Failure of prophylactic barbiturate coma in the treatment of severe head injury

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✓ 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 (7percnt;) 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.

Abstract

✓ 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 (7percnt;) 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.

The recorded mortality rate associated with severe head injury, in which the patient has been rendered comatose for at least 6 hours, unable to open his eyes, speak recognizable words, or obey commands, is between 40% and 50%.17 While some of this mortality is inevitable, an undetermined proportion of head injury fatality is avoidable. We and others have devoted much time and effort to delineating factors that mediate a poor outcome in an attempt to lower mortality caused by head injury to the absolute minimum.2,12,17,18

The importance of intracranial hematomas, raised intracranial pressure (ICP), and the early insults of systemic arterial hypoxemia and hypotension has previously been stressed.2,16–18 Adams1 has demonstrated a 90% prevalence of ischemic brain damage in fatal head injuries. This can be statistically linked to the presence of these brain insults during life. By the aggressive, prompt, and intensive management of head-injury patients, including rapid diagnosis and evacuation of intracranial hematomas, artificial ventilation, and continuous monitoring and control of ICP, we believe we have reduced the overall mortality rate in severely head-injured patients from 50% to 40% without a corresponding increase in morbidity.17 In this study we define two subgroups of patients in whom the mortality rate remains distressingly high. These are patients with intradural hematomas large enough to require surgical decompression and those with no mass lesion whose best motor response consists of flexor or extensor posturing. We describe a randomized controlled trial of prophylactic barbiturate therapy in these patients, in whom we have previously recorded a mortality rate of over 60% and a prevalence of intracranial hypertension of over 70%.

Use of barbiturates in patients with neurological disease is not new. As early as 1972, barbiturates were reported to protect against brain ischemia.3,7,8,19,25,27 Barbiturates have also been shown to lower elevated ICP.9,10,23,24 Their use was subsequently extended to include patients with other causes of intracranial hypertension, such as Reye's syndrome11 and hypoxia.14 Barbiturates, specifically pentobarbital, were employed by Marshall and others12,21,22 and recommended as part of the treatment of severe head injury. To date, however, no controlled study has shown a beneficial effect of prophylactic pentobarbital coma in patients with severe head injury.15

There are two possible approaches in trying to define the role of pentobarbital coma in head injury. The first is to assume that the benefit of pentobarbital lies primarily in its capacity to lower elevated ICP and keep it within the normal range.12,21,22 For such a study, pentobarbital is given only when ICP rises above a predetermined level, regardless of the severity of the injury. The second approach is to focus on the possible protective effects of barbiturates in improving outcome from severe head injury. In that case, barbiturates are started as soon as possible after the head injury, regardless of the ICP, and are continued for a prescribed period of time. We elected to pursue the second course in this particular study.

Clinical Material and Methods

This series 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 of these patients were managed at this institution between January, 1979, and April, 1983. Once the diagnosis had been made and informed consent obtained, the cases were randomly drawn for placement into a control group (26 cases) and a barbiturate-treated group (27 cases). All patients were treated with the same protocol of aggressive resuscitation, prompt diagnosis, and treatment of mass lesions, followed by intensive care and monitoring as previously described.2,26 All patients underwent computerized tomography scanning on the day of admission, and 4 days, 1 week, and 2 weeks after admission, then whenever indicated by the clinical situation. Intracranial hypertension was vigorously managed with hyperventilation, cerebrospinal fluid drainage, and mannitol as required.

The barbiturate-treated patients also received intravenous pentobarbital as follows. A loading dose was initially calculated at 5 to 10 mg/kg; however, the patient was given sufficient pentobarbital to achieve burst suppression on the electroencephalogram (EEG). Burst suppression was used as an easily recognizable end point to show when pentobarbital was having some effect on the brain, until pentobarbital levels could be determined. The EEG was monitored during induction of barbiturate coma and throughout the course of treatment. After the initial loading dose, pentobarbital was given hourly, initially as a bolus, and then in the latter part of the study as a continuous infusion. After initial burst suppression was achieved, a maintenance dose of approximately 1 to 3 mg/kg was given. This was adjusted to maintain a serum level of 25 to 45 mg%. In addition to these measures, arterial pressure, pulmonary capillary wedge pressure, and ICP were monitored continuously. Blood pressure was maintained above 100 mm Hg systolic, or at a cerebral perfusion pressure of at least 60 mm Hg, and sufficient colloid and crystalloid was given to keep the pulmonary capillary wedge pressure between 10 and 15 mm Hg. If this was not sufficient, then a dopamine infusion was begun. If hypotension continued to be a problem, the dose of pentobarbital was decreased. The treated group received pentobarbital for at least 72 hours and then the barbiturate was slowly discontinued. If ICP increased above a mean of 25 mm Hg, then the pentobarbital was restarted. In both groups of patients, electrolytes and arterial blood gases were maintained in the normal range.

Patients with a known history of serious heart disease, hypertension, or liver disease were excluded from the study. All patients received dexamethasone (4 mg/6 hrs) and prophylactic anticonvulsants (phenytoin sodium, 300 mg/day). No action was taken to lower body temperature; however, in the treated group, body temperature tended to fall to approximately 95°F. Body temperature was not allowed to drop below 93°F. If, despite intensive management, ICP rose over 25 mm Hg in control cases, pentobarbital was not administered. All surviving patients have been followed for at least 1 year, and the neurological status at 1 year has been used for determination of outcome for the purpose of this report.

Forty-five patients (22 control and 23 pentobarbital-treated patients) had early measurement of multimodality evoked potentials (MEP's), consisting of auditory and somatosensory brain-stem and visual and somato-sensory near-field responses. In the pentobarbital-treated group, these studies were obtained after induction of barbiturate coma so that drug effects were present (mean Day 2). Follow-up MEP studies were also attempted in both groups of patients (mean Day 15). Fifteen patients in the treated group and 14 control patients underwent both initial and follow-up MEP studies; the remaining patients either had died or were inaccessible for follow-up study. Detailed methods for performing MEP studies and analysis of the waveforms are presented elsewhere.5,6 Briefly, all evoked potential data were analyzed off-line and assigned a grade of abnormality based on a clinical evoked potential grading system. The system is based primarily on waveform complexity and ranges from Grade I to Grade IV, indicating potentials that are normal (Grade I), mildly abnormal (Grade II), severely abnormal (Grade III), or absent (Grade IV). These grades were assigned for each potential in a given modality, and patients were categorized based on their worst grade. The MEP data were compared for a particular patient between two time points, and between groups across the two time points of study.

Results

The randomization was effective in producing a close match between control and barbiturate-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 (Table 1).

TABLE 1

Comparison of control and pentobarbital-treated groups*

FactorsControl GroupTreated Group
no. of cases2627
sex (% male)85.292.6
mean age (yrs)35.1 ± 15.031.1 ± 15.9
neurological findings
 posturing/flaccid (%)77.877.8
 impaired oculocephalic (%)40.729.6
 fixed pupil (%)63.051.9
 Glasgow Coma Scale score4.9 ± 2.35.1 ± 1.7
other clinical factors
 surgical mass (%)4663.0
 diffuse injury (%)5437
 shift on CT (%)63.074.1
 elevated ICP (% over 20 mm Hg)22.229.6
early insults
 hypoxia (pO2 = 60 mm Hg) (%)34.625.9
 hypotensive (BP = 90 mm Hg) (%)15.411.1
 mannitol on admission (%)84.685.2

There were no statistical differences between the control and pentobarbital-treated groups. CT = computerized tomography; ICP = intracranial pressure; BP = blood pressure.

Mean ± standard deviation.

Outcome at 1 year was graded using the Glasgow Outcome Scale and patients were grouped according to whether they had a good outcome or were moderately disabled, severely disabled, vegetative, or dead. There were 10 control patients and 11 pentobarbital-treated patients in the good outcome and moderately disabled groups. Sixteen control patients and 16 pentobarbital-treated patients were severely disabled, vegetative, or dead (Table 2). The cause of death, medical or neurological, was equally distributed in each group (Table 2). Among patients suffering a neurological death, six in each group died of uncontrollable intracranial hypertension.

TABLE 2

Outcome and cause of death in each group

OutcomeControl GroupTreated Group
good53
moderately disabled58
severely disabled31
vegetative01
dead1314
cause of death*
 neurological death89
 medical death55
no. of cases2627

Cause of death was subdivided into neurological and medical. Six patients in each of the control and pentobarbital-treated groups died of uncontrollable intracranial pressure (neurological death).

Within the treated group, we examined the time of pentobarbital administration, how much pentobarbital was used as an initial loading dose, drug blood levels achieved, how many patients actually achieved EEG burst suppression, and appropriate pentobarbital blood levels. In 22 of 27 patients, the exact time of injury could be determined. Pentobarbital coma was satisfactorily induced in all but three of the patients within 24 hours of injury, and by 15 hours in more than half of the group. All were started on therapy by 36 hours. Table 3 shows the peak pentobarbital serum levels achieved. In 22 patients pentobarbital was given until the EEG showed burst suppression. Burst suppression was not documented in three patients and not achieved due to hypotension in one. In one patient the EEG recordings were isoelectric.

TABLE 3

Highest blood pentobarbital level in treated group

Pentobarbital Level (mg%)No. of Cases
10–206*
21–308
31–4010
41–503
total cases27

Five of these six patients had drug levels of only 10 to 20 mg% due to persistent hypotension.

MEP's and Outcome

Grade I and II MEP's recorded early after injury in severely head-injured patients are indicative of a favorable outcome, while Grade III and IV MEP's are rarely compatible with survival or recovery of consciousness (with the exception of a focal abnormality). Table 4 also shows results of the initial MEP study compared with outcome for patients in both groups. Although outcome did differ according to the MEP findings (MEP Grades I–II versus Grades III–IV), there were no differences between the pentobarbital and control groups regarding MEP predictions of outcome.

TABLE 4

Initial multimodality evoked potential (MEP) grade related to outcome in each group*

MEP GradesControl GroupTreated Group
G/MS/VDTotalG/MS/VDTotal 
I–II6041071210
III–IV3191332712
total cases2322

There was no statistical difference between groups. G/M = good or moderately disabled; S/V = severely disabled or vegetative; D = dead.

Intracranial Pressure

To determine the effects of pentobarbital on ICP, the data were analyzed in a number of ways. It was first established that ICP at the onset was similar in both groups. Next, the effect of the drug on hourly ICP was analyzed using a time-series analysis. This analysis showed that during the first 4 days there was no significant difference in hourly levels of ICP between the control patients and those receiving pentobarbital (Table 5). The number of patients dying from uncontrollable intracranial hypertension was also the same (Table 2), as was the number of doses of mannitol required in each group (average 2.3 doses/control patient versus 2.4 doses/treated patient). 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. This demonstrates the failure of pentobarbital to show a protective effect in preventing increases in ICP.

TABLE 5

Intracranial pressure (ICP), arterial pressure, and temperature in the first 4 days in both groups

FactorControl Group (26 Cases)Treated Group (27 Cases)Difference of Two Means
MeanSD*SDMeanSD*SD  
ICP (mm Hg)19.513.08.318.512.18.5not significant
arterial pressure (mm Hg)107.514.313.196.07.513.4p < 0.0001
body temperature (°F)99.41.61.996.23.53.9p < 0.0001

Inter-patient standard deviation(SD).

Inter-patient SD.

Discussion

In attempting to determine the efficacy of a certain drug regimen, it is imperative that simultaneous control patients be observed in the therapeutic trial and that the control patients be as similar to the treated patients as possible in those clinical variables that are important for outcome. The important clinical variables in patients with severe head injury appear to be age, cause of injury, Glasgow Coma Scale score, presence of signs of brain-stem dysfunction, presence or absence of mass lesion, and the occurrence of early systemic insults, such as hypoxia and ischemia.2,12,16–18 Table 1 shows that, in our study, there is no statistical difference between the two groups when considering these variables, and that the goal of adequate randomization was achieved between both groups. Only four patients had a Glasgow Coma Scale score of 8 or greater on admission. However, these patients had mass lesions requiring surgical decompression and deteriorated into coma during the pretreatment evaluation period. Having established adequate randomization, the results of the trial were examined in several ways: 1) outcome, 2) effects on ICP, and 3) the incidence of complications.

It is important to establish that the treated patient in fact receives adequate doses of pentobarbital. Twenty-one of the 27 treated patients had levels over 20 mg% and 22 reached burst suppression. Five of the six patients who were unable to reach levels of pentobarbital over 20 mg% had arterial hypotension, despite adequate cardiovascular monitoring, aggressive use of fluid replacement to maintain pulmonary capillary wedge pressure between 10 and 15 mm Hg, and the use of intravenous dopamine infusion to raise arterial pressure.

The most important and undesirable side effect of pentobarbital was arterial hypotension. This was considered to be due to peripheral vasodilatation and to some extent to the depressive effect of pentobarbital on cardiac contractility. Arterial hypotension (systolic blood pressure < 80 mm Hg) occurred in 14 patients (54%) in the treated group and in only two patients (7%) in the untreated group. This occurred despite continual pulmonary capillary wedge pressure monitoring, cardiac output determinations, the vigorous use of fluids to maintain wedge pressure of 10 to 15 mm Hg, and a dopamine drip as indicated to maintain systolic blood pressure over 100 mm Hg. In fact, this was the reason that five of six patients failed to achieve pentobarbital levels over 20 mg%.

Other complications besides hypotension included pulmonary infection (pneumonia), central nervous system (CNS) infection, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and sepsis (Table 6). Both groups had an equally high incidence of pneumonia, 16 in the control group (61%) and 17 (63%) in the treated group. However, the incidence of sepsis and CNS infection was higher in the treated group than in the control patients, but this was not statistically significant. The SIADH occurred fairly frequently in both groups. The occurrence of an acute respiratory disease syndrome (ARDS) appeared to be somewhat higher in the treated group (seven versus three cases); however, since these patients also had pneumonia, sepsis, and hypoxia on admission, it was difficult to be absolutely sure which patient had a true ARDS and which had hypoxia from other causes, such as pneumonia or aspiration.

TABLE 6

Occurrence of complications in each group*

ComplicationControl GroupTreated Group
pneumonia1617
ARDS37
sepsis49
SIADH58
CNS infection26
GI bleed42
hypotension (systolic blood pressure < 80 mm Hg)214 (p < 0.001)

Hypotension was the only complication showing a statistically significant difference between the two groups. ARDS = acute respiratory disease syndrome; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; CNS = central nervous system; GI = gastrointestinal.

It is important to distinguish between the ability of pentobarbital to lower ICP and its ability to improve the outcome from severe head injury. They are not necessarily the same. We believe that pentobarbital coma can lower ICP,13,21 and we do, in fact, employ it in the acute situation when all other methods have failed (that is, in the operating room in patients with mass lesions or cerebral swelling), as do others.13,20,23 However, we have found no improvement in outcome when pentobarbital is used prophylactically as described above in severely head-injured patients with or without elevated ICP, with acute subdural hematoma, with intracerebral hematomas, or with no mass lesion but motor posturing.

Any therapy in this high-risk group should not only be effective but should also not worsen the patient's condition. Although there appeared to be no increase in poor outcome, there was certainly a high incidence of hypotension and sepsis in the treated group. One may say that an insufficient number of patients was used in this study. However, if a statistical method using the Bayesian theory of predictive distribution is used,4 a table can be generated that will indicate the possibility of showing a significant effect given a certain increase in the patient population. Such a table was developed for this series of patients based on our current results with 53 patients (Table 7). Based on this, if we were to double our patient population, we would still have less than a 10% chance of finding a significant effect of pentobarbital as used in this study. Based on the above study, we do not feel it would be advantageous for us to continue with the therapeutic trial. The use of high doses of pentobarbital coma in the treatment of severe head injuries is a difficult therapeutic endeavor requiring extensive monitoring and intensive care management. While the use of barbiturates in high doses can lower ICP and may be required when all other methods fail, based on our data we cannot recommend the prophylactic use of pentobarbital coma in the treatment of patients with severe head injury. In addition, we believe that its use is accompanied by significant side effects that can potentially worsen the condition of a patient with a severe head injury.

TABLE 7

Probability of a significant difference between control and treatment groups*

No. of Additional PatientsProbability
100.005
200.070
300.112
400.143
500.165

Probability calculated as a function of additional patients in each group according to the statistical formula of Choi and Smith.4 Significance: p < 0.05.

References

  • 1.

    Adams JH: The neuropathology of head injuriesVinken PJBruyn GW (eds): 23. Amsterdam: North-Holland19753565

  • 2.

    Becker DPMiller JDYoung HFet al: Diagnosis and treatment of head injury in adultsYoumans JR (ed): Neurological Surgeryed 2. Philadelphia: WB Saunders1982419382083

  • 3.

    Breivik HSafar PSands Pet al: Clinical feasibility trials of barbiturate therapy after cardiac arrest. Crit Care Med 6:2282441978Crit Care Med 6:

  • 4.

    Choi SSmith PJ: Termination of clinic trials after inadequate sample acquisition when the treatment differences are small: experience of controlled trials of head trauma patients. Controlled Clin Trials Controlled Clin Trials

  • 5.

    Greenberg RPMayer DJBecker DPet al: Evaluation of brain function in severe human head trauma with multimodality evoked potentials. Part 1: Evoked brain-injury potentials, methods, and analysis. J Neurosurg 47:1501621977J Neurosurg 47:

  • 6.

    Greenberg RPNewlon PGHyatt MSet al: Prognostic implications of early multimodality evoked potentials in severely head-injured patients. A prospective study. J Neurosurg 55:2272361981J Neurosurg 55:

  • 7.

    Hoff JTSmith ALHankinson HLet al: Barbiturate protection from cerebral infarction in primates. Stroke 6:28331975Stroke 6:

  • 8.

    Ignelzi RJ: Protective effect of pentobarbital on ischemic brain cell nuclei. Neurosurgery 8:5625661981Ignelzi RJ: Protective effect of pentobarbital on ischemic brain cell nuclei. Neurosurgery 8:

  • 9.

    Ishii S: Brain-swelling. Studies of structural, physiologic and biochemical alterationsCaveness WFWalker AE (eds): Head Injury. Philadelphia: JB Lippincott1966276299Head Injury.

  • 10.

    Marshall LFBruce DABruno Let al: Role of intracranial pressure monitoring and barbiturate therapy in malignant intracranial hypertension. Case report. J Neurosurg 47:4814841977J Neurosurg 47:

  • 11.

    Marshall LFShapiro HMRauscher Aet al: Pentobarbital therapy for intracranial hypertension in metabolic coma. Reye's syndrome. Crit Care Med 6:151978Crit Care Med 6:

  • 12.

    Marshall LFSmith RWShapiro HM: The outcome with aggressive treatment in severe head injuries. Part II: Acute and chronic barbiturate administration in the management of head injury. J Neurosurg 50:26301979J Neurosurg 50:

  • 13.

    Michenfelder JD: The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 41:2312361974Michenfelder JD: The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 41:

  • 14.

    Michenfelder JDTheye RA: Cerebral protection by thiopental during hypoxia. Anesthesiology 39:5105171973Anesthesiology 39:

  • 15.

    Miller JD: Barbiturates and raised intracranial pressure. Ann Neurol 6:1891931979Miller JD: Barbiturates and raised intracranial pressure. Ann Neurol 6:

  • 16.

    Miller JDBecker DPWard JDet al: Significance of intracranial hypertension in severe head injury. J Neurosurg 47:5035161977J Neurosurg 47:

  • 17.

    Miller JDButterworth JFGudeman SKet al: Further experience in the management of severe head injury. J Neurosurg 54:2892991981J Neurosurg 54:

  • 18.

    Miller JDSweet RCNarayan Ret al: Early insults to the injured brain. JAMA 240:4394421978JAMA 240:

  • 19.

    Moseley JILaurent JPMolinari GF: Barbiturate attenuation of the clinical course and pathologic lesions in a primate stroke model. Neurology 25:8708741975Neurology 25:

  • 20.

    Pierce EC JrLambertsen CJDeutsch Set al: Cerebral circulation and metabolism during thiopental anesthesia and hyperventilation in man. J Clin Invest 41:166416711962J Clin Invest 41:

  • 21.

    Rea GLRockswold GL: Barbiturate therapy in uncontrolled intracranial hypertension. Neurosurgery 12:4014041983Neurosurgery 12:

  • 22.

    Rockoff MAMarshall LFShapiro HM: High-dose barbiturate therapy in humans: a clinical review of 60 patients. Ann Neurol 6:1941991979Ann Neurol 6:

  • 23.

    Shapiro HMGalindo AWyte SRet al: Rapid intraoperative reduction of intracranial pressure with thiopentone. Br J Anaesthesia 45:105710611973Br J Anaesthesia 45:

  • 24.

    Shapiro HMWyte SRLoeser J: Barbiturate-augmented hypothermia for reduction of persistent intracranial hypertension. J Neurosurg 40:901001974J Neurosurg 40:

  • 25.

    Smith ALHoff JTNielsen SLet al: Barbiturate protection in acute focal cerebral ischemia. Stroke 5:171974Stroke 5:

  • 26.

    Ward JDBecker DP: Head traumaShoemaker WThompson LHolbrook P (eds): Textbook of Critical Care. Philadelphia: WB Saunders1984926928Textbook of Critical Care.

  • 27.

    Yatsu FMDiamond IGraziano Cet al: Experimental brain ischemia: protection from irreversible damage with a rapid-acting barbiturate (methohexital). Stroke 3:7267321972Stroke 3:

This work was supported by Grant NS 12587-09 from the National Institutes of Health.

Article Information

Address reprint requests to: John D. Ward, M.D., Division of Neurological Surgery, Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, MCV Station, Richmond, Virginia 23298.

© AANS, except where prohibited by US copyright law.

Headings

References

1.

Adams JH: The neuropathology of head injuriesVinken PJBruyn GW (eds): 23. Amsterdam: North-Holland19753565

2.

Becker DPMiller JDYoung HFet al: Diagnosis and treatment of head injury in adultsYoumans JR (ed): Neurological Surgeryed 2. Philadelphia: WB Saunders1982419382083

3.

Breivik HSafar PSands Pet al: Clinical feasibility trials of barbiturate therapy after cardiac arrest. Crit Care Med 6:2282441978Crit Care Med 6:

4.

Choi SSmith PJ: Termination of clinic trials after inadequate sample acquisition when the treatment differences are small: experience of controlled trials of head trauma patients. Controlled Clin Trials Controlled Clin Trials

5.

Greenberg RPMayer DJBecker DPet al: Evaluation of brain function in severe human head trauma with multimodality evoked potentials. Part 1: Evoked brain-injury potentials, methods, and analysis. J Neurosurg 47:1501621977J Neurosurg 47:

6.

Greenberg RPNewlon PGHyatt MSet al: Prognostic implications of early multimodality evoked potentials in severely head-injured patients. A prospective study. J Neurosurg 55:2272361981J Neurosurg 55:

7.

Hoff JTSmith ALHankinson HLet al: Barbiturate protection from cerebral infarction in primates. Stroke 6:28331975Stroke 6:

8.

Ignelzi RJ: Protective effect of pentobarbital on ischemic brain cell nuclei. Neurosurgery 8:5625661981Ignelzi RJ: Protective effect of pentobarbital on ischemic brain cell nuclei. Neurosurgery 8:

9.

Ishii S: Brain-swelling. Studies of structural, physiologic and biochemical alterationsCaveness WFWalker AE (eds): Head Injury. Philadelphia: JB Lippincott1966276299Head Injury.

10.

Marshall LFBruce DABruno Let al: Role of intracranial pressure monitoring and barbiturate therapy in malignant intracranial hypertension. Case report. J Neurosurg 47:4814841977J Neurosurg 47:

11.

Marshall LFShapiro HMRauscher Aet al: Pentobarbital therapy for intracranial hypertension in metabolic coma. Reye's syndrome. Crit Care Med 6:151978Crit Care Med 6:

12.

Marshall LFSmith RWShapiro HM: The outcome with aggressive treatment in severe head injuries. Part II: Acute and chronic barbiturate administration in the management of head injury. J Neurosurg 50:26301979J Neurosurg 50:

13.

Michenfelder JD: The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 41:2312361974Michenfelder JD: The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 41:

14.

Michenfelder JDTheye RA: Cerebral protection by thiopental during hypoxia. Anesthesiology 39:5105171973Anesthesiology 39:

15.

Miller JD: Barbiturates and raised intracranial pressure. Ann Neurol 6:1891931979Miller JD: Barbiturates and raised intracranial pressure. Ann Neurol 6:

16.

Miller JDBecker DPWard JDet al: Significance of intracranial hypertension in severe head injury. J Neurosurg 47:5035161977J Neurosurg 47:

17.

Miller JDButterworth JFGudeman SKet al: Further experience in the management of severe head injury. J Neurosurg 54:2892991981J Neurosurg 54:

18.

Miller JDSweet RCNarayan Ret al: Early insults to the injured brain. JAMA 240:4394421978JAMA 240:

19.

Moseley JILaurent JPMolinari GF: Barbiturate attenuation of the clinical course and pathologic lesions in a primate stroke model. Neurology 25:8708741975Neurology 25:

20.

Pierce EC JrLambertsen CJDeutsch Set al: Cerebral circulation and metabolism during thiopental anesthesia and hyperventilation in man. J Clin Invest 41:166416711962J Clin Invest 41:

21.

Rea GLRockswold GL: Barbiturate therapy in uncontrolled intracranial hypertension. Neurosurgery 12:4014041983Neurosurgery 12:

22.

Rockoff MAMarshall LFShapiro HM: High-dose barbiturate therapy in humans: a clinical review of 60 patients. Ann Neurol 6:1941991979Ann Neurol 6:

23.

Shapiro HMGalindo AWyte SRet al: Rapid intraoperative reduction of intracranial pressure with thiopentone. Br J Anaesthesia 45:105710611973Br J Anaesthesia 45:

24.

Shapiro HMWyte SRLoeser J: Barbiturate-augmented hypothermia for reduction of persistent intracranial hypertension. J Neurosurg 40:901001974J Neurosurg 40:

25.

Smith ALHoff JTNielsen SLet al: Barbiturate protection in acute focal cerebral ischemia. Stroke 5:171974Stroke 5:

26.

Ward JDBecker DP: Head traumaShoemaker WThompson LHolbrook P (eds): Textbook of Critical Care. Philadelphia: WB Saunders1984926928Textbook of Critical Care.

27.

Yatsu FMDiamond IGraziano Cet al: Experimental brain ischemia: protection from irreversible damage with a rapid-acting barbiturate (methohexital). Stroke 3:7267321972Stroke 3:

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