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1.  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
2.  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
3.  Ondansetron Does Not Reduce the Shivering Threshold in Healthy Volunteers 
British journal of anaesthesia  2006;96(6):732-737.
Summary
Background
Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (trigging core temperatures) in humans.
Methods
Ten healthy volunteers were studied on two days: Control and Ondansetron (intravenous infusion to plasma concentrations of 278 (57) ng mL−1, 234 (55) ng mL−1, and 243 (58) ng mL−1at the sweating, vasoconstriction, and shivering thresholds, respectively); this corresponded to ≈50 mg of ondansetron which is roughly ten times the dose used for postoperative nausea and vomiting. Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction, and shivering thresholds after compensating for changes in mean-skin temperature. Data were analyzed with paired t tests and presented as means (SD)s; P<0.05 was statistically significant.
Results
Ondansetron did not change the sweating (Control: 37.4 (0.4)°C, Ondansetron: 37.6 (0.3)°C, P=0.16), vasoconstriction (37.0 (0.5) vs. 37.1 (0.3)°C; P=0.70), or shivering threshold (36.3 (0.5) vs. 36.3 (0.6)°C; P=0.76). No sedation was observed on either study day.
Conclusions
Ondansetron, therefore, appears to have little potential for facilitating induction of therapeutic hypothermia.
doi:10.1093/bja/ael101
PMCID: PMC1502385  PMID: 16675509
Thermoregulation; ondansetron; therapeutic hypothermia
4.  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
5.  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
6.  Surface cooling for induction of mild hypothermia in conscious healthy volunteers - a feasibility trial 
Critical Care  2011;15(5):R248.
Introduction
Animal and human studies suggest beneficial outcome effects of mild hypothermia for stroke, for acute myocardial infarction, and for cardiogenic shock. The aim of this study was to investigate the feasibility and safety of non-invasive surface cooling for induction and maintenance of mild hypothermia (32 to 34°C) in healthy, conscious volunteers.
Methods
The trial was set at a clinical research ward in a tertiary care center, and included 16 healthy male volunteers 18 to 70 years old. Surface cooling was established by a novel non-invasive cooling pad with an esophageal target temperature of 32 to 34°C and maintenance for six hours. Shivering-control was achieved with meperidine and buspirone and additional administration of magnesium in eight subjects.
Results
The primary endpoint to reach a target temperature of 32 to 34°C was only reached in 6 of the 16 participating subjects. Temperatures below 35°C were reached after a median cooling time of 53 minutes (38 to 102 minutes). Cooling rate was 1.1°C/h (0.7 to 1.8°C). Additional administration of magnesium had no influence on cooling rate. At no time during the cooling procedure did the participants report uncomfortable conditions for which termination of cooling had to be considered. No severe skin damage was reported.
Conclusions
Cooling to body temperature below 35°C by the use of non-invasive surface cooling is feasible and safe in conscious healthy volunteers. Further studies are needed to investigate an altered cooling protocol to achieve temperatures below 35°C.
Trial Registration
ISRCTN: ISRCTN50530495
doi:10.1186/cc10506
PMCID: PMC3334799  PMID: 22018242
human experimentation; hypothermia; magnesium; myocardial infarction; safety; stroke; temperature
7.  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
8.  Determinants of Pneumonia Risk During Endovascular Hypothermia 
Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. Previously, we demonstrated the feasibility of thrombolysis combined with endovascular hypothermia and an antishivering regimen, but pneumonia occurred more often in cooled patients. We sought to identify whether any factors could be identified that increased pneumonia risk. We examined 26 patients who underwent endovascular hypothermia. Pneumonia was assessed and scored as present by the treating physician without prespecified definitions or surveillance protocols. Using logistic regression, we examined the risk of pneumonia; the effects of age, weight, body mass index (BMI), body surface area, respiration rate, heart rate, blood pressure, baseline National Institutes of Health Stroke Scale (NIHSS), gender, shivering, and area under the curve below 34°C; and total meperidine dose, individually and in a multivariable model. Pneumonia was reported by site investigators in 13 subjects (50%). In univariate analyses, BMI and baseline NIHSS emerged as the baseline variables that were independently associated with risk of pneumonia. Multivariable logistic regression analysis identified baseline NIHSS as marginally associated with risk of pneumonia, after adjustment for BMI (OR: 1.19, 95% CI: 0.98, 1.43; p=0.0740). In a group of hypothermia patients suffering a 50% reported incidence of pneumonia, we found no variables that explained risk other than baseline NIHSS. Future trials should include rigorous definitions of pneumonia and prespecified surveillance methods to minimize case ascertainment bias. Measures to prevent pneumonia are needed in all patients treated with hypothermia.
doi:10.1089/ther.2012.0021
PMCID: PMC3604784  PMID: 23667781
9.  Effect of ramosetron on shivering during spinal anesthesia 
Korean Journal of Anesthesiology  2010;58(3):256-259.
Background
Shivering associated with spinal anesthesia is uncomfortable and may interfere with monitoring. The aim of this study is to evaluate the effect of ramosetron, a serotonin-3 receptor antagonist, on the prevention of shivering during spinal anesthesia.
Methods
We enrolled 52 patients who were ASA I or II and who had undergone knee arthroscopy under spinal anesthesia. Warmed (37°) lactated Ringer's solution was infused over 15 minutes before spinal anesthesia. Patients were randomly allocated to a control group (group S, N = 26) or study group (group R, N = 26). Spinal anesthesia was performed with a 25-G Quincke-type spinal needle between the lumbar 3-4 interspace with 2.2 ml 0.5% hyperbaric bupivacaine. For patients allocated in groups S and R, 2 ml 0.9% saline and 0.3 mg ramosetron, respectively, was intravenously injected immediately before intrathecal injection at identical times. Shivering and spinal block levels were assessed immediately after the completion of subarachnoid injection, as well as 5, 10, 15, 20, 25, 30, 60, and 120 minutes after spinal anesthesia. Systolic and diastolic blood pressures, heart rate, and peripheral oxygen saturation were also recorded. Core temperatures were measured by tympanic thermometer and recorded before and during spinal anesthesia at 30-minute intervals.
Results
Shivering was observed in 2 patients in group R and 9 patients in group S (P = 0.038, odds ratio = 6.14, 95% C.I. = 1.08-65.5). The difference in core temperature between the groups was not significant.
Conclusions
Compared to control, ramosetron is an effective way to prevent shivering during spinal anesthesia.
doi:10.4097/kjae.2010.58.3.256
PMCID: PMC2872836  PMID: 20498774
Ramosetron; Shivering; Spinal anesthesia; Thermoregulation
10.  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
11.  Effects of preoperative magnesium therapy on arrhythmias and myocardial ischemia during off-pump coronary surgery 
Annals of Thoracic Medicine  2009;4(3):137-139.
BACKGROUND:
Heart manipulation during off-pump coronary artery bypass surgery may cause hemodynamic instability, and temporary coronary arterial occlusion may lead to myocardial ischemia. To reduce this, perioperative β-blocking agents or calcium antagonists can be administrated. The effects of perioperative administration of magnesium on myocardial function were studied in patients undergoing coronary artery bypass grafting.
OBJECTIVE:
The aim of the study was to evaluate the effects of preoperative magnesium administration on perioperative hemodynamia, ventricular arrhythmias and myocardial protection.
MATERIALS AND METHODS:
We reviewed 2 groups of patients undergoing off-pump coronary artery bypass surgery – 24 patients (control group) that had not received preoperative intravenous infusion of magnesium and 23 patients (treatment group) that had received preoperative intravenous magnesium sulfate.
RESULTS:
The results demonstrated that it had reduced the heart rate, changes of ST segments, the need of β-blocking agents and the use of intra-operative intra-aortic balloon pump and the inotropic usage.
CONCLUSION:
This treatment may provide hemodynamic optimization during off-pump coronary artery bypass.
doi:10.4103/1817-1737.53355
PMCID: PMC2714568  PMID: 19641645
Ischemia and arrhythmia; magnesium effects; off-pump coronary surgery
12.  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
13.  Overview of Therapeutic Hypothermia 
Therapeutic Hypothermia has proven neuroprotective effects in global cerebral ischemia. Indications for hypothermia induction include cardiac arrest and neonatal asphyxia. The two general methods of induced hypothermia are either surface cooling or endovascular cooling. Hypothermia should be induced as early as possible to achieve maximum neuroprotection and edema blocking effect. Endovascular cooling has the benefit of shorter time to reach target temperature but catheter insertion requires expertise and training, which may be a barrier to widespread availability. The optimum method of cooling is yet to be determined but a multimodal approach is necessary to address three phases of cooling: induction, maintentance, and re-warm. Specifying core practitioners who are well-versed in established guidelines can help integrate the multidisciplinary team that is needed to successfully implement cooling protocols. Reducing shivering to make heat exchange more efficient with tighter temperature control enables quicker time to target temperature and avoids re-warming which can lead to inadvertent increase in intracranial pressure and cerebral edema. Promising applications but yet to be determined is whether hypothermia treatment can improve outcomes in acute ischemic stroke or traumatic brain injury.
doi:10.1007/s11940-012-0201-x
PMCID: PMC3519955  PMID: 23007950
Hypothermia; Therapeutic hypothermia; Cardiac arrest; Cerebral ischemia; Surface cooling; Endovascular cooling; Shivering; Neuroprotection; Treatment
14.  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
15.  Combined Neuroprotective Modalities Coupled with Thrombolysis in Acute Ischemic Stroke: A Pilot Study of Caffeinol and Mild Hypothermia 
Background
Both caffeinol and hypothermia are neuroprotective in preclinical models of transient middle cerebral artery occlusion. We tested whether combining caffeinol and hypothermia with t-PA in acute stroke patients is safe and feasible.
Methods
20 patients with acute ischemic stroke were treated with caffeinol (caffeine 8-9 mg/kg + ethanol 0.4g/kg IV X 2 hours, started by 4 hrs after symptom onset) and hypothermia (started by 5 hrs and continued for 24 hrs (target temp 33-35°C) followed by 12 hrs of rewarming). IV t-PA was given to eligible patients. Meperidine and buspirone were used to suppress shivering.
Results
All patients received caffeinol, and most reached target blood levels. Cooling was attempted in 18 patients via endovascular (n=8) or surface (n=10) approaches. Two patients were not cooled due to catheter or machine failure. Thirteen patients reached target temperature; average time from symptom onset was 9hrs, 43min. The last 5 hypothermia patients received surface cooling with iced saline induction and larger doses of meperidine; all patients reached target temperature, on average within 2hrs 30min from induction and 6hrs 21min from symptom onset. Three patients died: one from symptomatic hemorrhage, one from malignant cerebral edema, and one from unrelated medical complications. No adverse events were attributed to caffeinol. One patient had reduced respiratory drive due to meperidine, requiring BiPAP.
Discussion
Combining caffeinol with hypothermia in acute stroke patients given IV t-PA is feasible. A prospective placebo-controlled randomized study is needed to further assess safety and to test the efficacy of caffeinol, hypothermia or both.
doi:10.1016/j.jstrokecerebrovasdis.2008.09.015
PMCID: PMC2673088  PMID: 19251183
16.  Magnesium Sulfate as a Second-Line Tocolytic Agent for Preterm Labor: A Randomized Controlled Trial in Kyushu Island 
Journal of Pregnancy  2011;2011:965060.
Objectives. We evaluated the efficacy of magnesium sulfate as a second-line tocolysis for 48 hours. Materials and Methods. A multi-institutional, simple 2-arm randomized controlled trial was performed. Forty-five women at 22 to 34 weeks of gestation were eligible, whose ritodrine did not sufficiently inhibit uterine contractions. After excluding 12 women, 33 were randomly assigned to either magnesium alone or combination (ritodrine and magnesium). The treatment was determined as effective if the frequency of uterine contraction was reduced by 30% at 48 hours of the treatment. Results. After magnesium sulfate infusion, 90% prolonged their pregnancy for >48 hours. Combination therapy was effective in 95% (18/19), which was significantly higher than 50% (7/14) for magnesium alone. Conclusion. This randomized trial revealed that combination therapy significantly reduced uterine contractions, suggesting that adjuvant magnesium with ritodrine is recommended, rather than changing into magnesium alone, when uterine contractions are intractable with ritodrine infusion.
doi:10.1155/2011/965060
PMCID: PMC3135123  PMID: 21773032
17.  Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? 
Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.
doi:10.1038/jcbfm.2010.44
PMCID: PMC2949207  PMID: 20354545
acute stroke; animal models; clinical trials; hypothermia; shivering MR spectroscopy
18.  Role of magnesium sulfate in neuroprotection in acute ischemic stroke 
Aims:
To study the effect of intravenous magnesium sulfate infusion on clinical outcome of patients of acute stroke.
Materials and Methods:
Sixty consecutive cases of acute ischemic stroke hospitalised within 24 h of an episode of stroke were taken as subjects. All subjects underwent a computed tomography head, and those found to have evidence of bleed/space-occupying lesions were excluded from the study. The subjects taken up for the study were divided into two groups of 30 subjects each. Both the groups received the standard protocol management for acute ischemic stroke. Subjects of Group 1 additionally received intravenous magnesium sulfate as initial 4 g bolus dose over 15 min followed by 16 g as slow infusion over the next 24 h. In all the subjects of the two study groups, serum magnesium levels were estimated at the time of admission (Day 0), Day 1 and Day 2 of hospitalization using an atomic absorption spectrometer.
Statistical Analysis Used:
Scandinavian stroke scores were calculated on Day 3, day of discharge and Day 28. Paired t-test was employed for comparison of stroke scores on Day 3, day of discharge and Day 28 within the same group and the unpaired t-test was used for the intergroup comparison, i.e. comparison of stroke scores of control group with corresponding stroke scores of magnesium group.
Results:
Comparison of stroke scores on Day 3 and day of discharge, on the day of discharge and Day 28 and on Day 3 and Day 28 in the magnesium group produced a t-value of 5.000 and P <0.001, which was highly significant. However, the comparison of the mean stroke scores between the magnesium and the control groups on Day 3, day of discharge and Day 28 yielded a P-value of >0.05, which was not significant.
Conclusions:
The study failed to document a statistical significant stroke recovery in spite of achieving a significant rise in serum magnesium level, more than that necessary for neuroprotection, with an intravenous magnesium sulfate regime.
doi:10.4103/0972-2327.99705
PMCID: PMC3424793  PMID: 22919188
Ischemic stroke; magnesium sulfate; neuroprotection
19.  Thermoregulation: Physiological and Clinical Considerations during Sedation and General Anesthesia 
Anesthesia Progress  2010;57(1):25-33.
Abstract
Mild hypothermia is common during deep sedation or general anesthesia and is frequently associated with patient discomfort and shivering. Greater declines in temperature can produce an even greater number of significant detrimental effects. This article reviews principles of thermoregulation and influences of anesthetic agents. An understanding of these will provide a foundation for strategies to reduce heat loss and better manage patient discomfort when it occurs.
doi:10.2344/0003-3006-57.1.25
PMCID: PMC2844235  PMID: 20331336
Sedation; General anesthesia; Thermoregulation; Hypothermia; Shivering
20.  The effects of magnesium on the course of atrial fibrillation and coagulation in patients with atrial fibrillation undergoing mitral valve annuloplasty 
Korean Journal of Anesthesiology  2011;61(3):210-215.
Background
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Magnesium has been reported to be effective in reducing the incidence or prophylaxis of AF. Magnesium is also an essential constituent of many enzyme systems and plays a physiological role in coagulation regulation. The aim of the present study was to examine the effects of magnesium, whether magnesium infusion might decrease the incidence of AF and induce hypocoagulable state in patients with AF, who were undergoing mitral valve annuloplasty.
Methods
This prospective laboratory study was performed using blood from patients with AF undergoing mitral valve annuloplasty. The radial artery was punctured with a 20 gauge catheter and used for monitoring continuous arterial pressure and blood sampling. After anesthesia induction, 4 g of magnesium was mixed with 100 ml normal saline and infused for 5 minutes. Magnesium, calcium, activated clotting time (ACT) and thromboelastographic parameters were checked before and 60 minutes after the magnesium infusion. The electrocardiography changes after magnesium infusion were also checked before commencing cardiopulmonary bypass.
Results
After magnesium infusion, the serum level of magnesium increased significantly but serum calcium did not change significantly. ACT did not change significantly before or after magnesium infusion. The thromboelastographic parameters showed no significant changes before or after magnesium infusion. None of the patients converted to sinus rhythm from AF after the magnesium infusion.
Conclusions
A magnesium infusion did not influence the course of AF and coagulation in patients during prebypass period with AF undergoing mitral valve annuloplasty.
doi:10.4097/kjae.2011.61.3.210
PMCID: PMC3198181  PMID: 22025942
Atrial fibrillation; Magnesium; Mitral valve annuloplasty; Thromboelastography
21.  Role of magnesium sulfate in aneurysmal subarachnoid hemorrhage management: A meta-analysis of controlled clinical trials 
Asian Journal of Neurosurgery  2011;6(1):26-31.
Background:
There has been longstanding controversy over the use of magnesium sulfate infusion in the medical management of aneurysmal subarachnoid hemorrhage (SAH). Several clinical trials evaluating the beneficial effects of magnesium on cerebral vasospasm and their poor outcome have been published. However, results from the majority of these studies have been inconclusive. This meta-analysis was performed to evaluate the effectiveness of magnesium on patient outcomes after aneurysmal SAH.
Materials and Methods:
PubMed and the Cochrane library were searched for controlled clinical trials assessing the efficacy of magnesium sulfate infusion after aneurysmal SAH. Eight studies consisting of 936 patients were included.
Results:
There was a decreased risk of poor outcome at 3–6 months after SAH in magnesium treatment groups when compared to placebo [0.78 (95% CI 0.66–0.93)]. Poor outcome was defined as severe disability, persistent vegetative state, or death, as measured by the Glasgow outcome scale (GOS), extended Glasgow outcome scale (GOSE) or modified Rankin scale (mRS). The risk of mortality after SAH was unaffected by magnesium treatment [RR 0.68 (95% CI 0.58–1.27)].
Conclusion:
Magnesium sulfate infusion decreases risk of poor outcome after aneurysmal SAH. Current studies in the literature do not suggest a role for magnesium sulfate in mortality reduction after SAH.
doi:10.4103/1793-5482.85632
PMCID: PMC3205548  PMID: 22059101
Cerebral vasospasm; delayed cerebral ischemia; magnesium sulfate; subarachnoid hemorrhage
22.  AMP-dependent hypothermia affords protection from ischemic brain injury 
In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.
doi:10.1038/jcbfm.2012.181
PMCID: PMC3564206  PMID: 23211965
A1R; AMP; hypothalamus; hypothermia; stroke
23.  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
24.  Synergistic effect of intrathecal fentanyl and bupivacaine in spinal anesthesia for cesarean section 
BMC Anesthesiology  2005;5:5.
Background
Potentiating the effect of intrathecal local anesthetics by addition of intrathecal opiods for intra-abdominal surgeries is known. In this study by addition of fentanyl we tried to minimize the dose of bupivacaine, thereby reducing the side effects caused by higher doses of intrathecal bupivacaine in cesarean section.
Methods
Study was performed on 120 cesarean section parturients divided into six groups, identified as B8, B10 and B 12.5 8.10 and 12.5 mg of bupivacaine mg and FB8, FB10 and FB 12.5 received a combination of 12.5 μg intrathecal fentanyl respectively. The parameters taken into consideration were visceral pain, hemodynamic stability, intraoperative sedation, intraoperative and postoperative shivering, and postoperative pain.
Results
Onset of sensory block to T6 occurred faster with increasing bupivacaine doses in bupivacaine only groups and bupivacaine -fentanyl combination groups. Alone lower concentrations of bupivacaine could not complete removed the visceral pain. Blood pressure declined with the increasing concentration of Bupivacaine and Fentanyl. Incidence of nausea and shivering reduces significantly whereas, the postoperative pain relief and hemodynamics increased by adding fentanyl. Pruritis, maternal respiratory depression and changes in Apgar score of babies do not occur with fentanyl.
Conclusion
Spinal anesthesia among the neuraxial blocks in obstetric patients needs strict dose calculations because minimal dose changes, complications and side effects arise, providing impetus for this study. Here the synergistic, potentiating effect of fentanyl (an opiod) on bupivacaine (a local anesthetic) in spinal anesthesia for cesarian section is presented, fentanyl is able to reduce the dose of bupivacaine and therefore its harmful effects.
doi:10.1186/1471-2253-5-5
PMCID: PMC1159169  PMID: 15904498
25.  Physiology and Pharmacology of Hypothermia 
Western Journal of Medicine  1983;138(2):227-232.
Homoiothermic organisms react to hypothermia by shivering and thermogenesis to retain their euthermic state. This reactive homeostatic mechanism recruits a strong sympathetic response, which must be suppressed by anesthesia and adjuvants during induced hypothermia. Below 30° C there is significant neural and organ depression associated with cold narcosis. Cardiac arrhythmias and ventricular fibrillation are grave developments when the core temperature is below 28° C. Proper cardiopulmonary support must be instituted in a patient who has induced or accidental hypothermia at these severely hypothermic levels.
Although clinical hypothermia is used to protect the brain and the heart from ischemic insults during an operation, it induces a complex array of physiologic changes in the body that must be appreciated so that optimal care may be provided to a patient.
Images
PMCID: PMC1010688  PMID: 6837026

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