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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.

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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.

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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.

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INTRODUCTION: The 'emergency department (ED) pharmacist' is an integrated part of the ED interdisciplinary team in many countries, which have shown to improve medication safety and reduce costs related to hospitalisations. In Norway, few EDs are equipped with ED pharmacists, and research describing effects on patients has not been conducted. The aim of this study is to investigate the impact of introducing clinical pharmacists to the interdisciplinary ED team. In this multicentre study, the intervention will be pragmatically implemented in the regular operation of three EDs in Northern Norway; Tromsø, Bodø and Harstad. Clinical pharmacists will work as an integrated part of the ED team, providing pharmaceutical care services such as medication reconciliation, review and/or counselling. The primary endpoint is 'time in hospital during 30 days after admission to the ED', combining (1) time in ED, (2) time in hospital (if hospitalised) and (3) time in ED and/or hospital if re-hospitalised during 30 days after admission. Secondary endpoints include time to rehospitalisation, length of stay in ED and hospital and rehospitalisation and mortality rates. METHODS AND ANALYSIS: We will apply a non-randomised stepped-wedge study design, where we in a staggered way implement the ED pharmacists in all three EDs after a 3, 6 and 9 months control period, respectively. We will include all patients going through the three EDs during the 12-month study period. Patient data will be collected retrospectively from national data registries, the hospital system and from patient records. ETHICS AND DISSEMINATION: The Regional Committee for Medical and Health Research Ethics and Local Patient Protection Officers in all hospitals have approved the study. Patients will be informed about the ongoing study on a general basis with ads on posters and flyers. TRIAL REGISTRATION NUMBER: NCT04722588.

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OBJECTIVE: Inotropic drugs are frequently administered in hypothermic patients to support an assumed inadequate circulation, but their pharmacologic properties at reduced temperatures are largely unknown. Thus we estimated dopamine pharmacokinetics as well as left ventricular function and global hemodynamics after dopamine infusions at various core temperatures in a pig model of surface cooling and rewarming. DESIGN: Prospective, randomized, open, placebo-controlled experimental study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Sixteen healthy, anesthetized juvenile (2-3 months) castrated male pigs. INTERVENTIONS: After normothermic infusions of dopamine at different doses (4, 8, and 16 µg/kg/min), effects of dopamine (n = 8) or saline (n = 8) were tested at 25 °C and during rewarming (30-34 °C). MEASUREMENTS AND MAIN RESULTS: Dopamine half-time was 5.4 ± 0.7 min at normothermia, increased to 11.6 ± 0.8 min at 25 °C, but returned to control during rewarming at 34-35 °C. Dopamine infusion at 25 °C elevated dopamine plasma concentration four-fold compared to the same infusion rate at normothermia, leading to increased systemic vascular resistance index not seen at normothermia. Also, in contrast to the dopamine-mediated increase in cardiac index observed at normothermia, high-dose dopamine at 25 °C left cardiac index unchanged despite a concomitant increase in heart rate, since stroke index decreased by 43%. During rewarming, cardiovascular effects of dopamine at moderate hypothermia (30-34 °C) were principally similar to responses during normothermia. CONCLUSIONS: Pharmacodynamic effects and pharmacokinetics of dopamine are maintained during the rewarming phase at moderate hypothermia. However, at 25 °C dopamine pharmacokinetics were seriously altered and dopamine failed to increase cardiac index since stroke index was reduced with incrementing dosages. Properties of the low-flow, high-viscosity circulatory state, combined with altered pharmacokinetics of dopamine, may explain lack of beneficial--and potentially harmful--effects from dopamine administration at 25 °C.

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INTRODUCTION: We developed a minimally invasive, closed chest pig model with the main aim to describe hemodynamic function during surface cooling, steady state severe hypothermia (one hour at 25°C) and surface rewarming. METHODS: Twelve anesthetized juvenile pigs were acutely catheterized for measurement of left ventricular (LV) pressure-volume loops (conductance catheter), cardiac output (Swan-Ganz), and for vena cava inferior occlusion. Eight animals were surface cooled to 25°C, while four animals were kept as normothermic time-matched controls. RESULTS: During progressive cooling and steady state severe hypothermia (25°C) cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), maximal deceleration of pressure in the cardiac cycle (dP/dt(min)), indexes of LV contractility (preload recruitable stroke work, PRSW, and maximal acceleration of pressure in the cardiac cycle, dP/dt(max)) and LV end diastolic and systolic volumes (EDV and ESV) were significantly reduced. Systemic vascular resistance (SVR), isovolumetric relaxation time (Tau), and oxygen content in arterial and mixed venous blood increased significantly. LV end diastolic pressure (EDP) remained constant. After rewarming all the above mentioned hemodynamic variables that were depressed during 25°C remained reduced, except for CO that returned to pre-hypothermic values due to an increase in heart rate. Likewise, SVR and EDP were significantly reduced after rewarming, while Tau, EDV, ESV and blood oxygen content normalized. Serum levels of cardiac troponin T (TnT) and tumor necrosis factor-alpha (TNF-α) were significantly increased. CONCLUSIONS: Progressive cooling to 25°C followed by rewarming resulted in a reduced systolic, but not diastolic left ventricular function. The post-hypothermic increase in heart rate and the reduced systemic vascular resistance are interpreted as adaptive measures by the organism to compensate for a hypothermia-induced mild left ventricular cardiac failure. A post-hypothermic increase in TnT indicates that hypothermia/rewarming may cause degradation of cardiac tissue. There were no signs of inadequate global oxygenation throughout the experiments.

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