A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan. Treatment of traumatic brain injury with moderate hypothermia. Little benefit from mild hypothermia therapy for severely head injured patients with low intracranial pressure. Hypothermia therapy after traumatic brain injury in children. Lack of effect of induction of hypothermia after acute brain injury. A phase II study of moderate hypothermia in severe brain injury. Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases.
The criteria for the use of mild hypothermia (34 degrees C) in severely head injured patients have not been standardized. A prospective randomized controlled trial was conducted to determine whether mild hypothermia is essential in the treatment of severely head injured patients with low intracranial pressure (ICP).
                At 11 medical centers, 91 severely head injured patients with an admission Glasgow Coma Scale score of 8 or less in whom ICP could be maintained below 25 mm Hg by conventional therapies were divided randomly into two groups: the mild hypothermia group (HT group, 45 patients) and the normothermia group (NT group, 46 patients). Patients in the HT group were exposed to mild hypothermia (34 degrees C) for 48 hours, followed by rewarming at 1 degrees C per day for 3 days, whereas patients in the NT group were exposed to normothermia (37 degrees C) for 5 days. The two groups were similar with respect to prognostic factors, and there was no difference in clinical outcome at 3 months postinjury. During treatment, there was a significantly greater use of neuromuscular blocking agents in the HT group (p = 0.011). During the initial 2 weeks postinjury, the incidences of pneumonia, meningitis, leukocytopenia, thrombocytopenia, hypernatremia, hypokalemia, and hyperamylasemia were significantly higher in the HT than in the NT group (p < 0.05).
                Mild hypothermia should not be used for the treatment of severely head injured patients with low ICP because this therapy conveys no advantage over normothermia in such patients. Traumatic brain injury initiates several metabolic processes that can exacerbate the injury. There is evidence that hypothermia may limit some of these deleterious metabolic responses.
                In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in 82 patients with severe closed head injuries (a score of 3 to 7 on the Glasgow Coma Scale). The patients assigned to hypothermia were cooled to 33 degrees C a mean of 10 hours after injury, kept at 32 degrees to 33 degrees C for 24 hours, and then rewarmed. A specialist in physical medicine and rehabilitation who was unaware of the treatment assignments evaluated the patients 3, 6, and 12 months later with the use of the Glasgow Outcome Scale.
                The demographic characteristics and causes and severity of injury were similar in the hypothermia and normothermia groups. At 12 months, 62 percent of the patients in the hypothermia group and 38 percent of those in the normothermia group had good outcomes (moderate, mild, or no disabilities). The adjusted risk ratio for a bad outcome in the hypothermia group was 0.5 (95 percent confidence interval, 0.2 to 1.2). Hypothermia did not improve the outcomes in the patients with coma scores of 3 or 4 on admission. Among the patients with scores of 5 to 7, hypothermia was associated with significantly improved outcomes at 3 and 6 months (adjusted risk ratio for a bad outcome, 0.2; 95 percent confidence interval, 0.1 to 0.9 at both intervals), although not at 12 months (risk ratio, 0.3; 95 percent confidence interval, 0.1 to 1.0).
                Treatment with moderate hypothermia for 24 hours in patients with severe traumatic brain injury and coma scores of 5 to 7 on admission hastened neurologic recovery and may have improved the outcome. This study was performed to determine whether mild hypothermia therapy is essential for the treatment of severely head injured patients in whom intracranial pressure (ICP) can be maintained below 20 mm Hg by using conventional therapies.
                Sixteen consecutive severely head injured patients fulfilled the following criteria: the patient's ICP was maintained below 20 mm Hg by using fluid restriction, hyperventilation, and high-dose barbiturate therapy; and the patient had a Glasgow Coma Scale score of 8 or less on admission. After conventional therapies had been applied, the patients were divided randomly into two groups: the mild hypothermia group (HT group; eight patients) and the normothermia group (NT group; eight patients). The HT group received mild hypothermia (intracranial temperature 34 degrees C) therapy for 48 hours followed by rewarming at 1 degree C per day for 3 days, whereas the NT group received normothermia (intracranial temperature 37 degrees C) therapy for 5 days. Specimens of cerebrospinal fluid (CSF) taken from an intraventricular catheter every 24 hours were analyzed for the presence of excitatory amino acids ([EAAs] glutamate, aspartate, and glycine) and cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, IL-8, and IL-10). The two groups did not differ significantly in patient age, neurological status, or level of ICP. There were no significant differences in daily changes in CSF concentrations of EAAs and cytokines between the two groups. The incidence of pneumonia was slightly higher in the HT group compared with the NT group (p = 0.059). The incidence of diabetes insipidus associated with hypernatremia was significantly higher in the HT group compared with that in the NT group (p < 0.01). The two groups did not differ with respect to their clinical outcomes.
                The authors recommend normothermia therapy for the treatment of severely head injured patients in whom ICP can be maintained at lower than 20 mm Hg by using conventional therapies, because mild hypothermia therapy does not convey any advantage over normothermia therapy in such patients. Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown.
                In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5 degrees C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0 degrees C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months.
                A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1+/-1.2 degrees C and 36.9+/-0.5 degrees C, respectively. At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14). There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P=0.06). There was more hypotension (P=0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups.
                In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality. (Current Controlled Trials number, ISRCTN77393684 [controlled-trials.com].).
                Copyright 2008 Massachusetts Medical Society. 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.
                The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury.
                The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group.
                Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury. 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. Recent experimental studies have demonstrated that mild hypothermia at about 34 degrees C can be effective in the control of intracranial hypertension. A randomized controlled study of mild hypothermia was carried out in 33 severely head-injured patients. All patients fulfilled the following criteria: 1) persistent intracranial pressure (ICP) greater than 20 mm Hg despite fluid restriction, hyperventilation, and high-dose barbiturate therapy; 2) an ICP lower than the mean arterial blood pressure; and 3) a Glasgow Coma Scale score of 8 or less. The patients were divided into two groups: one received mild hypothermia (16 patients) and one served as a control group (17 patients). Mild hypothermia significantly reduced the ICP and increased the cerebral perfusion pressure. Eight patients (50%) in the hypothermia group and three (18%) in the control group survived (p < 0.05), while five (31%) in the hypothermia group and 12 (71%) in the control group died of uncontrollable intracranial hypertension (p < 0.05). In five patients in the hypothermia group, cerebral blood flow was measured by the hydrogen clearance method and arteriojugular venous oxygen difference was evaluated before and during mild hypothermia. Mild hypothermia significantly decreased the cerebral blood flow, arteriojugular venous oxygen difference, and cerebral metabolic rate of oxygen (p < 0.01). The results of this preliminary investigation suggest that mild hypothermia is a safe and effective method to control traumatic intracranial hypertension and to improve mortality and morbidity rates. The objective of this study was to determine the efficacy of mild hypothermia via selective head cooling as a neuroprotective therapy in term infants with perinatal asphyxia.
                Full-term newborns who had 5 min Apgar scores <6, first arterial blood gas pH<7.10 or BD>15 mEq/l, and with the clinical signs of encephalopathy were enrolled within 6 h after birth. Patients were randomized to receive mild hypothermia treatment via selective head cooling for a total of 72 h or receive routine treatment as a control. Brain hypoxic-ischemic injury was quantified based on the head computed tomographic scan (CT scan) at postnatal age 5-7 days and a Neonatal Behavioral Neurological Assessment (NBNA) score at 7-10 days of life.
                A total of 58 patients (30 hypothermia, 28 control) completed the study. Hypothermia was well tolerated in this study and attenuated the hypoxic-ischemic brain injury due to perinatal asphyxia. Head CT scan demonstrated moderate to severe hypoxic-ischemic changes in only 4/30 cases from the hypothermic group. In contrast, 18/28 cases in the control group showed moderate to severe hypoxic-ischemic changes (chi (2)=15.97, P<0.01). Brain hypothermia also significantly improved the NBNA score (32+/-2 in the hypothermic group vs 28+/-3 in the control group, P<0.01).
                Our results suggest that selective head cooling may be used as a neuroprotective therapy in term neonates with perinatal asphyxia. A long-term follow-up study is needed to further validate the results of this study. The goal of this study was to investigate the protective effects of long-term (3-14 days) mild hypothermia therapy (33-35 degrees C) on outcome in 87 patients with severe traumatic brain injury (TBI) (Glasgow Coma Scale score < or = 8).
                In 43 patients assigned to a mild hypothermia group, body temperatures were cooled to 33 to 35 degrees C a mean of 15 hours after injury and kept at 33 to 35 degrees C for 3 to 14 days. Rewarming commenced when the individual patient's intracranial pressure (ICP) returned to the normal level. Body temperatures in 44 patients assigned to a normothermia group were maintained at 37 to 38 degrees C. Each patient's outcome was evaluated 1 year later by using the Glasgow Outcome Scale. One year after TBI, the mortality rate was 25.58% (11 of 43 patients) and the rate of favorable outcome (good recovery or moderate disability) was 46.51% (20 of 43 patients) in the mild hypothermia group. In the normothermia group, the mortality rate was 45.45% (20 of 44 patients) and the rate of favorable outcome was 27.27% (12 of 44 patients) (p < 0.05). Induced mild hypothermia also markedly reduced ICP (p < 0.01) and inhibited hyperglycemia (p < 0.05). The rates of complication were not significantly different between the two groups.
                The data produced by this study demonstrate that long-term mild hypothermia therapy significantly improves outcomes in patients with severe TBI.
There is no evidence that hypothermia is beneficial in the treatment of head injury. Hypothermia may be effective in reducing death and unfavourable outcomes for traumatic head injured patients, but significant benefit was only found in low quality trials. Low quality trials have a tendency to overestimate the treatment effect. The high quality trials found no decrease in the likelihood of death with hypothermia, but this finding was not statistically significant and could be due to the play of chance. Hypothermia should not be used except in the context of a high quality randomised controlled trial with good allocation concealment.