Accidental hypothermia (AH) is a serious medical condition caused by exposure to cold or a decrease in metabolic rate, which can lead to a drop in body core temperature below 35◦C. This condition can cause significant physiological changes in the body, which can have long-lasting effects on multiple organ systems. In this article, we summarize the recent publication "Physiological Changes in Subjects Exposed to Accidental Hypothermia" by Bjertnæs et al. Understanding these changes is crucial for effective treatment and improving patient outcomes, and this article aims to help spread the knowledge.
The severity of AH severity is classified based on body core temperature, with mild hypothermia causing tachypnea and arrhythmia risk, and severe hypothermia below 28°C associated with respiratory rate reduction, increased risk of severe cardiac dysrhythmias, and high mortality rates. The physiological changes caused by hypothermia can have long-lasting effects on multiple organ systems. Successful resuscitation from hypothermic cardiac arrest (HCA) depends on the circumstances causing AH, quality and length of CPR, and types of treatments given, with extracorporeal life support (ECLS) being an established treatment for rewarming. However, survival rates differ between victims of witnessed cardiac arrest and those developing asphyxia and acidosis before the heart stops. The temperature limit to which the human body can be actively cooled followed by hours of hypothermic cardiac arrest and still maintain a potential for successful resuscitation is unknown.
Temperature homeostasis is a thoroughly regulated balance between heat production and dissipation. AH occurs when heat loss is greater than heat production. Skeletal muscles generate heat under physical activity and by shivering thermogenesis, which might increase heat production by up to five times. Cold triggers the formation of the hormone Thyrotropin- Releasing Hormone (TRH) in the brain, which through hormones from the thyroid gland stimulates heat production, together with a noradrenergic stress response. The cold-induced stress response also stimulates heat production from brown adipose tissue, by an uncoupling mechanism in the mitochondria, resulting in heat production instead of the normal production of adenosine triphosphate (ATP). This mechanism is most prevalent in babies, but recent studies suggest that it may play a role in adults as well. The main increase in metabolic rate in adults, however, is through shivering.
The effect of hypothermia on the heart
The article delves deep into how hypothermia affects the heart and is associated with myocardial dysfunction. Previous studies have shown a decrease in cardiac output (CO) during hypothermia that fails to return to normal even after rewarming despite myocardial blood flow (MBF) returning to pre-hypothermic values, and this may be a limiting factor for survival after AH. In rats, when the aortic arch temperature was lowered to 13-15◦C, CO fell to 13% of its control value. As the metabolism decreases by 7% per ◦C fall in body core temperature, a spontaneous breathing patient may experience a 75% reduction in metabolism at a body core temperature of 26◦C, leading to a corresponding decrease in CO. Therefore, if cardiac arrest occurs at or below this temperature, it may be possible to maintain adequate oxygen delivery through external cardiopulmonary resuscitation (CPR). ECG changes during hypothermia may include sinus bradycardia, AV-block, widened QRS complex, QT prolongation, or pulseless electrical activity (PEA). A concept known as "autonomic conflict" was introduced in 2012, which occurs upon rapid submersion and breath holding in water below 15◦C, leading to simultaneous stimulation of both the sympathetic and the parasympathetic nervous systems, causing arrhythmias that frequently lead to unexpected deaths in cold water. Autonomic conflict includes the cold shock response and the diving response, which triggers a strong excitation of cardiac vagal motor neurons causing sinus bradycardia and expiratory apnea. Reduced cardiac contractility has been observed during deep hypothermia, which is believed to be caused by reduced myocyte calcium (Ca2+)-sensitivity in association with increased phosphorylation of Troponin I. Meanwhile, in mild hypothermia, left ventricular contractility increases as compared to the situation at 37◦C, and diastolic relaxation appears to be delayed independent of heart rate. However, more research is needed to determine the extent of myocardial dysfunction in hypothermic patients and the mechanisms behind it.
The effects of vasoactive, antiarrhythmic, and inotropic drugs on victims of AH are unclear, as there is little evidence on the subject. The recommendations for treatment are mostly based on animal experiments, as studies on humans are lacking. After rewarming from severe AH, there is a risk of "rewarming shock," which can lead to acute cardiac failure. Inotropic drugs have been tested to prevent this, but the effects of anti-arrhythmic and inotropic medicines are still uncertain, and international guidelines are cautious about their use. In addition, the hypothermic heart is relatively unresponsive to defibrillation, pacing, and vasoactive and anti-arrhythmic drugs when the body core temperature is below 30°C. Recent meta-analyses have shown that vasopressor medications such as adrenaline or vasopressin have higher success rates in achieving the return of spontaneous circulation (ROSC) in severely hypothermic animals with ventricular fibrillation than placebos. Adrenaline affects cardiac contractility by stimulating myocyte sarcolemmal β-adrenoceptors, allowing for greater Ca2+ influx with each depolarization. This is partly why adrenaline has a positive inotropic effect during normothermia. Levosimendan, a combined calcium sensitizer and phosphodiesterase 3 (PDE3) inhibitor, has shown positive inotropic effects during hypothermia and rewarming in rats but has only been documented anecdotally in humans and is thought to be ineffective in the resuscitation of individuals with a core temperature below 30°C. The use of dopamine and levosimendan as inotropic and vasoactive support for the resuscitation of patients with HCA needs further study.
According to the article, prehospital resuscitation of hypothermic patients should only be rejected if the cause of cardiac arrest is due to a lethal injury, fatal illness, prolonged asphyxia, or incompressible chest stiffness. CPR should start immediately if the patient is diagnosed without pulses after checking for one minute, and a mechanical chest-compression device should be used to avoid interruption during transport. The European Resuscitation Council recommends the same technique for chest compression and ventilation rates for hypothermic patients as for normothermic patients with cardiac arrest. Adrenaline injections should be avoided when the body core temperature is below 30°C, and if ventricular fibrillation persists after three attempts of defibrillation, further attempts should be postponed until the patient is warmed to a body core temperature above 30°C. CPR should be performed continuously for periods of at least five minutes, alternating with periods of no longer than five minutes without CPR in patients with a body core temperature between 28 and 20°C or with an unknown body core temperature. In patients with a body core temperature below 20°C, CPR should be interrupted maximally for 10 minutes.
The effect of hypothermia on Respiration
The article also discusses the potential benefits of cardiovascular responses triggered by breath-holding and face immersion in cases of drowning and asphyxia. Studies have shown that intermittent periods of apnea and face immersion lead to a reduction in cardiac output and an increase in systemic vascular resistance, thereby conserving oxygen and redistributing circulation to the myocardium and brain. The increase in vertebral artery blood flow could potentially increase the rate of brain cooling, reducing the cerebral metabolic oxygen demand and prompting a more successful outcome from drowning. Successful resuscitation after prolonged periods of HCA after submersion has been reported, suggesting that the diving response may contribute to protecting people from brain anoxia.
In cases of AH, respiratory rate and depth decrease as the body temperature falls, leading to CO2 accumulation and respiratory acidosis. Mucociliary function and cough reflexes are also depressed, increasing the risk of secrete stagnation and pneumonia. Studies have shown that lung mechanics are affected during cooling and rewarming, with a drop in lung compliance during deep hypothermia that normalizes upon rewarming, but decreases again on further warming. However, in mechanically ventilated patients undergoing therapeutic hypothermia after cardiac arrest, there were significant decreases in PaCO2 and airway pressure and increased lung compliance. Similarly, in full-term infants with hypoxic ischemic encephalopathy, PaO2/FIO2 ratio increased with a decrease in PaCO2 during hypothermia, suggesting reduced oxygen consumption and CO2 production.
The effect of hypothermia on pH
The pH of a solution changes with temperature, but the ratio of [H+] and [OH-] ions remains the same, maintaining acid/base neutrality. Hypothermia can disrupt intracellular neutrality and cellular function if pH is corrected by adjusting an apparent respiratory alkalosis. Blood gas values measured at 37°C in hypothermic patients may not reflect actual levels. The pH-stat strategy may be delusive and lead to unphysiological blood gas concentrations, while the alpha-stat strategy may be preferred. CO2 is a cerebral vasodilator, and increased levels can counteract a leftward shift of the oxyhemoglobin dissociation curve, facilitating the release of O2 to the tissues. The article discusses two different strategies for managing acid-base balance in hypothermic patients: the pH-stat and alpha-stat strategies. The pH-stat strategy involves correcting for the effect of hypothermia on pH and PCO2, which means that CO2 is added to the breathing mixture to maintain normal levels of PCO2 and pH. This approach is based on the theory that cellular metabolism is affected by pH and temperature changes, and that correcting pH values for temperature leads to a better physiological state. The alpha-stat strategy, on the other hand, accepts the values measured at 37°C without any correction. This approach is based on the idea that intracellular pH is determined by the ratio of protonated to non-protonated intracellular proteins and therefore remains constant, independent of temperature changes. The article suggests that the pH-stat strategy may be more appropriate for children, while the alpha-stat strategy may be more suitable for adults.
The effect of hypothermia on the Liver
The liver produces most of the coagulation factors, and hypothermia strongly inhibits the enzymatic reactions of the coagulation cascade, even when coagulation factor levels were normal. The liver also plays an important role in the metabolism and clearance of drugs from circulation, but displays reduced capability in patients undergoing therapeutic hypothermia. For example, a study assessed the clearance of the drug midazolam and found that the plasma concentrations increased five-fold in hypothermic patients, and there was a >100-fold decrease in systemic clearance of midazolam when BCT fell below 35◦C. This was due to the depressed activity of cytochrome P450 detoxification enzymes responsible for the clearance of many commonly used drugs.
The effect of hypothermia on the Kidneys
Studies show that lowering body core temperature (BCT) in rats can lead to a reduction in renal blood flow and glomerular filtration rate, which may be due to constriction of afferent arterioles and increased blood viscosity. However, a meta-analysis of patients who underwent thoracic aortic surgery in deep hypothermic circulatory arrest found no evidence that hypothermia per se damages the kidneys.
The effect of hypothermia on Electrolyte balance
Non-survivors of AH often present with lactic acidosis, electrolyte, and fluid disturbances. High serum potassium concentrations, traditionally a marker of asphyxia, have been considered a limiting factor for successful resuscitation in victims of HCA. However, there have been reports of successful resuscitation even in patients with extremely high serum potassium concentrations. Generally, AH patients with poor outcomes present with lower pH and higher concentrations of potassium, creatinine, sodium, and lactate in parallel with more severe coagulation disorders. However, decisions to continue or terminate CPR should not be based solely on laboratory parameters.
The effect of hypothermia on the vascular system
An increase in hemoglobin, hematocrit, and blood viscosity is often seen in victims of AH. Induction of hypothermia is associated with extravasation of water and proteins that might result in edema of most organs, except for the lungs, maybe due to the hypothermia-induced increase in pulmonary vascular resistance. The mechanisms responsible for hypothermia-induced fluid shifts are poorly understood. In addition to fluid extravasation, water, and electrolytes are lost due to "cold diuresis" resulting from peripheral vasoconstriction. To prevent further heat loss, fluid replacement should only take place with liquids heated to 38-42◦C prior to intravenous administration. Warm crystalloid fluids should be administered based on general principles for fluid replacement, and vasopressors should be used with caution to antagonize hypotension. The authors suggest that medical providers should be cautious about administering large volumes of isotonic saline, as this may worsen acidosis, and they should also be aware that the use of vasopressors may increase the risk of arrhythmias and compromise peripheral circulation, which can be particularly problematic in patients at risk for frostbite.
Treatment with Extracorporeal life support
Extracorporeal life support (ECLS) is an established treatment for rewarming patients in AH, especially for those presenting with hypothermic cardiac arrest. ECLS activates host defense and can affect the degree of multiorgan failure and outcome after rewarming. ECLS can be carried out with conventional cardiopulmonary bypass (CPB), miniaturized CPB (MCPB), or an ECMO system, with each method having its advantages and disadvantages. ECMO has the additional advantage of extending cardiopulmonary support for days if the patient displays cardiopulmonary insufficiency after rewarming. Recent studies have found that rewarming with ECMO increases the chance of surviving HCA as compared with CPB.
In conclusion, accidental hypothermia (AH) and hypothermic cardiac arrest are medical emergencies that require prompt treatment with the goal of rewarming and resuscitation. Successful resuscitation and rewarming are heavily dependent on the circumstances causing the hypothermia, the quality and length of CPR, and the availability of extracorporeal life support (ECLS). Additionally, male sex, high initial body temperature, low pH, and high serum potassium are factors associated with a lower chance of survival. The use of ECLS for rewarming HCA patients has been shown to significantly increase the chances of survival compared to traditional rewarming methods.
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