Induction Of Mild Hypothermia Research Articles

Effects of mild induced hypothermia during experimental sepsis*

The potential advantages of lowering core temperature during sepsis are to lower energy requirement and to activate various cell-protecting pathways. We experimentally investigated whether postconditioning temperature modifications influence survival duration during experimental sepsis. A prospective, randomized, experimental animal study. University laboratory. Eighteen male Sprague-Dawley rats (median 326 g, range 310-347 g). After anesthesia, experimental sepsis was induced by cecal ligation and perforation. The animals were subsequently assigned a core temperature range: normothermia (37 degrees C), hyperthermia (42 degrees C), and mild hypothermia (32 degrees C). Anesthesia and analgesia were continuously maintained until death. Plasma lactate and pyruvate concentrations were measured at sepsis induction (H0), 4 hrs later (H4), and/or at the time of death. A significant increase in lactate concentration was observed at the time of death in the 42 degrees C group (p = .04). Lactate-to-pyruvate ratio increased in the 32 degrees C (at H4) and 42 degrees C (at the time of death) groups (p = .04). A linear correlation between a longer survival duration and a lower assigned core temperature was observed (from 61 +/- 10 mins at 42 degrees C to 289 +/- 17 mins at 37 degrees C and to 533 +/- 69 mins at 32 degrees C; R = .959, p < .0001). The current results demonstrate that postconditioning hypothermia was associated with increased survival duration during experimental sepsis. Whether the observed benefits on survival duration are due to potential impacts on energy metabolism or to an anti-inflammatory effect of hypothermia requires further investigation.

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

Several randomized controlled trials have suggested that mild induced hypothermia may improve neurologic outcome in comatose cardiac arrest survivors. This systematic review of randomized controlled trials was designed to determine if mild induced hypothermia improves neurologic outcome, decreases mortality, or is associated with an increased incidence of adverse events. The following databases were reviewed: Cochrane Controlled Trials Register (Issue 4, 2005), MEDLINE (January 1966 to November 2005), EMBASE (1980 to November 2005), CINAHL (1982 to November 2005) and Web of Science (1989 to November 2005). For each included study, references were reviewed and the primary author contacted to identify any additional studies. Studies that met inclusion criteria were randomized controlled trials of adult patients (>18 years of age) with primary cardiac arrest who remained comatose after return of spontaneous circulation. Patients had to be randomized to mild induced hypothermia (32 degrees C-34 degrees C) or normothermia within 24 hours of presentation. Only studies reporting pre-determined outcomes including discharge neurologic outcome, mortality or significant treatment-related adverse events were included. There were no language or publication restrictions. Four studies involving 436 patients, with 232 cooled to a core temperature of 32 degrees C-34 degrees C met inclusion criteria. Pooled data demonstrated that mild hypothermia decreased in-hospital mortality (relative ratio [RR] 0.75; 95% confidence interval [CI], 0.62-0.92) and reduced the incidence of poor neurologic outcome (RR 0.74; 95% CI, 0.62-0.84). Numbers needed to treat were 7 patients to save 1 life, and 5 patients to improve neurologic outcome. There was no evidence of treatment-limiting side effects. Therapeutically induced mild hypothermia decreases in-hospital mortality and improves neurologic outcome in comatose cardiac arrest survivors. The possibility of treatment-limiting side effects cannot be excluded.

Critical Time Window for Intra-Arrest Cooling With Cold Saline Flush in a Dog Model of Cardiopulmonary Resuscitation

Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (n=9), mild hypothermia (34 degrees C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (n=8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (P=0.012). Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible.

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF.

Induction of mild hypothermia with infusion of cold (4 °C) fluid during ongoing experimental CPR

Introduction: Therapeutic hypothermia after resuscitation has been shown to improve the outcome regarding neurological state and to reduce mortality. The earlier hypothermia therapy is induced probably the better. We studied the induction of hypothermia with a large volume of intravenous ice-cold fluid after cardiac arrest during ongoing cardiopulmonary resuscitation (CPR). Methods: Twenty anaesthetised piglets were subjected to 8 min of ventricular fibrillation, followed by CPR. They were randomized into two groups. The hypothermic group was given an infusion of 4 °C acetated Ringer's solution 30 ml/kg at an infusion rate of 1.33 ml/kg/min, starting after 1 min of CPR. The control group received the same infusion at room temperature. All pigs received a bolus dose of vasopressin after 3 min of CPR. After 9 min, defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). Core temperature and haemodynamic variables were measured at baseline and repeatedly until 180 min after ROSC. Cortical cerebral blood flow was measured, using Laser-Doppler flowmetry. Results: All pigs had ROSC, except one animal in the hypothermic group. Only one animal in the hypothermic group died during the observation period. The calculated mean temperature reduction was 1.6 ± 0.35 °C (S.D.) in the hypothermic group and 1.1 ± 0.37 °C in the control group ( p = 0.009). There was no difference in cortical cerebral blood flow and haemodynamic variables. Conclusion: Inducing hypothermia with a cold infusion seems to be an effective method that can be started even during ongoing CPR. This method might warrant consideration for induction of early therapeutic hypothermia in cardiac arrest victims.

Mild Hypothermia Improves Survival After Prolonged, Traumatic Hemorrhagic Shock in Pigs

Clinical studies have demonstrated improved survival after cardiac arrest with induction of mild hypothermia (34 degrees C). Infusion of ice-cold saline seems beneficial. The American Heart Association recommends therapeutic hypothermia for comatose survivors of cardiac arrest. For hemorrhagic shock (HS), laboratory studies suggest that mild hypothermia prolongs the golden hour for resuscitation. Yet, the effects of hypothermia during HS are unclear since retrospective clinical studies suggest that hypothermia is associated with increased mortality. Using a clinically relevant, large animal model with trauma and intensive care, we tested the hypothesis that mild hypothermia, induced with intravenous cold saline (ice cold or room temperature) and surface cooling, would improve survival after HS in pigs. Pigs were prepared under isoflurane anesthesia. After laparotomy, venous blood (75 mL/kg) was continuously withdrawn over 3 hours (no systemic heparin). At HS 35 minutes, the spleen was transected. At HS 40 minutes, pigs were divided into three groups (n = 8, each): 1) Normothermia (Norm)(38 degrees C), induced with warmed saline; 2) Mild hypothermia (34 degrees C) induced with i.v. infusion of 2 degrees C saline (Hypo-Ice) and surface cooling; and 3) Mild hypothermia (34 degrees C), induced with room temperature (24 degrees C) i.v. saline (Hypo-Rm) and surface cooling. Fluids were given when mean arterial pressure (MAP) was <30 mmHg. At HS 3 hours, shed blood was returned and splenectomy was performed. Intensive care was continued to 24 hours. At 24 hours, there were two survivors in the Norm group, four in the Hypo-Ice group and seven in the Hypo-Rm group (p < 0.05 versus the Norm group, Log Rank). Time required to achieve 34 degrees C was 17 +/- 9 minutes in the Hypo-Ice group and 15 +/- 4 minutes in the Hypo-Rm group (NS). Compared with the Hypo-Rm group, the Hypo-Ice group required less saline during early HS (321 +/- 122 versus 571 +/- 184 mL, p < 0.05). The Hypo-Ice group also had higher lactate levels than the Hypo-Rm group (p < 0.05). Hypothermia did not cause any increase in bleeding compared with normothermia. Mild hypothermia during HS, induced by infusion of room temperature saline and surface cooling, improves survival in a clinically relevant model of HS and trauma. However, the use of iced saline in this model had detrimental effects and did not cool the animal more quickly than room temperature fluids. These findings suggest that optimal methods for induction of hypothermia need to be addressed for each potential indication, e.g. cardiac arrest versus HS.

Review: mild induced hypothermia does not reduce mortality or severe disability in moderate to severe head injury

Alderson P, Gadkary C, Signorini DF. Therapeutic hypothermia for head injury. Cochrane Database Syst Rev 2004;(4):CD001048. Q Does mild induced hypothermia reduce mortality and improve long term function in patients...

Mild Hypothermia for Acute Liver Failure

Brain edema with intracranial hypertension is a major complication in patients with acute liver failure. Current therapies for this complication include a variety of pharmacologic and interventional measures, some of which are frequently associated with adverse effects or contraindications. Even though these measures usually allow the control of intracranial hypertension for a certain period of time, recurrence is common. New therapies are therefore needed. Increasing clinical and experimental evidence suggests that induction of mild hypothermia (32 degrees C-35 degrees C) may be a therapeutic alternative. Similar to traumatic brain injury or brain stroke, induction of mild hypothermia seems highly effective to reduce intracranial pressure in patients with acute liver failure. Several mechanisms by which mild hypothermia may prevent brain edema and intracranial hypertension in this condition have been disclosed and may include beneficial effects on ammonia metabolism, as well as on the disturbances of brain osmolarity, cerebrovascular hemodynamics, brain glucose metabolism, inflammation, and others. Improvement of systemic hemodynamics and amelioration of liver injury may be other benefits of the systemic induction of mild hypothermia, but the impact of potential adverse events, such as infection, should also be taken into account. At a time when mild hypothermia is increasingly used in several specialized centers, performance of a randomized controlled trial seems critical to confirm the benefits of mild hypothermia in acute liver failure and to provide adequate guidelines for its use.

Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest—a feasibility study

Objective: Mild therapeutic hypothermia has shown to improve neurological outcome after cardiac arrest. Our study investigated the efficacy and safety of cold simple intravenous infusions for induction of hypothermia after cardiac arrest preceding further cooling and maintenance of hypothermia by specialised endovascular cooling. Methods: All patients admitted after cardiac arrest of presumed cardiac aetiology were screened. Patients enrolled received 2000 ml of ice-cold (4 °C) fluids via peripheral venous catheters. As soon as possible endovascular cooling was applied even if the cold infusions were not completed. The target temperature was defined as 33 ± 1 °C. All temperatures recorded were measured via bladder-temperature probes. The primary endpoint was the time from return of spontaneous circulation to reaching the target temperature. Secondary endpoints were changes in haemodynamic variables, oxygenation, haemoglobin, clotting variables and neurological outcome. Results: Out of 167 screened patients 26 (15%) were included. With a total amount of 24 ± 7 ml/kg cold fluid at 4 °C the temperature could be lowered from 35.6 ± 1.3 °C on admission to 33.8 ± 1.1 °C. The target temperature was reached 185 ± 119 min after return of spontaneous circulation, 135 ± 112 min after start of infusion, and 83 ± 85 min after start of endovascular cooling. Except for two patients showing radiographic signs of mild pulmonary edema no complications attributable to the infusions could be observed. Thirteen patients (50%) survived with favourable neurological outcome. Conclusion: Our results indicate that induction of mild hypothermia with infusion of cold fluids preceding endovascular cooling is safe and effective.

A new method for inducing hypothermia during cardiac arrest

It has been shown that hypothermia induced after successful resuscitation of comatose survivors of ventricular fibrillation cardiac arrest improves survival and neurologic function. Recent studies also suggest that earlier induction of hypothermia may yield even more improvement. We sought to determine if a new pump system, in addition to vigorous external chest compression, could rapidly induce hypothermia during cardiopulmonary resuscitation in a porcine model of cardiac arrest. Nine pigs (25-37 kg) were instrumented with micromanometers and thermocouple probes. Two 8-Fr catheters were placed into the femoral veins. Cardiac arrest was induced with 60-Hz current. After 5 mins of no support, chest compression was performed by a circumferential pneumatic bladder (vest-cardiopulmonary resuscitation). Blood was withdrawn from one catheter by a pump system that maximized flow by servo-control of inlet pressure, was cooled, and was returned through the other catheter. Four dogs were instrumented similarly, and cooling was performed during normal circulation. In the pigs, baseline temperatures were (mean +/- SEM) 37 +/- 1 degree C. With blood cooling in the external chiller to 10 degrees C, cerebral and right atrial temperatures were reduced by 0.49 +/- 0.09 and 0.67 +/- 0.21 degrees C/min, respectively, for 10 mins. With blood cooling in the external chiller to 4 degrees C, cerebral and right atrial temperatures were reduced by 0.61 +/- 0.18 and 1.56 +/- 0.33 degrees C/min, respectively. Cerebral cooling lagged behind right atrial cooling. There was a strong correlation between coronary perfusion pressure (aortic to right atrial mean decompression-phase pressure) and cerebral cooling rate (r = .79; p < .022). Rates of cooling during normal circulation in dogs were similar. Rapid induction of mild hypothermia is feasible with a system that uses venous access, standard access techniques, and external chest compression. Induction of mild hypothermia during cardiac arrest in the field appears feasible and may allow the benefit of very early induction of hypothermia to be determined in patients.

Effect of delayed induction of postischemic hypothermia on spinal cord damage induced by transient ischemic insult in rabbits

This study was performed to determine the effect of delayed induction of mild hypothermia after transient spinal cord ischemia in rabbits. Abdominal aortic occlusion was performed for 15 minutes to induce spinal cord ischemia at a rectal temperature of 37.3 +/- 0.3 degrees C. Four groups of rabbits were investigated: Group 1 (n = 8) was subjected to ischemia and reperfused at the same temperature for 7 hours; Group 2 (n = 8) was subjected to ischemia and reperfused at the same temperature for 1 hour, followed by 6 hours of systemic hypothermia (32.5 +/- 0.5 degrees C); Group 3 (n = 8) was subjected to ischemia, reperfusion at the same temperature for 3 hours and then 6 hours of systemic hypothermia (32.5 +/- 0.5 degrees C); and Group 4 (n = 8) comprised non-ischemic controls. Neurological status of all rabbits in Groups 1-3 was recorded and animals were sacrificed 1 week after ischemic injury. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. Mean modified Tarlov's score at 1 week after ischemic insult was 0.5 +/- 0.8 in Group 1, compared to 43 +/- 1.5 in Group 2 and 2.9 +/- 1.8 in Group 3. Mean total number of surviving neurons within examined sections of spinal cord was significantly greater for Groups 2 and 3 compared with Group 1 (Group 1, 81 +/- 66.1; Group 2, 293.4 +/- 110.9; Group 3, 227.1 +/- 105.5; p < 0.001). Delayed postischemic hypothermia induced within 3 hours after reperfusion significantly reduces ischemia-induced spinal cord neuronal damage in rabbits.

Induction and maintenance of mild hypothermia by surface cooling in non-intubated subjects

Mild induced hypothermia holds promise as an effective therapy for acute ischemic stroke. We developed a novel strategy to rapidly induce and maintain mild hypothermia in unanesthetized, non-intubated subjects as a model for the treatment of acute stroke patients. We induced and maintained mild hypothermia (tympanic membrane temperature 34°C–35°C) for over 5 hours in 10 healthy volunteers. All subjects received 1000 mg of acetaminophen orally and meperidine intravenously for comfort and suppression of shivering. In phase 1, subjects (n=5) were cooled using Arctic Sun Energy Transfer Pads (Medivance, Inc., Louisville, CO) with manual temperature control. In phase 2, subjects (n=5) were cooled using the Arctic Sun® Energy Transfer Pads™ connected to the Arctic Sun Model 200 Temperature control module (Medivance, Inc.). Core temperatures were measured at the tympanic membrane and rectum. All subjects reached the target tympanic temperature range. The mean time to reach a tympanic temperature of 35°C was 90±53 minutes (1.4°C/hour) in phase 2. The most common side effect was nausea, observed in 30% of subjects. There was no statistically significant change in heart rate, blood oxygenation, or diastolic blood pressure compared with baseline; systolic blood pressure was significantly elevated for the 180 minute time point only (140±20mm Hg v 122±13mm Hg; P = .042). We developed a method to rapidly and comfortably induce and maintain mild hypothermia in unanesthetized, non-intubated humans. Further study to optimize the pharmacologic inhibition of thermoregulation and to assess tolerability over longer durations is warranted.

Therapeutic hypothermia for head injury.

Induced hypothermia has been used in the treatment of head injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials. To estimate the effects of mild induced hypothermia in moderate and severe head injury on mortality, long-term functional outcome, complications, and short-term control of intracranial pressure (ICP). We searched the Injuries Group Specialised register (last searched in 2001), Medline, EMBASE and the Cochrane Controlled Trials Register. We handsearched conference proceedings and checked reference lists of relevant articles. Randomised controlled trials of mild hypothermia to 34-35 Celsius for a t least 12 hours versus control (open or normothermia) in patients with any closed head injury requiring hospitalisation. Two reviewers independently assessed all trials. Data on death, Glasgow Outcome Scale, complications and ICP were sought and extracted, either from published material or by contacting the investigators. Odds ratios and 95% confidence intervals were calculated for each trial on an intention-to-treat basis. Quantitative synthesis of data on complications other than pneumonia or ICP was not attempted. Trials of immediate and deferred hypothermia were analysed separately. We found 12 trials with 812 participants. Active immediate hypothermia was associated with an odds ratio for death of 0.88, (771 patients, OR 0.88, 95% CI 0.63 to 1.21), and 0.75 for odds of being dead or severely disabled, (746 patients, OR 0.75, 95% CI 0.56 to 1.00). Hypothermia treatment was associated with a statistically significant increase in odds of pneumonia (281 patients, OR 1.95, 95% CI 1.18 to 3.23). The trial of deferred hypothermia (33 patients) reported a huge but not statistically significant reduction in the odds of death at 6 months, (OR 0.21, 95% CI 0.04 to 1.05). For death or severe disability deferred hypothermia was associated with an odds ratio of 0.10 (95% CI 0.01 to 1.00). There is no evidence that hypothermia is beneficial in the treatment of head injury. The earlier, encouraging, trial results have not been repeated in larger trials. The reasons for this are unclear. Hypothermia increases the risk of pneumonia and has other potentially harmful side effects. Therefore, it would seem inappropriate to use this intervention outside of controlled trials in subgroups of patients for whom there is good reason to think the treatment would be beneficial.

Early hyperthermia after traumatic brain injury in children: Risk factors, influence of length of stay, and effect on short-term neurologic status.

Early hyperthermia after traumatic brain injury in children: Risk factors, influence of length of stay, and effect on short-term neurologic status. Natale JE, Joseph JG, Helfaer MA, Shaffner DH. Crit Care Med 2000; 28:2608–2615. Hyperthermia worsens outcome in virtually all animal models of acute brain injury. This is true whether hyperthermia occurs during or after the insult. In adult humans, the natural history of acute brain injury (for example, cardiac arrest, subarachnoid hemorrhage, and traumatic brain injury) includes a high incidence of spontaneous hyperthermia (Albrecht et al. Mayo Clin Proc 1998; 73:629—35). It has been argued that this hyperthermia should be treated to reduce severity of secondary insults after hospitalization. There is no data on the frequency of hyperthermia in children suffering from acute brain injury. Accordingly, the authors of this report retrospectively examined the medical records of 117 children hospitalized for traumatic brain injury (TBI). The cases occurred between 1995 and 1997. The median age of the children was 5.4 years. Patients with TBI were hospitalized in the pediatric intensive care unit (PICU) if their Glasgow Coma Scale (GCS) score was <15 or if there were other co-existing medical indications. Induction of mild hypothermia was not part of the treatment regimen. In addition to examining for evidence of fever, the investigators noted the following data: demographic characteristics, preinjury condition (especially recent preinjury antibiotic use), extracranial injuries, injury severity, initial computerized tomography (CT) scan, early physiologic response (such as glycemic and hemodynamic status), and medical care (for example, requirements for surgery). When possible, established scoring systems were used for each attribute. Outcome was measured by the PICU discharge GCS score and by the length of PICU stay. The data were subjected to bivariate analysis and logistic regression procedures to define risk factors for hyperthermia and to segregate the outcome predictive value of hyperthermia from known determinants other than length of PICU stay. All patients were neurologically intact before injury. Admission median GCS score was 12. Early hyperthermia (defined as a recorded value >38.5oC) was observed in 29.9% of patients. Early risk factors for hyperthermia were limited to injury severity, initial head CT, and early physiologic response to injury (primarily arterial hypotension). Factors associated with a low GCS score at PICU discharge were injury severity, early physiologic response (including hyperglycemia, leukocytosis, hypoxia, hypotension, and hyperthermia), and surgery during PICU stay. Factors associated with prolonged PICU stay were extracranial injuries, injury severity, early physiologic response including hyperthermia, and surgery during PICU stay. Logistic regression analysis showed that early hyperthermia predicted length of PICU stay independent from injury severity, hypotension, leukocytosis, or hyperglycemia. The results of this retrospective analysis in pediatric patients are in agreement with those found in adults. A hyperthermic response to TBI is common. However, the incidence of hyperthermia observed in this series was about one-half that observed in adults. This might be explained by the fact that this data was collected after it had become recognized that hyperthermia might be detrimental and therefore was more aggressively treated. Regardless, the incidence in children remained relatively high. There are no prospective controlled trials that have examined the effects of prophylactic avoidance of hyperthermia on outcome in patients with TBI and therefore any recommendations remain speculative. However there is no evidence for a beneficial effect of hyperthermia on the injured brain. In contrast, there is consistent evidence from laboratory models of acute brain injury that demonstrate adverse outcome effects from either early or delayed hyperthermia. This allows a reasonable conclusion to be made that hyperthermia, now known to frequently accompany TBI, should be aggressively treated. (DSW)

No additional neuroprotection provided by barbiturate-induced burst suppression under mild hypothermic conditions in rats subjected to reversible focal ischemia.

Mild-to-moderate hypothermia is increasingly used for neuroprotection in humans. However, it is unknown whether administration of barbiturate medications in burst-suppressive doses-the gold standard of neuroprotection during neurovascular procedures-provides an additional protective effect under hypothermic conditions. The authors conducted the present study to answer this question. Thirty-two Sprague-Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion and randomly assigned to one of four treatment groups: 1) normothermic controls; 2) methohexital treatment (burst suppression); 3) induction of mild hypothermia (33 degrees C); and 4) induction of mild hypothermia plus methohexital treatment (burst suppression). Local cerebral blood flow was continuously monitored using bilateral laser Doppler flowmetry and electroencephalography. Functional deficits were quantified and recorded during daily neurological examinations. Infarct volumes were assessed histologically after 7 days. Methohexital treatment, mild hypothermia, and mild hypothermia plus methohexital treatment reduced infarct volumes by 32%, 71%, and 66%, respectively, compared with normothermic controls. Furthermore, mild hypothermia therapy provided the best functional outcome, which was not improved by additional barbiturate therapy. The results of this study indicate that barbiturate-induced burst suppression is not required to achieve maximum neuroprotection under mild hypothermic conditions. The magnitude of protection afforded by barbiturates alone appears to be modest compared with that provided by mild hypothermia.

Hypothermia differentially increases extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun terminal kinase activation in the hippocampus during reperfusion after asphyxial cardiac arrest

Mitogen-activated protein kinases are signal transduction mediators that have been implicated in cell survival and cell death. This study characterized the activation of pathways in the hippocampus during reperfusion after global cerebral ischemia, as well as the influence of a regimen of hypothermia that reduces ischemic cell death in the hippocampus. Circulatory arrest was induced in rats by 8 min of asphyxia. Relative levels of phosphorylated and total extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were measured in the hippocampus after 6, 12 or 24 h of reperfusion using immunoblotting. Asphyxia induced a progressive increase in phosphorylated extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun N-terminal kinase, but no change in phosphorylated p38 mitogen-activated protein kinase. Induction of mild hypothermia (33°C) during reperfusion increased extracellular signal-regulated kinase phosphorylation and produced a smaller increase in stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation at 24 h. Hypothermia did not alter extracellular signal-regulated kinase activation in rats not subjected to ischemia. Extracellular signal-regulated kinase activation was associated with an increase in phosphorylation of the mitogen-activated protein kinase kinase 1/2, and was inhibited by administration of the specific mitogen-activated protein kinase kinase 1/2 inhibitor SL327. Immunohistochemical staining showed an increase in active extracellular signal-regulated kinase in the CA1, CA2, CA3 and dentate gyrus regions of the hippocampus after ischemia and reperfusion. In contrast, active stress-activated protein kinase/c-Jun N-terminal kinase immunoreactivity was most intense in the CA3 and dentate gyrus regions. These data demonstrate that both extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun N-terminal kinase pathways are activated during the first 24 h of reperfusion after global cerebral ischemia, and that hypothermia increases the activation of extracellular signal-regulated kinase relative to stress-activated protein kinase/c-Jun N-terminal kinase. Thus, an increase in extracellular signal-regulated kinase activation may be associated with improved neuronal survival after ischemic injury.

Etomidate vs. propofol for craniotomy: does it make a difference?

O-20 Introduction: Etomidate (E) is not used in TIVA regimens because of high osmolarity and suppression of cortisol synthesis. Limitations due to hyperosmolarity do not apply with a new lipid emulsion version Etomidat-Lipuro™ and suppression of cortisol synthesis is not a factor in patients receiving corticosteroid treatment as part of the peri-operative protocol. This warrants a reassessment of etomidate. We have compared E to propofol (P) as the hypnotic component of i.v. anaesthesia for elective craniotomy. Methods: With ethics committee approval and written informed consent, 20 consecutive ASA I-III patients were randomly allocated to receive an equipotent infusion of either E or P, supplemented with sufentanil. All patients received dexamethasone at induction and for 5 days postoperatively. Blood samples were taken before induction, during anaesthesia and at 24 h and on the 7th day. Results: Arterial blood pressure was lower and induction of mild hypothermia more rapid with P. Cortisol concentration decreased from 16 to 2 mg dL−1 in both groups with the minimum at 24 h, followed by complete recovery at day 7. Triglycerides increased in both groups, significantly more with E. Conclusion: Effects of E and P on cortisol concentration in patients receiving dexamethasone are identical. The more pronounced increase of triglycerides with E reflects the higher lipid content. P is a more powerful vasodilator, reflected both by a lower mean arterial pressure (macrocirculation) and more rapid cooling (microcirculation). We conclude that etomidate is a suitable alternative to propofol for intracranial surgery, when transient hypertriglyceridaemia and delayed cooling are considered acceptable.

Society of Neurosurgical Anesthesia and Critical Care

Society of Neurosurgical Anesthesia and Critical Care

Resuscitative hypothermia

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.