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Concept: Hypothermia


The head warming in hypothermic victims is an alternative way of heat donation, which does not inhibit shivering and does not impede the access to the patient’s chest. It seems to be a safe method in mild hypothermia. The authors of the review article “Accidental hypothermia - an update” suggest this way of heat donation, without indicating precisely, in which group of patients it can be applied. In severe hypothermia, the brain-protective effect of cold is well known. The decreased need of oxygen allows good neurological outcome after long lasting cardiac arrest. Therefore, in deep hypothermia, the brain tissue should be rather insulated from the heat source than warmed.

Concepts: Brain, Hypoglycemia, Asystole, Hypothermia, Therapeutic hypothermia, Heat transfer, Drowning, Shivering


Background Delayed graft function, which is reported in up to 50% of kidney-transplant recipients, is associated with increased costs and diminished long-term graft function. The effect that targeted mild hypothermia in organ donors before organ recovery has on the rate of delayed graft function is unclear. Methods We enrolled organ donors (after declaration of death according to neurologic criteria) from two large donation service areas and randomly assigned them to one of two targeted temperature ranges: 34 to 35°C (hypothermia) or 36.5 to 37.5°C (normothermia). Temperature protocols, which were initiated after authorization was obtained for the organ to be donated and for the donor’s participation in the study, ended when organ donors left the intensive care unit for organ recovery in the operating room. The primary outcome was delayed graft function in the kidney recipients, which was defined as the requirement for dialysis during the first week after transplantation. Secondary outcomes were the rates of individual organs transplanted in each treatment group and the total number of organs transplanted from each donor. Results The study was terminated early, on the recommendation of an independent data and safety monitoring board, after the interim analysis showed efficacy of hypothermia. At trial termination, 370 organ donors had been enrolled (180 in the hypothermia group and 190 in the normothermia group). A total of 572 patients received a kidney transplant (285 kidneys from donors in the hypothermia group and 287 kidneys from donors in the normothermia group). Delayed graft function developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02). Conclusions Mild hypothermia, as compared with normothermia, in organ donors after declaration of death according to neurologic criteria significantly reduced the rate of delayed graft function among recipients. (Funded by the Health Resources and Services Administration; number, NCT01680744 .).

Concepts: Chronic kidney disease, Kidney, Nephrology, Organ, Hypothermia, Organ transplant, Kidney transplantation, Organ donation


BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therpeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of lidocaine in newborns with perinatal asphyxia during moderate hypothermia, and to develop an effective and safe dosing regimen. METHODS: Hypothermic newborns with perinatal asphyxia and lidocaine for seizure control were included. Efficacy was studied using continuous amplitude-integrated electroencephalography. Safety was assessed using continuous cardiac monitoring. An optimal dosing regimen was developed with simulations using data from a pharmacokinetic model. Plasma samples were collected during hypothermia on consecutive mornings. RESULTS: A total of 22 hypothermic and 26 historical normothermic asphyxiated newborns with lidocaine were included. A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed for lidocaine add-on therapy. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. None of the newborns experienced cardiac arrythmias. Hypothermia reduced lidocaine clearance by 24% compared with normothermia. A novel dosing regimen was developed an initial bolus loading dose of 2 mg/kg, for patients with body weight 2.0-2.5 kg followed by consecutive continuous infusions of 6 mg/kg/h (for 3.5 h), 3 mg/kg/h (for 12 h), 1.5 mg/kg/h (for 12 h), or for patients with bodyweights 2.5-4.5 kg 7 mg/kg/h (for 3.5 h), 3.5 mg/kg/h (for 12 h), 1.75 mg/kg/h (for 12 h), before stopping. CONCLUSIONS: Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia in asphyxiated neonates.

Concepts: Infant, Hypothermia, Epilepsy, Anticonvulsant, Seizure, Status epilepticus, Diazepam, Asphyxia


To determine the accuracy of axillary temperature relative to core rectal temperature during whole-body therapeutic hypothermia for moderate-to-severe hypoxic-ischaemic encephalopathy.

Concepts: Hypothermia, Rectum, Cryobiology


Clinical symptoms of acute 3,4-methylenedioxymethamphetamine (MDMA) intoxication and malignant hyperthermia have many similarities. At present, however, there is contradictory evidence concerning the malignant hyperthermia trigger potency of MDMA.

Concepts: Medical terms, Symptom, Hypothermia, Hyperthermia, Malignant hyperthermia, Serotonin syndrome


Background. There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting. Case report. A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient’s AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10-37 U/L) and 104 IU/L (ref 12-78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2). Discussion. Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed. Conclusions. Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.

Concepts: Asthma, Patient, Liver, Hypothermia, Toxicology, Paracetamol, Paracetamol toxicity, Hepatotoxicity


Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

Concepts: Infant, Metabolism, Physiology, Nuclear magnetic resonance, Hypothermia, Cerebral cortex, Therapeutic hypothermia, Neuroprotection


BACKGROUND: Induction of mild therapeutic hypothermia (TH; temperature 32-34°C) has become standard of care in many hospitals for comatose survivors of cardiac arrest. Pyrexia, or fever, is known to be detrimental in patients with neurologic injuries such as stroke or trauma. The incidence of pyrexia in the postrewarming phase of TH is unknown. We attempted to determine the incidence of fever after TH and hypothesized that those patients who were febrile after rewarming would have worse clinical outcomes than those who maintained normothermia in the postrewarming period. METHODS: Retrospective data analysis of survivors of out-of-hospital cardiac arrest (OHCA) over a period of 29 months (December 2007 to April 2010). Inclusion criteria: OHCA, age >18, return of spontaneous circulation, and treatment with TH. Exclusion criteria: traumatic arrest and pregnancy. Data collected included age, sex, neurologic outcome, mortality, and whether the patient developed fever (temperature > 100.4°F, 38°C) within 24 hours after being fully rewarmed to a normal core body temperature after TH. We used simple descriptive statistics and Fisher exact test to report our findings. RESULTS: A total of 149 patients were identified; of these, 82 (55%) underwent TH. The mean age of the TH cohort was 66 years, and 28 (31%) were female. In all, 54 patients survived for >24 hours after rewarming and were included in the analysis. Among the analyzed cohort, 28 (52%) of 54 developed fever within 24 hours after being rewarmed. Outcome measures included in-hospital mortality as well as neurologic outcome as defined by a dichotomized Cerebral Performance Category (CPC) score. When comparing neurologic outcomes between the groups, 16 (57%) of 28 in the postrewarming fever group had a poor outcome (CPC score 3-5), while 15 (58%) of 26 in the no-fever group had a favorable outcome (P = .62). In the fever group, 15 (52%) of 28 died, while in the no-fever group, 14 (54%) of 26 died (P = .62). CONCLUSION: Among a cohort of patients who underwent mild TH after OHCA, more than half of these patients developed pyrexia in the first 24 hours after rewarming. Although there were no significant differences in outcomes between febrile and nonfebrile patients identified in this study, these findings should be further evaluated in a larger cohort. Future investigations may be needed to determine whether postrewarming temperature management will improve the outcomes in this population.

Concepts: Hypothalamus, Hospital, Cardiac arrest, Thermoregulation, Hypothermia, Hyperthermia, Fever, Shivering


: To identify whether therapeutic hypothermia in newborns with hypoxic ischemic encephalopathy affects gentamicin pharmacokinetics.

Concepts: Infant, Hypothermia, Neurology, Hypoxia, Cerebral hypoxia, Hypothermia therapy for neonatal encephalopathy


Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Ono et al., 2008) and influenza patients. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-preadministered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms.

Concepts: Hypothermia, Influenza, Acetylcholine, Nicotinic acetylcholine receptor, Oseltamivir, Neuraminidase, Viral neuraminidase, Mecamylamine