Moderate Therapeutic Hypothermia Research Articles

Current and Future Role of Therapeutic Hypothermia

Therapeutic moderate hypothermia has been advocated for use in traumatic brain injury, stroke, cardiac arrest-induced encephalopathy, neonatal hypoxic-ischemic encephalopathy, hepatic encephalopathy, and spinal cord injury, and as an adjunct to aneurysm surgery. In this review, we address the trials that have been performed for each of these indications, and review the strength of the evidence to support treatment with mild/moderate hypothermia. We review the data to support an optimal target temperature for each indication, as well as the duration of the cooling, and the rate at which cooling is induced and rewarming instituted. Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic encephalopathy. For traumatic brain injury, a recent meta-analysis suggests that cooling may increase the likelihood of a good outcome, but does not change mortality rates. For many of the other indications, such as stroke and spinal cord injury, trials are ongoing, but the data are insufficient to recommend routine use of hypothermia at this time.

Multiplex Assessment of Cytokine and Chemokine Levels in Cerebrospinal Fluid following Severe Pediatric Traumatic Brain Injury: Effects of Moderate Hypothermia

This study performed a comprehensive analysis of cerebrospinal fluid (CSF) cytokine levels after severe traumatic brain injury (TBI) in children using a multiplex bead array assay and to evaluate the effects of moderate hypothermia on cytokine levels. To this end, samples were collected during two prospective randomized controlled trials of therapeutic moderate hypothermia in pediatric TBI. Thirty-six children with severe TBI (Glasgow Coma Scale [GCS] score of <or=8) and 10 children with negative diagnostic lumbar punctures. All children with TBI had continuous monitoring of intracranial pressure and CSF drainage via an intraventricular catheter. Moderate hypothermia (32-33 degrees C) was maintained for 48 h in 17 patients, and they were slowly re-warmed at 48-72 h. A multiplex bead array assay was used to analyze serial CSF samples (<18 h, 24 +/- 6 h, 48 +/- 6 h, and 72 +/- 6 h) for 21 pro-and anti-inflammatory cytokines and chemokines. Interleukin (IL)-8 and transforming growth factor beta were measured by enzyme-linked immunosorbant assay (ELISA). There was a strong correlation (Spearman correlation coefficient = 0.92, p < 0.001) between multiplex assay and ELISA for IL-8. Pro-inflammatory IL-1beta, -6 and -12p70, anti-inflammatory IL-10 and chemokines IL-8 and MIP-1alpha were increased after TBI compared to controls, p < 0.05; however, there was no association between cytokines and age, gender, initial GCS, or outcome. Hypothermia did not attenuate the increases in CSF cytokine levels after TBI versus normothermia. This investigation confirmed that the multiplex bead array assay is a useful method to measure CSF cytokine levels. Severe TBI in infants and children induces increases in pro- and anti-inflammatory cytokines and chemokines. It is the first clinical report of increased levels of MIP-1alpha after TBI in any patient population and the most comprehensive assessment of cytokines after TBI to date. Moderate therapeutic hypothermia did not attenuate the increase in CSF cytokine levels in children after TBI.

Therapeutic Hypothermia for Global and Focal Ischemic Brain Injury—A Cool Way to Improve Neurologic Outcomes

Therapeutic hypothermia (TH) has been employed as a neuroprotective strategy for a wide array of clinical problems since the late 1940s. Animal studies have determined that the neuroprotective effect of hypothermia is pleiotropic, impacting many steps in both the ischemic cascade and reperfusion injury. Interest in the neuroprotective effects of TH for ischemic brain injury has been resurgent, fueled by both recent positive and negative clinical trials. A review of preclinical and clinical reports on TH in adult patients is provided in this article. Animal data and several large clinical studies of mild to moderate TH (32 degrees C-34 degrees C) for global cerebral ischemia describe favorable neurologic outcomes, with few adverse effects. However, clinical implementation for global ischemia remains poor. Some animal data support a role for TH in focal cerebral ischemia, if instituted soon after the onset of ischemia, and in the setting of reperfusion. Clinical studies of TH for focal cerebral ischemia have so far been equivocal. The available data suggest that, despite sharing some common components in the ischemic cascade, focal and global cerebral ischemia are pathophysiologically disparate, and may respond to different neuroprotective strategies. TH is a safe, effective neuroprotective strategy for global cerebral ischemia. Because of the neuroprotective efficacy of TH in adult comatose survivors of cardiac arrest, neurologists should advocate the implementation of this strategy. TH for focal ischemia is a promising therapeutic option, but requires more basic and clinical investigation.

Analysis of Neuronal, Glial, Endothelial, Axonal and Apoptotic Markers Following Moderate Therapeutic Hypothermia and Anesthesia in the Developing Piglet Brain

Hypothermia (HT) by whole body (WBC) or selective head cooling (SHC) reduces hypoxic-ischemic (HI) brain injury; however, whether prolonged hypothermia and/or anesthesia disrupts immature brain development, eg, increases apoptosis, is unknown. Anesthesia increases apoptosis in immature animals. We investigated whether neuroprotective hypothermia and anesthesia disrupts normal brain development. Thirty-eight pigs <24 h old were randomized between five groups and were killed after 72 h: eighteen received a global hypoxic-ischemic insult under anesthesia, eight subsequently cooled by SHC with WBC to T(rectal) 34.5 degrees C for 24 h, followed by 48 h normothermia (NT) at T(rectal) 39.0 degrees C, while 10 remained normothermic. Sixteen underwent anesthetized sham hypoxic-ischemic, six then following normothermia and 10 following hypothermia protocols. There were four normothermic controls. The hypothermia groups demonstrated significant brain hypothermia. In the hypoxic-ischemic groups this conferred approximately 60% neuroprotection reducing histological injury scores in all brain areas. Immunohistochemical/histochemical analyses of neuronal, glial, endothelial, axonal, transcriptional apoptotic markers in areas devoid of histological lesions revealed no hypothermia/normothermia group and differences whether exposed to hypoxic-ischemic or not. Neither 36-h anesthesia nor 24-h hypothermia produced adverse effects at 4-day survival on a panel of brain maturation/neural death markers in newborn pigs. Longer survival studies are necessary to verify the safety of hypothermia in the developing brain.

Postresuscitative Intensive Care: Neuroprotective Strategies after Cardiac Arrest

Cardiac arrest is a common disease in the United States, and many patients will die as a result of the neurological damage suffered during the anoxic period, or will live in a neurologically debilitated state. When cardiopulmonary-cerebral resuscitation results in the return of spontaneous circulation, intensive care is required to optimize neurological recovery. Such "brain-oriented" therapies include routine care, such as positioning and maintenance of volume status; optimization of cerebral perfusion, with the use of vasopressors if needed; management of increased intracranial pressure with agents such as hypertonic saline; assuring adequate oxygenation and avoiding hypercapnia; aggressive fever control; intensive glucose control, with the use of an insulin drip if needed; and management of seizures if they occur. To date, no neuroprotectant medications have been shown to improve neurological outcome. Induced moderate therapeutic hypothermia is utilized as a neuroprotective maneuver. Future treatment options and advanced monitoring techniques are also discussed. Further study to optimize neuroprotective strategies when treating patients who survive cardiac arrest is needed.

Supplementary Comment on “Effect of Therapeutic Moderate Hypothermia on Multi-drug Resistance Protein 1-Mediated Transepithelial Transport of Drugs”

Supplementary Comment on “Effect of Therapeutic Moderate Hypothermia on Multi-drug Resistance Protein 1-Mediated Transepithelial Transport of Drugs”

Effect of Therapeutic Moderate Hypothermia on Multi-drug Resistance Protein 1-Mediated Transepithelial Transport of Drugs

To clarify the effect of therapeutic moderate hypothermia on drug distribution, transepithelial transport via multi-drug resistance protein 1 (MDR1) (also called P-glycoprotein or ABCB1) was evaluated at various temperatures in vitro using LLC-GA5-COL150 cells, which were established by transfecting human MDR1 complementary deoxyribonucleic acid into kidney epithelial LLC-PK(1) cells and express MDR1 on the apical membrane. MDR1 is expressed in the blood-brain barrier to limit drug distribution to the brain by exporting exogenous substances including calcium blockers and antiarrhythmic drugs. Digoxin was used as a typical substrate, as well as the non-substrate tetracycline and paracellular marker inulin. MDR1-mediated transport of digoxin decreased at lower temperatures. Transport of tetracycline also decreased at lower temperatures, probably due to changes in membrane fluidity. However, no change was found at over 32 degrees C, suggesting that passive diffusion does not change during moderate hypothermia. The distribution of MDR1 substrates should be considered during hypothermic conditions, as the clinical outcome could be affected.

Hypothermia and Cerebral Ischemia: Mechanisms and Clinical Applications.

Wake Forest University School of Medicine, Winston-Salem, North Carolina. petrozza@wfubmc.eduHypothermia and Cerebral Ischemia: Mechanisms and Clinical Applications. By Carolina M. Maier, Ph.D., and Gary K. Steinberg, M.D., Ph.D. Totowa, New Jersey, Humana Press, 2003. Pages: 192. Price: $99.50.Hypothermia as a protective therapy and a treatment for cerebral ischemia in multiple settings has a long and storied history. Many anesthesiologists and intensivists have seen the prominence, the waning, and now the resurgence of therapeutic hypothermia within their professional lifetimes. Hypothermia and Cerebral Ischemia: Mechanisms and Clinical Applications is intended to provide a comprehensive review of mild hypothermia, including the therapeutic potential of the methodology, limitations, and recent developments in both basic and clinical research.One of the pleasures of reading this book is the evident effort which the editors Carolina A. Maier, Ph.D., and Gary K Steinberg, M.D., Ph.D., both from Stanford University, Stanford, California, expended on organizing the multiauthored text. The initial chapters contain a review of moderate hypothermia in experimental animal models primarily, and the middle chapters discuss current clinical practice and clinical trials. The third section of the book summarizes several studies performed primarily at single European centers in stroke patients. The summative chapter attempts to highlight future directions for the therapeutic applications of moderate hypothermia. Each chapter is organized with a concise historical view of hypothermia in the relevant experimental or clinical context, followed by presentations of important research studies and then a discussion of possible mechanisms of action, with a final concluding section on future directions for research.While the text is multiauthored with several international contributors, repetition of information is kept to a minimum, particularly in the initial chapters discussing experimental models of moderate hypothermia. Evidence of careful editing throughout the text is apparent by references to material or discussion in previous chapters where appropriate. In addition, the book is nicely illustrated with appropriate tables and images from experimental trials, which serve to highlight the teaching points within each chapter.Perhaps because a busy clinician has little time to explore the experimental basis for common therapies, this reader found the initial five chapters of this text to be most enjoyable. The concise discussions of the experimental rationale for moderate hypothermia followed by exploration of its application for the prevention and treatment of focal cerebral ischemia, traumatic brain injury, and postischemic injury were excellent. In contrast, the latter chapters of the text, which highlighted clinical trials and clinical methods of application of moderate hypothermia, were occasionally uneven in the amount of detail provided about clinical trials, research protocols, and patient groups.An obvious issue with a text that attempts to provide a comprehensive review of multiple applications of a technique in diverse groups of patients with many clinical scenarios is the issue of the current relevance of the information. The best asset of this text is its use to provide a foundation from which a clinician can best interpret new data. There are many practitioners, particularly those who specialize in neuroanesthesia and critical care, who are undoubtedly familiar with the myriad of mechanisms now identified as having a role in patient outcome after cerebral ischemia. However, a significant group of clinicians still exists who believe that an individual therapy such as hypothermia or a particular anesthetic might be the next “magic bullet.” Useful reading of the text such as Hypothermia and Cerebral Ischemia: Mechanisms and Clinical Applications at the point where one is initially exposed to the concepts of cerebral protection or neurosurgical anesthesia or professional interest is aroused through a clinical scenario might prove to be extremely valuable in broadening the knowledge base of many practitioners.This eminently readable text would be a valuable edition to the library of anesthesiology trainees who develop an interest in “cerebral protection” as they become familiar with concepts of neurosurgical anesthesia, critical care, and cerebral preservation within the operating room. In addition, this text serves as a strong foundation for those involved in the care of patients with devastating neurosurgical and neurologic disease as well the general practitioner of anesthesiology whose intellectual curiosity propels one to understand the background, limitations, and methodologies of current highly publicized clinical trials using therapeutic moderate hypothermia and other cerebral protection modalities.Wake Forest University School of Medicine, Winston-Salem, North Carolina. petrozza@wfubmc.edu

Active hypothermia in the management of head injuries.

For over half a century scientists and clinicians have been attempting to discover if moderate therapeutic hypothermia (32–34°C) is beneficial in the treatment of severe brain injury. Deep hypothermia (15–22°C) has long been recognized as one method of achieving neuroprotection, but is not without serious implications and risks to the patient. However, hyperthermia among headinjured patients is known to be associated with a worse outcome as compared to a normothermic cohort. Early work suggested that hypothermia could protect the brain after traumatic head injury.

Moderate hypothermia in severe head injuries: the present and the future.

The use of therapeutic moderate hypothermia for treating severe traumatic brain injury has been reported for more than 50 years. However, the most intense investigation of this treatment has occurred during the last 10 to 15 years. Virtually all preclinical studies have documented a robust treatment effect, not only in terms of reduced excitotoxicity and cerebral acidosis, but also in terms of histologic preservation and improved behavioral outcomes. Several single-center and small multicenter clinical trials conducted during the last decade also demonstrated benefit of early and late therapeutic hypothermia. However, a multicenter trial reported in February 2001 that included nearly 400 patients found no notable differences in neurologic outcomes in matched patients with head injuries who were treated with 48 hours of therapeutic moderate hypothermia compared with those kept at normal temperature. Findings from this study did suggest that rapid rewarming of patients with head injuries may be deleterious. A subgroup of young patients (less than 45 years of age) who were kept normovolemic showed a trend toward improved outcomes when treated with hypothermia. Current investigations, particularly in the preclinical arena, are focusing on combination therapy. To date, however, the addition of fibroblast growth factor, cyclosporine, or interleukin (IL)-10 to therapeutic moderate hypothermia has not been found to provide greater benefit than either therapy when used alone. Future investigations are aimed at further identifying the physiologic mechanisms responsible for secondary brain injury and ways in which other novel combination therapies may be expected to improve outcomes.

Effects of Hypothermia on Excitatory Amino Acids and Metabolism in Stroke Patients

The objective of this study was to assess the effect of therapeutic moderate hypothermia on excitatory amino acids and metabolism by applying cerebral microdialysis in patients suffering from space-occupying middle cerebral artery infarction. This was an open, prospective, observational study of 12 patients undergoing moderate hypothermia (33 degrees C) as rescue therapy for large, life-threatening middle cerebral artery infarction. Microdialysis probes were placed concomitantly with intracranial pressure (ICP) measuring devices in the frontal lobe of the infarcted and/or noninfarcted hemisphere. Using the CMA 600 Microdialysis Autoanalyzer, we analyzed glutamate, glycerol, pyruvate, and lactate. According to follow-up cranial CT scans, 3 different compartments of microdialysis measurements could be defined. First, noninfarcted brain tissue had stable dialysate concentrations but a significant effect of hypothermia on glutamate (2.6 versus 3.6 micromol/L), lactate (1.8 versus 3 mmol/L), and pyruvate (50 versus 95.8 micromol/L). Second, measurements from peri-infarct tissue had a significant effect of hypothermia on glutamate (4.8 versus 12.6 micromol/L), glycerol (58 versus 82 micromol/L), lactate (0.7 versus 1.3 mmol/L), and pyruvate (13.3 versus 36.8 micromol/L). Third, dialysate concentrations obtained from irreversibly damaged tissue were excessive for glutamate (453 micromol/L), glycerol (1187 micromol/L), lactate (12 micromol/L), and pyruvate (4 micromol/L). In this extreme compartment, no effect of hypothermia was observed. Cerebral microdialysis is a safe and feasible bedside method for neurochemical monitoring indicating normal brain tissue, potentially salvageable brain tissue, and irreversibly damaged areas in stroke. We could demonstrate that hypothermia decreases glutamate, glycerol, lactate, and pyruvate in the "tissue at risk" area of the infarct but not within the infarct core. Thus, future treatment strategies for life-threatening stroke should be guided by close neurochemical monitoring.

Reversible hypophosphatemia during moderate hypothermia therapy for brain-injured patients.

Because plasma potassium, which may similarly change as plasma phosphate (P), decreases during moderate hypothermia, plasma P, a requisite electrolyte for the cell function, may alter during therapeutic moderate hypothermia for brain-injured patients. In 22 such patients who underwent moderate hypothermia or were treated with normothermia, plasma concentrations of P and other chemicals were examined. A prospective study. The intensive care unit of a medical university hospital. In 15 consecutive patients with brain injury who underwent moderate hypothermia and 7 serial patients treated with normothermia, plasma concentrations of P, potassium, glucose, blood gas tension and pH, daily urine volume, and water balance were examined. Inequality in the numbers of patients of the two groups was the result of patient exclusion because of multiple trauma, aluminum hydroxide administrations, hyperventilation, preexisting diabetes mellitus, or administration of insulin. Daily blood sampling was done around 8 am. Inclusion criteria included a Glasgow Coma Scale score assessment < or = 8 at admission to the emergency room and evidence of injury on computerized tomography scanning of the brain. Hypothermia decreased plasma P levels as compared with those of normothermia within 4 days after the injury (this period was similar to the duration of the hypothermic phase in the hypothermia group). Such reduction related to changes in blood glucose levels, but not to any in the urine volume, or water balance. The P decrease occurred during the hypothermic phase, but subsequently there was a recovery of P after the rewarming phase. The changes in plasma potassium levels were similar to those in plasma P concentrations during the course. Such changes were accompanied by a recovery of decreased heart rate that occurred during the hypothermic phase. The results suggest that moderate hypothermia of 32-33 degrees C decreases plasma P levels. Further studies are required to examine whether P repletion may overcome certain hemodynamic derangements during moderate hypothermia in brain-injured patients.

Effects of hypothermia on thrombin-induced brain edema formation

Recent studies have shown that thrombin plays an important role in brain edema formation after intracerebral hemorrhage (ICH). The possible mechanisms of thrombin-induced brain edema formation include blood–brain barrier (BBB) disruption and inflammatory response involving polymorphonuclear (PMN) leukocyte. Animal experiments have revealed that moderate therapeutic hypothermia improves pathological and functional outcome in various models of brain injury. In this study, we examined the effect of hypothermia on thrombin-induced brain edema formation. Effects of hypothermia on BBB permeability and the accumulation of PMN leukocytes were also determined to clarify the protective mechanism of hypothermia in this model. Anesthetized adult rats received an injection of 10 Units of thrombin into the basal ganglia. Animals were separated into the normothermic and hypothermic groups, which were housed in a room maintained at 25°C and in a cold room maintained at 5°C, respectively, for 24 h after the thrombin injection. The brain temperature in rats housed in a cold room reduced temporarily to approximately 30°C and then gradually recovered to 35°C by the end of the observation. Brain water content in the basal ganglia was significantly reduced in rats treated with hypothermia compared to the normothermic rats (84.3±0.2 vs. 82.4±0.1%; P<0.01). The decrease of brain water content was accompanied with a significant reduction in BBB permeability to Evan’s blue dye and in accumulation of PMN leukocytes. This study indicates that hypothermic treatment significantly reduces thrombin-induced brain edema formation in the rat. Inhibition of thrombin-induced BBB breakdown and inflammatory response by hypothermia appear to contribute to brain protection in this model. Hypothermic treatment may provide an approach to potentially reduce ongoing edema after ICH.

Activated cytokine production in patients with accidental hypothermia

We have demonstrated recently that therapeutic moderate hypothermia of 32–33°C, induced by surface cooling under the administration of narcotics, sedatives and muscle relaxant, suppresses cytokine production after traumatic brain injury. We present here the first documented case report of augmented cytokine production in two accidental hypothermia patients, unconscious 84- (acute immersion) and 87- (non-immersion) year-old women, whose rectal temperatures were below 28°C. The victims were artificially ventilated after sedation with midazolam and buprenorphine in accordance with our protocol. Rewarming at the rate of approximately 1°C/h was done by blowing forced-air with appropriate fluid resuscitation. Plasma interleukin(IL)-6 and/or IL-8 levels were measured using ELISA in the patients. In both patients, plasma IL-6 levels on admission were already elevated and the cytokine levels further increased during and after the rewarming period. In the patient with the poorer prognosis, the plasma IL-8 level on admission was not elevated remarkably but after rewarming the level rose significantly. Augmented IL-6 production in accidental hypothermia was sustained for 6 days in the patient with the poorer prognosis but not in the subject with good recovery, who was treated with anti-thrombin III in the early phase. Since the mechanisms for developing accidental hypothermia were different, simple comparisons between the two cases should be limited. But, these findings may suggest a need for testing a hypothesis whether cytokine modulation could be a therapeutic approach worthy of consideration. The results presented here also suggest that in hypothermia, changes in cytokine release may vary depending on procedures such as the anesthetic drugs used, the duration of the therapy, or the rate of rewarming from hypothermia.

Combating hyperthermia in acute stroke: a significant clinical concern.

Moderate elevations of brain temperature, when present during or after ischemia or trauma, may markedly worsen the resulting injury. We review these provocative findings, which form the rationale for our recommendation that physicians treating acute cerebral ischemia or traumatic brain injury diligently monitor their patients for incipient fever and take prompt measures to maintain core-body temperature at normothermic levels. In standardized models of transient forebrain ischemia, intraischemic brain temperature elevations to 39 degrees C enhance and accelerate severe neuropathological alterations in vulnerable brain regions and induce damage to structures not ordinarily affected. Conversely, the blunting of even mild spontaneous postischemic hyperthermia confers neuroprotection. Mild hyperthermia is also deleterious in focal ischemia, particularly in reversible vascular occlusion. The action of otherwise neuroprotective drugs in ischemia may be nullified by mild hyperthermia. Even when delayed by 24 hours after an acute insult, moderate hyperthermia can still worsen the pathological and neurobehavioral outcome. Hyperthermia acts through several mechanisms to worsen cerebral ischemia. These include (1) enhanced release of neurotransmitters; (2) exaggerated oxygen radical production; (3) more extensive blood-brain barrier breakdown; (4) increased numbers of potentially damaging ischemic depolarizations in the focal ischemic penumbra; (5) impaired recovery of energy metabolism and enhanced inhibition of protein kinases; and (6) worsening of cytoskeletal proteolysis. Recent studies demonstrate the feasibility of direct brain temperature monitoring in patients with traumatic and ischemic injury. Moderate to severe brain temperature elevations, exceeding core-body temperature, may occur in the injured brain. Cerebral hyperthermia also occurs during rewarming after hypothermic cardiopulmonary bypass procedures. Several studies have now shown that elevated temperature is associated with poor outcome in patients with acute stroke. Finally, recent clinical trials in severe closed head injury have shown a beneficial effect of moderate therapeutic hypothermia. The acutely ischemic or traumatized brain is inordinately susceptible to the damaging influence of even modest brain temperature elevations. While controlled clinical investigations will be required to establish the therapeutic efficacy and safety of frank hypothermia in patients with acute stroke, the available evidence is sufficiently compelling to justify the recommendation, at this time, that fever be combatted assiduously in acute stroke and trauma patients, even if "minor" in degree and even when delayed in onset. We suggest that body temperature be maintained in a safe normothermic range (eg, 36.7 degrees C to 37.0 degrees C [98.0 degrees F to 98.6 degrees F]) for at least the first several days after acute stroke or head injury.

Significance of multimodal cerebral monitoring under moderate therapeutic hypothermia for severe head injury.

The therapeutic significance of moderate hypothermia and cerebral monitorings was assessed in the 10 patients with severe head injury. Cooling was begun as soon as possible after admission, using water blankets under general anesthesia. Jugular venous or tympanic temperature of patients was maintained at 32 degrees C for 3 to 5 days, then rewarming at the rate of 1 degree C a day was started. The intracranial pressure was controllable less than 20 mmHg under hypothermia. Moderate hypothermia reduced the jugular venous lactate (33.5%) as well as the cerebral blood flow velocity at M1 portion of middle cerebral artery (CBFV-M1) measured by transcranial Doppler (7.2%), while increase of the jugular venous oxygen saturation (SjO2) (17.9%) was observed in a majority of the patients. Our results demonstrated that moderate therapeutic hypothermia significantly reduced cerebral circulation and metabolism. Measurement of SjO2 and CBFV-M1 seems to be useful for estimation of cerebral circulation and metabolism in therapeutic hypothermia.

Therapeutic Moderate Hypothermia for Severe Traumatic Brain Injury

Use of therapeutic hypothermia to treat patients with severe traumatic brain injury was described more than 50 years ago. Unexpected improvement in some of these patients was attributed to hypothermia, but none of the early studies systematically evaluated the efficacy of hypothermia, and many patients were thought to have been harmed by the treatment, particularly when cooled below 30°C or when cooled for longer than 48 hours. Recent investigations have found that therapeutic moderate hypothermia (32–34°C) for relatively brief durations can improve histological and behavioral outcome following experimental brain injury. Cooling to this degree and duration has not been implicated as a cause for the cardiac arrhythmias, coagulation abnormalities, or infections attributed to hypothermia in the earlier studies. These laboratory investigations also defined several neurochemical mechanisms through which hypothermia may limit secondary brain injury and brain swelling. Four clinical trials of therapeutic moderate hypothermia were completed during the past three years; each detected a beneficial effect from cooling patients with severe traumatic brain injury to 32 to 34°C for up to 48 hours. In the largest of these studies, therapeutic moderate hypothermia was shown to cause a significant improvement in neurological outcomes 3, 6, and 12 months after injury for those patients with an initial Glasgow Coma Scale score of 5 to 7. The improvement in outcome for these patients was associated with a hypothermia-induced reduction of intracranial pressure and cerebrospinal fluid levels of interleukln-1β and glutamate.

The use of moderate therapeutic hypothermia for patients with severe head injuries: A preliminary report : Marion DW, Obrist WD, Carlier PM, et al. J Neurosurg 79:354, 1993

The use of moderate therapeutic hypothermia for patients with severe head injuries: A preliminary report : Marion DW, Obrist WD, Carlier PM, et al. J Neurosurg 79:354, 1993

The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report.

The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report.

The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report

Animal research suggests that moderate therapeutic hypothermia may improve outcome after a severe head injury, but its efficacy has not been established in humans. The authors randomly assigned 40 consecutively treated patients with a severe closed head injury (Glasgow Coma Scale score 3 to 7) to either a hypothermia or a normothermia group. Using cooling blankets and cold saline gastric lavage, patients in the hypothermia group were cooled to 32 degrees to 33 degrees C (brain temperature) within a mean of 10 hours after injury, maintained at that temperature for 24 hours, and rewarmed to 37 degrees to 38 degrees C over 12 hours. Patients in the normothermia group were maintained at 37 degrees to 38 degrees C during this time. Deep-brain temperatures were monitored directly and used for all temperature determinations. Intracranial pressure (ICP), cerebral blood flow (CBF), and cerebral metabolic rate for oxygen (CMRO2) were measured serially for all patients. Hypothermia significantly reduced ICP (40%) and CBF (26%) during the cooling period, and neither parameter showed a significant rebound increase after patients were rewarmed. Compared to the normothermia group, the mean CMRO2 in the hypothermia group was lower during cooling and higher 5 days after injury. Three months after injury, 12 of the 20 patients in the hypothermia group had moderate, mild, or no disabilities; eight of the 20 patients in the normothermia group had improved to the same degree. Both groups had a similar incidence of systemic complications, including cardiac arrhythmias, coagulopathies, and pulmonary complications. It is concluded that therapeutic moderate hypothermia is safe and has sustained favorable effects on acute derangements of cerebral physiology and metabolism caused by severe closed head injury. The trend toward better outcome with hypothermia may indicate that its beneficial physiological and metabolic effects limit secondary brain injury.