Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review.
Topic: Hyperthermia

During the past 7 years, considerable new evidence has accumulated supporting the use of prophylactic hypothermia for traumatic brain injury (TBI). Studies can be divided into 2 broad categories: studies with protocols for cooling for a short, predetermined period (e.g., 24-48 h), and those that cool for longer periods and/or terminate based on the normalization of intracranial pressure (ICP). There have been no systematic reviews of hypothermia for TBI that include this recent new evidence.

PICO
Population: Patients with traumatic brain injury
Intervention: Prophylactic hypothermia
Comparison: Standard care or no hypothermia treatment
Outcomes: Effectiveness of prophylactic hypothermia in improving outcomes for traumatic brain injury patients

Included studies:
title: Lack of effect of induction of hypothermia after acute brain injury.
abstract: Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury.
title: Time course of intracranial hypertension after traumatic brain injury.
abstract: High intracranial pressure (HICP) may be a very early event after traumatic brain injury (TBI), but in most cases, especially when contusions and edema develop over time, HICP will worsen over succeeding days. This study describes the incidence and severity of elevated intracranial pressure (ICP) after TBI and attempts to document its time course. In this prospective study, 201 TBI patients in whom ICP was monitored for more than 12 h were evaluated. ICP was measured, digitalized, and analyzed after manual filtering. The number of episodes of HICP and the mean ICP value for every 12-h interval were calculated. When monitoring was concluded, the highest mean ICP collected in every patient was identified. A total of 21,000 h of ICP monitoring were recorded. Active treatment to prevent or reduce HICP was used in 200 patients. HICP was documented in 155 cases. Half of the patients had their highest mean ICP during the first 3 days after injury, but many showed delayed ICP elevation, with 25% showing highest mean ICP after day 5. In these cases, HICP was significantly worse and required more intense therapies.
title: The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report.
abstract: 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.
title: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
abstract: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.
title: Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans.
abstract: Moderate hypothermia may reduce subsequent neuronal damage after traumatic brain injury. Interleukin (IL)-6 may have a role in the pathogenesis of traumatic neuronal damage or repair. Using the enzyme-linked immunological sorbent assay (ELISA), we serially measured IL-6 levels in plasma obtained from the radial artery (systemic) and internal jugular vein (regional) in 13 cerebral trauma patients who underwent hypothermia of 32-33 degrees C ranged from 4-9 days postinjury and 10 head-injured patients who were maintained at normothermic levels (36-37 degrees C). In both patient populations, surface cooling was used since even in the normothermic group, cooling was needed to maintain patient temperature in the normothermic range. All patients were mechanically ventilated after injection of midazolam and vecuronium. The administration of these agents were continued until the end of the study. Hypothermia was typically maintained for four days, however, in some cases based upon CT findings and/or intra-cranial pressure change, the duration was prolonged. No significant differences were found between the two groups in age, gender and Glasgow Coma Scale upon admission. Further, no differences were found in terms of the classification of computed tomography findings or the occurrence of pupillary abnormalities on admission. The patients in this study had not sustained either abdominal or thoracic trauma. Before inducing hypothermia, IL-6 levels in the arterial and internal jugular venous blood exceeded the normal range. Specifically, the internal jugular plasma levels were significantly higher than those in the arterial plasma. While IL-6 levels in the normothermic group did not decrease even at 4 days postinjury, the plasma cytokine levels fell at both sites sharply after moderate hypothermia. The cytokine suppression found in the hypothermic group continued even after rewarming in these patients showing an improved clinical course, but not in those whose condition worsened. In addition to these changes in cytokine levels, the Glasgow Outcome Scale at 6 months postinjury was significantly higher in the hypothermic group than in the normothermia group. Based on the above, this clinical study with its small patient sample size suggests the need for further prospective randomized studies to examine the role of cytokine suppression in the beneficial effects of moderate hypothermia in patients with traumatic brain injury.
title: Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury.
abstract: Therapeutic hypothermia may improve outcome in patients with severe head injury, but clinical studies have produced conflicting results. We hypothesised that the severe side effects of artificial cooling might have masked the positive effects in earlier studies, and we treated a large group of patients with severe head injury with hypothermia using a strict protocol to prevent the occurrence of cooling-induced side effects.
title: The influence of mild hypothermia on ICP, CPP and outcome in patients with primary and secondary brain injury.
abstract: Aim of this study was to examine the hypothesis that only a subgroup of patients with lesser primary brain damage after severe head injury may benefit from therapeutic hypothermia. We prospectively analysed 72 patients with severe head injury, randomized into groups with (n = 37) and without (n = 35) hypothermia of 34 degrees C maintained for 72 hours. The influence of hypothermia on ICP, CPP and neurological outcome was analysed in the context of the extent of primary brain damage. Patients with normothermia and primary lesions (n = 17) values: GCS on admission 5 (median), ICP 18.9 (mean), CPP 73 (mean), GOS 4 (median). Patients with normothermia and extracerebral hematomas (n = 20): GCS 4, ICP 16, CPP 71, GOS 3. Patients with hypothermia and primary lesions (n = 21): GCS 4,62, ICP 10, 81, CPP 78,1, GOS 4. Patients with hypothermia and extracerebral hematomas (n = 14): GCS 5, ICP 13.2, CPP 78, GOS 5. Hypothermia decreased ICP and increased CPP regardless of the type of brain injury. Hypothermia was not able to improve outcome in patients with primary brain lesions but this pilot study suggests that it significantly improves outcome in patients with extracerebral hematomas.
title: Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury.
abstract: To compare the effect of long-term mild hypothermia versus short-term mild hypothermia on the outcome of 215 severe traumatic brain injured patients with cerebral contusion and intracranial hypertension. At three medical centers, 215 patients aged 18 to 45 years old with an admission Glasgow Coma Scale < or =8 within 4 h after injury were randomly divided into two groups: long-term mild hypothermia group (n = 108) for 5+/-1.3 days mild hypothermia therapy and short-term mild hypothermia group (n = 107) for 2+/-0.6 days mild hypothermia therapy. All patients had intracranial hypertension and frontotemporoparietal contusion with midline shift >1 cm confirmed on computed tomographic scan. Glasgow Outcome Scale at 6-month follow-up, 47 cases had favorable outcome (43.5%), and other 61 cases had unfavorable outcome (56.5%) in the long-term mild hypothermia group. However, only 31 cases had favorable outcome (29.0%), and other 76 cases had unfavorable outcome (71.0%) in the short-term mild hypothermia group (P < 0.05). The intracranial pressure significantly rebounded after rewarming in the short-term mild hypothermia group, but not in the long-term mild hypothermia (P < 0.05). Furthermore, the incidence of stress ulcer, epilepsy, pulmonary infection, intracranial infection did not significantly differ between the two groups (P > 0.05). Compared with short-term mild hypothermia, long-term mild hypothermia significantly improves the outcome of severe traumatic brain injured patients with cerebral contusion and intracranial hypertension without significant complications. Our data suggest that 5 days of long-term cooling is more efficacious than 2 days of short-term cooling when mild hypothermia is used to control refractory intracranial hypertension in patients with severe traumatic brain injury.
title: Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study.
abstract: We prospectively investigated non-invasive selective brain cooling (SBC) in patients with severe traumatic brain injury. Sixty-six in-patients were randomized into three groups. In one group, brain temperature was maintained at 33 - 35 degrees C by cooling the head and neck (SBC); in a second group, mild systemic hypothermia (MSH; rectal temperature 33 - 35 degrees C) was produced with a cooling blanket; and a control group was not exposed to hypothermia. Natural rewarming began after 3 days. Mean intracranial pressure 24, 48 or 72 h after injury was significantly lower in the SBC group than in the control group. Mean serum superoxide dismutase levels on Days 3 and 7 after injury in the SBC and MSH groups were significantly higher than in the control group. The percentage of patients with a good neurological outcome 2 years after injury was 72.7%, 57.1% and 34.8% in the SBC, MSH and control groups, respectively. Complications were managed without severe sequelae. Non-invasive SBC was safe and effective.
title: Psychoactive drug interactions.
abstract: Interactions can arise from serial or simultaneous administration of 2 or more drugs. Interactions with other medications can enhance or diminish either the clinical usefulness of a drug, or its toxic effects. Interactions can arise from changes in absorption, protein binding, metabolism, excretion or activity at a common site of action. Drug interactions of clinical interest to psychiatrists are described. The drugs include: stimulants, neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, anticonvulsants, and sedatives and hypnotics.
title: A phase II study of moderate hypothermia in severe brain injury.
abstract: Forty-six patients with severe nonpenetrating brain injury [Glasgow Coma Scale (GCS) 4-7] were randomized to standard management at 37 degrees C (n = 22) and to standard management with systemic hypothermia to 32 to 33 degrees C (n = 24). The two groups were balanced in terms of age (Wilcoxon's rank sum test, p > 0.95), randomizing GCS (chi-square test, p = 0.54), and primary diagnosis. Cooling was begun within 6 h of injury by use of cooling blankets. Metocurine and morphine were given hourly during induction and maintenance of hypothermia. Rewarming was at a rate of 1 degree C per 4 h beginning 48 h after intravascular temperature had reached 33 degrees C. Muscle relaxants and sedation were continued until core temperature reached 35 degrees C. There were no cardiac or coagulopathy-related complications. Seizure incidence was lower in the hypothermia group (Fisher's exact text, p = 0.019). Sepsis was seen more commonly in the hypothermia group, but difference was not statistically significant (chi-square test). Mean Glasgow Outcome Scale (GOS) score at 3 months after injury showed an absolute increase of 16% (i.e., 36.4-52.2%) in the number of patients in the Good Recovery/Moderate Disability (GR/MD) category as compared with Severe Disability/Vegetative/Dead (SD/V/D) (chi-square test, p > 0.287). Based on evidence of improved neurologic outcome with minimal toxicity, we believe that phase III testing of moderate systemic hypothermia in patients with severe head injury is warranted.
title: Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children.
abstract: To determine whether moderate hypothermia (HYPO) (32-33 degrees C) begun in the early period after severe traumatic brain injury (TBI) and maintained for 48 hours is safe compared with normothermia (NORM) (36.5-37.5 degrees C).
title: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
abstract: Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest.
title: Moderate hypothermia improves imbalances of thromboxane A2 and prostaglandin I2 production after traumatic brain injury in humans.
abstract: To examine the levels of thromboxane B2 (TXB2) and 6-keto prostaglandin F1alpha (6-keto PGF1alpha) production in arterial and internal jugular bulb sera in patients with traumatic brain injury (TBI). TBI is associated with arachidonate release and may be associated with an imbalance of vasoconstricting and vasodilating cyclooxygenase metabolites.
title: Therapeutic effect of mild hypothermia on severe traumatic head injury.
abstract: To investigate the therapeutic effect of mild hypothermia on severe traumatic brain injury.
title: Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury.
abstract: The therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury were studied.
title: The effect of hypothermia on the incidence of delayed traumatic intracerebral hemorrhage.
abstract: Hypothermia has been shown to cause coagulation abnormalities, primarily related to platelet dysfunction. We reviewed coagulation function and the incidence of delayed traumatic intracerebral hemorrhage in a series of 36 patients with severe head injuries (Glasgow Coma Scale 3-7) enrolled in a prospective, randomized, clinical trial of therapeutic moderate hypothermia. Patients were randomized to a normothermic group (n = 16) or to a group cooled to 32 to 33 degrees C within 6 hours of injury (n = 20). Prothrombin times, partial thromboplastin times, and platelet counts were obtained in the emergency room and then again within 24 hours of randomization. Delayed traumatic intracerebral hemorrhage occurred in 6 of 20 (30%) hypothermic patients and 5 of 16 (31%) normothermic patients. In the hypothermic group, 9 of 17 patients had an increased prothrombin time during hypothermic therapy, as opposed to 11 of 16 in the normothermic group during the corresponding time period. The partial thromboplastin time was prolonged in 2 of 17 hypothermic patients and 2 of 16 normothermic patients. Three patients in the hypothermic group and one in the normothermic group developed thrombocytopenia (a platelet count of less than 100,000). There were no significant differences between the two groups in the incidence of delayed traumatic intracerebral hemorrhage, in measured coagulopathy, or in the mean values of measured coagulation parameters. Although the possibility of a hypothermia-induced coagulopathy has not yet been excluded, the short-term use of hypothermia does not appear to increase the risk for intracranial hemorrhagic complications in head injuries.
title: Moderate hypothermia therapy for patients with severe head injury.
abstract: To evaluate the effect and safety of early moderate hypothermia therapy (MHT) on patients with head injury by using parallel-control test.
title: Discrete cerebral hypothermia in the management of traumatic brain injury: a randomized controlled trial.
abstract: Hypothermia has been extensively evaluated in the management of traumatic brain injury (TBI), but no consensus as to its effectiveness has yet been reached. Explanatory hypotheses include a possible confounding effect of the neuroprotective benefits by adverse systemic effects. To minimize the systemic effects, the authors evaluated a selective cerebral cooling system, the CoolSystem Discrete Cerebral Hypothermia System (a "cooling cap"), in the management of TBI.