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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.)

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.)

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.)

The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Coagulation defects related to severe trauma, trauma-induced coagulopathy (TIC), have a number of causal factors including: major blood loss with consumption of clotting factors and platelets, and dilutional coagulopathy after administration of crystalloids and colloids to maintain blood pressure. In addition, activation of the fibrinolytic system or hyperfibrinolysis, hypothermia, acidosis, and metabolic changes can also affect the coagulation system. All of these directly affect fibrinogen polymerization and metabolism. Other bleeding-related deficiencies usually develop later in massive bleeding related to severe multiple trauma. In major blood loss, fibrinogen reaches a critical value earlier than other procoagulatory factors, or platelets. The question of the critical threshold value is presently the subject of heated debate. A threshold of 100 mg dl(-1) has been recommended, but recent clinical data have shown that at a fibrinogen level of <150-200 mg dl(-1), there is already an increased tendency to peri- and postoperative bleeding. A high fibrinogen count exerts a protective effect with regard to the amount of blood loss. In multiple trauma patients, priority must be given to early and effective correction of impaired fibrin polymerization by administering fibrinogen concentrate.

Aims: It is well known that physostigmine (PHY) and other anticholinesterase (anti-ChE) agents induce hypothermia in rodents but little is known about the mechanism of action. Because arginine vasopressin (AVP) has been found to be an endogenous antipyretic molecule in the CNS, we determined if PHY-induced hypothermia is linked to the endogenous release of AVP., Main Methods: Core temperature and motor activity were monitored by telemetry in rats maintained at an ambient temperature of 25 degrees C. Tail skin temperature was also measured at 30min intervals to estimate nonevaporative heat loss. The central cholinergic antagonist, scopolamine (1mg/kg; ip) and an AVP V(1) receptor antagonist (30microg/kg; ip) were administered during the period of PHY (200microg/kg; sc) induced hypothermia at 10am. Plasma AVP concentration and plasma cholinesterase (ChE) activity were measured at 50min after administration of PHY or scopolamine, respectively., Key Findings: PHY led to a rapid reduction in core temperature concomitant with a marked increase in heat loss from the tail. The hypothermic response of PHY was blocked by the AVP V(1) receptor antagonist. Administration of scopolamine also reversed the hypothermic responses and led to marked elevations in motor activity. Plasma AVP levels increased markedly at 50min after PHY and plasma ChE activity was significantly reduced by PHY., Significance: The results clearly demonstrate that PHY-induced hypothermia was blocked by the AVP V(1) antagonist and associated with elevations in plasma AVP, suggesting a novel role for AVP in the mechanism of action of anti-ChE agents.

Background: alpha(2)-Adrenoceptor agonists are currently used as primary sedative agents in high dependency patients who are at high risk of sepsis. Clinical surveillance of such patients relies in part on their ability to mount appropriate responses to infection, in particular thermal responses. Thermoregulatory responses to infection are well studied in the rat and in this species, and humans, infection can induce febrile, hypothermic, or mixed hypothermic and febrile responses. The involvement of noradrenergic systems in thermal responses to infection prompted the hypothesis that ligands that act on adrenoceptors may interfere with the normal thermal responses to infection., Methods: In this study on rats, the effect of infusion of the selective alpha(2)-agonist, mivazerol, on hypothermic and plasma corticosterone responses induced by bacterial lipopolysaccharide (LPS) was investigated., Results: Clinically effective doses of mivazerol (4.8 and 10 microg kg(-1) h(-1)) had no effect on body temperature alone. However, mivazerol significantly inhibited the typical thermoregulatory response to bacterial LPS in a dose-dependent manner. This effect was mimicked by the selective alpha(2)-agonist, UK14304-18 (6 microg kg(-1) h(-1)), and antagonized by the alpha(2)-antagonist, RX811059A (7 microg kg(-1) h(-1)). The alpha(2)-ligands had no effect on basal or LPS-induced corticosterone levels., Conclusions: These data suggest that early thermoregulatory responses to infection can be selectively antagonized by ligands that activate alpha(2)-adrenoreceptors. High dependency patients receiving alpha(2)-adrenoceptor agonists may not be capable of mounting a normal thermal response to infecting organisms and clinical monitoring using core temperature to detect infection may therefore be unreliable in these vulnerable patients.

Introduction: There are no available data addressing the potential clinical risks of open-water swimming competitions., Objective: Address the risks of hypothermia and hypoglycemia during a 10-km open-water swimming competition in order to alert physicians to the potential dangers of this recently-introduced Olympic event., Methods: This was an observational cross-sectional study, conducted during a 10-km open-water event (water temperature 21 degrees C). The highest ranked elite open-water swimmers in Brazil (7 men, 5 women; ages 21+/-7 years old) were submitted to anthropometrical measurements on the day before competition. All but one athlete took maltodextrine ad libitum during the competition. Core temperature and capillary glycemia data were obtained before and immediately after the race., Results: Most athletes (83%) finished the race with mild to moderate hypothermia (core temperature <35 degrees C). The body temperature drop was more pronounced in female athletes (4.2+/-0.7 degrees C vs. male: 2.7+/-0.8 degrees C; p=0.040). When data from the athlete who did not take maltodextrine was excluded, capillary glycemia increased among athletes (pre 86.6+/-8.9 mg/dL; post 105.5+/-26.9 mg/dL; p=0.014). Time to complete the race was inversely related to pre- competition body temperature in men (r=-0.802; p=0.030), while it was inversely correlated with the change in capillary glycemia in women (r=-0.898; p=0.038)., Conclusion: Hypothermia may occur during open-water swimming events even in elite athletes competing in relatively warm water. Thus, core temperature must be a chief concern of any physician during an open-water swim event. Capillary glycemia may have positive effects on performance. Further studies that include more athletes in a controlled setting are warranted.

Background: A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSeven), may be used to improve haemostasis but potential interactions with different volume expanders are poorly understood., Methods: Clot formation was measured by thromboelastography (TEG) using blood from healthy volunteers. In vitro effects of rFVIIa with haemodilution, acidosis, and hypothermia were examined. Conditions were induced by dilution with NaCl (0.9%), lactated Ringer's solution, albumin 5%, or hydroxyethyl starch (HES) solutions [MW (molecular weight) 130-670 kDa]; by adjusting pH to 6.8 with 1 M HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer; or by reducing temperature to 32 degrees C. We also studied the effect of low vs high MW HES (MW 200 vs 600 kDa) and rFVIIa on in vivo bleeding time (BT) in rabbits., Results: Haemodilution progressively altered TEG parameters. rFVIIa improved TEG parameters in the presence of acidosis, hypothermia or 20% haemodilution (P<0.05). At 40% haemodilution, the rFVIIa effect was diminished particularly with high MW HES. In vivo, rFVIIa shortened the BT (P<0.05) with low but not high MW HES., Conclusions: Efficacy of rFVIIa was affected by the degree of haemodilution and type of volume expander, but not by acidosis or hypothermia.

Purpose: We aimed to study effect of melatonin on the blood oxygen transport during hypothermia and rewarming in rats., Material/methods: Cold exposure was performed on male rats (body weight 220-270 g, n=48) for 120 minutes under the box water temperature of 19 degrees C; rewarming took the next 120 min, with a mean rate of 0.06 degrees C/min. Melatonin was administered intraperitoneally 30 min before the cold exposure (bolus doses of 0.1, 1 or 10 mg/kg, or 1 mg/kg*day for 4 days). Haemoglobin-oxygen affinity was evaluated by p50 (blood pO2 at its 50% O2 saturation) determined by the "mixing" method at 37 degrees C, pH 7.4 and pCO2 40 mm Hg (p50stand) and at actual pH, pCO2 and temperature (p50act)., Results: After hypothermia and rewarming, the values of p50stand and p50act were 31.5+/-0.28 and 30.2+/-0.61 mm Hg, respectively. The 0.1 mg/kg of melatonin virtually did not change these values, whereas the larger doses increased them. This effect was maximal after the prolonged (4 days) melatonin administration: p50stand rose by 5.4% (p<0.05) and p50act--by 12.9 (p<0.05) compared with rats without the melatonin treatment. Melatonin affected the mechanisms of O2 transport by decreasing the haemoglobin-oxygen affinity (shifting the oxygen dissociation curve of haemoglobin rightwards) and promoting the tissue oxygenation, thereby enhancing the body's resistance to cold., Conclusions: The melatonin effect mediated by haemoglobin-oxygen affinity change may be used for the correction of metabolic disorders and the improvement of the body's resistance to low environmental temperature.

Nitric oxide (NO) has high affinity to heme and by interaction with oxyhemoglobin (HbO2) is converted into nitrate to form methemoglobin (MetHb) as a side product. In combining with deoxy-Hb NO yields a stable molecule of nitrosyl-hemoglobin (HbFe(II)NO) that can further be converted into nitrate and hemoglobin (Hb). In addition, Hb was shown to transport NO in a form of S-nitrosohemoglobin (SNO-Hb). These features of the Hb and NO interaction are important for blood oxygen transport including hemoglobin-oxygen affinity (HOA). The present investigation was aimed to study the blood oxygen transport indices (pO2, pCO2, pH, HOA, etc.) in rats under hypothermia combined with a modification of L-arginine-NO pathway. To modify the L-arginine-NO pathway, rats were administered with N(G)-nitro-L-arginine methyl ester (L-NAME), L-arginine, or sodium nitroprusside (SNP) intravenously before cooling. A substantial impairment of oxygen delivery and development of hypoxia, with an important contribution of HOA into the latter accompanied the deep hypothermia in rats. All the experimental groups developed metabolic acidosis, less pronounced in rats treated with L-arginine only. In the experiments with a modification of the L-arginine-NO pathway, an enhanced cold resistance, attenuated oxygen deficiency, and a weaker oxyhemoglobin dissociation curve (ODC) shift leftwards were observed only after the administration of L-arginine. Neither SNP nor L-NAME had not any protective effects. L-Arginine lowered the value of standard P50 (pO2, corresponding to 50% Hb saturation with oxygen at 37 degrees C, pH 7.4, and pCO2 = 40 mmHg). The actual P50 (at actual pH, pCO2 and temperature) decreased by approximately 15 mmHg and was significantly higher than that under hypothermia without the drug treatment (21.03 +/- 0.35 vs 17.45 +/- 0.60 mmHg). NO also can contribute to this system through different mechanisms (HOA modification, vascular tone regulation, peroxynitrite formation, and effects).

A 49-year-old man with herpes simplex encephalitis at age 22 was admitted with hypotension (90/60 mm Hg) and hypothermia (33.7 degrees C). His blood pressure was 80-90/50-60 mm Hg, with temperatures averaging 35 degrees C, for at least 3 years before admission. Evaluation of his hypothermia and hypotension revealed a low free triiodothyronine, low normal thyrotropin, luteinizing hormone < 2 mIU/L, follicle stimulating hormone <3 mIU/L, and low testosterone of 1.39 ng/dL. A baseline cortisol of 13.9 microg/dL was stimulated to 41.8 microg/dL with corticotropin, indicating he had partial anterior hypopituitarism with an intact pituitary-adrenal axis. Posterior pituitary function was normal. MRI revealed a "bright" posterior pituitary on a T1-weighted image, further indicating a normal posterior pituitary. Extensive decreased T1-weighting on MRI in the right and left temporal lobes was consistent with encephalomalacia. With thyroid hormone replacement, his blood pressure increased to 110/70 mm Hg with a temperature of 37 degrees C.

The purpose of this study was to determine whether serum potassium concentration (SK) can predict resuscitation outcome in a canine model of severe hypothermic cardiac arrest. Fifteen adult mongrel anesthetized dogs were immersed to the neck in a 4 degrees C water bath and ventilated with room air, with ventilation halved at 45 min and stopped at 90 min. After cardiac arrest, 14 of the dogs were kept in the water bath for periods of 2-7 h, and another was held in arrest for 13 h. Following 10 min of closed chest cardiopulmonary resuscitation (CPR) (simulating a short transport time to a hospital), animals were placed on cardiopulmonary bypass and rapidly rewarmed. With appearance of ventricular fibrillation, animals were defibrillated up to three times. Standard advanced cardiac life support was initiated at a core temperature (Tc) of 30 degrees C. Eight of the 15 dogs had return of spontaneous circulation (ROSC), at Tc ranging from 30.4 to 36.5 degrees C. The eight dogs with ROSC did not differ from the seven without ROSC in time to arrest (128 +/- 48 versus 128 +/- 23 min) (mean +/- SD) or Tc at arrest (18.1 +/- 2.2 versus 17.9 +/- 3.1 degrees C), but had higher Tc at the end of the arrest period (9.7 +/- 3.0 versus 5.2 +/- 2.0 degrees C), reflecting a shorter arrest period in the dogs with ROSC (225 +/- 95 versus 420 +/- 193 min). SK (mEq liter(-1)) did not differ between dogs with and without ROSC at baseline (3.5 +/- 0.4 versus 3.7 +/- 0.4) or at arrest (3.4 +/- 0.7 versus 4.3 +/- 2.2), but there was a trend toward higher SK at the end of arrest in the group without ROSC (4.6 +/- 1.5 versus 9.4 +/- 6.3; range 3.2-7.8 versus 3.5-21.4; p = .053). SK was similar after 10 min of CPR in the groups with and without ROSC (6.6 +/- 2.9 versus 9.0 +/- 2.4; range 2.5-11.1 versus 4.5-11.0; p = .107). SK after 10 min of CPR was higher in some animals with ROSC (9.6 and 11.1) than in others which did not have ROSC (4.5 and 7.9). We conclude that very high SK following prolonged hypothermic cardiac arrest may be suggestive of an inability to resuscitate. However, SK after both prolonged hypothermic cardiac arrest and a brief period of CPR is not a good predictor of resuscitation using cardiopulmonary bypass rewarming in an animal model.

Study Objective: To evaluate the accuracy of the nasal septum site for pulse oximetry measurement of arterial oxyhemoglobin saturation (SpO2) in hypothermic patients., Design: Prospective study., Setting: Operating theater of a public hospital., Patients: Fourteen hypothermic (temperature 34.6 degrees C to 36 degrees C) patients (eight males and six females) undergoing a major surgical abdominal procedure., Interventions: Fifty estimations of SpO2 were simultaneously made by a flex sensor probe applied at the nasal septum site and by a finger sensor probe using a pulse oximeter. The results were compared with arterial oxygen saturation (SaO2) as measured by arterial blood gas sampling., Measurements and Main Results: In 18% of the estimations, the finger probe produced unmeasurable results. The nasal septum probe did not produce any unmeasurable results (p = 0.0055). In the remaining 41 estimations, a comparison of the measurements from the nasal septum versus the controls showed a mean difference of 0.15 and a limit of agreement of -0.106 to +0.398. A comparison difference of 2.27 and a limit of agreement of 1.986 to 2.551., Conclusion: Monitoring SpO2 at the nasal septum site is more reliable than monitoring it at the finger site in hypothermic patients.

Because spermine and spermidine have caused hypothermia in rodent experiments, we tested the hypothesis that these polyamines accumulate in some elderly convalescent patients and that this accumulation could predispose to lower body temperature. Fourteen healthy young, seven healthy older, and 47 convalescent elderly subjects had serum spermine and spermidine concentrations measured by high-pressure liquid chromatography. The mean +/- SD spermine values were 18 +/- 10, 24 +/- 15, and 40 +/- 54 ng/ml, respectively. The values for spermidine were 28 +/- 10, 38 +/- 29, and 76 +/- 46 ng/ml, respectively. The differences between the young and convalescent elderly were statistically significant for both compounds. Rectal temperatures were measured in 39 elderly convalescent subjects with a thermometer designed for accuracy at low temperatures. These subjects were stratified into a warm and cool half based on a median rectal temperature of 37 degrees C. There was an association between having high spermine levels and being in the cool half of the elderly convalescent group (P less than 0.05). We conclude that some elderly convalescent patients have high levels of spermidine and spermine and that these high spermine levels may be associated with lower body temperature.