The potential risks associated with perioperative hypothermia have been extensively studied and can be classified into several broad categories (Table 2). Coagulopathic concerns in perioperative hypothermia include impaired platelet aggregation and increased blood loss. Inhibition of platelet aggregation in the setting of hypothermia has been demonstrated both in vivo and in vitro . Platelet activation in normal volunteers demonstrates inhibition of platelet aggregation at hypothermic temperatures, through both impaired release of thromboxane A2, which is necessary for the initial plug formation, and enzymes in the coagulation cascade. Notably, these inhibitory effects of hypothermia were all completely reversed by rewarming the blood to 37 °C . Mildly hypothermic temperatures seem to lead to increased blood loss. In one systematic review of blood loss in mildly hypothermic patients, the relative risk for transfusion increased by approximately 22%, and a single degree Celsius significantly increases blood loss by approximately 16% .
Hypothermia has been shown to induce mechanisms for increased infection risk including vasoconstriction, impaired tissue healing, and reduced immune cell function. In vitro models demonstrate significant impairments in human peripheral polymorphonuclear leukocyte chemotaxis, phagocytic engulfment, phagocytic digestion, and oxygen consumption in temperatures less than 37 °C . Clinical effects of hypothermia include decreased white blood cell counts, as well as suppression of hyperinflammatory responses . Sympathetic stimulation causes vasoconstriction in skin, arms, and legs leading to diminished skin and extremity blood flow, thus potentially increasing risk for bed sores and surgical site infection . Perioperative hypothermia prolongs postoperative catabolism, and inhibits deposition of collagen, thus contributing to impaired tissue healing . The link between perioperative hypothermia and increased wound infection rates has been demonstrated in multiple surgical settings, which include trauma laparotomy, colorectal resection, hernia repair, varicose vein ablation, and breast surgery [27,28,29,30,30].
Electrolyte disturbances during perioperative hypothermia include a compartmental shift of potassium ions, leading to hypokalemia as low as 2.3 ± 0.4 mEq/l observed in some patients [31, 32]. Similarly, intracellular shifting of magnesium and phosphate should be monitored. Additional solute shifts encountered during hypothermia include hyperglycemia, whereby lowering of basal body temperature impairs insulin release, increasing glucose levels, leading to impairment of leukocyte function and thus decreased immunity . Alterations in the absorption of the ascending loop of Henle, as well as systemic vasoconstriction leading to reflex diuresis, are thought to contribute to cold-induced diuresis seen in some patients, necessitating the vigilant monitoring of volume status .
It has been shown that hypothermia increases drug concentration and prolongs drug response in multiple clinical and animal studies. Numerous mechanisms contribute to reduced hepatic drug clearance including reduction in blood flow, alterations in the plasma protein and drug binding properties, and intrinsic enzymatic rate fluctuations. Similarly, changes observed in renal filtration, active secretion, and absorption all contribute to the altered pharmacokinetics in hypothermic patients .
Hypothermia impacts the pharmacological effect of muscle relaxants, volatile anesthetics, opiate anesthetics, and β-adrenoceptor agonists. Heier et al. reported that the duration of action of and time to spontaneous recovery from vecuronium-induced muscle blockade increased in the setting of 34.5 °C . Leslie et al. demonstrated that, in the setting of 34 °C, atracurium duration of action was significantly increased in healthy volunteers . In regards to volatile anesthetics, decreases in isoflurane requirements have been observed in children as temperature decreases, from 1.69 ± 0.14% at 37 °C to 1.22 ± 0. 5% at 31 °C, theorized to be an effect from the reduction in CYP2E1 activity seen in reduced temperatures . Puig et al. demonstrated that the effectiveness of morphine significantly decreased at 30 °C as compared to 40 °C in pig ileum, while in another study a single 1 mg/kg bolus injection of morphine in dogs led to significant decrease in mean arterial pressure in hypothermia but not in normothermia [38, 39]. β-Adrenergic mediated cardiovascular responses have been shown to be significantly blunted when core temperatures were kept at 33 °C .
Cardiovascular effects of hypothermia include systemic hypotension, bradycardia, and prolongation of the QTc interval. Therapeutic hypothermia has been positively associated with a prolongation of the QTc (> 460 ms), increasing risk for ventricular fibrillation and ventricular tachycardia independently . Increased catecholamine levels seen in hypothermic patients can lead to increased myocardial oxygen demand and cardiac output. Common ECG changes observed include increased PR interval, QRS widening, and J-wave appearance, with subsequent significant increases in arrhythmias such as atrial fibrillation and ventricular fibrillation when temperatures are reduced below 30 °C [33, 42].
Shivering can be induced in patients with core temperature reductions as low as 0.5 °C. This physiological stressful event is triggered through increased neuronal efferent outflow to skeletal muscle and feedback oscillations due to spindle stretch reflexes, leading to involuntary oscillatory movements . Therapeutic interventions to prevent shivering and its complications (increased metabolic rate, oxygen consumption, and CO2 production leading to acidosis) include alpha-2 agonists (clonidine, dexmetatomidine) that lead to reduced sympathetic activity and central regulation of vasoconstrictor tone, as well as meperidine, mechanistically thought to be induced through kappa opiate anti-shivering properties [43, 44].
After the conclusion of the hypothermic period, the phenomenon of rebound hypothermia is an independent predictor of increased mortality and neurologic morbidity in cardiac arrest patients who have undergone therapeutic hypothermia [33, 45].