Rewarming: facts and myths from the systemic perspective

Abstract

Introduction: Rewarming is a delicate phase of therapeutic hypothermia (TH). Adverse consequences of rewarming on the whole body may seriously limit the protective effects of hypothermia, leading to secondary injury. Thus, understanding, predicting, and managing possible systemic side effects of rewarming is important for guaranteeing TH efficacy. The aim of this brief report is to describe rewarming effects from a systemic perspective. Hemodynamics and imbalance in oxygen consumption and delivery: TH linearly decreases the metabolic rate of homeothermic organisms. During the cooling process, tissue oxygen consumption (VO2) slows by roughly 6%/��C reduction in body temperature [1,2], obeying the van't Hoff-Arrhenius law, which states that the rate of a biochemical reaction is halved for each 10��C decrease in temperature. The reduction in brain metabolism is similar [3]. In contrast, during rewarming, the possible appearance of a mismatch between total body oxygen demand and oxygen delivery (DO2) [4] has been recognized since the pioneer works of Hegnauer and colleagues on dogs [5] and Bigelow on humans [6]. Bigelow has described this side effect of rewarming as rewarming shock: 'This syndrome of acute acidosis, or rewarming shock, was characterized by a progressive decline in blood pH [...] associated with respiratory inadequacy [...]. A fall in blood pressure and tachycardia were features in some cases'. In more recent studies, rewarming shock after moderate TH seems to be a more infrequent eventuality, probably because TH management has been completely changed by the advent of ICUs and a far less hypothermic regimen. The mismatch between oxygen supply and consumption during rewarming could depend on numerous factors, including metabolic rate, abnormalities in oxygen extraction, cardiac output (CO), circulating blood volume, regional blood flow, pH, blood viscosity, and a shift in the hemoglobin dissociation curve. The physiopathology of this side effect of rewarming is not known. Rewarming from hypothermia is such a complex and metabolism-pervasive process to alter all of the possible determinants of a VO2/DO2 mismatch. Of the possible determinants of VO2/DO2, cardiac dysfunction has been the most investigated. Cooling determines a proportional decrease in cardiac output [1], heart rate, and mean arterial blood pressure, with no change in stroke volume and increased peripheral vascular resistance. During the maintenance stage of TH, the decrease in metabolic rate is equal to or greater than the decrease in cardiac output, and alteration of oxygen delivery is not a matter of concern. Preliminary clinical studies [7] and a recent meta-analysis [8] have shown a decrease in myocardial ischemic injury. Many of the alterations in the cardiovascular system occurring during hypothermia completely reverse during rewarming. Therefore, the rewarming phase could lead to a permanent deterioration of myocardial function and cardiac output. The pathophysiological mechanism underlying cardiac dysfunction induced by hypothermia rewarming has been studied by Tveita's group, first in vitro using a rat left ventricular papillary muscle [9] and then in vivo [10] in an intact rat model. These studies showed how postrewarming systolic left ventricular dysfunction can be related to decreased myofibrillar Ca2+ sensitivity due to increased troponin C phosphorylation. In addition, Blair and colleagues [11] and Morray and Pavlin [12] documented an increase in total oxygen consumption to values above prehypothermic controls in a dog model of rewarming after deep hypothermia. The authors suggested many possible explanations for this event. First, heterogeneous blood flow distribution [13] during hypothermia may determine areas of oxygen debt, with decreased or absent perfusion, that become hypoxic and generate lactate. During rewarming, these areas are reperfused and lactate re-enters normal oxidative pathways, consuming oxygen in the process. Second, with a return to normothermia, free radical oxidation [14,15] and inflammatory response to injury [16,17] could resume, leading to nonrespiratory utilization of oxygen and an increase of VO2 over pre-injury control. Third, shivering can occur during rewarming as a response to deviations from the temperature set point. The shivering response to maintain a constant core temperature is a concerted reaction involving skeletal muscle contraction and peripheral vasoconstriction. When shivering occurs during rewarming, it is associated with increased VO2 [18,19] and hemodynamic instability [20]. Cain and Bradley 21] and Schumacker and colleagues [22] have described abnormalities of peripheral oxygen extraction in dogs during hypothermia, even with adequate oxygen delivery. An alteration in the temperature transition of oxidative phosphorylation has been documented in an animal model. Leducq and colleagues presented evidence for an abnormal pattern of oxidative phosphorylation control that correlated with a transition in mitochondrial permeability and persisted after rewarming [23]. This phenomenon may cause alterations in oxygen utilization during and after rewarming. Kondratiev and colleagues addressed the problem of oxygen supply in a rat model of deep hypothermia (15��C) and rewarming [24]. The experiment demonstrated a reduction in cardiac output and oxygen delivery after prolonged deep hypothermia (15��C for 5 hours) compared with less prolonged exposure. The rewarming-related rightward shift of the oxygen hemoglobin saturation curve, which facilitates oxygen dissociation at the tissue level, compensated for compromised peripheral oxygen transport, leading to a stable oxygen supply. Knowing the events causing VO2/DO2 mismatch during rewarming is important in this phase of TH for monitoring and assuring adequate cerebral and whole body oxygen delivery. Low oxygen delivery accounts for the development of secondary injury, which limits the safety and effectiveness of TH. With this perspective in mind, we can suggest various measures to limit VO2/DO2 mismatch during rewarming. First, rewarming after TH should be done slowly and in a controlled manner [25]. Eshel, in a rat model of TH, showed how rapid rewarming from moderate hypothermia is associated with more acute hemodynamic alterations compared with slow rewarming [25]. Similar effects were described in humans [26] and pediatric patients [27] undergoing TH for hypoxic ischemic encephalopathy and deep intraoperative hypothermia (27��C), respectively, as well as in the work of Hanhela and colleagues [28] on adults undergoing cardiopulmonary bypass for cardiac surgery. Second, controlling pain, sedation, and preventing shivering should limit oxygen consumption. Michenfelder and colleagues [29], Rodriguez and colleagues [30], and Zwischenberger and colleagues [31] demonstrated that the suppression of shivering by neuromuscular blockade is an effective method for diminishing VO2. More recently, Badjata and colleagues [32] proposed a simple shivering grading tool, the Bedside Shivering Assessment Scale (BSAS), developed by assessing the correlation of bedside shivering and systemic metabolic stress quantified by indirect calorimetry. Using clinical observation of muscle involvement, the BSAS provides an accurate representation of shivering-related oxygen consumption. Accurately defining shivering intensity assures the possibility of a stepwise treatment for shivering. We recommend initially managing shivering with nonsedating interventions, such as correcting hypomagnesemia, or a serotonin (5-TH) 1A partial agonist like buspirone or meperidine. Meperidine has been demonstrated to effectively reduce VO2 augmentation associated with postoperative shivering at a dosage that does not cause respiratory depression [33]. When these first line interventions fail, sedation with shortacting sedative agents and neuromuscular blockade can be used. Third, oxygen content and transport should be optimized. Anemia and arterial desaturation must be avoided during rewarming. To date, no clinical trials have examined hemodynamic optimization in patients that have undergone TH, least of all during rewarming, and no evidence is currently available to indicate the best strategy for hemodynamic support in such a critical phase. We suggest a strict control of hemodynamics, with the aim of guaranteeing adequate oxygen delivery and avoiding VO2/DO2 mismatch, using at least continuous arterial pressure monitoring, volume balance and urine output surveillance, and frequent serum lactate measurements. In the case of hemodynamic instability, advanced monitoring capable of finer management could be useful. Thus, in this context, echocardiography and goal-directed hemodynamic optimization [34] may have a place. Treatment of systolic left ventricular impairment presents additional concerns. Pharmacological therapy with catecholamines presents substantial limitations [35,36], as the decreased myofilament Ca2+ sensitivity during rewarming significantly diminishes badrenoceptor effects. In addition, catecholamines determine elevated myocardial oxygen consumption and arrhythmogenesis. A recent study by Rungatscher and colleagues [37] tested the efficacy of levosimendan in improving myocardial dysfunction after rewarming from deep hypothermia in a rat model. Levosimendan, as a Ca2+ sensitizer, demonstrated better inotropic and lusitropic effects than epinephrine. Glycemic homeostasis: Animal models have shown that hypothermia induces alterations in blood glucose homeostasis via several mechanisms: reduced glucose utilization [38], decreased endogenous insulin secretion [39-41], and increased resistance to exogenous insulin [42,43]