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Concept: Hyperthermia


BACKGROUND: Hypohydration and hyperthermia are factors that may contribute to fatigue and impairment of endurance performance. The purpose of this study was to investigate the effectiveness of combining glycerol hyperhydration and an established precooling technique on cycling time trial performance in hot environmental conditions. METHODS: Twelve well-trained male cyclists performed three 46.4-km laboratory-based cycling trials that included two climbs, under hot and humid environmental conditions (33.3 +/- 1.1[degree sign]C; 50 +/- 6% r.h.). Subjects were required to hyperhydrate with 25 body mass (BM) of a 4[degree sign]C beverage containing 6% carbohydrate (CON) 2.5 h prior to the time trial. On two occasions, subjects were also exposed to an established precooling technique (PC) 60 min prior to the time trial, involving 14 BM ice slurry ingestion and applied iced towels over 30 min. During one PC trial, 1.2 BM glycerol was added to the hyperhydration beverage in a double-blind fashion (PC+G). Statistics used in this study involve the combination of traditional probability statistics and a magnitude-based inference approach. RESULTS: Hyperhydration resulted in large reductions (-0.6 to -0.7[degree sign]C) in rectal temperature. The addition of glycerol to this solution also lowered urine output (330 ml, 10%). Precooling induced further small (-0.3[degree sign]C) to moderate (-0.4[degree sign]C) reductions in rectal temperature with PC and PC+G treatments, respectively, when compared with CON (0.0[degree sign]C, P<0.05). Overall, PC+G failed to achieve a clear change in cycling performance over CON, but PC showed a possible 2% (30 s, P=0.02) improvement in performance time on climb 2 compared to CON. This improvement was attributed to subjects' lower perception of effort reported over the first 10 km of the trial, despite no clear performance change during this time. No differences were detected in any other physiological measurements throughout the time trial. CONCLUSIONS: Despite increasing fluid intake and reducing core temperature, performance and thermoregulatory benefits of a hyperhydration strategy with and without the addition of glycerol, plus practical precooling, were not superior to hyperhydration alone. Further research is warranted to further refine preparation strategies for athletes competing in thermally stressful events to optimize health and maximize performance outcomes.

Concepts: Physiology, Thermoregulation, Temperature, Hyperthermia, Humidity, The Trial, Normal human body temperature, Individual time trial


BACKGROUND: Healthcare claims databases have been used in several studies to characterize the risk and burden of chemotherapy-induced febrile neutropenia (FN) and effectiveness of colony-stimulating factors against FN. The accuracy of methods previously used to identify FN in such databases has not been formally evaluated. METHODS: Data comprised linked electronic medical records from Geisinger Health System and healthcare claims data from Geisinger Health Plan. Subjects were classified into subgroups based on whether or not they were hospitalized for FN per the presumptive “gold standard” (ANC <1.0x109/L, and body temperature >=38.30C or receipt of antibiotics) and claims-based definition (diagnosis codes for neutropenia, fever, and/or infection). Accuracy was evaluated principally based on positive predictive value (PPV) and sensitivity. RESULTS: Among 357 study subjects, 82 (23%) met the gold standard for hospitalized FN. For the claims-based definition including diagnosis codes for neutropenia plus fever in any position (n=28), PPV was 100% and sensitivity was 34% (95% CI: 24–45). For the definition including neutropenia in the primary position (n=54), PPV was 87% (78–95) and sensitivity was 57% (46–68). For the definition including neutropenia in any position (n=71), PPV was 77% (68–87) and sensitivity was 67% (56–77). CONCLUSIONS: Patients hospitalized for chemotherapy-induced FN can be identified in healthcare claims databases–with an acceptable level of mis-classification–using diagnosis codes for neutropenia, or neutropenia plus fever.

Concepts: Medicine, Health insurance, Positive predictive value, Negative predictive value, Thermoregulation, Hyperthermia, Fever, Febrile neutropenia


In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and, hence, understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 μg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5,000 μg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold-seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever-hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis, and the other, previously unknown, that drives inflammation-associated cold seeking.SIGNIFICANCE STATEMENTCold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold-induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH – a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders.

Concepts: Inflammation, Hypothalamus, Lipopolysaccharide, Thermoregulation, Hyperthermia, Fever, Endotoxin, Shivering


Whether fishes are sentient beings remains an unresolved and controversial question. Among characteristics thought to reflect a low level of sentience in fishes is an inability to show stress-induced hyperthermia (SIH), a transient rise in body temperature shown in response to a variety of stressors. This is a real fever response, so is often referred to as ‘emotional fever’. It has been suggested that the capacity for emotional fever evolved only in amniotes (mammals, birds and reptiles), in association with the evolution of consciousness in these groups. According to this view, lack of emotional fever in fishes reflects a lack of consciousness. We report here on a study in which six zebrafish groups with access to a temperature gradient were either left as undisturbed controls or subjected to a short period of confinement. The results were striking: compared to controls, stressed zebrafish spent significantly more time at higher temperatures, achieving an estimated rise in body temperature of about 2-4°C. Thus, zebrafish clearly have the capacity to show emotional fever. While the link between emotion and consciousness is still debated, this finding removes a key argument for lack of consciousness in fishes.

Concepts: Fish, Thermoregulation, Temperature, Hyperthermia, Bird, Mind, Fever, Buddhism


There are numerous causes of a raised core temperature. A fever occurring in sepsis may be associated with a survival benefit. However, this is not the case for non-infective triggers. Where heat generation exceeds heat loss and the core temperature rises above that set by the hypothalamus, a combination of cellular, local, organ-specific, and systemic effects occurs and puts the individual at risk of both short-term and long-term dysfunction which, if severe or sustained, may lead to death. This narrative review is part of a series that will outline the pathophysiology of pyrogenic and non-pyrogenic fever, concentrating primarily on the pathophysiology of non-septic causes.

Concepts: Inflammation, Hypothalamus, Thermoregulation, Temperature, Hyperthermia, Fever, Sepsis, The Core


PURPOSETo provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. METHODSA literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus.ResultsForty-seven articles from 43 studies met selection criteria.RecommendationsAntibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μ L for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott’s rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.

Concepts: Infectious disease, Medical terms, Infection, Risk, Chemotherapy, Thermoregulation, Hyperthermia, Neutropenia


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


Purpose The etiology, pathophysiology, clinical presentation, and management of drug-induced hyperthermia (DIH) syndromes are reviewed. Summary DIH syndromes are a rare and often overlooked cause of body temperature elevation and can be fatal if not recognized promptly and managed appropriately. There are five major DIH syndromes: (1) neuroleptic malignant syndrome, (2) serotonin syndrome, (3) anticholinergic poisoning, (4) sympathomimetic poisoning, and (5) malignant hyperthermia. The differential diagnosis of DIH syndromes can be challenging because symptoms are generally nonspecific, ranging from blood pressure changes and excessive sweating to altered mental status, muscle rigidity, convulsions, and metabolic acidosis. Evidence from the professional literature (per a MEDLINE search for articles published through November 2011) indicates that few currently available treatment options can reduce the duration of hyperthermia; therefore, prompt identification of the provoking agent based on the patient’s medication history, the clinical presentation, and the timing of symptom onset is essential to determine the appropriate treatment and mitigate potentially life-threatening sequelae. For all DIH syndromes, appropriate management includes the immediate discontinuation of the suspected offending agent(s) and supportive care (external cooling, volume resuscitation as needed); in some cases, pharmacologic therapy (e.g., a benzodiazepine, bromocriptine, dantrolene) may be appropriate, with the selection of a specific agent primarily determined by the medication history and suspected DIH syndrome. Conclusion DIH is a hypermetabolic state caused by medications and other agents that alter neurotransmitter levels. The treatment of DIH syndromes includes supportive care and pharmacotherapy as appropriate. Am J Health-Syst Pharm. 2013; 70:3442.

Concepts: Pharmacology, Medical terms, The Canon of Medicine, Hyperthermia, Medical diagnosis, Syndromes, Pharmaceutical drug, Neuroleptic malignant syndrome


Antithrombotic therapy with oral aspirin or clopidogrel (Plavix®) is associated with an attenuated skin vasodilator response and a greater rate of rise in core temperature in healthy, middle-aged individuals during passive heating in a water perfused suit. PURPOSE: The present double-blind, crossover study examined the functional consequences of 7 days of low-dose aspirin (ASA, 81 mg/day) vs.clopidogrel (CLO, 75 mg/day) treatment in 14 healthy, middle-aged (50-65 yrs) men and women during passive heating in air (40 min at 30°C, 40% rh) followed by exercise (60% O2peak). METHODS: Oral temperature (Tor) was measured in the antechamber (23.0 ± 0.1°C) before entering a warm environmental chamber. After 40 minutes of rest subjects cycled on a recumbent cycle ergometer for up to 120 minutes. Esophageal temperature (Tes) and laser Doppler flux were measured continuously, and the latter was normalized to maximal cutaneous vascular conductance (%CVCmax). RESULTS: Prior to entry into the environmental chamber there were no differences in Tor among treatments; however, after 40 minutes of rest in the heat, Tes was significantly higher for ASA and CLO vs. placebo (37.2±0.1°C, 37.3±0.1°C, vs. 37.0±0.1°C, both P<0.001), a difference that persisted throughout exercise (P<0.001 vs. placebo). The mean body temperature thresholds for the onset of cutaneous vasodilation were shifted to the right for both ASA and CLO during exercise (P<0.05). CONCLUSION: ASA and CLO resulted in elevated core temperatures during passive heat stress and shifted the onset of peripheral thermoeffector mechanisms toward higher body temperatures during exercise heat stress.

Concepts: Thermoregulation, Temperature, Hyperthermia, Thermodynamics, Heat, Entropy, Heat transfer, Normal human body temperature


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