Altered pharmacological effects of adrenergic agonists during hypothermia

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated. This article is also available via DOI:10.1186/s13049-016-0339-8Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiac dysfunction, calling for immediate pharmacologic intervention. Studies show that although cardiac pharmacologic support is applied when rewarming these patients, a lack of updated treatment recommendations exist. Mainly due to lack of clinical and experimental data, neither of the international guidelines includes information about pharmacologic cardiac support at temperatures below 30 °C. However, core temperature of accidental hypothermia patients is often reduced below 30 °C. Few human studies exploring effects of adrenergic drugs during hypothermia have been published, and therefore prevailing information is collected from pre-clinical studies. The most prominent finding in these studies is an apparent depressive effect of adrenaline on cardiac function when used in doses which elevate cardiac output during normothermia. Also noradrenaline and isoprenaline largely lacked positive cardiac effects during hypothermia, while dopamine is a more promising drug for supporting cardiac function during rewarming. Data and information from these studies are in support of the prevailing notion; not to use adrenergic drugs at core temperatures below 30 °

A novel ECG-biomarker for cardiac arrest during hypothermia

Background: Treatment of arrhythmias evoked by accidental or therapeutic hypothermia and rewarming remains challenging. We aim to find an ECG-biomarker that can predict ventricular arrhythmias at temperatures occurring in therapeutic and accidental hypothermia. Main body: Evaluation of ECG-data from accidental and therapeutic hypothermia patients and experimental data on ECG and ventricular fibrillation (VF) threshold in hypothermic New Zealand White Rabbits. VF threshold was measured in rabbit hearts cooled to moderate (31 °C) and severe (17 °C) hypothermia. QRS-interval divided by corrected QT-interval (QTc) was calculated at same temperatures. Clinical QRS/QTc data were obtained after a systematic literature review. Rabbit QRS/QTc values correlated with risk for VF (correlation coefficient: 0.97). Human QRS/QTc values from hypothermic patients, showed similar correlation with risk for ventricular fibrillation in the experimental data (correlation coefficient: 1.00). Conclusions: These calculations indicate that QRS/QTc has potential as novel biomarker for predicting risk of hypothermia-induced cardiac arrest. Our findings apply both to victims of accidental hypothermia and to patients undergoing therapeutic hypothermia during surgery or after e.g. cardiac arrest

Cooling to hypothermic circulatory arrest by immersion vs. cardiopulmonary bypass (CPB): Worse outcome after rewarming in immersion cooled pigs

Introduction: Cooling by cardiopulmonary bypass (CPB) to deep hypothermic cardiac arrest (HCA) for cardiac surgical interventions, followed by CPB-rewarming is performed on a routine basis with relatively low mortality. In contrast, victims of deep accidental hypothermia rewarmed with CPB generally have a much worse prognosis. Thus, we have developed an intact pig model to compare effects on perfusion pressures and global oxygen delivery (DO2) during immersion cooling versus cooling by CPB. Further, we compared the effects of CPB-rewarming between groups, to restitute cardiovascular function, brain blood flow, and brain metabolism. Materials and Methods: Total sixteen healthy, anesthetized juvenile (2–3 months) castrated male pigs were randomized in a prospective, open placebo-controlled experimental study to immersion cooling (IMMc, n = 8), or cooling by CPB (CPBc, n = 8). After 75 minutes of deep HCA in both groups, pigs were rewarmed by CPB. After weaning from CPB surviving animals were observed for 2 h before euthanasia. Results: Survival rates at 2 h after completed rewarming were 4 out of 8 in the IMMc group, and 8 out of 8 in the CPBc group. Compared with the CPBc-group, IMMc animals showed significant reduction in DO2, mean arterial pressure (MAP), cerebral perfusion pressure, and blood flow during cooling below 25◦C as well as after weaning from CPB after rewarming. After rewarming, brain blood flow returned to control in CPBc animals only, and brain micro dialysate-data showed a significantly increase in the lactate/pyruvate ratio in IMMc vs. CPBc animals Conclusion: Our data indicate that, although global O2 consumption was independent of DO2, regional ischemic damage may have taken place during cooling in the brain of IMMc animals below 25◦C. The need for prolonged extracorporeal membrane oxygenation (ECMO) should be considered in all victims of accidental hypothermic arrest that cannot be weaned from CPB immediately after rewarming

Maintaining intravenous volume mitigates hypothermia-induced myocardial dysfunction and accumulation of intracellular Ca2+

Previous research exploring pathophysiological mechanisms underlying circulatory collapse after rewarming victims of severe accidental hypothermia has documented post-hypothermic cardiac dysfunction and hypothermia-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) in myocardial cells. The aim of the present study was to examine if maintaining euvolaemia during rewarming mitigates cardiac dysfunction and/or normalizes elevated myocardial [Ca2+]i. A total of 21 male Wistar rats (300 g) were surface cooled to 15◦C, then maintained at 15◦C for 4 h, and subsequently rewarmed to 37◦C. The rats were randomly assigned to one of three groups: (1) non-intervention control (n = 7), (2) dextran treated (i.v. 12 ml/kg dextran 70; n = 7), or (3) crystalloid treated (24 ml/kg 0.9% i.v. saline; n = 7). Infusions occurred during the first 30 min of rewarming. Arterial blood pressure, stroke volume (SV), cardiac output (CO), contractility (dP/dtmax) and blood gas changes were measured. Post-hypothermic changes in [Ca2+]i were measured using the method of radiolabelled Ca2+ ( 45Ca2+). Untreated controls displayed post-hypothermic cardiac dysfunction with significantly reduced CO, SV and dP/dtmax. In contrast, rats receiving crystalloid or dextran treatment showed a return to pre-hypothermic control levels of CO and SV after rewarming, with the dextran group displaying significantly better amelioration of post-hypothermic cardiac dysfunction than the crystalloid group. Compared to the post-hypothermic increase in myocardial [Ca2+]i in non-treated controls, [Ca2+]i values with crystalloid and dextran did not increase to the same extent after rewarming. Volume replacement with crystalloid or dextran during rewarming abolishes posthypothermic cardiac dysfunction, and partially mitigates the hypothermia-induced elevation of [Ca2+]i

Enhanced Blood Clotting After Rewarming From Experimental Hypothermia in an Intact Porcine Model

Introduction: Due to functional alterations of blood platelets and coagulation enzymes at low temperatures, excessive bleeding is a well-recognized complication in victims of accidental hypothermia and may present a great clinical challenge. Still, it remains largely unknown if hemostatic function normalizes upon rewarming. The aim of this study was to investigate effects of hypothermia and rewarming on blood coagulation in an intact porcine model. Methods: The animals were randomized to cooling and rewarming (n = 10), or to serve as normothermic, time-matched controls (n = 3). Animals in the hypothermic group were immersion cooled in ice water to 25°C, maintained at 25°C for 1 h, and rewarmed to 38°C (normal temperature in pigs) using warm water. Clotting time was assessed indirectly at different temperatures during cooling and rewarming using a whole blood coagulometer, which measures clotting time at 38°C. Results: Cooling to 25°C led to a significant increase in hemoglobin, hematocrit and red blood cell count, which persisted throughout rewarming. Cooling also caused a transiently decreased white blood cell count that returned to baseline levels upon rewarming. After rewarming from hypothermia, clotting time was significantly shortened compared to pre-hypothermic baseline values. In addition, platelet count was significantly increased. Discussion/Conclusion: We found that clotting time was significantly reduced after rewarming from hypothermia. This may indicate that rewarming from severe hypothermia induces a hypercoagulable state, in which thrombus formation is more likely to occur

Autoregulation of Cerebral Blood Flow During 3-h Continuous Cardiopulmonary Resuscitation at 27°C

Introduction: Victims of accidental hypothermia in hypothermic cardiac arrest (HCA) may survive with favorable neurologic outcome if early and continuous prehospital cardiopulmonary resuscitation (CPR) is started and continued during evacuation and transport. The efficacy of cerebral autoregulation during hypothermic CPR is largely unknown and is aim of the present experiment. Methods: Anesthetized pigs (n = 8) were surface cooled to HCA at 27°C before 3 h continuous CPR. Central hemodynamics, cerebral O2 delivery (DO2) and uptake (VO2), cerebral blood flow (CBF), and cerebral perfusion pressure (CPP) were determined before cooling, at 32°C and at 27°C, then at 15 min after the start of CPR, and hourly thereafter. To estimate cerebral autoregulation, the static autoregulatory index (sARI), and the CBF/VO2 ratio were determined. Results: After the initial 15-min period of CPR at 27°C, cardiac output (CO) and mean arterial pressure (MAP) were reduced significantly when compared to corresponding values during spontaneous circulation at 27°C (−66.7% and −44.4%, respectively), and remained reduced during the subsequent 3-h period of CPR. During the first 2-h period of CPR at 27°C, blood flow in five different brain areas remained unchanged when compared to the level during spontaneous circulation at 27°C, but after 3 h of CPR blood flow in 2 of the 5 areas was significantly reduced. Cooling to 27°C reduced cerebral DO2 by 67.3% and VO2 by 84.4%. Cerebral VO2 was significantly reduced first after 3 h of CPR. Cerebral DO2 remained unaltered compared to corresponding levels measured during spontaneous circulation at 27°C. Cerebral autoregulation was preserved (sARI > 0.4), at least during the first 2 h of CPR. Interestingly, the CBF/VO2 ratio during spontaneous circulation at 27°C indicated the presence of an affluent cerebral DO2, whereas after CPR, the CBF/VO2 ratio returned to the level of spontaneous circulation at 38°C. Conclusion: Despite a reduced CO, continuous CPR for 3 h at 27°C provided sufficient cerebral DO2 to maintain aerobic metabolism and to preserve cerebral autoregulation during the first 2-h period of CPR. This new information supports early start and continued CPR in accidental hypothermia patients during rescue and transportation for in hospital rewarming