Duration Of Hypothermia Research Articles

What can you do to protect the newborn brain?

Hypoxic-ischemic brain injury is a leading cause of mortality and morbidity in neonates. Treating such injury by interrupting the excitotoxic-oxidative cascade is of immense importance. This review will focus on novel techniques of neuroprotection and describe the latest advances in established therapeutic methods. Although the primacy of therapeutic hypothermia in treating hypoxic-ischemic encephalopathy is well established, recent research establishes that the arbitrarily chosen regimen of cooling to 33°C for 72 h may indeed be the most appropriate method. The optimal duration of antenatal magnesium therapy for neuroprotection remains unsettled, though it is reassuring that even 12 h or less of magnesium therapy results in comparable neurological outcomes. Combining adjuvant therapies such as melatonin or erythropoietin with therapeutic hypothermia results in favorable neurological outcomes compared with hypothermia alone. Finally, stem cell-based therapies show considerable potential in preclinical studies. Significant advances have occurred in the management of neonatal brain injury. With establishment of the optimal temperature and duration of hypothermia, combinatory therapies using adjuncts hold the greatest promise. Promising preclinical approaches such as stem cell-based therapy and use of noble gases need to be confirmed with clinical trials.

Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135.

Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 2.8-1959 nM) and CB2 (EC50 = 6.5-206 nM) receptors, with the fluorinated analogues generally showing increased CB1 receptor potency (∼2-5 times). Additionally, the cannabimimetic activities and relative potencies of JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 in vivo were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3-10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs in vivo. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 > 5F-PB-22 = JWH-018 > AM-2201 > APICA = STS-135 = XLR-11 > UR-144).

Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest

AimHypothermia is recommended by international guidelines for treatment of unconscious survivors of cardiac arrest to improve neurologic outcomes. However, temperature management is often underutilized because it may be difficult to implement. The present study evaluated the efficacy of pharmacologically induced hypothermia on survival and neurological outcome in rats resuscitated from cardiac arrest. MethodsCardiac arrest was induced for 10min in 120 rats. Sixty-one rats were resuscitated and randomized to normothermia, physical cooling or pharmacological hypothermia 5min after resuscitation. Pharmacological hypothermia rats received a combination of ethanol, vasopressin and lidocaine (HBN-1). Physical hypothermia rats were cooled with intravenous iced saline and cooling pads. Rats in the pharmacological hypothermia group received HBN-1 at ambient temperature (20°C). Normothermic rats were maintained at 37.3±0.2°C. ResultsHBN-1 (p<0.0001) shortened the time (85±71min) to target temperature (33.5°C) versus physical hypothermia (247±142min). The duration of hypothermia was 17.0±6.8h in the HBN-1 group and 17.3±7.5h in the physical hypothermia group (p=0.918). Survival (p=0.034), neurological deficit scores (p<0.0001) and Morris Water Maze performance after resuscitation (p=0.041) was improved in the HBN-1 versus the normothermic group. HBN-1 improved survival and early neurological outcome compared to the physical hypothermia group while there was no significant difference in performance in the Morris water maze. ConclusionHBN-1 induced rapid and prolonged hypothermia improved survival with good neurological outcomes after cardiac arrest suggesting that pharmacologically induced regulated hypothermia may provide a practical alternative to physical cooling.

Risk factors for hemodynamics change after cabg surgery in southwest of Iran.

Coronary artery diseases are the first and most common cause of death in all ages. Heart surgery, as a common therapeutic intervention for patients with coronary artery disease, is considered a necessary treatment. However, patients demonstrate several pre- and post-operative complications. Among the common postoperative complications of coronary artery bypass grafting (CABG) are hemodynamic changes that are still considered a major problem. This study was to determine the extent of hemodynamic changes after coronary artery grafting along with relevant factors in patients under open heart surgery hospitalized in the heart surgery intensive care units. This was a descriptive study, and the sample population consisted of patients who had undergone coronary artery bypass surgery in Ahvaz Golestan Hospital. Files of 100 patients qualified to take part in the study were selected by employing the simple sampling method, and the required information was extracted from them using a checklist. The chi-square test and regression analysis were used to analyze the data. Research findings indicated that 35% of patients experienced postoperative systolic blood pressure changes out of the normal range, 45% experienced diastolic blood pressure changes, Moreover, the relationship of hemodynamic variables with interfering factors such as body mass index (BMI), ejection fraction, history of myocardial infraction, duration of cardiopulmonary machine use, hypothermia, and levels of hemoglobin and hematocrit was found to be significant. Findings of this research can be used for planning on the early prevention, diagnosis and treatment of the possible complications that can be experienced by patients undergoing coronary artery bypass grafting. This will result in the improvement of the quality of care provided to these patients.

Effects of methylprednisolone on neuroprotective effects of delay hypothermia on spinal cord injury in rat.

Study DesignA retrospective study.PurposeThe aim of this study was to evaluate the effects of delayed hypothermia on spinal cord injuries in rats. In addition, the effect of methylprednisolone on therapeutic window of hypothermia was evaluated.Overview of LiteratureSeveral studies have demonstrated that early hypothermia is the most effective neuroprotective modality. However, delayed hypothermia seems to be more practical for patients with traumatic spinal cord injuries. A combination of hypothermia and other neuroprotective methods, such as using methylprednisolone, may help extend the therapeutic window of hypothermia.MethodsOne hundred and twenty male rats were categorized into six groups. The rats in five groups were subjected to spinal cord injury using the weight drop method, followed by treatment, consisting of early hypothermia, late hypothermia, late hypothermia plus methylprednisolone, or methylprednisolone only. Biochemical tests including catalase, malondialdehyde, and superoxide level were evaluated in the injured spinal cord. Behavioral functions of the hind limb were evaluated by Basso-Battle-Bresnaham locomotor rating scale and tail-flick tests.ResultsFunctional and biochemical evaluation showed both early and late hypothermia had significant neuroprotective effects. The treated groups did not differ significantly from one another in the behavioral tests. Hypothermia had better biochemical results compared to methylprednisolone. Also, methylprednisolone was shown to extend the therapeutic window of delayed hypothermia.ConclusionsHypothermia showed a significant neuroprotective effect, which can be improved with further studies optimizing the duration of hypothermia and the rewarming period. Moreover, the therapeutic effect of the delayed hypothermia can be extended by methylprednisolone.

Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury.

RELATIONSHIP BETWEEN CD34/CD45 POSITIVE CELLS CONCENTRATION IN BLOOD OF HEART RECIPIENTS AND LEVEL OF GRAFT VASCULOPATHY RISK BIOMARKERS

Aim. To determine the relationship between CD34/CD45 positive cells number in peripheral blood before and after heart transplantation (HTx) and plasma level of the biomarkers. Materials and methods. We studied 27 pts. (23 men; 40 ± 13 years) with heart failure caused by dilated (17 cases) or ischemic cardiomyopathy (10 cases) before and after HTx. CD34/CD45 positive cells were measured in peripheral blood before and 2–4 days after the operation by fl ow cytometry and expressed in number of the cells per 10 6 events, plasma level of the biomar- kers – by ELISA. Results. The number of CD34/CD45+ cells in pts. with heart failure (224 ± 166) was similar to those in healthy individuals (233 ± 120) and there was no signi fi cant difference in the cell number between pts. with dilated (253 ± 188) and ischemic cardiomyopathy (169 ± 100). The cell number did not correlate with age, sex, body weight, blood cells counts and preoperative levels of the biomarkers: PlGF, sCD40L, PAPP-A. In 2–5 days after HTx the cell number decreased to 103 ± 102. The cell number after HTx did not correlate with demographic and laboratory parameters, anesthesia, operation, ischemia and hypothermia duration, blood loss volume and preoperative levels of PlGF and PAPP-A but correlated with sCD40L level in pts. with ischemic cardiomyopathy. Conclusion: Circulating HSC number in patients with heart failure does not differ from those in healthy individuals and decreases after HTx. In patients with ischemic cardiomyopathy the cell number after transplantation associates with preoperative level of sCD40L – the negative predictor of vasculopathy.

Cooling Strategies Targeting Trauma

Therapeutic hypothermia and temperature management are currently being used in many institutions throughout the world to treat the devastating consequences of traumatic brain injury (TBI). In the 1990s and early 2000s, several single-institutional studies provided encouraging evidence for early cooling in improving outcome in patients with severe TBI. However, subsequent multicenter trials failed to show efficacy, with more recent studies emphasizing the importance of subpopulations of TBI patients being included in future hypothermia trials. This particular session brought together experts in the field of neurotrauma to discuss the status of managing hypothermia and fever control in the TBI population. Dr. John Povlishock, professor and chair, Department of Anatomy and Neurobiology at Virginia Commonwealth University, presented exciting preclinical data emphasizing the benefits of hypothermia in combination with various drugs in treating diffuse axonal injury and some of the vascular perturbations associated with TBI. This led to important discussions regarding what agents would be best to combine with hypothermia in future clinical studies. Dr. Shoji Yokobori, a visiting professor in the Department of Neurological Surgery at the University of Miami Miller School of Medicine, provided results concerning preclinical studies where hypothermia was tested in a decompression model of subdural hematoma. These studies emphasized the benefits of cooling the brain before decompression surgery and emphasized a potential subgroup of TBI patients that could benefit from early cooling. Dr. Yasuhiro Kuroda, professor, Department of Emergency Medicine, Kagawa University School of Medicine, presented new data concerning a clinical trial in TBI assessing the effects of hypothermia compared to strict normothermia in patients with severe TBI. Additional discussions concerned the limitations of showing the benefit of hypothermia in this heterogeneous patient population. Finally, Prof. Kees Polderman, Department of Critical Care Medicine, University of Pittsburgh, presented information regarding the ongoing Eurotherm 32–35 clinical study targeting TBI. This interesting study is using intracranial pressure (ICP) as a guide to direct the depth and duration of hypothermia in terms of patient management. Together, these studies emphasize the complexity of our severe TBI human population but also emphasize the significant progress we have made in this challenging field.

Marked changes in platelet count and function following pediatric congenital heart surgery

Reduced hemostatic capacity is common following congenital heart surgery using cardiopulmonary bypass (CPB). The etiology is multifactorial with dilutional coagulopathy, as well as platelet adhesion and activation in the CPB circuit and oxygenator. The purpose of the present study was to evaluate platelet count and function in children following CPB. In a prospective, observational study comprising 40 children, platelet count and function (Multiplate Analyzer(®)) were measured before surgery, immediately after bypass, and on the first postoperative day. Furthermore, conventional coagulation analysis and thromboelastometry (ROTEM(®)) were carried out. A significant decrease in platelet count was observed immediately after coming of bypass (P < 0.001) and persisted to the first postoperative day (P = 0.002). Platelet function was reduced immediately after bypass after induction with ADP (P < 0.001) or TRAP (P = 0.03). The duration of CPB correlated significantly with the decrease in platelet count (r = -0.62, P = 0.0001) and reduction in platelet function (r = -0.42-0.63; P < 0.01). Moderate to deep hypothermia during CPB was associated with a decreased platelet function (P = 0.01-0.12), whereas cyanosis or previous heart surgery caused no further changes in platelet function following CPB. Both platelet count and platelet function were significantly reduced after CPB in children undertaken correctional heart surgery. Duration of CPB and hypothermia was associated with significant changes in platelet function.

Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke.

Objective: To investigate whether the intermittent hypothermia (IH) protects neurons against ischemic insult and the potential molecular targets using an in vitro ischemic model of oxygen glucose deprivation (OGD).Methods: Fetal rat cortical neurons isolated from Day E18 rat embryos were subjected to 90-min OGD and hypothermia treatments during reoxygenation before examining the changes in microscopic morphology, cell viability, microtubule- associated protein 2 (MAP-2) release, intracellular pH value and calcium, reactive oxygen species (ROS) generation, mitochondrial membrane potential (△Ψm) and neuronal death using cell counting kit (CCK-8), enzyme-linked immunosorbent assay (ELISA), BCECF AM, Fluo-3 AM, DCFH-DA and dihydroethidium (DHE), JC-1 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively.Results: 90-min OGD induced morphologic abnormalities, cell viability decline, MAP-2 release, intracellular acidosis, calcium overload, increased ROS generation, △Ψm decrease and cell death in primary neurons, which was partially inhibited by continuous hypothermia (CH) and intermittent hypothermia (IH). Interestingly, 6-h CH was insufficient to reduce intracellular calcium overload and stabilize mitochondrial membrane potential (△Ψm), while 12-h CH was effective in reversing the above changes. All IH treatments (6×1 h, 4×1.5 h or 3×2 h) effectively attenuated intracellular free calcium overload, inhibited ROS production, stabilized mitochondrial membrane potential (△Ψm) and reduced delayed cell death in OGD-treated cells. However, only IH intervals longer than 1.5 h appeared to be effective in preventing cell viability loss and intracellular pH decline.Conclusion: Both CH and IH were neuroprotective in an in vitro model of ischemic stroke, and in spite of shorter hypothermia duration, IH could provide a comparable neuroprotection to CH.

Abstract 183: Appropriate Prolongation of Therapeutic Hypothermia Reduces Myocardial Damage After Prolong Cardiac Arrest

Background: Therapeutic hypothermia improves myocardial dysfunction and survival in cardiac arrest survivors. However, whether the duration of hypothermia should be prolonged in according to the duration of cardiac arrest to mitigate excess myocardial damage has not been clarified. Hypothesis: Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage after prolong cardiac arrest. Methods: The animals were equally randomized to NormoT(normothermia), 5H1, 5H2, 7H1, 7H2 and 7H4 groups. VF was induced and untreated for 5 minutes (NormoT, 5H1, 5H2) or 7 minutes (7H1, 7H2, 7H4), followed by 1 minutes of CPR, and then one electric shock of 5 J. Therapeutic hypothermia was initiated at simultaneously at the start of CPR with intravenous administration of 4°C saline and fan. After ROSC, hypothermia was maintained for 1hour (5H1, 7H1), 2 hours (5H2, 7H2) and 4 hours (7H4), respectively. Results: The plasma Troponin-I and FABP concentration at 2 nd hour following ROSC was significantly lower in the 5H2 and 7H4 groups than in the other groups (except the 7H2 group) (Figure). At 4 th hour after ROSC, The 5H2 and 7H4 groups showed less myocytolysis and apoptosis (Tunel staining) in the myocardium when compared with the other groups. Six out of 12 animals in both the 5H2 and 7H4 groups survived 72 hours after ROSC, whereas only 3 out of 12 animals in the 5H1 and 7H2 groups, and only 1 out of 12 animals in the 7H1 and NormoT groups. At the 72 nd hour, the 5H2 and 7H4 groups showed less myocardial fibrosis when compared with the groups. Conclusion: Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage in prolong cardiac arrest.

Abstract 181: Relation between Electrocardiographic Changes and Neurologic Outcomes in Patients Treated with Hypothermia after Out-of-hospital Ventricular Fibrillation Cardiac Arrest: J-PULSE-Hypo Registry

Background: The 2010 American Heart Association Guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) recommend that comatose adult patients with return of spontaneous circulation (ROSC) after out-of-hospital ventricular fibrillation (VF) cardiac arrest should receive therapeutic hypothermia (Class I). However, it remains unclear whether therapeutic hypothermia is effective for cardiac arrest patients whose have VF initially, but not at hospital arrival. Methods: We conducted a multicenter retrospective study at 14 institutions to evaluate the effect of therapeutic hypothermia on out-of-hospital cardiac arrest between January 2005 and March 2011. The study committee entrusted each hospital with the timing of cooling, cooling methods, target temperature, duration, and rewarming rate. Patients were divided into the VF-VF group, VF-PEA (pulseless electrical activity) group, and VF-Asystole group according to the pre-hospital initial rhythm and the hospital arrival rhythm, and neurologic outcomes at 90 days after cardiac arrest were compared. A favorable outcome was defined as a Cerebral Performance Category (CPC) of 1-2. Results: A total of 135 patients were studied. There were no significant differences among the VF-VF group (n=83), the VF-PEA group (n=35), and the VF-Asystole group (n=17) in age, sex, frequency of witnessed cardiac arrest, the presence of bystander CPR, time to achieving target temperature, or duration of therapeutic hypothermia. The rate of favorable outcomes was higher in the VF-VF group (46%) than in the VF-PEA group (23%; p&lt;0.01) and the VF-Asystole group (6%; p&lt;0.01). Multivariate analysis showed that VF rhythm at hospital arrival was an independent predictor of favorable outcomes at 90 days after cardiac arrest. Conclusions: Our results suggest that therapeutic hypothermia after ROSC most effectively improves neurologic outcomes in patients who have VF initially as well as at hospital arrival, with no ROSC by the time of hospital arrival. Additional therapeutic strategies are needed to improve neurologic outcomes in patients who have VF initially with no ROSC and a rhythm other than VF at hospital arrival.

Abstract 332: Simulation to Derive the Operating Characteristics of a Bayesian Adaptive Clinical Trial Design to Determine Optimal Duration of Hypothermia Following Out-of-Hosptial Cardiac Arrest

Introduction: Therapeutic hypothermia (TH) improves outcomes in comatose survivors of cardiac arrest, but optimal duration of cooling is unknown. An innovative adaptive trial may address this question efficiently and with fewer prior assumptions, but its complexity requires simulation to characterize the trial’s power and accuracy. Objective: To evaluate the operating characteristics (OC) of an adaptive clinical trial designed to characterize the TH duration response relationships for patients with shockable and non-shockable rhythms. Methods: The proposed ICECAP trial design uses a flexible, Bayesian normal dynamic linear model to estimate the relationship between duration of TH and 90 day modified Rankin Scale. The trial initially allocates 150 patients equally to 12, 24, or 48 hrs of cooling and models duration-response. The model then iteratively refines itself using response adaptive randomization ratios updated every 100 subsequent enrollments to time windows from 6 to 72 hours as needed to identify transitions in duration-response. Shockable and non-shockable rhythms are fitted separately. Sample sizes from 1600-2300 were simulated. The design was tested under hypothetical scenarios of no treatment effect, small, medium and large effects, and harm (outcomes worsen with duration). Each combination of sample size and scenario was simulated 1000 times. Results: The proportion of trials correctly identifying the target duration (for both rhythm types) ranged from 72% (N=1600), to 81% (N=2300). A sample size of 1800 had 85% power to select the target (the true or larger adjacent) duration. OC remained robust in specific challenging scenarios including a very early plateau with similar efficacy at 18-72 hours, and an inverted U with efficacy upsloping to 18 hours and diminishing from 30-72 hours. In the null scenario, identical outcomes for all durations from 6-72 hours, the design only incorrectly identifies a winning dose in 4-7% of trials. It was also efficient in this scenario, terminating 35% of trials early for futility. In harm scenarios, trials terminate early 86% of the time. Conclusions: The ICECAP trial design performs well under a variety of scenarios. Flexible, adaptive Bayesian trial designs are promising and ready to be implemented.

Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation

Although peripherally released interleukin (IL)-10 has a critical regulatory role in limiting fever in mild-to-moderate forms of inflammation, its role in regulating the more complex thermoregulatory manifestations of hypothermia and fever noted during severe inflammation is less clear. Using cytokine antagonism, we therefore investigated the involvement of peripherally released IL-10 in mediating hypothermia, fever and inflammation induced by intraperitoneal (IP) administration of a large dose of lipopolysaccharide (LPS). Male Wistar rats (200-250 g) were anaesthetized and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were randomly assigned to receive IL-10 antiserum (IL-10AS) or normal sheep serum IP, 4 h before receiving an IP injection of LPS (10 mg/kg) or phosphate-buffered saline (PBS). Inflammatory responses were measured in plasma and tissue samples (spleen, liver and brain) at 90 min and 6 h after the IP injection of LPS or PBS. Administration of LPS induced an initial period of hypothermia (~90 min) after which fever developed. Pre-treating rats with IL-10AS abolished the LPS-induced increase in plasma IL-10 levels, attenuated the hypothermia and increased the amplitude of the fever. Moreover, IL-10AS pre-treatment augmented the LPS-induced increase in plasma levels of tumor necrosis factor-alpha (90 min and 6 h), IL-1β (90 min), prostaglandin E2 (90 min) and IL-6 (6 h), in the periphery, but not the hypothalamus, over the duration of hypothermia and fever. Via its action on the synthesis of inflammatory mediators in the spleen and liver, endogenous IL-10 plays a crucial regulatory role in mediating hypothermia and fever during severe aspectic (LPS-induced) systemic inflammation.

Systematic Review and Meta-Analysis of Therapeutic Hypothermia in Animal Models of Spinal Cord Injury

BackgroundTherapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously.MethodsIn this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group.ResultsSystemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI −3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature.ConclusionSystemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies.

Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor

The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years. Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration. Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine's dose-response curve. Furthermore, this prolongation of nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally. We have shown that the pharmacological effects of inhibiting nicotine's metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine's bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.

Regional Hypothermia Inhibits Spinal Cord Somatosensory-Evoked Potentials without Neural Damage in Uninjured Rats

Both the therapeutic effects of regional hypothermia (RH) and somatosensory-evoked potentials (SSEP) have been intensively studied; however, the in vivo relationship between the two remains unknown. The primary focus of the current study was to investigate the impact of RH on SSEP in uninjured rats, as well as the neural safety of RH on neuronal health. An epidural perfusion model was used to keep local temperature steady by adjusting perfusion speed at 30°C, 26°C, 22°C, and 18°C for 30 min, respectively. Total hypothermic duration lasted up to 3 h. Neural signals were recorded at the end of each hypothermic period, as well as before cooling and after spontaneous rewarming. In addition, the Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale was used to evaluate the effects of RH pre- and post-operative, combined with hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. The results showed a marked declining trend in SSEP amplitude, as well as a significant prolongation in latency only during profound hypothermia (18°C). The BBB scale remained consistent at 21 throughout the entire process, signifying that no motor function injury was caused by RH. In addition, H&E and FJC staining did not show obvious histological injury. These findings firmly support the conclusion that RH, specifically profound RH, inhibits spinal cord SSEP in both amplitude and latency without neural damage in uninjured rats.

Abstracts from the 3rd Annual Therapeutic Hypothermia and Temperature Management ConferenceMarch 4–5, 2013Miami, FL

Abstracts from the 3rd Annual Therapeutic Hypothermia and Temperature Management ConferenceMarch 4–5, 2013Miami, FL

Prolonged hypothermia for neurological protection.

Treatment with mild hypothermia induced after cardiopulmonary resuscitation has become a standard of care, but optimal timing and duration of hypothermia remains unclear. We present a 66-year-old man admitted after an out-of-hospital cardiac arrest. Because of his severe hypoxemia, cardiopulmonary instability, and respiratory acidosis after resuscitation, he was continued on therapeutic hypothermia until his hypoxia resolved. As a result, the patient was kept at the goal hypothermic temperature of 33°C for a total of 48 hours, compared with the usual 24-hour standard, with excellent sustained neurological recovery. This case documents the usefulness of extending hypothermia when applied to severely unstable patients and suggests that a sliding-target approach may be applied on a patient-by-patient basis.

Drug Dosing During Hypothermia

Hypothermia is a proven neuroprotective therapy in neonates with moderate to severe hypoxic ischemic encephalopathy (HIE). Recent randomized control trials have demonstrated that whole body cooling to 33 to 34°C for 72 hours when initiated within 6 hours after birth of infants with a greater than 35 week gestational age increases survival and the rate of survival-free-disability.1,2 The efficacy of therapeutic hypothermia has led to expanded clinical implementation, and has resulted in the need for an understanding of the effects of reduced body temperature on drug disposition. This fact is particularly true in HIE patients due to the longer duration (up to 72 hours) of hypothermia and the difficulty in identifying adverse drug events from disease pathogenesis in neonates.