Failure of prophylactic barbiturate coma in the treatment of severe head injury. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema. Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial.
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. 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. 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. 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. Continued elevations in Intracranial Pressure (ICP) following traumatic or ischemic compromise are known to cause markedly increased morbidity and mortality. Because of the side effects of barbiturates including hypotension and prolonged recovery time, the use of shorter-acting anesthetic agents to control ICP has been considered. Etomidate, when administered by continuous infusion, has been shown to decrease cerebral metabolism resulting in a secondary decrease in cerebral blood flow with minimal changes in cerebral perfusion pressure. We initially intended to randomize 20 patients prospectively into a study protocol that would assess the effects of either pentobarbital or the cardioprotective agent etomidate on ICP and cardiac performance. Given the sequelae of the therapy, we were only able to randomize seven patients with cerebral edema refractory to medical management to receive either etomidate or pentobarbital in a blinded fashion. Three patients who received etomidate developed renal compromise (mean low creatinine clearance 41 ml/min, range 37-44 ml/min) which was initially noted at 24 hours. We believed that this represented an adverse effect that was probably related to the study drug and the study was stopped. Each patient received a 0.30 mg/kg IV induction of etomidate and then 0.02 mg/kg/min continuous infusion for 24-72 hours titrated burst suppression. All patients also received dexamethasone 2 mg IV every six hours to prevent the adrenocortical insufficiency that might occur as a consequence of etomidate-induced suppression of cortisol synthesis. Intracranial pressure decreased (mean = 12mmHg) following the initiation of etomidate. Cardiac parameters remained unchanged (cardiac output 4.8 +/- .6 liters/min).(ABSTRACT TRUNCATED AT 250 WORDS) Experimental research has demonstrated that the level of neuroprotection conferred by the various barbiturates is not equal. Until now no controlled studies have been conducted to compare their effectiveness, even though the Brain Trauma Foundation Guidelines recommend that such studies be undertaken. The objectives of the present study were to assess the effectiveness of pentobarbital and thiopental in terms of controlling refractory intracranial hypertension in patients with severe traumatic brain injury, and to evaluate the adverse effects of treatment.
                This was a prospective, randomized, cohort study comparing two treatments: pentobarbital and thiopental. Patients who had suffered a severe traumatic brain injury (Glasgow Coma Scale score after resuscitation < or = 8 points or neurological deterioration during the first week after trauma) and with refractory intracranial hypertension (intracranial pressure > 20 mmHg) first-tier measures, in accordance with the Brain Trauma Foundation Guidelines.
                A total of 44 patients (22 in each group) were included over a 5-year period. There were no statistically significant differences in ' baseline characteristics, except for admission computed cranial tomography characteristics, using the Traumatic Coma Data Bank classification. Uncontrollable intracranial pressure occurred in 11 patients (50%) in the thiopental treatment group and in 18 patients (82%) in the pentobarbital group (P = 0.03). Under logistic regression analysis--undertaken in an effort to adjust for the cranial tomography characteristics, which were unfavourable for pentobarbital--thiopental was more effective than pentobarbital in terms of controlling intracranial pressure (odds ratio = 5.1, 95% confidence interval 1.2 to 21.9; P = 0.027). There were no significant differences between the two groups with respect to the incidence of arterial hypotension or infection.
                Thiopental appeared to be more effective than pentobarbital in controlling intracranial hypertension refractory to first-tier measures. These findings should be interpreted with caution because of the imbalance in cranial tomography characteristics and the different dosages employed in the two arms of the study. The incidence of adverse effects was similar in both groups.
                (Trial registration: US Clinical Trials registry NCT00622570.).
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.