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Hypothermia is a critical consequence of extreme cold exposure that increases the risk of cold-related injury and death in humans. While the initiation of cytoprotective mechanisms including the process of autophagy and the heat shock response (HSR) is crucial to cellular survival during periods of stress, age-related decrements in these systems may underlie cold-induced cellular vulnerability in older adults. Moreover, whether potential sex-related differences in autophagic regulation influence the human cold stress response remain unknown. We evaluated the effect of age and sex on mechanisms of cytoprotection (autophagy and the HSR) and cellular stress (apoptotic signaling and the acute inflammatory response) during ex vivo hypothermic cooling. Venous blood samples from 20 healthy young (10 females; mean [SD]: 22 [2] years) and 20 healthy older (10 females; 66 [5] years) adults were either isolated immediately (baseline) for peripheral blood mononuclear cells (PBMCs) or exposed to water bath temperatures maintained at 37, 35, 33, 31, or 4 °C for 90 min before PBMC isolation. Proteins associated with autophagy, apoptosis, the HSR, and inflammation were analyzed via Western blotting. Indicators of autophagic initiation and signaling (LC3, ULK1, and beclin-2) and the HSR (HSP90 and HSP70) increased when exposed to hypothermic temperatures in young and older adults (all p ≤ 0.007). Sex-related differences were only observed with autophagic initiation (ULK1; p = 0.015). However, despite increases in autophagic initiators ULK1 and beclin-2 (all p < 0.001), this was paralleled by autophagic dysfunction (increased p62) in all groups (all p < 0.001). Further, apoptotic (cleaved-caspase-3) and inflammatory (IL-6 and TNF-α) signaling increased in all groups (all p < 0.001). We demonstrated that exposure to hypothermic conditions is associated with autophagic dysfunction, irrespective of age or sex, although there may exist innate sex-related differences in cytoprotection in response to cold exposure as evidenced through altered autophagic initiation., Competing Interests: Declaration of Competing interest No conflict of interest, financial or otherwise, are declared by the author(s)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hypothermia on admission is associated with increased mortality in preterm infants. Drugs administered to pregnant women is implicated in its occurrence. Since magnesium sulfate has a myorelaxant effect, we aimed evaluating the association of hypermagnesemia at birth and admission hypothermia (axillary temperature <36.5°C) in preterm infants., Methods: We performed a secondary analysis of a prospective cohort study database including inborn infants <34 weeks, without congenital malformations. Hypermagnesemia was considered if the umbilical magnesium level > 2.5 mEq/L. Maternal and neonatal variables were used to adjust the model, submitted to the multivariate hierarchical modelling process., Results: We evaluated 249 newborns with median birth weight and gestational age of 1375 (IQR 1020-1375) g and 31 (IQR 28-32) weeks, respectively. Hypermagnesemia occurred in 28.5% and admission hypothermia occurred in 28.9%. In the univariate analysis, the following variables were identified as being associated with admission hypothermia: hypermagnesemia (OR 3.71; CI 2.06-6.68), resuscitation (OR 2.39; CI 1.37-4.19), small to gestational age (OR 1.91; CI1.03-3.53), general anesthesia (OR 3.34; CI 1.37-8.13), birth weight (OR 0.998; CI 0.998-0.999) and gestational age (OR 0.806; CI 0.725-0.895). In the hierarchical regression model, hypermagnesemia remained independent associated with admission hypothermia (OR 3.20; CI 1.66-6.15), as well as birth weight (OR 0.999; CI 0.998-0.999) and tracheal intubation (3.83; CI 1.88-7.80)., Conclusion: Hypermagnesemia was associated with an increased risk of admission hypothermia, as did tracheal intubation and lower birth weight.

Background: Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model., Methods: Wistar rats were exposed to an ambient temperature of -20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia., Results: There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology., Conclusions: rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH., Competing Interests: Declaration of competing interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2021 Elsevier Inc. All rights reserved.)

The aim of this study was to examine the central action of taurine on body temperature and food intake in neonatal chicks under control thermoneutral temperature (CT) and high ambient temperature (HT). Intracerebroventricular injection of taurine caused dose-dependent hypothermia and reduced food intake under CT. The mRNA expression of the GABA A receptors, GABA A R-α1 and GABA A R-γ, but not that of GABA B R, significantly decreased in the diencephalon after central injection of taurine. Subsequently, we found that picrotoxin, a GABA A R antagonist, attenuated taurine-induced hypothermia. Central taurine significantly decreased the brain concentrations of 3-methoxy-4-hydroxyphenylglycol, a major metabolite of norepinephrine; however, the concentrations of serotonin, dopamine, and the epinephrine metabolites, 3,4-hydroxyindoleacetic acid and homovanillic acid, were unchanged. Although hypothermia was not observed under HT after central injection of taurine, plasma glucose and uric acid levels were higher, and plasma sodium and calcium levels were lower, than those in chicks under CT. In conclusion, brain taurine may play a role in regulating body temperature and food intake in chicks through GABA A R. The changes in plasma metabolites under heat stress suggest that brain taurine may play an important role in maintaining homeostasis in chicks., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Hemorrhagic shock and encephalopathy syndrome (HSES) is the most severe form of acute encephalopathy that progresses rapidly, often resulting in death or severe neurological sequelae. We report the case of a 4-year-old girl with HSES with shock and impaired consciousness., Patient and Methods: Blood test results showed hypercytokinemia, and the 4-year-old patient was immediately admitted to the intensive care unit. Within 4 h of symptom onset, she received mild brain hypothermia therapy with a target body temperature of 35°C. Methylprednisolone pulse, high dose immunoglobulin, and large doses of circulatory drugs were administered., Results: After 72 h of brain hypothermia therapy, targeted temperature management with a target body temperature between 36°C and 37°C was continued for 96 h. The patient was diagnosed with HSES based on acute encephalopathy with shock, hypercytokinemia, low platelet count, coagulation disorder, renal damage, and intestinal bleeding. Magnetic resonance imaging results revealed no signs of any specific acute encephalopathy. She was discharged without neurological sequelae 28 days after symptom onset., Conclusions: Mild brain hypothermia therapy initiated in the early stages followed by targeted temperature management may be an effective way to improve neurological outcomes in children suffering from HSES.

Background: Adipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored., Objective: Our study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults., Design: Nineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity., Main Outcome Measures: Plasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA)., Results: Plasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P  = 0.03), and inversely correlated with MR sFF (coefficient, -404; P  = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects., Conclusion: Higher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults., Highlights: A higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity., (© Endocrine Society 2020.)

The mean population age of the United States continues to increase, and data suggest that by the year 2060 the population of people over the age of 65 will more than double, providing a potentially massive strain on health care systems. Research demonstrates individuals 65 and older continue to consume ethanol, often at high levels. However, preclinical animal models are still being developed to understand how ethanol might interact with the aged population. The current experiments investigated differential body temperature responses in aged rats compared to adult rats and adolescent rats. Aged (19 months of age), adult (70 days of age), or adolescent (30 days of age) male Sprague Dawley rats were administered 1.0 g/kg, 2.0 g/kg, or 3.0 g/kg ethanol, intraperitoneally (i.p.), in a balanced Latin square design. Prior to ethanol administration, a core body temperature via an anal probe was obtained, and then repeatedly determined every 60 min following ethanol exposure for a total of 360 min. In addition, a blood sample was obtained from a tail nick 60, 180, and 300 min following the ethanol injection to investigate the relationship of ethanol levels and body temperature in the same animals. Aged rats had significantly greater reductions in body temperature compared to either adult or adolescent rats following both the 2.0 g/kg and 3.0 g/kg ethanol injection. Additionally, adolescent rats cleared ethanol significantly faster than aged or adult animals. These experiments suggest body temperature regulation in aged rats might be more sensitive to acute ethanol compared to adult rats or adolescent rats. Future studies are needed to identify the neurobiological effects underlying the differential sensitivity in aged rats to ethanol., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Sepsis is the main cause of death in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)., Objectives: Our aim was to identify admission risk factors predictive of bacteremia and the accompanying clinical or biochemical markers associated with positive blood cultures., Methods: A retrospective cohort study over a 14-year period (2003-2016) was performed., Results: The study included 176 patients with SJS (n = 59), SJS-TEN overlap (n = 51), and TEN (n = 66). During hospitalization, bacteremia developed in 52 patients (29.5%), who experienced poorer outcomes, including higher intensive care unit admission (P < .0005), longer length of stay (P < .0005), and higher mortality (P < .0005). There were 112 episodes of bacteremia, and isolates included Acinetobacter baumannii (27.7%, n = 31) and Staphylococcus aureus (21.4%, n = 24). On multivariate analysis, clinical factors present at admission that were predictive of bacteremia included hemoglobin ≤10 g/dL (odds ratio [OR] 2.4, confidence interval [CI] 2.2-2.6), existing cardiovascular disease (OR 2.10, CI 2.0-2.3), and body surface area involvement ≥10% (OR 14.3, CI 13.4-15.2). The Bacteremia Risk Score was constructed with good calibration. Hypothermia (P = .03) and procalcitonin ≥1 μg/L (P = .02) concurrent with blood culture sampling were predictive of blood culture positivity., Limitations: This is a retrospective study performed in a reference center., Conclusion: Hemoglobin ≤10 g/dL, cardiovascular disease, and body surface area involvement ≥10% on admission were risk factors for bacteremia. Hypothermia and elevated procalcitonin are useful markers for the timely detection of bacteremia., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The identification of hypothermia as the cause of death remains challenging in forensic pathology because of unspecific radiological, morphological, and biochemical results. Hyperemia, edema, and petechial hemorrhages within the cerebral parenchyma were described in cases of death by hypothermia. On the other hand, the effect of low temperatures in the brain has been speculated to cause local injuries on a cellular level with potential occurrences of necrosis and inflammation. In the study herein described, endocan, alkaline phosphatase, neuron-specific enolase, S100 protein subunit B, glial fibrillary acidic protein, and C-reactive protein were measured in postmortem serum from femoral blood and cerebrospinal fluid in a series of hypothermia fatalities and control cases. The combination of data collected failed to identify a specific biochemical profile for death by hypothermia in postmortem serum and/or the cerebrospinal fluid, thus suggesting that an alternative panel of brain damage biomarkers indicative of diffuse hypoxic brain injury needs to be defined in hypothermia fatalities.

Postmortem diagnosis of extreme-weather-related deaths is a challenging forensic task. Here, we present a state-of-the-art study that employed attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy in combination with Chemometrics for postmortem diagnosis of fatal hypothermia/hyperthermia by biochemical investigation of plasma in rats. The results of principal component analysis (PCA) and spectral analysis revealed that plasma samples from the fatal hypothermia, fatal hyperthermia, and control groups, are substantially different from each other based on the spectral variations associated with the lipid, carbohydrate and nucleic acid components. Two partial least squares-discriminant analysis (PLS-DA) classification models (hypothermia-nonhypothermia and hyperthermia-nonhyperthermia binary models) with a 100% accuracy rate were constructed. Subsequently, internal cross-validation was performed to assess the robustness of these two models, which resulted in 98.1 and 100% accuracy. Ultimately, classification predictions of 42 unknown plasma samples were performed by these two models, and both models achieved 100% accuracy. Additionally, our results demonstrated that hemolysis and postmortem hypothermic/hyperthermic effects did not weaken the prediction ability of these two classification models. In summary, this work demonstrates ATR-FTIR spectroscopy's great potential for postmortem diagnosis of fatal hypothermia/hyperthermia.

Aim: Evidence of existing guidelines for the on-site triage of avalanche victims is limited and adherence suboptimal. This study attempted to find reliable cut-off values for the identification of hypothermic avalanche victims with reversible out-of-hospital cardiac arrest (OHCA) at hospital admission. This may enable hospitals to allocate extracorporeal life support (ECLS) resources more appropriately while increasing the proportion of survivors among rewarmed victims., Methods: All avalanche victims with OHCA admitted to seven centres in Europe capable of ECLS from 1995 to 2016 were included. Optimal cut-off values, for parameters identified by logistic regression, were determined by means of bootstrapping and exact binomial distribution and served to calculate sensitivity, rate of overtriage, positive and negative predictive values, and receiver operating curves., Results: In total, 103 avalanche victims with OHCA were included. Of the 103 patients 61 (58%) were rewarmed by ECLS. Six (10%) of the rewarmed patients survived whilst 55 (90%) died. We obtained optimal cut-off values of 7 mmol/L for serum potassium and 30 °C for core temperature., Conclusion: For in-hospital triage of avalanche victims admitted with OHCA, serum potassium accurately predicts survival. The combination of the cut-offs 7 mmol/L for serum potassium and 30 °C for core temperature achieved the lowest overtriage rate (47%) and the highest positive predictive value (19%), with a sensitivity of 100% for survivors. The presence of vital signs at extrication is strongly associated with survival. For further optimisation of in-hospital triage, larger datasets are needed to include additional parameters., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway., Competing Interests: The authors declare no conflict of interest.

What Is Known and Objective: Hypothermia is the current standard therapy for asphyxiated neonates with hypoxic-ischaemic encephalopathy (HIE). Gentamicin is used for the empirical treatment of early-onset neonatal sepsis. We investigated the influence of hypothermia treatment on gentamicin pharmacokinetics and suggested the appropriate dosing recommendations for gentamicin in neonates with HIE receiving hypothermia treatment., Methods: We searched studies published until February 2017 in MEDLINE using PubMed, EMBASE and the Cochrane Library. Three independent reviewers screened the literature and extracted data from each study. All of the studies that reported the blood concentrations or pharmacokinetic parameters of gentamicin in hypothermic neonates with HIE were included in this review. Articles were excluded if they were not original research., Result and Discussion: A total of 8 observational studies met the inclusion criteria. Meta-analyses were performed in which the mean difference of gentamicin for the trough concentration and clearance between hypothermic and normothermic neonates were 0.81 mg/L (95% confidence interval [-0.07, 1.69]) and -0.21 mL/kg/min (95% confidence interval [-0.31, -0.12]), respectively. The factors affecting gentamicin clearance in hypothermic neonates with HIE were gestational age, birthweight and serum creatinine., What Is New and Conclusion: Gentamicin clearance is decreased in neonates with HIE receiving hypothermia treatment compared to those not receiving hypothermia treatment. Modified gentamicin dosing regimens are required to avoid potential toxicity related to higher concentrations during hypothermia treatment., (© 2018 John Wiley & Sons Ltd.)

Maternal separation, hypoxia, and hypothermia are common stressors in the premature neonate. Using our rat model of human prematurity, we evaluated sexual dimorphisms in the long-term effects of these neonatal stressors on behavior of the hypothalamic-pituitary-adrenal (HPA) axis in adult rats. Neonatal rats were exposed daily on postnatal days 2 to 6 to maternal separation with normoxia, with hypoxia allowing spontaneous hypothermia, with hypothermia per se, and with hypoxia while maintaining isothermia with external heat. The major findings were that (a) prior maternal-neonatal separation during the first week of postnatal life attenuated the plasma ACTH and corticosterone response to restraint stress in adult male but not female rats, (b) prior neonatal hypothermia augmented the plasma ACTH and corticosterone response to restraint stress in adult male rats, but not female rats, and (c) changes in hypothalamic, pituitary, and adrenal mRNA expression did not account for most of these HPA axis effects. Most of the programming effects on adult HPA axis was attributed to prior maternal-neonatal separation alone (with normoxia) because the addition of hypoxia with spontaneous hypothermia, hypothermia per se, and hypoxia while preventing hypothermia during maternal-neonatal separation had minimal effects on the HPA axis. These results may inform strategies to prevent sexually dimorphic sequelae of neonatal stress including those due to medical interventions.

Aims: Currently, the decision to initiate extracorporeal life support for patients who suffer cardiac arrest due to accidental hypothermia is essentially based on serum potassium level. Our goal was to build a prediction score in order to determine the probability of survival following rewarming of hypothermic arrested patients based on several covariates available at admission., Methods: We included consecutive hypothermic arrested patients who underwent rewarming with extracorporeal life support. The sample comprised 237 patients identified through the literature from 18 studies, and 49 additional patients obtained from hospital data collection. We considered nine potential predictors of survival: age; sex; core temperature; serum potassium level; mechanism of hypothermia; cardiac rhythm at admission; witnessed cardiac arrest, rewarming method and cardiopulmonary resuscitation duration prior to the initiation of extracorporeal life support. The primary outcome parameter was survival to hospital discharge., Results: Overall, 106 of the 286 included patients survived (37%; 95% CI: 32-43%), most (84%) with a good neurological outcome. The final score included the following variables: age, sex, core temperature at admission, serum potassium level, mechanism of cooling, and cardiopulmonary resuscitation duration. The corresponding area under the receiver operating characteristic curve was 0.895 (95% CI: 0.859-0.931) compared to 0.774 (95% CI: 0.720-0.828) when based on serum potassium level alone., Conclusions: In this large retrospective study we found that our score was superior to dichotomous triage based on serum potassium level in assessing which hypothermic patients in cardiac arrest would benefit from extracorporeal life support. External validation of our findings is required., (Copyright © 2018 Elsevier B.V. All rights reserved.)

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT 1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT 1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT 1A receptor agonists in humans. NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT 1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31-0.63mg/kg p.o.). The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Aim: The aim of the present study was to assess the ability of the biomarkers neuron-specific enolase (NSE) and S100 calcium-binding protein b (S100b) to predict mortality and poor neurologic outcome after 30days in patients admitted with severe accidental hypothermia., Methods: Consecutive patients with severe accidental hypothermia, defined as a core temperature <32°C, were included. Patients were treated with active rewarming and/or extracorporeal life support (ECLS) using extra corporeal circulation (ECC) and/or extra corporeal membrane oxygenation (ECMO). The day following admission blood was analyzed for NSE and S100b. Follow-up was conducted after 30days and poor neurologic outcome was defined as a Cerebral Performance Category (CPC) score of 3-5. The predictive value of NSE and S100b was assessed as the area under the receiver-operating characteristics curve (AUC)., Results: A total of 34 patients were admitted with a diagnosis of severe accidental hypothermia and 29 (85%) were resuscitated from cardiac arrest. ECLS was initiated in 27 (79%) of patients. The day following admission three (9%) patients had died and one (3%) patient was awake, and accordingly, NSE and S100b were analyzed in 30 unconscious and/or sedated patients. NSE and S100b achieved AUCs of 0.93 and 0.88, respectively, for prediction of 30day mortality and AUCs of 0.88 and 0.87, respectively, for prediction of poor neurologic outcome., Conclusions: In patients remaining unconscious the day following admission for severe accidental hypothermia, the biomarkers NSE and S100b appear to be solid predictors of mortality and poor neurologic outcome after 30days., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Blood potassium is the main prognostic biomarker used for triage in hypothermic cardiac arrest. The aim of this review was to assess the impact of hypothermia on blood potassium levels and compare the underlying pathophysiological theories., Methods: The Medline electronic database was searched via PubMed for articles published from January 1970 to December 2016. The search strategy included studies related to hypothermia and potassium levels. The relevant literature on clinical studies and experimental studies was reviewed by the authors., Results: Among the 50 studies included in the review, 39 (78%) reported a decrease in blood potassium levels upon hypothermia onset. Hypothermic hypokalaemia is linked to an intracellular shift rather than an actual net loss. The intracellular shift is caused by a variety of factors such as enhanced functioning of Na+K+ATPase, beta-adrenergic stimulation, pH and membrane stabilisation in deep hypothermia. In contrast, hypothermia can act as an aggravating factor in severe trauma with hyperkalaemia being an indicator of an irreversible state of cell death. An increase in the blood potassium level during hypothermia may result from a lack of enzyme functioning at cold temperatures and blocked active transport., Conclusion: Hypothermia causes an initial decrease of potassium levels; however, the final stage of hypothermic cardiac arrest can induce hyperkalaemia due to cell lysis and final depolarisation. Better understanding the physiopathology of potassium levels during accidental hypothermia could be critically important to better select patients who could benefit from aggressive resuscitation therapy such as extracorporeal cardiopulmonary resuscitation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Solubilities of respiratory gasses in water, saline, and plasma decrease with rising temperatures and solute concentrations. Henry's Law, C = α·P, states that the equilibrium concentration of a dissolved gas is solubility times partial pressure. Solubilities in the water of a solution depend on temperature and the content of other solutes. Blood temperatures may differ more than 20°C between skin and heart, and an erythrocyte will undergo that range as blood circulates. The concentrations of O 2 and CO 2 are the driving forces for diffusion, exchanges, and for reactions. We provide an equation for O 2 and CO 2 solubilities, α, that allows for continuous changes in temperature, T, and solution density, ρ, in dynamically changing states:[Formula: see text]This two-exponential expression with a density scalar γ, and a density exponent β, accounts for solubility changes due to density changes of an aqueous solution. It fits experimental data on solubilities in water, saline, and plasma over temperatures from 20 to 40°C, and for plasma densities, ρ sol up to 1.020 g/ml with ~0.3% error. The amounts of additional bound O 2 (to Hb) and CO 2 (bicarbonate and carbamino) depend on the concentrations in the local water space and the reaction parameters. During exercise, solubility changes are large; both ρ sol and T change rapidly with spatial position and with time. In exercise hemoconcentration plasma, ρ sol exceeds 1.02, whereas T may range over 20°C. The six parameters for O 2 and the six for CO 2 are constants, so solubilities are calculable continuously as T and ρ sol change. NEW & NOTEWORTHY Solubilities for oxygen and carbon dioxide are dependent on the density of the solution, on temperature, and on the partial pressure. We provide a brief equation suitable for hand calculators or mathematical modeling, accounting for these factors over a wide range of temperatures and solution densities for use in rapidly changing conditions, such as extreme exercise or osmotic transients, with better than 0.5% accuracy., (Copyright © 2017 the American Physiological Society.)

Metformin is a first-line oral antidiabetic therapy for patients with type 2 diabetes mellitus. Metformin-associated lactate acidosis (MALA) is a well-known, life-threatening, but rare side effect of metformin therapy. Chronic kidney disease (CKD) patients have a much greater risk of MALA. We report the case of a severe refractory MALA despite hemodialysis (HD) treatment, associated with hypoglycemia, hypothermia, and bradycardia in a neglected and thus untimely-recognized CKD patient with type 2 diabetes mellitus. Despite the recent rehabilitation of metformin as a treatment of choice for type 2 diabetes mellitus, the drug should be prescribed with caution as it can be associated with life-threatening refractory acidosis, particularly in CKD patients. Moreover, HD treatment could occasionally be ineffective, resulting in a fatal outcome.
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Objectives: Improved congenital heart defect (CHD) operations have reduced operative mortality to 3%. The major concern is now long-term neurological outcomes. We measured plasma glial fibrillary acidic protein (GFAP), an early marker of brain injury, during different phases of cardiopulmonary bypass (CPB), to correlate the increase of GFAP to clinical parameters or specific operative phases., Methods: We performed a prospective, single-centre, observational study in children undergoing cardiac operations. We studied 69 children with CHD and biventricular heart physiology: 26 had tetralogy of Fallot; 17 transposition of the great arteries; and 26 ventricular/atrial septal defects with or without associated arch defects. GFAP levels were measured by ELISA at different stages of CPB. We recorded clinical and surgical parameters and applied multivariable and logistic regressions to assess which parameters were independent predictors of variations in plasma GFAP., Results: GFAP increased during CPB and peaked at the end of rewarming. Multivariable regression showed degree of hypothermia as the only significant independent predictor of GFAP increase, adjusted for age, prematurity, type of CHD, cyanosis, aortic cross-clamp time, haemodilution, neurological risk time interval and rewarming rate. Temperature nadir and neurological risk time interval were significant independent predictors of a GFAP value  > 0.46 ng/ml., Conclusions: Hypothermia degree during CPB is correlated with GFAP plasma increase in children with biventricular heart defects undergoing surgical repair. Rewarming is the most critical CPB phase for GFAP increase. The implication of high plasma GFAP is still under evaluation. Follow-up studies are ongoing to assess the reliability of GFAP as a marker of brain injury and/or as a predictor of neurodevelopmental abnormalities., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Myxedema coma (MC), a medical emergency defined as severe hypothyroidism leading to altered mental status, is more common in older women with hypothyroidism., Methods/results: A 7-year-old Caucasian male with chromosome 1q deletion presented with altered mental status preceded by milestone regression. His presenting labs results were: thyroid-stimulating hormone (TSH) 0.501 μIU/ml and free thyroxine (T4) <0.5 ng/dl. His morning cortisol level was 8.1 μg/dl with repeat testing, while TSH was 1.119 μIU/ml and free T4 was 0.5 ng/dl. Low-dose cosyntropin test showed baseline and peak cortisol levels of 1.9 and 16 μg/dl, respectively. Aside from altered mental status, heart block was present in addition to hypothermia and hypercarbia. Diffuse cerebral cortical and corpus callosum atrophy were seen on MRI. An intravenous (i.v.) stress dose of hydrocortisone was administered for 24 h prior to an i.v. loading dose of levothyroxine. His activity level subsequently returned to baseline within 48 h after treatment had been initiated., Conclusion: Though MC is rare, occurring mainly with noncompliance in primary hypothyroidism, it may occur at the diagnosis of secondary hypothyroidism. Based on features like hypothermia, hypoventilation, and cardiovascular instability occurring in the setting of central hypothyroidism, it should be suspected and managed urgently in order to avert the associated high mortality resulting from treatment delays., (© 2016 S. Karger AG, Basel.)

Alterations in platelet function are a common finding in surgical procedures involving cardiopulmonary bypass and hypothermia. Although the combined impact of hypothermia and artificial circulation on platelets has been studied before, the ultimate strategy to safely minimize the risk for bleeding and thrombosis is yet unknown. The aim of this study was to evaluate the use of a mock circulation loop to study the impact of hypothermia for platelet-related hemostatic changes. Venous blood was collected from healthy adult humans (n = 3). Closed mock circulation loops were assembled, each consisting of a centrifugal pump, an oxygenator with integrated heat exchanger, and a hardshell venous reservoir. The experiment started with the mock circulation temperature set at 37°C (T0 [0 h]). Cooling was then initiated at T1 (+2 h), where temperature was adjusted from 37°C to 32°C. Hypothermia was maintained from T2 (+4 h) to T3 (+28 h). From that point in time, rewarming from 32°C to 37°C was initiated with similar speed as cooling. From time point T4 (+30 h), normothermia (37°C) was maintained until the experiment ended at T5 (+32 h). Blood samples were analyzed in standard hematological tests: light transmission aggregometry (LTA) (arachidonic acid [AA], adenosine diphosphate [ADP], collagen [COL], thrombin-receptor-activating-peptide-14 [TRAP]), multiple electrode aggregometry (MEA) (AA, ADP, COL, TRAP), and rotational thromboelastometry (ROTEM) (EXTEM, FIBTEM, PLTEM). Hemoglobin, hematocrit, and platelet count decrease more substantially during temperature drop (37-32°C) than during hypothermia maintenance. Hb and Hct continue to follow this trend during active rewarming (32-37°C). PC increase from the moment active rewarming was initiated. None of the values return to the initial values. LTA values demonstrate a similar decrease in aggregation after stimulation with the platelet agonists between the start of the mock circulation and the start of cooling. Except for platelet stimulation using COL, this trend continues during temperature drop from 37°C to 32°C. LTA values using AA and TRAP demonstrate a considerable decline in platelet function throughout the experiment that was most pronounced after 24 h of circulation at 32°C. LTA values using ADP and COL further decline after rewarming. MEA ADP, ASPI, and COL identify platelet dysfunction patterns analogous with LTA, between the start of the mock circulation and the start of cooling. Except for MEA TRAP, this trend continues during temperature drop from 37°C to 32°C. MEA ASPI and ADP demonstrate a considerable decline in platelet function throughout the experiment, which was most pronounced after 24 h of circulation at 32°C. For MEA COL and TRAP, further decline in platelet function is observed after rewarming. This study quantitatively assessed the effect of temperature changes on platelet function during experimental mock circulation demonstrating a considerable decline in platelet function during hypothermia without uniform recovery of platelet function observed after rewarming., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Purpose: A newly developed fluid warmer (ThermoSens®) has a direct blood warming plate, which can result in hemolysis or red blood cell injury during heating. Therefore, to evaluate the safety of heating blood products with a fluid warmer, we conducted laboratory tests to study hemolysis and erythrocyte rheology., Methods: We used outdated human blood taken from a Korean blood bank. Packed red blood cells mixed with 100 mL isotonic saline was passed through the fluid warmer. Blood flow was achieved by either gravity or 300 mmHg pressure. Blood samples were analyzed before and after heating for hemolysis marker and erythrocyte rheology parameters., Results: The temperatures at the outlet were higher than 38°C at gravity and 300 mmHg pressure, respectively. There were no significant differences in hemolysis markers (hemoglobin, hematocrit, lactate dehydrogenase, and plasma free hemoglobin) or erythrocyte rheology (deformability, disaggregating shear stress, and aggregation index) between before and after heating (p >  0.05) except LDH at gravity (p = 0.0001)., Conclusion: The ThermoSens® fluid warmer caused no erythrocyte injury or negative effects on rheology during heating. Regarding medical device development, hemorheologic analysis can be useful for safety evaluation of medical devices that directly contact blood for temperature modulation.

Facing coagulation disorders after acute trauma., Problems/objectives: Trauma is the leading cause of mortality for persons between one and 44 years of age, essentially due to bleeding complications., Methodology: We screened the PubMed, Scopus and Cochrane Library databases, using specific keywords. Only publications in English were considered., Main Results: The pathophysiology of trauma-induced coagulopathy (TIC) is complex and includes the classic "lethal triad" (i.e., haemodilution, acidosis, hypothermia) but may also include activation of protein C, endothelial and platelet dysfunction, and fibrinogen depletion. The time between trauma and treatment of the resultant massive bleeding should be as short as possible using techniques for rapid control of bleeding and avoiding aggravating factors (hypothermia, metabolic acidosis and hypocalcaemia). If given within three hours of injury, tranexamic acid (TXA) reduces all causes of mortality in trauma patients and reduces transfusion requirements. In a bleeding patient, crystalloids are preferred to colloids and the ratio of fresh frozen plasma to packed red blood cells should be at least 1:2. Damage control surgery (DCS) should be considered for patients who present with, or are at risk for developing, the "lethal triad", multiple life-threatening injuries or shock, and in mass casualty situations. DCS can also aid in the evaluation of the extent of tissue injuries and the control of haemorrhage and infection. Finally, there is currently no evidence of the added value of laboratory assays in the management of TIC., Conclusions: TIC appears quickly after trauma and should be anticipated and detected as soon as possible. TXA plays a central role in the management of such patients. Each institution should establish a local algorithm for the management of bleeding patients.

Aim: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia., Methods: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site., Results: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively., Conclusions: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

The objective of this research was to evaluate postmortem changes concerning electric charge of human erythrocytes and thrombocytes in fatal accidental hypothermia. The surface charge density values were determined on the basis of the electrophoretic mobility measurements of the cells conducted at various pH values of electrolyte solution. The surface charge of erythrocyte membranes after fatal accidental hypothermia increased compared to the control group within whole range of experimental pH values. Moreover, a slight shift of the isoelectric point of erythrocyte membranes towards high pH values was observed. The surface charge of thrombocyte membranes in fatal accidental hypothermia decreased at low pH compared to the control group. However, at pH range 4-9, the values increased compared to the control group. The isoelectric point of thrombocyte membranes after fatal accidental hypothermia was slightly shifted towards low pH values compared to the control group. The observed changes are probably connected with the partial destruction and functional changes of the blood cell structure.

Background: Some patients with sepsis are found with accompanying mild hypothermia (ACMH); however, the effects of ACMH on the patients with sepsis are poorly understood., Objective: To compare the impacts of ACMH and artificial mild hypothermia (ATMH) on mortality, systemic inflammatory reactions, and organ functions in mice with sepsis., Methods: Septic mouse models were induced and divided into ACMH, un-hypothermia, keep normothermia, and ATMH groups, according to the anal temperature and the thermic intervention strategy. The mortality rate, serum levels of tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and interleukin (IL)-4 and liver and renal functions of the mice in each group were recorded. Liver, lung, and renal tissues of the mice were stained and examined under optic microscope., Results: The mortality rate in the ACMH group was the lowest among all the sepsis groups. Increased serum levels of TNF-α, IFN-γ, and IL-4 and impairments of the liver and renal functions were found in the septic mice. The serum levels of TNF-α, IFN-γ, and IL-4 were significantly lower and the liver and renal functions of ACMH group were not impaired significantly as compared with other sepsis groups. Pathological examinations of the lung, liver, and renal tissues showed that the ACMH group were with the lowest pathological score among all the sepsis groups., Conclusion: Accompanying mild hypothermia and ATMH could both reduce mortalities in mice with sepsis, and ACMH could reduce mortality even lower, and more alleviate systemic inflammatory responses and the damages in lung, kidney, and other organs were lighter., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction Hyperlactataemia is associated with adverse outcomes in trauma cases. It is thought to be the result of anaerobic respiration during hypoperfusion. This produces much less energy than complete aerobic glycolysis. Low body temperature in the injured patient carries an equally poor prognosis. Significant amounts of energy are expended in maintaining euthermia. Consequently, there may be a link between lactate levels and dysthermia. Hyperlactataemia may be indicative of inefficient energy production and therefore insufficient energy to maintain euthermia. Alternatively, significant amounts of available oxygen may be sequestered in thermoregulation, resulting in anaerobic respiration and lactate production. Our study investigated whether there is an association between lactate levels and admission body temperature in hip fracture patients. Furthermore, it looked at whether there is a difference in the mean lactate levels between hip fracture patients with low (<36.5°C), normal (36.5-37.5°C) and high (>37.5°C) body temperature on admission, and for patients who have low body temperature, whether there is a progressive rise in serum lactate levels as body temperature falls. Methods The admission temperature and serum lactate of 1,162 patients presenting with hip fracture were recorded. Patients were divided into the euthermic (body temperature 36.5-37.5°C), the pyrexial (>37.5°C) and those with low body temperature (<36.5°C). Admission lactate and body temperature were compared. Results There was a significant difference in age between the three body temperature groups (p=0.007). The pyrexial cohort was younger than the low body temperature group (mean: 78 vs 82 years). Those with low body temperature had a higher mean lactate level than the euthermic (2.2mmol/l vs 2.0mmol/l, p=0.03). However, there was no progressive rise in serum lactate level as admission temperature fell. Conclusions The findings suggest that in hip fracture patients, the body attempts initially to maintain euthermia, incurring an oxygen debt. This would explain the difference in lactate level between the low body temperature and euthermic cohorts. The fact that there is no correlation with the degree of temperature depression and lactate levels indicates that the body does not fuel thermohomeostasis indefinitely with oxygen. Instead, in part, it abandons thermoregulatory mechanisms. Consequently, in this population, active rewarming may be indicated rather than depending on patients' own thermogenic ability.

The effect of hypothermia on the in vivo pharmacokinetics of midazolam was evaluated, with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28 °C. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of midazolam were estimated using the Michaelis-Menten equation. The Km of CYP3A2 midazolam remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32 or 28 °C by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28 °C. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: To determine whether hypothermia within 24 hours of sepsis diagnosis is associated with development of persistent lymphopenia, a feature of sepsis-induced immunosuppression., Design: Retrospective cohort study., Setting: A 1,200-bed university-affiliated tertiary care hospital., Patients: Adult patients diagnosed with bacteremia and sepsis within 5 days of hospital admission between January 1, 2010, and July 31, 2012., Interventions: None., Measurements and Main Results: Leukocyte counts were recorded during the first 4 days following sepsis diagnosis. Persistent lymphopenia was defined as an absolute lymphocyte count less than 1.2 cells/μL×10(3) present on the fourth day after diagnosis. Of the 445 patients with sepsis included, hypothermia developed in 64 patients (14.4%) (defined as a body temperature<36.0°C) within 24 hours of sepsis diagnosis. Hypothermia was a significant independent predictor of persistent lymphopenia (adjusted odds ratio, 2.70 [95% CI, 1.10, 6.60]; p=0.03) after accounting for age, disease severity, comorbidities, source of bacteremia, and type of organism. Compared with the nonhypothermic patients, hypothermic patients had higher 28-day (50.0% vs 24.9%, p<0.001) and 1-year mortality (60.9% vs 47.0%, p=0.001)., Conclusions: Hypothermia is associated with higher mortality and an increased risk of persistent lymphopenia in patients with sepsis, and it may be an early clinical predictor of sepsis-induced immunosuppression.

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes., (© 2015 S. Karger AG, Basel.)

Background: Fibrinogen concentrate treatment can improve coagulation during massive traumatic bleeding. The aim of this in vitro study was to determine whether fibrinogen concentrate, or a combination of factor XIII and fibrinogen concentrates, could reverse a haemodilution-induced coagulopathy during hypothermia., Methods: Citrated venous blood from 10 healthy volunteers was diluted in vitro by 33% with 130/0.42 hydroxyethyl starch (HES) or Ringer's acetate (RAc). The effects of fibrinogen concentrate corresponding to 4 gram per 70 kg, or a combination of the same dose of fibrinogen with factor XIII (20 IU per kg), were measured using rotational thromboelastometry (ROTEM). The blood was analysed at 33°C or 37°C with ROTEM EXTEM and FIBTEM reagents. Clotting time (CT), clot formation time (CFT), alpha angle (AA) and maximal clot formation (MCF) were recorded., Results: Fibrinogen with or without factor XIII improved all ROTEM parameters in either solution irrespective of temperature, with the exception of EXTEM-AA and EXTEM-CFT in HES haemodilution. Fibrinogen increased FIBTEM-MCF more in the samples diluted with RAc than HES, particularly in presence of factor XIII., Conclusions: Fibrinogen improved in vitro haemodilution-induced coagulopathy at both 33°C and 37°C, though more efficiently after crystalloid than HES haemodilution. Factor XIII had an additional effect on FIBTEM-MCF, but only after crystalloid dilution.

Background: Previous research aimed at ameliorating hypothermia-induced cardiac dysfunction has shown that inotropic drugs, that stimulate the cAMP, - PKA pathway via the sarcolemmal β-receptor, have a decreased inotropic effect during hypothermia. We therefore wanted to test whether levosimendan, a calcium sensitizer and dose-dependent phosphodiesterase 3 (PDE3) inhibitor, is able to elevate stroke volume during rewarming from experimental hypothermia., Methods: A rat model designed for circulatory studies during experimental hypothermia (4h at 15°C) and rewarming was used. The following three groups were included: (1) A normothermic group receiving levosimendan, (2) a hypothermic group receiving levosimendan the last hour of stable hypothermia and during rewarming, and (3) a hypothermic placebo control group. Hemodynamic variables were monitored using a Millar conductance catheter in the left ventricle (LV), and a pressure transducer connected to the left femoral artery. In order to investigate the level of PKA stimulation by PDE3 inhibition, myocardial Ser23/24-cTnI phosphorylation was measured using Western-blot., Results: After rewarming, stroke volume (SV), cardiac output (CO) and preload recruitable stroke work (PRSW) were restored to within pre-hypothermic values in the levosimendan-treated animals. Compared to the placebo group after rewarming, SV, CO, PRSW, as well as levels of Ser23/24-cTnI phosphorylation, were significantly higher in the levosimendan-treated animals., Conclusion: The present data shows that levosimendan ameliorates hypothermia-induced systolic dysfunction by elevating SV during rewarming from 15°C. Inotropic treatment during rewarming from hypothermia in the present rat model is therefore better achieved through calcium sensitizing and PDE3 inhibition, than β-receptor stimulation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Effects of hypothermia and rewarming on thrombomodulin, catecholamines and heat shock transcription factor 1 (HSF1) were studied in rats. The aims of this study were to clarify whether cold stress, under anesthesia, is sufficient to change levels of thrombomodulin in healthy endothelium and in the circulation and whether adrenaline, noradrenaline and HSF1 could act as regulators in the process. Rats were divided into control, mild hypothermia (2 and 4.5 hours at + 21 °C; MH1, MH2), severe hypothermia (2 and 4.5 h at + 10 °C; SH1, SH2) and two rewarming groups (2 h at + 10 °C followed by 2 h at + 21 °C or 3 h at + 28 °C; SHW1, SHW2) (n = 15/group, except n = 6 in MH1). Fentanyl-fluanisone-midazolam was used as anesthetic. Low levels of thrombomodulin in plasma and myocardial arterioles/venules measured by ELISA and immunohistochemistry were associated with significant increase of thrombomodulin transcript level in SH1 rats analyzed by quantitative PCR. Plasma adrenaline correlated negatively with the relative amount of myocardial thrombomodulin transcripts and positively with plasma thrombomodulin in SH. Transcript levels of thrombomodulin and HSF1 correlated strongly (r = 0.83; p < 0.001) in SH. Plasma/urine ratio of thrombomodulin and plasma adrenaline (r = 0.87; p = 0.005) or noradrenaline (r = 0.78; p = 0.023) were strongly correlated in SHW1 rats. Hence, cellular and soluble levels of thrombomodulin are modified by cold stress in healthy rats, possibly via catecholamines and HSF1.

Few large-scale investigations have looked at the oxyhemoglobin ratio (%O2-Hb) or the carboxyhemoglobin ratio (%CO-Hb) in fatal hypothermia and death by fire as applicable to forensic medicine. We therefore retrospectively examined right and left cardiac blood samples for both %O2-Hb and %CO-Hb in 690 forensic autopsy cases. We therefore sought to establish reference values for the above forensic diagnoses, to compare %O2-Hb in fatal hypothermia with or without cardiopulmonary resuscitation (CPR), and to compare the relationship between %CO-Hb and smoking history. All %O2-Hb and %CO-Hb data were obtained during or immediately after autopsies using a portable CO-oximeter. Death by carbon monoxide (CO) intoxication and death by fire were excluded from the analysis involving smoking history. In fatal hypothermia, %O2-Hb in the left cardiac blood was significantly higher than that in the right cardiac blood, providing important evidence for fatal hypothermia. Furthermore, %O2-Hb in the left cardiac blood increases with CPR but that in the right cardiac blood increases in parallel. No correlation was observed between rectal temperature and %O2-Hb in the right and left cardiac blood, indicating that it is unlikely that postmortem cooling increases %O2-Hb in cardiac blood. %CO-Hb in smokers was significantly higher than that in non-smokers, although the number of cigarettes smoked did not appear to be significant. When assessing death by fire, we identified that %CO-Hb of >10% was a reliable marker of antemortem CO inhalation, regardless of smoking history., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

β-hydroxybutyrate concentrations were determined in blood and synovial fluid in a series of medico-legal cases including hypothermia fatalities, individuals found dead in a cold environment and non-hypothermia cases with various, non-traumatic causes of death. Hypothermia was considered to be the cause of death according to circumstantial elements indicating exposure to cold, autopsy findings, biochemical investigation results and exclusion of other causes of death. The intention of this study was to characterize β-hydroxybutyrate distribution in synovial fluid and assess its usefulness for the postmortem diagnosis of antemortem abnormalities in blood β-hydroxybutyrate levels. Unenhanced CT scans, autopsies, histology, neuropathology, toxicology, and biochemistry were systematically performed. Within the limited number of subjects included in the study, the results indicate that abnormalities in antemortem β-hydroxybutyrate blood levels, as may be observed in hypothermia fatalities, are reflected in postmortem synovial fluid values. These preliminary findings notwithstanding, synovial fluid analysis to determine β-hydroxybutyrate is unlikely to be generally applied due to the more invasive collection technique it requires and could be limited to special cases in which biological fluids systematically collected upon autopsy are unavailable., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to early life stress may affect circadian processes and induce a latent circadian disturbance evident after exposure to later life stress. Disturbance of the normal regulation of circadian rhythmicity is surmised to be an etiological factor in depression. We used postnatal maternal separation in rats to investigate how the early life environment might modify the circadian response to later life unpredictable and chronic stress. During postnatal days 2-14, male Wistar rats (n = 8 per group) were daily separated from their mothers for a period of either 180 min (long maternal separation; LMS) or 10 min (brief maternal separation; BMS). In adulthood, rats were exposed to chronic mild stress (CMS) for 4 weeks. Body temperature, locomotor activity and heart rate were measured and compared before and after CMS exposure. LMS offspring showed a delayed body temperature acrophase compared to BMS offspring. Otherwise, adult LMS and BMS offspring demonstrated similar diurnal rhythms of body temperature, locomotor activity and heart rate. Exposure to CMS provoked a stronger and longer lasting hypothermia in LMS rats than in BMS rats. The thermoregulatory response appears to be moderated by maternal care following reunion, an observation made in the LMS group only. The results show that early life stress (LMS) in an early developmental stage induced a thermoregulatory disturbance evident upon exposure to unpredictable adult life stressors.

Background: Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study, we investigated the effects of hypothermia on thrombin generation, clot formation, and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography, which can recapitulate hypothermia., Methods: Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway. Coagulation was initiated with 5pM tissue factor at temperatures 37°C, 32°C, and 27°C. Reactions were quenched over time, with soluble and insoluble components analyzed for thrombin generation, fibrinogen consumption, factor (f)XIII activation, and fibrin deposition. Global coagulation potential was evaluated through thromboelastography., Results: Data showed that thrombin generation in samples at 37°C and 32°C had comparable rates, whereas 27°C had a much lower rate (39.2 ± 1.1 and 43 ± 2.4 nM/min vs 28.6 ± 4.4 nM/min, respectively). Fibrinogen consumption and fXIII activation were highest at 37°C, followed by 32°C and 27°C. Fibrin formation as seen through clot weights also followed this trend. Thromboelastography data showed that clot formation was fastest in samples at 37°C and lowest at 27°C. Maximum clot strength was similar for each temperature. Also, percent lysis of clots was highest at 37°C followed by 32°C and then 27°C., Conclusions: Induced hypothermic conditions directly affect the rate of thrombin generation and clot formation, whereas global clot stability remains intact., (© 2013.)

The hormone thyroxine that regulates mammalian metabolism is carried and stored in the blood by thyroxine-binding globulin (TBG). We demonstrate here that the release of thyroxine from TBG occurs by a temperature-sensitive mechanism and show how this will provide a homoeostatic adjustment of the concentration of thyroxine to match metabolic needs, as with the hypothermia and torpor of small animals. In humans, a rise in temperature, as in infections, will trigger an accelerated release of thyroxine, resulting in a predictable 23% increase in the concentration of free thyroxine at 39°C. The in vivo relevance of this fever-response is affirmed in an environmental adaptation in aboriginal Australians. We show how two mutations incorporated in their TBG interact in a way that will halve the surge in thyroxine release, and hence the boost in metabolic rate that would otherwise occur as body temperatures exceed 37°C. The overall findings open insights into physiological changes that accompany variations in body temperature, as notably in fevers.

The state of the hemostatic system in the psycho-emotional and hypothermia in rats. It is shown that the psycho-emotional impact is accompanied by a hypercoagulable. "Clean" effect of hypothermia is characterized by the activation of anticoagulation and fibrinolysis. Thus, we have shown that the general hypothermia in the aquatic environment has a more pronounced effect on the hemostatic system than the psycho-emotional impact.

The possibilities of using morphological markers of fatal hypothermia are limited; therefore, other diagnostic criteria of deaths from hypothermia are being researched. The initiation of protective mechanisms against adverse effects of low temperatures results in activation of hormonal systems and development of characteristic biochemical changes that can be impaired by alcohol intoxication. The aim of the study was to assess the usefulness of determinations of the profile of free fatty acid concentrations as potential markers of hypothermia-related deaths, particularly in intoxicated victims. The study group consisted of blood samples collected during autopsies of 23 victims of hypothermia. The control group included blood samples collected from 34 victims of sudden, violent deaths at the scene of an incident (hangings and traffic accidents) and 10 victims who died because of post-traumatic subdural hematomas with prolonged agony. The study and control groups were divided into three subgroups according to blood alcohol concentrations: 0.0-0.99; 1.0-2.99 and ≥3.0‰. Statistical analysis in the individual subgroups demonstrated significant increases in concentrations of palmitic, stearic and oleic acids (P<0.05), independent of blood ethanol concentration. Palmitic, stearic and oleic acids can be considered the potential markers of fatal hypothermia, including the cases of intoxicated individuals., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Hypothermia, which can result from tissue hypoperfusion, body exposure, and transfusion of cold resuscitation fluids, is a major factor contributing to coagulopathy of trauma and surgery. Despite considerable efforts, the mechanisms of hypothermia-induced blood coagulation impairment have not been fully understood. We introduce a kinetic modeling approach to investigate the effects of hypothermia on thrombin generation., Methods: We extended a validated computational model to predict and analyze the impact of low temperatures (with or without concomitant blood dilution) on thrombin generation and its quantitative parameters. The computational model reflects the existing knowledge about the mechanistic details of thrombin generation biochemistry. We performed the analysis for an "average" subject, as well as for 472 subjects in the control group of the Leiden Thrombophilia Study., Results: We computed and analyzed thousands of kinetic curves characterizing the generation of thrombin and the formation of the thrombin-antithrombin complex (TAT). In all simulations, hypothermia in the temperature interval 31°C to 36°C progressively slowed down thrombin generation, as reflected by clotting time, thrombin peak time, and prothrombin time, which increased in all subjects (P < 10(-5)). Maximum slope of the thrombin curve was progressively decreased, and the area under the thrombin curve was increased in hypothermia (P < 10(-5)); thrombin peak height remained practically unaffected. TAT formation was noticeably delayed (P < 10(-5)), but the final TAT levels were not significantly affected. Hypothermia-induced fold changes in the affected thrombin generation parameters were larger for lower temperatures, but were practically independent of the parameter itself and of the subjects' clotting factor composition, despite substantial variability in the subject group. Hypothermia and blood dilution acted additively on the thrombin generation parameters., Conclusions: We developed a general computational strategy that can be used to simulate the effects of changing temperature on the kinetics of biochemical systems and applied this strategy to analyze the effects of hypothermia on thrombin generation. We found that thrombin generation can be noticeably impaired in subjects with different blood plasma composition even in moderate hypothermia. Our work provides mechanistic support to the notion that thrombin generation impairment may be a key factor in coagulopathy induced by hypothermia and complicated by blood plasma dilution.

In the course of hypothermia, biochemical changes occur that are associated with stimulation of protective thermogenic mechanisms as well as mobilization of internal energy resources mediated by the hormone system. The objective of the investigation was the assessment of validity of determinations of cortisol, cortisone and corticosterone as hypothermia markers in cases of fatal hypothermia combined with concomitant insobriety of the victims. The experimental group consisted of blood samples collected in the course of medico-legal autopsies of 23 hypothermia victims. The controls included blood samples originating from 34 victims of violent sudden deaths (deaths by hanging and traffic road accidents at the scene) and from ten individuals deceased after prolonged agony in consequence of post-traumatic subdural hematomas. In both groups, three subgroups were distinguished that included cases with ethanol levels within the following ranges: 0.0-0.99, 1.0-2.99 and ≥3.0‰. The comparison of determination results showed that irrespectively of blood ethanol concentration, cortisol, cortisone and corticosterone levels seen in hypothermia victims were significantly higher as compared to the controls (P<0.001)., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

There is growing interest in using hypothermia to prevent hypoxic damage in clinical and experimental models, although the mechanisms regulated by hypothermia are still unclear. As reactive oxygen and nitrogen species are the main factors causing cellular damage, our objective was to study the scope of hypothermia in preventing hypoxia-induced oxidative damage. We analysed systemic and hepatic indicators of oxidative stress after an acute hypoxic insult (10% oxygen in breathing air) in normothermic (37°C body temperature) and hypothermic conditions (22°C) in rats. Exposure to hypoxia resulted in tissue damage (aspartate aminotransferase increased from 54.6 ± 6.9 U l(-1) in control animals to 116 ± 1.9 U l(-1) in hypoxia, and alanine aminotransferase increased from 19 ± 0.8 to 34 ± 2.9 U l(-1)), oxidative stress (nitric oxide metabolites increased from 10.8 ± 0.4 μM in control rats to 23 ± 2.7 μM in hypoxia, and thiobarbituric reactive substances increased from 3.3 ± 0.2 to 5.9 ± 0.4 nm) and antioxidant consumption (reduced/oxidized glutathione ratio changed from 9.8 ± 0.3 to 6.8 ± 0.3). In contrast, when hypothermia was applied prior to hypoxia, the situation was reversed, with a reduction in aspartate aminotransferase (from 116 ± 1.9 in hypoxic animals to 63 ± 7.8 U l(-1) in animals exposed to hypothermia followed by hypoxia), alanine aminotransferase (from 34 ± 2.9 to 19 ± 0.9 U l(-1)), oxidative stress (nitric oxide metabolites decreased from 23 ± 2.7 to 17.8 ± 1.9 μM and thiobarbituric acid-reactive substances decreased from 5.9 ± 0.4 to 4.3 ± 0.2 nm) and antioxidant preservation (reduced/oxidized glutathione ratio changed from 6.8 ± 0.3 to 11.1 ± 0.1). Hypoxia induced a decrease in liver enzymatic antioxidant activities even during hypothermia. Both treatments, hypoxia and hypothermia, produced a similar increase in hepatic caspase-3 activity. In conclusion, hypothermia prevented the tissue damage and oxidative stress elicited by hypoxia. Our results provide new evidence concerning the protective mechanism of hypothermia in vivo.

Serum amylase (AMY) and gamma glutamyl transferase (GGT) are routine clinical markers for investigating pancreatic and hepatobiliary disorders, respectively, but are also increased in systemic deterioration following critical trauma and diseases. The present study investigated the postmortem levels in bilateral cardiac blood of medicolegal autopsy cases without decomposition (n=163), excluding those with pancreatic or hepatic injury, or preexisting pathologies, as well as prolonged death cases, to evaluate the changes due to systemic deterioration in the death process after fatal insults with special regard to intoxication, hyperthermia (heatstroke) and hypothermia (cold exposure). Serum AMY and GGT levels were virtually independent of postmortem interval. Serum AMY level was mostly higher than the clinical reference range, predominantly including salivary fractions, but was usually below 1000U/L except for fatal intoxication, which showed significant increases of total AMY as well as salivary and pancreatic fractions in bilateral cardiac blood. Serum levels of salivary and pancreatic AMY fractions showed tendencies to be related to pancreatic subcapsular and interstitial bleeding, respectively, which were relatively frequent and evident in mechanical asphyxiation, intoxication and hyperthermia (heatstroke). Serum GGT was often elevated (mostly below 300U/L) in cases other than hypothermia (cold exposure). These findings suggest postmortem serum AMY and GGT as indicators of the severity of systemic organ damage in death processes, especially in intoxication; however, elevated serum AMY and GGT levels over 1000 and 300U/L might indicate significant pancreatic and hepatobiliary pathologies, respectively, except for an elevated serum AMY level in intoxication., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The 2010 CPR Guidelines recommend that extracorporeal cardiopulmonary resuscitation (ECPR) using an emergency cardiopulmonary bypass (CPB) should be considered for patients with cardiac arrest. However, it is not yet clear whether this therapy can improve cerebral circulation and oxygenation in these patients. To clarify this issue, we evaluated changes of cerebral blood oxygenation (CBO) during ECPR using near-infrared spectroscopy (NIRS)., Methods: We employed NIRS to measure CBO in the bilateral frontal lobe in patients transported to the emergency room (ER) after out-of-hospital cardiac arrest between November 2009 and June 2011., Results: Fifteen patients met the above criteria. The tissue oxygenation index (TOI) on arrival at the ER was 36.5 %. This increased to 67.8 % during ECPR (P < 0.001). The one patient whose TOI subsequently decreased had a favorable neurological outcome., Conclusion: Increase of TOI during ECPR might reflect an improvement in cerebral blood flow, while decrease of TOI after ECPR might reflect oxygen utilization by the brain tissue as a result of neuronal cell survival. NIRS may be useful for monitoring cerebral hemodynamics and oxygen metabolism during CPR.

Background: Although "polar triiodothyronine (T(3)) syndrome" in chronic dwellers/workers in Antarctica has been established, alteration of the pituitary thyroid-axis upon accidental hypothermia is not well recognized. We report here a rare case of elevation of thyrotropin (TSH) upon accidental hypothermia., Patient Findings: A 75-year-old man was admitted because of consciousness disturbance.The mean outside temperature was approximately -2.0°C (28.4°F) but his house was inadequately heated. His rectal temperature was 29.5°C (85.1°F). Goiter was not palpable and pitting edema, not myxedema, was present. Serum TSH was elevated (28.3 mU/L, reference range 0.27-4.2), and free T(3) (FT(3)) and free thyroxine (FT(4)) lowered (FT(3), 3.25 pmol/L with a reference range of 4.00-7.85, and FT(4), 9.18 pmol/L with a reference range of 12.87-23.179), but thyroid-related autoantibodies were all negative. By the next morning, body temperature had risen to >36°C (>96.8°F) and there was no further recurrence of hypothermia. Serum TSH decreased exponentially and the patient's condition had become normal by day 22. FT(3) and FT(4) were found to be slightly lowered and elevated, respectively, during the same period, in the subnormal range. At the end of the observation period, the patient settled into the state known as "nonthyroidal illness syndrome.", Summary: Elevation of TSH in an elderly patient with accidental hypothermia was normalized after restoration of normal body temperature. Elevation of TSH upon accidental hypothermia was probably an adaptive response., Conclusions: In patients with accidental hypothermia, the possibility of an adaptive elevation of TSH should be borne in mind. This clearly warrants further studies of the adaptation of the pituitary-thyroid axis in patients with accidental hypothermia.

Objective: To describe a patient positive for the anti-aquaporin 4 antibody with hypothalamic lesions showing hypothermia, hypotension, hypersomnia, and obesity., Design: Case report., Setting: University hospital., Patient: We describe a 21-year-old woman who was positive for anti-aquaporin 4 antibody and presented with hypothermia, hypotension, and hypersomnia owing to bilateral hypothalamic lesions as the only abnormal clinical finding., Results: Immediate steroid administration resulted in significant improvement of the patient's vital signs and imaging findings; however, her cognitive impairment and sleepiness persisted, and she subsequently developed obesity. Decreased cerebrospinal fluid orexin levels and sleep studies confirmed the diagnosis of narcolepsy due to medical condition. Physicians should be aware that neuromyelitis optica spectrum disorders can initially involve the hypothalamus., Conclusions: We emphasize that measurement of anti-aquaporin 4 antibody is of clinical importance in the differential diagnosis of hypothalamic lesions.