High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. Failure of prophylactic barbiturate coma in the treatment of severe head injury. Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. 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. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Little benefit from mild hypothermia therapy for severely head injured patients with low intracranial pressure. A prospective, randomized, and controlled study of fluid management in children with severe head injury: lactated Ringer's solution versus hypertonic saline.
In a five-center study, 73 patients with severe head injury and elevated intracranial pressure (ICP) were randomly assigned to receive either a regimen that included high-dose pentobarbital or one that was otherwise similar but did not include pentobarbital. The results indicated a 2:1 benefit for those treated with the drug with regard to ICP control. When patients were stratified by prerandomization cardiac complications, the advantage increased to 4:1. A multiple logistic model considering treatment and selected baseline variables indicated a significant positive treatment effect of barbiturates, a significant effect of time from injury to randomization, and an interaction of treatment with cardiovascular complications. However, of 925 patients potentially eligible for randomization, only 12% met ICP randomization criteria. The results support the hypothesis that high-dose pentobarbital is an effective adjunctive therapy, but that it is indicated in only a small subset of patients with severe head injury. In certain subgroups of severely head-injured patients, the mortality rate remains unacceptably high. The authors describe a randomized, controlled trial of prophylactic pentobarbital therapy in a group of these patients. Pentobarbital was started as soon as possible after the head injury, regardless of the intracranial pressure (ICP), and was continued for a prescribed period of time. The study included 53 consecutive head-injured patients over the age of 12 years, who had either an acute intradural hematoma (subdural and/or intracerebral, large enough to warrant surgical decompression), or no mass lesion but whose best motor response was abnormal flexion or extension. All patients in the study were randomly assigned to a control group (26 cases) or a pentobarbital-treated group (27 cases) once the diagnosis had been made and informed consent obtained. All patients were treated with the same protocol of aggressive resuscitation, prompt diagnosis and treatment of mass lesions, and intensive care, with close follow-up monitoring. The randomization was effective in producing a close match between the control and treated groups with respect to age, sex distribution, cause of injury, neurological status, intracranial lesions, prevalence of early systemic insults, midline shift, and initial ICP. Outcome was essentially the same in each group. There was no difference between groups in the incidence of elevated ICP, the duration of ICP elevation, or the response of ICP elevations to treatment. Arterial hypotension occurred in 14 patients (54%) in the treated group and only two patients (7%) in the untreated group. Based on these data the authors cannot recommend the prophylactic use of pentobarbital coma in the treatment of patients with severe head injury. They also believe that its use is accompanied by significant side effects which can potentially worsen the condition of a patient with severe head injury. During 1977-1978, 127 patients with severe head injury were admitted and underwent intracranial pressure (ICP) monitoring. All patients had Glasgow Coma Scale (GCS) scores of 7 or less. All received identical initial treatment according to a standardized protocol. The patients' average age was 29 years; 60% had multiple trauma, and 35% needed emergency intracranial operations. Treatment for elevations of ICP was begun when ICP rose to 20 to 25 mm Hg, and included mannitol therapy and drainage of cerebrospinal fluid (CSF) when possible. Forty-three patients (34%) had ICP greater than or equal to 25 mm Hg; of these, 36 (84%) died. The mortality rate of the entire group was 46%. During 1979-1980, 106 patients with severe head injury were admitted and underwent ICP monitoring. Their average ager was 29 years; 51% had multiple trauma, and 31% underwent emergency intracranial surgery. All patients received the same standardized protocol as the previous series, with the exception of the treatment of ICP. In this present series: if ICP was 15 mm Hg or less (normal ICP), patients were continued on hyperventilation, steroids, and intensive care; if ICP was 16 to 24 mm Hg, mannitol was administered and CSF was drained; if ICP was 25 mm Hg or greater, the patients were randomized into a controlled barbiturate therapy study. Twenty-six patients (25%) had ICP's of 25 mm Hg or greater, compared to 34% in the previous series (p less than 0.05), and 18 of these 26 patients (69%) died. The overall mortality for this current series was 28% compared to 46% in the previous series (p less than 0.0005). This study reconfirms the high mortality rate if ICP is 25 mm Hg or greater; however, the data also document that early aggressive treatment based on ICP monitoring significantly lessens the incidence of ICP of 25 mm Hg or greater and reduces the overall mortality rate of severe head injury. 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. To establish the safety of intravenous dexanabinol in severe head injury.
                Prospective, randomized, double-blind, placebo- (vehicle) controlled, multicenter, escalating dose study of a single administration of drug (48 or 150 mg) or vehicle (1 or 3 mL).
                All Israeli neurosurgical intensive care units (a total of six units).
                Sixty-seven patients, aged 16-65 yrs, Glasgow Coma Scale score of 4-8, injured within 6 hrs of treatment.
                Intracranial pressure, cerebral perfusion pressure, blood pressure, and heart rate were measured continuously in the intensive care unit. Adverse medical events were recorded and clinical outcome was assessed by the Glasgow outcome scale throughout a 6-month follow-up period. A highly significant reduction in the percentage of time with intracranial pressure >25, cerebral perfusion pressure <50, and systolic blood pressure <90 mm Hg was observed in the drug-treated group. The nature and incidence of adverse medical events were similar in the two groups. The percentage of patients achieving good neurologic outcome on the Glasgow outcome scale was 21% and 14% higher in the drug-treated group at 3 and 6 months, respectively. Statistical analysis of these differences by a logistic model using dose, entry Glasgow coma scale score, and computed tomograph as covariates yielded p values for the effect of treatment of .03 and .14 at 3 and 6 months, respectively.
                Dexanabinol was safe and well tolerated in severe head injury. The treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without jeopardizing blood pressure. A trend toward faster and better neurologic outcome was also observed. 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. Fifty-nine patients were treated in a prospective, randomized comparison of pentobarbital and mannitol for the control of intracranial hypertension resulting from head injury. Patients with elevated intracranial pressure (ICP) after evacuation of intracranial hematomas were randomized to one of two treatment groups; mannitol initially or pentobarbital initially, followed by the second drug as required by further elevation of ICP. Similarly, patients with raised ICP but without hematomas requiring evacuation were randomly assigned to two treatment groups in an identical paradigm. Those with ICP elevation and no hematoma treated with pentobarbital as initial therapy had a 77% mortality compared to a 41% mortality for those with mannitol as initial treatment. Patients with evacuated hematomas had mortalities of 40% and 43% (no significant difference) for pentobarbital and mannitol respectively. In both no-hematoma and hematoma streams pentobarbital was less effective than mannitol for control of raised ICP. Multivariable statistical analysis indicates that pentobarbital coma is not better than mannitol for the treatment of intracranial hypertension and may be harmful in no-hematoma patients with intracranial hypertension after head injury. 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. Resuscitation in severe head injury may be detrimental when given with hypotonic fluids. We evaluated the effects of lactated Ringer's solution (sodium 131 mmol/L, 277 mOsm/L) compared with hypertonic saline (sodium 268 mmol/L, 598 mOsm/L) in severely head-injured children over the first 3 days after injury.
                An open, randomized, and prospective study.
                A 16-bed pediatric intensive care unit (ICU) (level III) at a university children's hospital.
                A total of 35 consecutive children with head injury.
                Thirty-two children with Glasgow Coma Scores of <8 were randomly assigned to receive either lactated Ringer's solution (group 1) or hypertonic saline (group 2). Routine care was standardized, and included the following: head positioning at 30 degrees; normothermia (96.8 degrees to 98.6 degrees F [36 degrees to 37 degrees C]); analgesia and sedation with morphine (10 to 30 microg/kg/hr), midazolam (0.2 to 0.3 mg/kg/hr), and phenobarbital; volume-controlled ventilation (PaCO2 of 26.3 to 30 torr [3.5 to 4 kPa]); and optimal oxygenation (PaO2 of 90 to 105 torr [12 to 14 kPa], oxygen saturation of >92%, and hematocrit of >0.30).
                Mean arterial pressure and intracranial pressure (ICP) were monitored continuously and documented hourly and at every intervention. The means of every 4-hr period were calculated and serum sodium concentrations were measured at the same time. An ICP of 15 mm Hg was treated with a predefined sequence of interventions, and complications were documented. There was no difference with respect to age, male/female ratio, or initial Glasgow Coma Score. In both groups, there was an inverse correlation between serum sodium concentration and ICP (group 1: r = -.13, r2 = .02, p < .03; group 2: r = -.29, r2 = .08, p < .001) that disappeared in group 1 and increased in group 2 (group 1: r = -.08, r2 = .01, NS; group 2: r = -.35, r2 =.12, p < .001). Correlation between serum sodium concentration and cerebral perfusion pressure (CPP) became significant in group 2 after 8 hrs of treatment (r = .2, r2 = .04, p = .002). Over time, ICP and CPP did not significantly differ between the groups. However, to keep ICP at <15 mm Hg, group 2 patients required significantly fewer interventions (p < .02). Group 1 patients received less sodium (8.0 +/- 4.5 vs. 11.5 +/- 5.0 mmol/kg/day, p = .05) and more fluid on day 1 (2850 +/- 1480 vs. 2180 +/- 770 mL/m2, p = .05). They also had a higher frequency of acute respiratory distress syndrome (four vs. 0 patients, p = .1) and more than two complications (six vs. 1 patient, p = .09). Group 2 patients had significantly shorter ICU stay times (11.6 +/- 6.1 vs. 8.0 +/- 2.4 days; p = .04) and shorter mechanical ventilation times (9.5 +/- 6.0 vs. 6.9 +/- 2.2 days; p = .1). The survival rate and duration of hospital stay were similar in both groups.
                Treatment of severe head injury with hypertonic saline is superior to that treatment with lactated Ringer's solution. An increase in serum sodium concentrations significantly correlates with lower ICP and higher CPP. Children treated with hypertonic saline require fewer interventions, have fewer complications, and stay a shorter time in the ICU.
There is no evidence that barbiturate therapy in patients with acute severe head injury improves outcome. Barbiturate therapy results in a fall in blood pressure in one in four patients. This hypotensive effect will offset any ICP lowering effect on cerebral perfusion pressure.