Serum enzyme levels during experimental hypothermia in man.

Deep surgical and accidental hypothermia cause elevations in serum enzyme levels, probably because of ultrastructural cell damage. Many variables hinder work on this problem in the clinical situation and the mechanism is obscure. Accordingly, enzymes and other physiological parameters were monitored in four subjects cooled four times, under controlled conditions in the laboratory, to a mean auditory canal temperature of 35.0 degrees C. Mild hypovolaemia and acidosis is occurred. Serum enzyme levels did not change significantly and it is concluded that elevations due to hypothermia cannot be studied in laboratory experiments on healthy volunteers who can only safely be cooled to 35 degrees C.     

Can the nervous system functions of mammals be restored during deep cooling without warming? New facts and the evolution of views

The article provides a review of publications on the most recent theory of cold-induced paralysis and cold-induced cells dying in mammals. Based on this theory, a method of rehabilitation of the nervous system functions was proposed in case of cold-induced paralysis with no tissue warming. The facts were provided describing rehabilitation of the physiological functions under deep hypothermia. Using this own and published data, the author provided the physiological analysis of the new data. He concluded that the physiological functions of homoiothermal animals and man can be maintained under very low body temperature. The author proposed the physiological actions to recover humans from deep accidental (in case of accidents) hypothermia. The new theory and the new facts allowed to propose new ideas on the origin to homoiothermy and natural hibernation in animals.     

Blocking of cold paralysis of physiological functions

For more than 100-year history of studying hypothermia a rewarming of a cooled organism was always considered as the only method of restoring the cold-paralysed physiological functions and the vital activity of an overcooled organism of homoiothermal animals and humans. The paper gives the results of applying the method developed at our Laboratory, of restoring the cold-paralysed important physiological functions after a continuous cooling of rats, without rewarming the animals.     

Influence of cooling rate on activity of ionotropic glutamate receptors in brain slices at hypothermia

Hypothermia is a known approach in the treatment of neurological pathologies. Mild hypothermia enhances the therapeutic window for application of medicines, while deep hypothermia is often accompanied by complications, including problems in the recovery of brain functions. The purpose of present study was to investigate the functioning of glutamate ionotropic receptors in brain slices cooled with different rates during mild, moderate and deep hypothermia. Using a system of gradual cooling combined with electrophysiological recordings in slices, we have shown that synaptic activity mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in rat olfactory cortex was strongly dependent on the rate of lowering the temperature. High cooling rate caused a progressive decrease in glutamate receptor activity in brain slices during gradual cooling from mild to deep hypothermia. On the contrary, low cooling rate slightly changed the synaptic responses in deep hypothermia. The short-term potentiation may be induced in slices by electric tetanization at 16  °C in this case. Hence, low cooling rate promoted preservation of neuronal activity and plasticity in the brain tissue.     

Physiological blocking of the mechanisms of the cold death

Physiological mechanisms of the cold paralyses of the main, most important functions during deep hypothermia of a homeothermic organism were studied. The reasons for the organism death upon deep cooling were revealed. The cold paralyses and the following organism death were shown to be accounted for to a great extent by the specific impairments in the ion exchange between the nervous cells of vegetative brain centers and the intercellular medium and the blood. Removing these impairments with the help of the methods developed in the authors laboratory allows the lost physiological functions of an organism to be restored for a time without rewarming the body.     

Accidental deep hypothermia with cardiac arrest. Prompt complete recovery after rewarming by extracorporeal circulation. Case report

BACKGROUND: Deep accidental hypothermia (core temperature <28 degrees C) is an uncommon medical emergency requiring rapid active core rewarming. Extracorporeal circulation has become the treatment of choice for deep hypothermic patients with cardiac arrest. CASE REPORT: We report on a 30-year-old patient who suffered from deep accidental hypothermia (core temperature 24.8 degrees C) and cardiac arrest by prolonged exposure to a cold urban environment as a consequence of severe ethylalcohol intoxication. The rewarming with the aid of extracorporeal circulation was initiated shortly after his arrival at the hospital. External cardiac massage was maintained until full ECC fl ow was established. The patient was weaned from extracorporeal circulation after 157 min, awaked 4 hours later and consequently extubated within 16 hours after rewarming with no neurological impairment. At 3-week follow-up, the patient was fully re-integrated in his work and personal life. CONCLUSION: This case demonstrates the excellent prognosis of a young victim in the case of deep accidental hypothermia with cardiac arrest, provided that deep hypothermia precedes the cardiac arrest and rewarming by extracorporeal circulation is immediately applied. Simultaneous ethyl alcohol intoxication can be considered a protective factor improving the patient's outcome. Complete recovery was achieved within 24 hours after the accident.     

Effect of calcium ion level in blood on physiological functions in rat subjected to immersion hypothermia

I.v. administration of disodium salt of the ethylenediamine tetra-acetic acid to continuously immersed white rats intensified the rats' amplitude and rate of the respiration movement. I.v. administration of calcium chloride to the cooled rats diminished by 11.3% the respiration movement amplitude and by 20.7%--the muscles electrical activity. The findings confirm important role of the calcium ions in infringement of physiological functions under conditions of hypothermia.     

Physiological blocking of the mechanisms of cold death: theoretical and experimental considerations

The cold inhibited functions of skin thermoreceptors, of the thermoregulation centre, and the respiration centre during deep hypothermia can be restored without rewarming the body. The methods used were developed to test the hypothesis that during deep hypothermia calcium ion concentration [Ca²⁺]_i in the cytoplasm increases. This causes a perturbation of cell metabolism, the impairment of cell membrane function that cause the inhibition of cell functioning, resulting in cell death. Such an increase in [Ca²⁺]_i most likely would result from an energy deficit in a deeply cooled cell, which would compromise the processes that maintain the [Ca²⁺]_i at about 10⁻⁷ M. These processes require large amounts of energy since they occur against a large concentration gradient. With the use of EDTA the extracellular concentration of Ca²⁺ has been lowered by 15–27%, so reducing the concentration gradient for Ca²⁺ between the cell and the medium and in consequence facilitated the process the extrusion of cell Ca²⁺.

During a period of cooling, sufficient to impair normal functioning, the experimental lowering of blood Ca²⁺ allowed the restoration of normal function without the need to rewarm. In such cases the animals survived after cooling the body to temperatures at which they would normally have succumbed. The data presented support the stated hypothesis that the impairment of cellular function in mammals by low temperatures is the result of an uncorrected rise in [Ca²⁺]_i.     

Resuscitation from cardiopulmonary arrest during accidental hypothermia due to exhaustion and exposure.

A 16-year-old boy with accidental hypothermia and cardiopulmonary arrest due to exhaustion and exposure was resuscitated after warming measures -- hot wet towels, hot water bottles, and hot water enemas and gastric lavage -- had increased his rectal temperature from 25.2 to 28.0 degrees C. Despite prolonged cardiopulmonary arrest, recovery was almost complete, with no evident cerebral damage. Cardiopulmonary resuscitation procedures should not be abandoned until the body temperature is more than 30 degrees C, because the prognosis in cases of accidental hypothermia without associated disease is excellent if cardiac function can be re-established.     

Is oxygen supply a limiting factor for survival during rewarming from profound hypothermia?

It has been postulated that unsuccessful resuscitation of victims of accidental hypothermia is caused by insufficient tissue oxygenation. The aim of this study was to test whether inadequate O2 supply and/or malfunctioning O2 extraction occur during rewarming from deep/profound hypothermia of different duration. Three groups of rats (n = 7 each) were used: group 1 served as normothermic control for 5 h; groups 2 and 3 were core cooled to 15 degrees C, kept at 15 degrees C for 1 and 5 h, respectively, and then rewarmed. In both hypothermic groups, cardiac output (CO) decreased spontaneously by > 50% in response to cooling. O2 consumption fell to less than one-third during cooling but recovered completely in both groups during rewarming. During hypothermia, circulating blood volume in both groups was reduced to approximately one-third of baseline, indicating that some vascular beds were critically perfused during hypothermia. CO recovered completely in animals rewarmed after 1 h (group 2) but recovered to only 60% in those rewarmed after 5 h (group 3), whereas blood volume increased to approximately three-fourths of baseline in both groups. Metabolic acidosis was observed only after 5 h of hypothermia (15 degrees C). A significant increase in myocardial tissue heat shock protein 70 after rewarming in group 3, but not in group 2, indicates an association with the duration of hypothermia. Thus mechanisms facilitating O2 extraction function well during deep/profound hypothermia, and, despite low CO, O2 supply was not a limiting factor for survival in the present experiments.     

Hemodynamic changes before and after short and prolonged periods of hypothermia in dogs

Dogs were cooled to 30 °C and either rewarmed immediately or after being kept at 30 °C for 6 hr. The acid-base balance was determined and hemodynamic data were collected. At the beginning of the rewarming period the arterial blood pressure and the left ventricular work output were increased after short hypothermia, but not after prolonged hypothermia. The survivors of prolonged hypothermia had had a higher arterial blood pressure and left ventricular work output before cooling began than did nonsurvivors. An additional load on the cardiovascular system (A-V shunt) was incompatible with survival. The so-called rewarming shock, therefore, appears to be cardiogenic, and the treatment of the victims of accidents causing hypothermia due to exposure should be directed against cardiogenic shock.     

Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

Exposure of rats to 1-15 Gy gamma radiation (60Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.     

Endocrine regulation of carbohydrate metabolism in hypometabolic animals

Experimental hypothermia and natural hibernation are two forms of hypometabolism with recognized physiological changes, including depression of endocrine and metabolic functions. To better understand functional changes, helox (i.e., helium and oxygen (80:20) mixtures) and low ambient temperatures have been used to induce hypothermia in hamsters and rats. Both clinical and biological survival, i.e., survival without recovery and survival with recovery from hypothermia, respectively, are related to depth and length of hypothermia. In the rat, body temperatures of 15 degrees C for periods greater than 6-10 h greatly restrict biological survival. The role of glucocorticoids in enhancing thermogenic capacity of rats was assessed using triamcinolone [correction of triamcinalone] acetonide. In the hamster, treatment with cortisone acetate prolonged both clinical and biological survival. Hypothermic hamsters continue utilizing circulating glucose until they become hypoglycemic and die. Hypothermic rats do not utilize glucose and respond with a significant hypoinsulinema. The role of endocrines in the regulation of carbohydrate homeostasis and metabolism differs in hibernation and hypothermia. Glucocorticoids influence the hypothermic response in both species, specifically by prolonging induction of hypothermia in rats and by prolonging survival in hypothermic hamsters.     

Survival time prediction in marine environments

One of the most challenging questions regarding aquatic search and rescue or recovery operations is the physiological status of the victims. A Probability of Survival Decision Aid (PSDA) was developed to predict survival time for hypothermia and dehydration during prolonged exposure in marine environments for a wide range of environmental conditions. PSDA calculates the survival time of a victim in the water or floating in an emergency craft as a function of environmental conditions, clothing and human anthropometric parameters. PSDA consists of a human thermoregulatory model and a Graphic User Interface, which manages inputs, run the model and display outputs. PSDA was validated using historical survival data and reports of accidental water immersions. For eight immersion victims of known height and weight, the victims’ predicted survival time was either in close agreement or greater than the observed survival time. Additional physiological data from case histories and/or controlled studies are needed to validate the PSDA and to expand its application to other hazardous situations. PSDA is intended to assist the search and rescue personnel in operation optimal planning.     

Myocardial gene expression profiling of rewarming shock in a rodent model of accidental hypothermia

Background

Severe accidental hypothermia represents a cardiovascular emergency associated with high mortality and poor recovery of cardiac function. The biochemical changes occurring within the heart during the development of hypothermia and subsequent resuscitation are not known.

Methods

By mRNA expression profiling, we have characterized gene expression changes occurring within the myocardium in an intact rat model of accidental hypothermia during cooling to a core temperature of 15 °C and subsequent rewarming to 37 °C. During the rewarming phase, these animals develop a profound low-output cardiac failure.

Results

Hypothermia induces expression of known mediators of thermotolerance, including heat-shock protein 70 and several factors involved in protection against apoptotic cell death. Upregulation of genes involved in autophagy and increased abundance of autophagosomal vesicles suggest involvement of autophagic degeneration in the development of myocardial dysfunction occurring during rewarming from hypothermia. Rewarming from hypothermia also induces expression of several pro-inflammatory genes involved in the nuclear factor kappa B (NFκB) signaling cascade.

Conclusions

Our data demonstrate that rewarming from hypothermia is associated with the induction of a cellular stress–response, including upregulation of autophagy and activation of pro-inflammatory signaling cascades. These data provide a framework for understanding the molecular changes that occur during induction of and rewarming from severe hypothermia, and identifies potential targets for cardioprotective interventions in resuscitation of victims of hypothermia.     

Effect of Mild Hypothermia on the Coagulation-Fibrinolysis System and Physiological Anticoagulants after Cardiopulmonary Resuscitation in a Porcine Model

The aim of this study was to evaluate the effect of mild hypothermia on the coagulation-fibrinolysis system and physiological anticoagulants after cardiopulmonary resuscitation (CPR). A total of 20 male Wuzhishan miniature pigs underwent 8 min of untreated ventricular fibrillation and CPR. Of these, 16 were successfully resuscitated and were randomized into the mild hypothermia group (MH, n = 8) or the control normothermia group (CN, n = 8). Mild hypothermia (33°C) was induced intravascularly, and this temperature was maintained for 12 h before pigs were actively rewarmed. The CN group received normothermic post-cardiac arrest (CA) care for 72 h. Four animals were in the sham operation group (SO). Blood samples were taken at baseline, and 0.5, 6, 12, 24, and 72 h after ROSC. Whole-body mild hypothermia impaired blood coagulation during cooling, but attenuated blood coagulation impairment at 72 h after ROSC. Mild hypothermia also increased serum levels of physiological anticoagulants, such as PRO C and AT-III during cooling and after rewarming, decreased EPCR and TFPI levels during cooling but not after rewarming, and inhibited fibrinolysis and platelet activation during cooling and after rewarming. Finally, mild hypothermia did not affect coagulation-fibrinolysis, physiological anticoagulants, or platelet activation during rewarming. Thus, our findings indicate that mild hypothermia exerted an anticoagulant effect during cooling, which may have inhibitory effects on microthrombus formation. Furthermore, mild hypothermia inhibited fibrinolysis and platelet activation during cooling and attenuated blood coagulation impairment after rewarming. Slow rewarming had no obvious adverse effects on blood coagulation.     

Cold Injury in Civil Disaster

Patients exposed to cold environment following a disaster may be suffering from local cold injury or from systemic cold injury (accidental hypothermia). The treatment of the former is well established and consists of rapid rewarming of the frozen parts and physical therapy; early amputation is not advisable. Recommendations for the assessment and treatment of total body cooling, based on case reports of accidental hypothermia, on the results of animal experiments and on the clinical experience with induced hypothermia, are not well established and are controversial. Since, at temperatures below 30° C., death may be caused by cardiac arrhythmias and since, at this low level, spontaneous rewarming may not be possible, active rewarming is recommended at this stage. At a higher temperature level, vigorous warming is dangerous, and the patient''s own regulatory mechanisms should be allowed to restore the temperature.     

Effects of prostaglandin antagonist SC-19220 on body temperature and on hyperthermic responses to prostaglandin E-1 and leukocytic pyrogen in the cat.

Intravenous injection of SC-19220 (3-9 mg/kg) caused dose-related hypothermic responses in cats. Repeated administration of SC-19220 resulted in tolerance to its hypothermic action. During SC-19220-induced hypothermia, the hyperthermic activity of both prostaglandin E-1 and leukocytic pyrogen was reduced or abolished. Neither prostaglandin E-1 nor leukocytic pyrogen was antagonized when given shortly after recovery from SC-19220-induced hypothermia or by doses of SC-19220 which did not cause hypothermia. Although these results may indicate a role of prostaglandins in normal physiological thermoregulation, it is also possible that production of hypothermia by SC-19220 is unrelated to prostaglandin antagonism.     

Physiological functions of bile acids in the body

A literary review and own data on the various physiological functions of bile acids in organism are given. The modern state of the problem on the bile salt role in lipid assimilation is reflected. The other functions of bile salts in the digestive tract are described. The regulating influence of bile acids on some metabolic processes in organism is shown. The alteration of membrane enzyme activity under the influence of bile acids possessing the detergent properties may play an important role in different pathological conditions. The significance of bile acid metabolism under physiological and pathological conditions is underlined.     

A Mathematical Model For Analysing Cellular Age-Response Functions In Terms of Physiological Age

A mathematical model is presented which facilitates the analysis of cellular age-response functions in terms of the physiological ages of the cells. Age-response functions are generally determined by obtaining synchronous cohorts of cells and measuring the sensitivity of the cohorts to the treatment agent at different times after selection (i.e., at several different chronological ages). the model described here uses data on the [³H]TdR labelling patterns of the cell population to determine the distribution of physiological ages for the cohorts at the times of treatment. the age-response function data are then analysed in terms of the physiological ages of the cells. the compartments used in the analysis may be chosen according to the biology of the system and the wishes of the experimenters and not imposed by the variability of the phase durations. the application of the model is illustrated using the age-response functions for EMT6 cells exposed to radiation and HeLa cells exposed to hydroxyurea.