by an additional four weeks of observation.
Results: Fatigue score was 85.4 (28.2) and 98.2 (26.9) in the ondansetron and placebo groups, respectively (NS). Ondansetron significantly reduced the fatigue score with more than 30% improvement on day 15 (57.1 (38.9); p<0.01), day 30 (54.5 (37.6); p<0.01), and day 60 (60.8 (37.3); p<0.01) whereas placebo did not. Overall, the reduction in fatigue was significantly higher with ondansetron compared with placebo (ANOVA for repeated measurements) for the whole follow up period (p = 0.03) or for the treatment period only (p = 0.04). Ondansetron also significantly reduced depression scores.
Conclusions: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron had a significant positive effect on fatigue in CHC. These observations support the concept that fatigue involves serotoninergic pathways and may encourage further evaluations of the efficacy of ondansetron on fatigue in chronic liver diseases.
doi:10.1136/gut.2004.055251
PMCID: PMC1774898  PMID: 16009690
fatigue; chronic hepatitis C; ondansetron; randomised controlled trial
23.  Intrathecal injection of magnesium sulfate: shivering prevention during cesarean section: a randomized, double-blinded, controlled study 
Korean Journal of Anesthesiology  2013;65(4):293-298.
Background
Regional anesthesia is known to significantly impair thermoregulation and predispose patients to hypothermia. We hypothesized that the addition of an intrathecal injection of magnesium sulfate (MgSO4) to bupivacaine would improve perioperative shivering in female patients undergoing elective caesarean section.
Methods
In a block-randomized, double-blinded, controlled trial 72 patients scheduled for elective caesarean section with spinal anesthesia were separated into two groups. In the treatment group, 2 ml of 0.5% bupivacaine plus 25 mg MgSO4 (0.5 ml) were injected intrathecally, and in the control group 2 ml of 0.5% bupivacaine plus 0.5 ml normal saline were injected intrathecally. Core temperature was measured before and after drug injection at predetermined intervals. Sedation was graded using the Ramsay sedation scale.
Results
No significant intergroup differences in appearance of shivering were seen immediately or at 5, 30, 40, 50, 60, and 90 min after block administration. However, at 10, 15, and 20 min post block, there was a significant difference in shivering. The group administered MgSO4 showed lower shivering grades compared with the control group. Core temperature was significantly reduced in the MgSO4 group compared to the normal saline group 30 min after blocking.
Conclusions
Intrathecal injection of MgSO4 improved perioperative shivering in female patients undergoing elective caesarean section.
doi:10.4097/kjae.2013.65.4.293
PMCID: PMC3822019  PMID: 24228140
Bupivacaine; Cesarean section; Magnesium sulfate; Shivering
24.  Central Activation of the A1 Adenosine Receptor (A1AR) Induces a Hypothermic, Torpor-Like State in the Rat 
The Journal of Neuroscience  2013;33(36):14512-14525.
Since central activation of A1 adenosine receptors (A1ARs) plays an important role in the induction of the hypothermic and hypometabolic torpid state in hibernating mammals, we investigated the potential for the A1AR agonist N6-cyclohexyladenosine to induce a hypothermic, torpor-like state in the (nonhibernating) rat. Core and brown adipose tissue temperatures, EEG, heart rate, and arterial pressure were recorded in free-behaving rats, and c-fos expression in the brain was analyzed, following central administration of N6-cyclohexyladenosine. Additionally, we recorded the sympathetic nerve activity to brown adipose tissue; expiratory CO2 and skin, core, and brown adipose tissue temperatures; and shivering EMGs in anesthetized rats following central and localized, nucleus of the solitary tract, administration of N6-cyclohexyladenosine. In rats exposed to a cool (15°C) ambient temperature, central A1AR stimulation produced a torpor-like state similar to that in hibernating species and characterized by a marked fall in body temperature due to an inhibition of brown adipose tissue and shivering thermogenesis that is mediated by neurons in the nucleus of the solitary tract. During the induced hypothermia, EEG amplitude and heart rate were markedly reduced. Skipped heartbeats and transient bradycardias occurring during the hypothermia were vagally mediated since they were eliminated by systemic muscarinic receptor blockade. These findings demonstrate that a deeply hypothermic, torpor-like state can be pharmacologically induced in a nonhibernating mammal and that recovery of normothermic homeostasis ensues upon rewarming. These results support the potential for central activation of A1ARs to be used in the induction of a hypothermic, therapeutically beneficial state in humans.
doi:10.1523/JNEUROSCI.1980-13.2013
PMCID: PMC3761054  PMID: 24005302
25.  Intermittent hypothermia 
Three patients who had suffered episodes of spontaneous hypothermia are described. Circulatory control was normal for their age but there was evidence of a persistent defect of thermoregulatory mechanisms. In all patients vascular thermoregulatory reflexes dependent upon peripheral receptors were active and in two patients reflex shivering could be obtained. There appeared, however, to be a failure of central thermoregulation as the vascular reflexes were active at abnormally low central temperatures and a fall in central temperature did not initiate shivering. It is concluded that in patients who have suffered spontaneous hypothermia there may be a persistent defect of central mechanisms subserving vasomotion and shivering, although thermoregulatory reflexes dependent upon peripheral receptors can be active. The reflex pathways for thermoregulation in man therefore have a separate integrity, physiologically independent of the central thermoregulatory mechanisms.
PMCID: PMC494340  PMID: 4714103

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