ß-adrenergic stimulation after rewarming does not mitigate hypothermia-induced contractile dysfunction in rat cardiomyocytes.

Victims of severe accidental hypothermia are frequently treated with catecholamines to counteract the hemodynamic instability associated with hypothermia-induced cardiac contractile dysfunction. However, we previously reported that the inotropic effects of epinephrine are diminished after hypothermia and rewarming (H/R) in an intact animal model. Thus, the goal of this study was to investigate the effects of Epi treatment on excitation-contraction coupling in isolated rat cardiomyocytes after H/R. In adult male rats, cardiomyocytes isolated from the left ventricle were electrically stimulated at 0.5 Hz and evoked cytosolic [Ca2+] and contractile responses (sarcomere length shortening) were measured. In initial experiments, the effects of varying concentrations of epinephrine on evoked cytosolic [Ca2+] and contractile responses at 37 °C were measured. In a second series of experiments, cardiomyocytes were cooled from 37 °C to 15 °C, maintained at 15 °C for 2 h, then rewarmed to 37 °C (H/R protocol). Immediately after rewarming, the effects of epinephrine treatment on evoked cytosolic [Ca2+] and contractile responses of cardiomyocytes were determined. At 37 °C, epinephrine treatment increased both cytosolic [Ca2+] and contractile responses of cardiomyocytes in a concentration-dependent manner peaking at 25-50 nM. The evoked contractile response of cardiomyocytes after H/R was reduced while the cytosolic [Ca2+] response was slightly elevated. The diminished contractile response of cardiomyocytes after H/R was not mitigated by epinephrine (25 nM) and epinephrine treatment reduced the exponential time decay constant (Tau), but did not increase the cytosolic [Ca2+] response. We conclude that epinephrine treatment does not mitigate H/R-induced contractile dysfunction in cardiomyocytes.

Functional recovery after accidental deep hypothermic cardiac arrest: Comparison of different cardiopulmonary bypass rewarming strategies.

Introduction: Using a porcine model of accidental immersion hypothermia and hypothermic cardiac arrest (HCA), the aim of the present study was to compare effects of different rewarming strategies on CPB on need for vascular fluid supply, level of cardiac restitution, and cerebral metabolism and pressures. Materials and Methods: Totally sixteen healthy, anesthetized castrated male pigs were immersion cooled to 20°C to induce HCA, maintained for 75 min and then randomized into two groups: 1) animals receiving CPB rewarming to 30°C followed by immersion rewarming to 36°C (CPB30, n = 8), or 2) animals receiving CPB rewarming to 36°C (CPB36, n = 8). Measurements of cerebral metabolism were collected using a microdialysis catheter. After rewarming to 36°C, surviving animals in both groups were further warmed by immersion to 38°C and observed for 2 h. Results: Survival rate at 2 h after rewarming was 5 out of 8 animals in the CPB30 group, and 8 out of 8 in the CPB36 group. All surviving animals displayed significant acute cardiac dysfunction irrespective of rewarming method. Differences between groups in CPB exposure time or rewarming rate created no differences in need for vascular volume supply, in variables of cerebral metabolism, or in cerebral pressures and blood flow. Conclusion: As 3 out of 8 animals did not survive weaning from CPB at 30°C, early weaning gave no advantages over weaning at 36°C. Further, in surviving animals, the results showed no differences between groups in the need for vascular volume replacement, nor any differences in cerebral blood flow or pressures. Most prominent, after weaning from CPB, was the existence of acute cardiac failure which was responsible for the inability to create an adequate perfusion irrespective of rewarming strategy.

Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia-Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate.

Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings. Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures-37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values. Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP. Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction.

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.

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.

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 (IMM c , n = 8), or cooling by CPB (CPB c , 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 IMM c group, and 8 out of 8 in the CPB c group. Compared with the CPB c -group, IMM c 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 CPB c animals only, and brain micro dialysate-data showed a significantly increase in the lactate/pyruvate ratio in IMM c vs. CPB c 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 IMM c 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.

Physiological Changes in Subjects Exposed to Accidental Hypothermia: An Update.

Background: Accidental hypothermia (AH) is an unintended decrease in body core temperature (BCT) to below 35°C. We present an update on physiological/pathophysiological changes associated with AH and rewarming from hypothermic cardiac arrest (HCA). Temperature Regulation and Metabolism: Triggered by falling skin temperature, Thyrotropin-Releasing Hormone (TRH) from hypothalamus induces release of Thyroid-Stimulating Hormone (TSH) and Prolactin from pituitary gland anterior lobe that stimulate thyroid generation of triiodothyronine and thyroxine (T4). The latter act together with noradrenaline to induce heat production by binding to adrenergic ß3-receptors in fat cells. Exposed to cold, noradrenaline prompts degradation of triglycerides from brown adipose tissue (BAT) into free fatty acids that uncouple metabolism to heat production, rather than generating adenosine triphosphate. If BAT is lacking, AH occurs more readily. Cardiac Output: Assuming a 7% drop in metabolism per °C, a BCT decrease of 10°C can reduce metabolism by 70% paralleled by a corresponding decline in CO. Consequently, it is possible to maintain adequate oxygen delivery provided correctly performed cardiopulmonary resuscitation (CPR), which might result in approximately 30% of CO generated at normal BCT. Liver and Coagulation: AH promotes coagulation disturbances following trauma and acidosis by reducing coagulation and platelet functions. Mean prothrombin and partial thromboplastin times might increase by 40-60% in moderate hypothermia. Rewarming might release tissue factor from damaged tissues, that triggers disseminated intravascular coagulation. Hypothermia might inhibit platelet aggregation and coagulation. Kidneys: Renal blood flow decreases due to vasoconstriction of afferent arterioles, electrolyte and fluid disturbances and increasing blood viscosity. Severely deranged renal function occurs particularly in the presence of rhabdomyolysis induced by severe AH combined with trauma. Conclusion: Metabolism drops 7% per °C fall in BCT, reducing CO correspondingly. Therefore, it is possible to maintain adequate oxygen delivery after 10°C drop in BCT provided correctly performed CPR. Hypothermia may facilitate rhabdomyolysis in traumatized patients. Victims suspected of HCA should be rewarmed before being pronounced dead. Rewarming avalanche victims of HCA with serum potassium > 12 mmol/L and a burial time >30 min with no air pocket, most probably be futile.

Physiological Impact of Hypothermia: The Good, the Bad, and the Ugly.

Hypothermia is defined as a core body temperature of <35°C, and as body temperature is reduced the impact on physiological processes can be beneficial or detrimental. The beneficial effect of hypothermia enables circulation of cooled experimental animals to be interrupted for 1-2 h without creating harmful effects, while tolerance of circulation arrest in normothermia is between 4 and 5 min. This striking difference has attracted so many investigators, experimental as well as clinical, to this field, and this discovery was fundamental for introducing therapeutic hypothermia in modern clinical medicine in the 1950s. Together with the introduction of cardiopulmonary bypass, therapeutic hypothermia has been the cornerstone in the development of modern cardiac surgery. Therapeutic hypothermia also has an undisputed role as a protective agent in organ transplantation and as a therapeutic adjuvant for cerebral protection in neonatal encephalopathy. However, the introduction of therapeutic hypothermia for organ protection during neurosurgical procedures or as a scavenger after brain and spinal trauma has been less successful. In general, the best neuroprotection seems to be obtained by avoiding hyperthermia in injured patients. Accidental hypothermia occurs when endogenous temperature control mechanisms are incapable of maintaining core body temperature within physiologic limits and core temperature becomes dependent on ambient temperature. During hypothermia spontaneous circulation is considerably reduced and with deep and/or prolonged cooling, circulatory failure may occur, which may limit safe survival of the cooled patient. Challenges that limit safe rewarming of accidental hypothermia patients include cardiac arrhythmias, uncontrolled bleeding, and "rewarming shock."

Effects of Cold Decompression on Hemodynamic Function and Decompression Sickness Risk in a Dry Diving Rat Model.

Background: Diving in cold water is thought to increase the risk of decompression sickness (DCS), especially if the diver is cold during decompression. In this study, we investigated hemodynamic function and DCS risk in an animal model, where cold decompression was followed by rewarming at the surface. Methods: Nine female Sprague Dawley rats had pressure-volume catheters inserted into their left heart ventricle and femoral artery before they were exposed to dry air dives in which their core temperature was normothermic during the bottom phase, cold (35°C) during decompression, and normothermic after the dive. Data from an earlier study were used as controls. The rats were compressed in air to 600kPa, maintained at pressure for 45min, and decompressed at 50kPa/min. Hemodynamic data were recorded before, during, and 60min after decompression. Venous gas bubbles were recorded in the right heart ventricle and pulmonary artery for 60min after the dive. Results and Conclusion: During decompression, cardiac output (CO), and stroke volume (SV) decreased equally in cold rats and controls. CO and SV were temporarily re-established at the surface, before falling again in the cold rats. There was no difference in post-dive venous bubble grades. However, as the post-dive fall in CO and SV could be a sign of gas emboli obstructing the pulmonary circulation, we cannot conclude whether the DCS risk was increased. More sensitive bubble detection methods are needed to elucidate this point.

Rewarming With Closed Thoracic Lavage Following 3-h CPR at 27°C Failed to Reestablish a Perfusing Rhythm.

Introduction: Previously, we showed that the cardiopulmonary resuscitation (CPR) for hypothermic cardiac arrest (HCA) maintained cardiac output (CO) and mean arterial pressure (MAP) to the same reduced level during normothermia (38°C) vs. hypothermia (27°C). In addition, at 27°C, the CPR for 3-h provided global O2 delivery (DO2) to support aerobic metabolism. The present study investigated if rewarming with closed thoracic lavage induces a perfusing rhythm after 3-h continuous CPR at 27°C. Materials and Methods: Eight male pigs were anesthetized, and immersion-cooled. At 27°C, HCA was electrically induced, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed by combining closed thoracic lavage and continued CPR. Organ blood flow was measured using microspheres. Results: After cooling with spontaneous circulation to 27°C, MAP and CO were initially reduced by 37 and 58% from baseline, respectively. By 15 min after the onset of CPR, MAP, and CO were further reduced by 58 and 77% from baseline, respectively, which remained unchanged throughout the rest of the 3-h period of CPR. During CPR at 27°C, DO2 and O2 extraction rate (VO2) fell to critically low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. During rewarming with closed thoracic lavage, all animals displayed ventricular fibrillation, but only one animal could be electro-converted to restore a short-lived perfusing rhythm. Rewarming ended in circulatory collapse in all the animals at 38°C. Conclusion: The CPR for 3-h at 27°C managed to sustain lower levels of CO and MAP sufficient to support global DO2. Rewarming accidental hypothermia patients following prolonged CPR for HCA with closed thoracic lavage is not an alternative to rewarming by extra-corporeal life support as these patients are often in need of massive cardio-pulmonary support during as well as after rewarming.

Effects of rewarming with extracorporeal membrane oxygenation to restore oxygen transport and organ blood flow after hypothermic cardiac arrest in a porcine model.

We recently documented that cardiopulmonary resuscitation (CPR) generates the same level of cardiac output (CO) and mean arterial pressure (MAP) during both normothermia (38 °C) and hypothermia (27 °C). Furthermore, continuous CPR at 27 °C provides O2 delivery (DO2) to support aerobic metabolism throughout a 3-h period. The aim of the present study was to investigate the effects of extracorporeal membrane oxygenation (ECMO) rewarming to restore DO2 and organ blood flow after prolonged hypothermic cardiac arrest. Eight male pigs were anesthetized and immersion cooled to 27 °C. After induction of hypothermic cardiac arrest, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed with ECMO. Organ blood flow was measured using microspheres. After cooling with spontaneous circulation to 27 °C, MAP and CO were initially reduced to 66 and 44% of baseline, respectively. By 15 min after the onset of CPR, there was a further reduction in MAP and CO to 42 and 25% of baseline, respectively, which remained unchanged throughout the rest of 3-h CPR. During CPR, DO2 and O2 uptake (V̇O2) fell to critical low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. Rewarming with ECMO restored MAP, CO, DO2, and blood flow to the heart and to parts of the brain, whereas flow to kidneys, stomach, liver and spleen remained significantly reduced. CPR for 3-h at 27 °C with sustained lower levels of CO and MAP maintained aerobic metabolism sufficient to support DO2. Rewarming with ECMO restores blood flow to the heart and brain, and creates a "shockable" cardiac rhythm. Thus, like continuous CPR, ECMO rewarming plays a crucial role in "the chain of survival" when resuscitating victims of hypothermic cardiac arrest.

Cardiovascular Effects of Epinephrine During Experimental Hypothermia (32°C) With Spontaneous Circulation in an Intact Porcine Model.

Aims: Rewarming from accidental hypothermia and therapeutic temperature management could be complicated by cardiac dysfunction. Although pharmacologic support is often applied when rewarming these patients, updated treatment recommendations are lacking. There is an underlying deficiency of clinical and experimental data to support such interventions and this prevents the development of clinical guidelines. Accordingly, we explored the clinical effects of epinephrine during hypothermic conditions. Materials and methods: Anesthetized pigs were immersion cooled to 32°C. Predetermined variables were compared at temperature/time-point baseline, after receiving 30 ng/kg/min and 90 ng/kg/min epinephrine infusions: (1) before and during hypothermia at 32°C, and after rewarming to 38°C (n = 7) and (2) a time-matched (5 h) normothermic control group (n = 5). Results: At 32°C, both stroke volume and cardiac output were elevated after 30 ng/kg/min administration, while systemic vascular resistance was reduced after 90 ng/kg/min. Epinephrine infusion did not alter blood flow in observed organs, except small intestine flow, and global O2 extraction rate was significantly reduced in response to 90 ng/kg/min infusion. Electrocardiographic measurements were unaffected by epinephrine infusion. Conclusion: Administration of both 30 ng/kg/min and 90 ng/kg/min at 32°C had a positive inotropic effect and reduced afterload. We found no evidence of increased pro-arrhythmic activity after epinephrine infusion in hypothermic pigs. Our experiment therefore suggests that ß1-receptor stimulation with epinephrine could be a favorable strategy for providing cardiovascular support in hypothermic patients, at core temperatures >32°C.

Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors - Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP.

INTRODUCTION: Cardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies have proposed vasodilation and afterload reduction through arteriole smooth muscle cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators. MATERIALS AND METHODS: Human phosphodiesterase-enzymes and inverted erythrocytes were utilized to evaluate how vasodilators sildenafil and vardenafil affected cellular efflux and enzymatic breakdown of cAMP and cGMP, at 37°C, 34°C, 32°C, 28°C, 24°C, and 20°C. The ability of both drugs to reach their cytosolic site of action was assessed at the same temperatures. IC50- and K i -values were calculated from dose-response curves at all temperatures, to evaluate temperature-dependent effects of both drugs. RESULTS: Both drugs were able to reach the intracellular space at all hypothermic temperatures, with no reduction compared to normothermia. Sildenafil IC50 and K i -values increased during hypothermia for enzymatic breakdown of both cAMP (IC50: 122 ± 18.9 µM at 37°C vs. 269 ± 14.7 µM at 20°C, p < 0.05) and cGMP (IC50: 0.009 ± 0.000 µM at 37°C vs. 0.024 ± 0.004 µM at 32°C, p < 0.05), while no significant changes were detected for vardenafil. Neither of the drugs showed significant hypothermia-induced changes in IC50 and K i- values for inhibition of cellular cAMP and cGMP efflux. CONCLUSION: Sildenafil and particularly vardenafil were ableto inhibit elimination of cGMP down to 20°C. As the cellular effects of these drugs can cause afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia. As in normothermia, both drugs showed higher selectivity for inhibition of cGMP-elimination than cAMP-elimination at low core temperatures, indicating that risk for cardiotoxic side effects is not increased by hypothermia.

Rewarming From Hypothermic Cardiac Arrest Applying Extracorporeal Life Support: A Systematic Review and Meta-Analysis.

Introduction: This systematic review and meta-analysis aims at comparing outcomes of rewarming after accidental hypothermic cardiac arrest (HCA) with cardiopulmonary bypass (CPB) or/and extracorporeal membrane oxygenation (ECMO). Material and Methods: Literature searches were limited to references with an abstract in English, French or German. Additionally, we searched reference lists of included papers. Primary outcome was survival to hospital discharge. We assessed neurological outcome, differences in relative risks (RR) of surviving, as related to the applied rewarming technique, sex, asphyxia, and witnessed or unwitnessed HCA. We calculated hypothermia outcome prediction probability score after extracorporeal life support (HOPE) in patients in whom we found individual data. P < 0.05 considered significant. Results: Twenty-three case observation studies comprising 464 patients were included in a meta-analysis comparing outcomes of rewarming with CPB or/and ECMO. One-hundred-and-seventy-two patients (37%) survived to hospital discharge, 76 of 245 (31%) after CPB and 96 of 219 (44 %) after ECMO; 87 and 75%, respectively, had good neurological outcomes. Overall chance of surviving was 41% higher (P = 0.005) with ECMO as compared with CPB. A man and a woman had 46% (P = 0.043) and 31% (P = 0.115) higher chance, respectively, of surviving with ECMO as compared with CPB. Avalanche victims had the lowest chance of surviving, followed by drowning and people losing consciousness in cold environments. Assessed by logistic regression, asphyxia, unwitnessed HCA, male sex, high initial body temperature, low pH and high serum potassium (s-K+) levels were associated with reduced chance of surviving. In patients displaying individual data, overall mean predictive surviving probability (HOPE score; n = 134) was 33.9 ± 33.6% with no significant difference between ECMO and CPB-treated patients. We also surveyed 80 case reports with 96 victims of HCA, who underwent resuscitation with CPB or ECMO, without including them in the meta-analysis. Conclusions: The chance of surviving was significantly higher after rewarming with ECMO, as compared to CPB, and in patients with witnessed compared to unwitnessed HCA. Avalanche victims had the lowest probability of surviving. Male sex, high initial body temperature, low pH, and high s-K+ were factors associated with low surviving chances.

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

NEW FINDINGS: What is the central question of this study? Detailed guidelines for volume replacement to counteract hypothermia-induced intravascular fluid loss are lacking. Evidence suggests colloids might have beneficial effects compared to crystalloids. Are central haemodynamic function and level of hypothermia-induced calcium overload, as a marker of cardiac injury, restored by fluid substitution during rewarming, and are colloids favourable to crystalloids? What is the main finding and its importance? Infusion with crystalloid or dextran during rewarming abolished post-hypothermic cardiac dysfunction, and partially mitigated myocardial calcium overload. The effects of volume replacement to support haemodynamic function are comparable to those using potent cardio-active drugs. These findings underline the importance of applying intravascular volume replacement to maintain euvolaemia during rewarming. ABSTRACT: 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+ (45 Ca2+ ). 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 post-hypothermic cardiac dysfunction, and partially mitigates the hypothermia-induced elevation of [Ca2+ ]i .

Resistance to ventricular fibrillation predicted by the QRS/QTc - Ratio in an intact rat model of hypothermia/rewarming.

Accidental hypothermia is associated with increased risk for arrhythmias. QRS/QTc is proposed as an ECG-marker, where decreasing values predict hypothermia-induced ventricular arrhythmias. If reliable it should also predict nonappearance of arrhythmias, observed in species like rat that regularly tolerate prolonged hypothermia. A rat model designed for studying cardiovascular function during cooling, hypothermia and subsequent rewarming was chosen due to species-dependent resistance to ventricular arrhythmias. ECG was recorded throughout the protocol. No ventricular arrhythmias occurred during experiments. QRS/QTc increased throughout the cooling period and remained above normothermic baseline until rewarmed. Different from the high incidence of hypothermia-induced ventricular arrhythmias in accidental hypothermia patients, where QRS/QTc ratio is decreased in moderate hypothermia; hypothermia and rewarming of rats is not associated with increased risk for ventricular fibrillation. This resistance to lethal hypothermia-induced arrhythmias was predicted by QRS/QTc.

Comparison Between Two Pharmacologic Strategies to Alleviate Rewarming Shock: Vasodilation vs. Inodilation.

Rewarming from hypothermia is often challenged by coexisting cardiac dysfunction, depressed organ blood flow (OBF), and increased systemic vascular resistance. Previous research shows cardiovascular inotropic support and vasodilation during rewarming to elevate cardiac output (CO). The present study aims to compare the effects of inodilatation by levosimendan (LS) and vasodilation by nitroprusside (SNP) on OBF and global oxygen transport during rewarming from hypothermia. We used an in vivo experimental rat model of 4 h 15°C hypothermia and rewarming. A stable isotope-labeled microsphere technique was used to determine OBF. Cardiac and arterial pressures were monitored with fluid-filled pressure catheters, and CO was measured by thermodilution. Two groups were treated with either LS (n = 7) or SNP (n = 7) during the last hour of hypothermia and throughout rewarming. Two groups served as hypothermic (n = 7) and normothermic (n = 6) controls. All hypothermia groups had significantly reduced CO, oxygen delivery, and OBF after rewarming compared to their baseline values. After rewarming, LS had elevated CO significantly more than SNP (66.57 ± 5.6/+30% vs. 54.48 ± 5.2/+14%) compared to the control group (47.22 ± 3.9), but their ability to cause elevation of brain blood flow (BBF) was the same (0.554 ± 0.180/+81 vs. 0.535 ± 0.208/+75%) compared to the control group (0.305 ± 0.101). We interpret the vasodilator properties of LS and SNP to be the primary source to increase organ blood flow, superior to the increase in CO.

Study of the Effects of 3 h of Continuous Cardiopulmonary Resuscitation at 27°C on Global Oxygen Transport and Organ Blood Flow.

AIMS: Complete restitution of neurologic function after 6 h of pre-hospital resuscitation and in-hospital rewarming has been reported in accidental hypothermia patients with cardiac arrest (CA). However, the level of restitution of circulatory function during long-lasting hypothermic cardiopulmonary resuscitation (CPR) remains largely unknown. We compared the effects of CPR in replacing spontaneous circulation during 3 h at 27°C vs. 45 min at normothermia by determining hemodynamics, global oxygen transport (DO2), oxygen uptake (VO2), and organ blood flow. METHODS: Anesthetized pigs (n = 7) were immersion cooled to CA at 27°C. Predetermined variables were compared: (1) Before cooling, during cooling to 27°C with spontaneous circulation, after CA and subsequent continuous CPR (n = 7), vs. (2) before CA and during 45 min CPR in normothermic pigs (n = 4). RESULTS: When compared to corresponding values during spontaneous circulation at 38°C: (1) After 15 min of CPR at 27°C, cardiac output (CO) was reduced by 74%, mean arterial pressure (MAP) by 63%, DO2 by 47%, but organ blood flow was unaltered. Continuous CPR for 3 h maintained these variables largely unaltered except for significant reduction in blood flow to the heart and brain after 3 h, to the kidneys after 1 h, to the liver after 2 h, and to the stomach and small intestine after 3 h. (2) After normothermic CPR for 15 min, CO was reduced by 71%, MAP by 54%, and DO2 by 63%. After 45 min, hemodynamic function had deteriorated significantly, organ blood flow was undetectable, serum lactate increased by a factor of 12, and mixed venous O2 content was reduced to 18%. CONCLUSION: The level to which CPR can replace CO and MAP during spontaneous circulation at normothermia was not affected by reduction in core temperature in our setting. Compared to spontaneous circulation at normothermia, 3 h of continuous resuscitation at 27°C provided limited but sufficient O2 delivery to maintain aerobic metabolism. This fundamental new knowledge is important in that it encourages early and continuous CPR in accidental hypothermia victims during evacuation and transport.