Slow Rewarming Group Research Articles

Rapid vs. Slow Rewarming for Management of Moderate to Severe Hypothermia in Low-Birth-Weight Pre-term Neonates—An Open Label Randomized Controlled Trial

Evidence is lacking regarding the optimal method of rewarming hypothermic low-birth-weight (LBW) pre-term neonates. We aim to evaluate the effect of rapid vs. slow rewarming in the management of moderate to severe hypothermia in LBW pre-term neonates. In this open label, randomized controlled trial, 100 LBW (<2.5 kg), pre-term (<37 weeks) neonates with moderate to severe hypothermia (<36°C) was randomized to two groups of 50 each and received either rapid (at >0.5°C/h) or slow (at ≤0.5°C/h) rewarming rate till normothermia. The primary outcome was stabilization score [TOPS (temperature, oxygenation, perfusion and saturation) and MSNS (modified sick neonatal score)] at baseline, 6 and 24 h and mortality until discharge. Other neonatal morbidities were assessed as secondary outcomes. Mean TOPS score and MSNS score at baseline, 6 and 24 h of admission as well as change in score from baseline were similar between the two groups. The median rewarming rate [interquartile range (IQR)] was higher in rapid rewarming group than in the slow rewarming group [5.05°C/h (3.54-7.71) vs. 0.71°C/h (0.60-0.90); p < 0.001]. The median rewarming time taken in rapid rewarming group was lesser compared with that in the slow rewarming group [0.31 h (IQR 0.13-0.75) vs. 2.05 h (IQR 1.11-3.03); p < 0.001]. Mortality in rapid rewarming and slow rewarming group was similar [7/50 vs. 5/50; OR 1.46 (0.43-4.97), p = 0.538]. Rapid rewarming was as effective and safe as slow rewarming in the management of moderate to severe hypothermia in LBW pre-term neonates with similar short-term neonatal outcomes. CTRI/2018/01/011187.

Slow versus fast rewarming after hypothermic circulatory arrest: effects on neuroinflammation and cerebral oedema.

Among the factors that could determine neurological outcome after hypothermic circulatory arrest (HCA) rewarming is rarely considered. The optimal rewarming rate is still unknown. The goal of this study was to investigate the effects of 2 different protocols for rewarming after HCA on neurological outcome in an experimental animal model. Forty-four Sprague Dawley rats were cooled to 19 ± 1°C body core temperature by cardiopulmonary bypass (CPB). HCA was maintained for 60 min. Animals were randomized to receive slow (90 min) or fast (45 min) assisted rewarming with CPB to a target temperature of 35°C. After a total of 90 min of reperfusion in both groups, brain samples were collected and analysed immunohistochemically and with immunofluorescence. In 10 rats, magnetic resonance imaging was performed after 2 and after 24 h to investigate cerebral perfusion and cerebral oedema. Interleukin 6, chemokine (C-C motif) ligand 5, intercellular adhesion molecule 1 and tumour necrosis factor α in the hippocampus are significantly less expressed in the slow rewarming group, and microglia cells are significantly less activated in the slow rewarming group. Magnetic resonance imaging analysis demonstrated better cerebral perfusion and less water content in brains that underwent slow rewarming at 2 and 24 h. Slow rewarming after HCA might be superior to fast rewarming in neurological outcome. The present experimental study demonstrated reduction in the inflammatory response, reduction of inflammatory cell activation in the brain, enhancement of cerebral blood flow and reduction of cerebral oedema when slow rewarming was applied.

Increased PINK1/Parkin-mediated mitophagy explains the improved brain protective effects of slow rewarming following hypothermia after cardiac arrest in rats

Cerebral ischemia-reperfusion (I/R) after cardiac arrest (CA) induces mitochondrial dysfunction, and the timely removal of damaged mitochondria by mitophagy is reported to protect against cerebral I/R injury. Therapeutic hypothermia (TH) has become an important component of postresuscitation care for patients who return to spontaneous circulation after CA. Previous studies have shown that TH can activate mitophagy and can contribute a protective effect; however, the optimal rewarming rate and underlying mechanism of rewarming following TH remain largely unexplained. Here, we investigated the effects of different rewarming rates and whether mitophagy is involved in rewarming. After 5 min of asphyxial CA following 4 h of cooling, Sprague-Dawley rats were randomized into the normothermia, hypothermia, slow rewarming (0.5 °C/h) and fast rewarming (4 °C/h) groups. The hypothermia group was kept cool until tissue harvest, the rewarming duration for the slow rewarming group and fast rewarming group was 6 h and 45 min, respectively. We found that slowly rewarmed rats had better survival at 72 h than normothermic rats and fast-rewarmed rats (70%, 25.71%, and 50%, respectively) and higher neurological deficit scores (NDSs), in which the medians were 57.33, 26, and 28.83, respectively. In addition, we explored the underlying mechanism during this process and found that PINK1/Parkin-mediated mitophagy was activated during hypothermia in the slow rewarming group but was inhibited in the fast rewarming group. Further inhibition of mitophagy in the slowly rewarmed rats resulted in severe apoptosis and decreased the mean NDS from 58.39 to 33.11, indicating the protective role of mitophagy. Moreover, the fast rewarming group exhibited deficiencies in PINK1 expression and mitophagy activity and marked accumulation of reactive oxygen species (ROS). Overall, our results highlighted a neuroprotective role of PINK1/Parkin-mediated mitophagy during slow rewarming after hypothermia.

Abstract 103: Rewarming Speed Affects Cardiopulmonary and Neurological Functions After Deep Hypothermic Cardiac Arrest

Introduction: The optimal rewarming rate from accidental or induced deep hypothermia is still unknown. Fast extracorporeal rewarming by extracorporeal circulation has been associated with cardiac dysfunction, pulmonary edema and poor neurologic outcome. Hypothesis: This study investigates whether the speed of rewarming after deep hypothermic cardiac arrest has neurological and cardiopulmonary effects. Methods: Thirty male Sprague-Dawley adult rats (450-550g) were rapidly cooled (ice packs) until 15°C core body temperature. Deep hypothermic cardiac arrest was maintained for 60 min. Thereafter rats were randomised to receive slow (90 minutes) or fast (30 minutes) rewarming by cardiopulmonary bypass to a target temperature of 35°C. After 90 minutes of reperfusion all animals underwent hemodynamic assessment by biventricular pressure-volume analysis, brain MRI and heart, lungs and brain were collected. Results: Slow rewarming preserved cardiac systolic and diastolic functions, ventricular arterial coupling and endothelium dependent relaxation. Lung edema was attenuated after slow rewarming. Cardimyocytes pro-survival kinases ERK and Akt activation were significantly higher in the slow rewarming group. MRI demonstrated enhancement of cerebral blood flow and reduction of cerebral edema after slow rewarming. Neurologic inflammatory response measured by IL-6, ICAM-1, CCL5 and TNF-α expression was significantly decreased in the slow rewarming group. Oxidative stress assessed by malondialdehyde was significantly reduced after slow rewarming. Conclusion: Slow rewarming by extracorporeal circulation after deep hypothermic cardiac arrest might improve systolic and diastolic function, preserve ventricular-arterial coupling, attenuate cerebral perfusion impairment and reduce neuronal damage.

Effect of slow versus rapid rewarming on jugular bulb oxygen saturation in adult patients undergoing open heart surgery.

Background:A debate has appeared in the recent literature about the optimum rewarming strategy (slow vs. rapid) for the best brain function. This study was designed to compare the effect of slow versus rapid rewarming on jugular bulb oxygen saturation (SjO2) in adult patients undergoing open heart surgery.Materials and Methods:A total of 80 patients undergoing valve and adult congenital heart surgery were randomly allocated equally to rapid rewarming group 0.5 (0.136)°C/min and slow rewarming group 0.219 (0.055)°C/min in jugular bulb sampling was taken before, during and after surgery. Surgery was done at cardiopulmonary bypass (CPB) temperature of 28-30°C and rewarming was performed at the end of the surgical procedure.Results:CPB time, rewarming period were significantly longer in the slow rewarming group. Significant difference was observed in the number of the desaturated patients (SjO2 ≤ 50%) between the two groups; 14 (35%) in rapid rewarming versus 6 (15%) in the slow rewarming group; P = 0.035 by Fisher's exact test.Conclusions:Slow rewarming could reduce the incidence of SjO2 desaturation during rewarming in adult patients undergoing open heart surgery.

High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndrome: a clinicopathological study

The rewarming phase after therapeutic hypothermia in cerebral ischemia appears crucial as rapid rewarming may lead to rebound phenomena and enhance deleterious ischemic effects. We hypothesized that slow and controlled rewarming after moderate hypothermia is superior to fast rewarming in rats subjected to 90 min temporary middle cerebral artery occlusion (tMCAO).Two experiments were designed: (i) 34 rats were randomly assigned to either normothermic treatment, to hypothermia (33°C) with rapid rewarming within 20 min, or to hypothermia with slow rewarming within 2 h after 4 h of hypothermia starting 2 h after tMCAO. Infarct size, neuroscore, myeloperoxidase and aquaporin 4 (AQP4) positive cells were assessed on day 5 after tMCAO. (ii) In 15 rats, striatal cerebral microdialysis was performed from 1.5 h before until 8 h after tMCAO. Total infarct volume was largest in the normothermic group (89.9 ± 16.8 mm3) followed by the fast rewarming group (69.2 ± 12.6 mm3), and a significantly smaller infarct volume in the slow rewarming group (41.1 ± 6.6 mm3, p < 0.05). Neurological functions improved in both hypothermia groups at day 5 after tMCAO (Neuroscore median 2.5 in normothermia vs. 1.5 in both hypothermia groups) though without any difference between slowly and fast rewarmed animals. Periinfarct expression of AQP4 was less prominent in slowly rewarmed animals as was the count of MPO-positive cells in subcortical regions. Glutamate release was significantly higher at 4 distinct time points in the control group. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia.

Hypothermia in acute stroke—Slow versus fast rewarming: An experimental study in rats

The rewarming phase after therapeutic hypothermia in cerebral ischemia appears crucial as rapid rewarming may lead to rebound phenomena and enhance deleterious ischemic effects. We hypothesized that slow and controlled rewarming after moderate hypothermia is superior to fast rewarming in rats subjected to 90 min temporary middle cerebral artery occlusion (tMCAO). Two experiments were designed: (i) 34 rats were randomly assigned to either normothermic treatment, to hypothermia (33°C) with rapid rewarming within 20 min, or to hypothermia with slow rewarming within 2 h after 4 h of hypothermia starting 2 h after tMCAO. Infarct size, neuroscore, myeloperoxidase and aquaporin 4 (AQP4) positive cells were assessed on day 5 after tMCAO. (ii) In 15 rats, striatal cerebral microdialysis was performed from 1.5 h before until 8 h after tMCAO. Total infarct volume was largest in the normothermic group (89.9 ± 16.8 mm 3) followed by the fast rewarming group (69.2 ± 12.6 mm 3), and a significantly smaller infarct volume in the slow rewarming group (41.1 ± 6.6 mm 3, p < 0.05). Neurological functions improved in both hypothermia groups at day 5 after tMCAO (Neuroscore median 2.5 in normothermia vs. 1.5 in both hypothermia groups) though without any difference between slowly and fast rewarmed animals. Periinfarct expression of AQP4 was less prominent in slowly rewarmed animals as was the count of MPO-positive cells in subcortical regions. Glutamate release was significantly higher at 4 distinct time points in the control group. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia.

Uncomplicated rapid posthypothermic rewarming alters cerebrovascular responsiveness.

Recently, we focused on the cerebrovascular protective effects of moderate hypothermia after traumatic brain injury, noting that the efficacy of posttraumatic hypothermia is related to the rate of posthypothermic rewarming. In the current communication, we revisit the use of hypothermia with varying degrees of rewarming to ascertain whether, in the normal cerebral vasculature, varying rates of rewarming can differentially affect cerebrovascular responsiveness. Pentobarbital-anesthetized rats equipped with a cranial window were randomized to 3 groups. In 1 group, a 1-hour period of hypothermia (32 degrees C) followed by slow rewarming (over 90 minutes) was used. In the remaining 2 groups, either a 1- or 2-hour period of hypothermia was followed by rapid rewarming (within 30 minutes). Vasoreactivity to hypercapnia and acetylcholine was assessed before, during, and after hypothermia. Additionally, the vascular responses to sodium nitroprusside (SNP) and pinacidil, a K(ATP) channel opener, were also examined. Hypothermia itself generated modest vasodilation and reduced vasoreactivity to all utilized agents. The slow rewarming group showed restoration of normal vascular responsivity. In contrast, hypothermia followed by rapid rewarming was associated with continued impaired responsiveness to acetylcholine and arterial hypercapnia. These abnormalities persisted even with the use of more prolonged (2-hour) hypothermia. Furthermore, posthypothermic rapid rewarming impaired the dilator responses of SNP and pinacidil. Posthypothermic rapid rewarming caused cerebral vascular abnormalities, including a diminished response to acetylcholine, hypercapnia, pinacidil, and SNP. Our data with acetylcholine and SNP suggest that rapid rewarming most likely causes abnormality at both the vascular smooth muscle and endothelial levels.

Slow rewarming improves jugular venous oxygen saturation during rewarming

There have been many studies regarding the etiology of postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery. Although its etiology remains unresolved, one possible factor related to postoperative cognitive dysfunction is a reduced internal jugular venous oxygen hemoglobin saturation (SjvO2) during the rewarming period. The purpose of this study was to examine the effect of rewarming rates on SjvO2 during rewarming. One-hundred patients scheduled for elective CABG surgery were randomly divided into two groups; control group (0.48 +/- 0.09 degrees C, n = 50), slow rewarming group (0.24 +/- 0.09 degrees C, n = 50). After the induction of anesthesia, a fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to monitor SjvO2 continuously. Hemodynamic parameters, arterial and jugular venous blood gases were measured at nine time-points. Cerebral desaturation (defined as a SjvO2 value below 50%) during rewarming was more frequent in the control group than in the slow group. Cerebral desaturation time (duration when SjvO2 was less than 50%) and the ratio of the cerebral desaturation time to the total CPB time in the control group differed significantly from those in the slow group (control group: 17 +/- 11 min, 12 +/- 4%, slow group: 10 +/- 8 min, 7 +/- 4%, respectively, P < 0.05). There was no significant difference in mini-mental state examination on the day before the operation nor at 1 month after the surgery among four values (the day before the operation: control group; 48 +/- 8, slow group; 48 +/- 7, at one month after the surgery: control group; 46 +/- 7, slow group; 45 +/- 9). A slow rewarming rate could reduce the chance of a decrease in SjvO2 during rewarming.

Effects of hypothermia and rewarming on evoked potentials during transient focal cerebral ischemia in cats

We examined the effects of mild to moderate hypothermia and the influence of rewarming on electrophysiological function using somatosensory evoked potentials (SEPs) in transient focal ischemia in the brain. Nineteen cats underwent 60 min of left middle cerebral artery occlusion under normothermic (36 ° -37 ° C, n = 6) or hypothermic (30 ° -31 ° C, n = 13) conditions followed by 300 min of reperfusion with slow (120 min, n = 6) or rapid (30 min, n = 7) rewarming. Whole-body hypothermia was induced during ischemia and the first 180 min of reperfusion. SEPs and regional cerebral blood flow were measured before and during ischemia and during reperfusion. The specific gravity of gray and white matter was examined as the indicator of edema. During rewarming, SEP amplitudes recovered gradually. After rewarming, SEPs in the normothermic and rapid rewarming groups remained depressed (20%-40% of pre-occlusion values); however, recovery of SEPs was significantly enhanced in the slow rewarming group (p < 0.05). Hypothermia followed by slow rewarming reduced edema in gray and white matter. Rapid rewarming did not reduce edema in the white matter. The recovery of SEPs correlated with the extent of brain edema in transient focal ischemia. Rapid rewarming reduced the protective effect of hypothermia. [Neurol Res 2002; 24: 621-626]

Slow Rewarming Has No Effects on the Decrease in Jugular Venous Oxygen Hemoglobin Saturation and Long-Term Cognitive Outcome in Diabetic Patients

The purpose of this study was to examine the effects of rewarming rate on internal jugular venous oxygen hemoglobin saturation (Sjvo2) during the rewarming period, and long-term cognitive outcome in diabetic patients. We studied 30 diabetic patients scheduled for elective coronary artery bypass graft surgery. As a control, 30 age-matched nondiabetic patients were identified. The diabetic patients were randomly divided into two groups: the Slow Rewarming group (n = 15) (mean rewarming speed: 0.22° ± 0.07°C/min, mean ± sd) or the Standard Rewarming group (Standard group) (n = 15) (mean rewarming speed: 0.46° ± 0.09°C/min, mean ± sd). After the induction of anesthesia, a fiberoptic oximetry catheter was inserted into the right jugular bulb to monitor Sjvo2 continuously. Hemodynamic variables and arterial and jugular venous blood gases were measured at nine time points. All patients underwent a battery of neurologic and neuropsychologic tests on the day before the operation and at 4 mo after surgery. The Sjvo2 values in the Standard group were decreased during the rewarming period compared with at the induction of anesthesia (P < 0.05). There was a significant difference in the Sjvo2 value in the Control group between standard rewarming and slow rewarming during rewarming periods (Standard Control group: 51% ± 8%, Slow Control groups: 58% ± 5%) (P < 0.05). However, there was no difference in the Sjvo2 value in diabetic patients between standard rewarming and slow rewarming during the rewarming period. The rewarming rates (odds ratio: 0.8; 95% confidence interval: 0.5–1.3;P = 0.6) had no correlation with cognitive impairment at 4 mo after the surgery. Diabetes (odds ratio: 1.6; 95% confidence interval: 0.9–2.6;P = 0.04) was a factor in relation to cognitive impairment at 4 mo after the surgery. We concluded that a slow rewarming rate had no effects on the reduction in Sjvo2 value and long-term cognitive outcome in diabetic patients.

Exacerbation of traumatically induced axonal injury by rapid posthypothermic rewarming and attenuation of axonal change by cyclosporin A.

Although considerable attention has been focused on the use of posttraumatic hypothermia, little consideration has been given to the issue of posthypothermic rewarming and its potentially damaging consequences. In this communication, the authors examine the issue of rapid posthypothermic rewarming compared with gradual rewarming while exploring the potential utility of cyclosporin A (CsA) administration for attenuating any rapid rewarming-induced axonal change. Male Sprague-Dawley rats were subjected to impact-acceleration injury and then their body temperature was lowered to 32 degrees C for 1 hour postinjury. After hypothermia, rewarming to normothermic levels was accomplished either within a 20-minute period (rapid rewarming) or over a 90-minute period (slow rewarming). Some animals in the rapid rewarming group received intrathecal infusion of either CsA or its vehicle, whereas the rats in the slow rewarming group received vehicle alone. Both the CsA and its vehicle were administered immediately before initiation of rewarming. Twenty-four hours postinjury the animals' brains were processed for visualization of amyloid precursor protein (APP), a marker of traumatic axonal injury. The APP-positive axonal density in the gradually rewarmed group receiving vehicle was statistically significantly reduced in comparison with the rapidly rewarmed, vehicle-treated group. For the group undergoing rapid rewarming and treatment with CsA, a statistically significant reduction was also found in the density of the APP profiles compared with the rapidly rewarmed, vehicle-treated group. The results of this study show that rapid rewarming exacerbates traumatically induced axonal injury, which can be significantly attenuated by administering CsA.