Dexamethasone and severe head injury

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1 J Neurosurg 5:307-36, 979 Dexamethasone and severe head injury A prospective double-blind study PAUL R. COOPER, M.D., SARAH MOODY, R.N., W. KEMP CLARK, M.D., JOEL KIRKPATRICK, M.D., KENNETH MARAVILLA, M.D., A. LAWRENCE GOULD, PH.D., AND WANZER DRANE, PH.D. Division of Neurosurgery, Department of Pathology, and Department of Radiology, University of Texas Southwestern Medical School, Dallas, Texas; Department of Statistics, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania; and Department of Statistics, Southern Methodist University, Dallas, Texas u, A prospective double-blind study of the effects of dexamethasone administration on the outcome of patients with severe head injuries was performed. Patients were stratified for severity of neurological injury and were treated with placebo, low-dose dexamethasone (6 mg/day), or high-dose dexamethasone (96 mg/day) for a period of 6 days. Outcome was evaluated at 6 months following injury. Of the 76 patients available for analysis, a good outcome was achieved in 37% of placebo-treated patients, % of low-dose-treated patients, and 29% of high-dose-treated patients. These differences are not statistically significant. Similarly dexamethasone administration had no statistically significant effect on intracranial pressure patterns or serial neurological examinations during hospitalization. Gastrointestinal bleeding occurred in only one patient. Good outcome was associated with age under 0 years, lighter depth of coma on admission, and the preservation of brain-stem reflexes upon admission. A recalculation of data in previous clinical series purporting to show an improvement in outcome as a result of corticosteroid therapy shows no significant difference in outcome when steroid- and placebo-treated patients are compared. In our series, 90% of all deaths were caused by recurrent intracranial hematomas, medical complications, or diffuse brain injuries with parenchymal hemorrhage and tissue disruption -- causes of death which cannot be affected by corticosteroid therapy. The study suggests that dexamethasone in either high or low dosages has no significant effect on morbidity and mortality following severe head injury. KEY WORDS 9 dexamethasone 9 corticosteroids 9 head injury 9 coma intracranial pressure T HE efficacy of corticosteroid administration in the management of the edema associated with primary and metastatic brain tumors is well established. '2'~,28 The results of studies to investigate the effects of corticosteroids on experimental brain injury are, however, contradictory. 5`x6`~~ Similarly, the usefulness of corticosteroids in the management of severe head injury in humans remains controversial. Sparacio, et al., 32 Gobiet, et al., ~a Faupel, et al., 9 and Ransohoff 3~ believe that corticosteroids are effective in improving outcome from severe head injury. Several standard neurosurgical textbooks 2,9'~~ recommend corticosteroids for the treatment of severe head injury. On the other hand, Gutterman and Shenkin, ~ Alexander, ~ and Hoyt, et al., 7 conclude that steroids do not improve the morbidity or mortality of head injury. Demopoulos, et al., 8 provided the theoretical basis for the failure of steroids to affect outcome in head injury. Previous clinical studies had one or more of the following defects: too few patients to draw statistically valid conclusions, lack of "blinding" of the investigators, inadequate controls, failure to stratify patients according to pretreatment severity of injury, inadequate steroid dosage regimens, failure to clearly define outcome, and failure to perform postmortem examinations to establish the location and nature of lesions causing death. There is a need to establish if corticosteroid administration significantly affects outcome in patients J. Neurosurg. / Volume 5 / September,

2 P. R. Cooper, et al. 5,,, ~ c~ 3 o (3 o (p I0 o 9 (.9 0'),~ 8 _J (.9 7,~ oo hill SillS lllee,,,,, Islsl sllsl INITIAL GRADY COMA GRADE FIG.. Relationship between Glasgow Coma score (GCS) and Grady Coma grade. With two exceptions: admission Grady Coma Grade 3 = GCS 6 to 8; Grady Coma Grade = GCS to 5, Grady Coma Grade 5 = GCS 3. with severe head trauma. This randomized prospective double-blind study was done in an attempt to answer that question. Clinical Material and Methods All patients with severe head injury admitted to the Parkland Memorial Hospital emergency room after July 7, 977, were treated with endotracheal intubation, hyperventilation, and intravenous mannitol. Systemic hemorrhage was controlled and hypotension was treated. After resuscitation was completed, but within hour of admission to the emergency room, patients were evaluated according to a modified version of the Grady Coma Scale: n Grade 0 = alert, oriented, may have posttraumatic amnesia; children may be irritable, but are alert Grade = lethargic, uncooperative, or belligerent, but does not lapse into sleep if left undisturbed; may or may not be oriented Grade 2 = stuporous; sleeps if undisturbed but arousable; may or may not be oriented; follows commands Grade 3 = deep stupor; moves purposefully or semi-purposefully only to deep pain; may have focal motor findings Grade = decerebrate or decorticate; non-purposeful response to deep pain; dilated pupils; absent corneal or impaired oculocephalic reflex Grade 5 = flaccid; does not respond to stimuli with any movements; may or may not be apneic. The Glasgow Coma score aa was also determined for each patient and there was excellent correlation between the Grady Coma grade and the Glasgow Coma score (Fig. ). Patients in Grady Coma Grades 3,, or 5 were entered in the study. Several patients in Grady Coma Grades 3 to 5 were not entered because of failure to gain informed consent from relatives, prior administration of corticosteroids, or arrival in the emergency room more than 6 hours after injury. Each patient was stratified according to Grady Coma grade and assigned to one of the following three treatment regimens using a random allocation schedule: ) "low-dose" dexamethasone phosphate (Decadron) ( mg/ml); initial dose of 0 mg (2.5 ml); mg ( ml) every 6 hours thereafter for 6 days; 2) "high-dose" dexamethasone phosphate (2 mg/ml); initial dose of 60 mg (2.5 ml); 2 mg ( ml) every 6 hours thereafter for 6 days; and 3) placebo, consisting of water and preservative (sodium bisulfite, methylparaben, propylparaben) given in volumes identical to the high- and low-dose groups. The initial dose of medication was given intravenously. All subsequent doses were administered intramuscularly. A gradual decrease in medication was begun 7 days following injury and doses were stopped by Day. Children (aged 6 years or younger) were given weight-related doses of medication. All medication and placebo was supplied by Merck, Sharp and Dohme Research Laboratories in identical coded vials containing colorless solutions. The code key was kept by the research staff at Merck, Sharp and Dohme Laboratories. Computerized tomography (CT) was utilized for initial diagnostic evaluation of most patients. Angiography was employed only when the CT scanner was not working. When indicated, craniotomy was performed for evacuation of intracranial mass lesions. Intracranial pressure (ICP) was measured in the postoperative period using an intraventricular or subdural catheter. In patients without lesions necessitating operation, an ICP monitor was inserted shortly after CT scanning. Elevations of ICP in the posttraumatic period were treated according to the methods of Miller, et al. ~7 When ICP remained below 20 mm Hg for at least 8 hours the monitoring device was removed. The Glasgow Coma score was recorded on Days, 3, 7, and. Each patient's outcome was assessed 6 months following injury by the criteria of Jennett and Bond: TM good recovery (may have non-disabling sequelae); moderate disability (independent but disabled); severe disability (conscious but dependent); persistent vegetative state (awake but not sentient); and dead. 308 J. Neurosurg. / Volume5 / September, 979

3 Dexamethasone and severe head injury Features total no, of cases 27 sex--male 9 female 8 mean age (yrs) 22.8 mean admission Glasgow Coma Score 5.37 patients with systemic injuries* 2 patients with blood gas abnormalities~ 9 patients with hypotension:~ 5 focal brain injuries 5 diffuse brain injuries 22 etiology of trauma fall auto/passenger auto/pedestrian 2 motorcycle blow to head gunshot wound 2 unknown 0 TABLE Clinical features of patient sample Placebo Low Dose High Dose Total No. Percent No. Percent No. Percent No. Percent *Systemic injuries include long-bone, abdominal, and/or chest injuries. tpco2 > 5 mm Hg; po2 < 60 mm Hg. :~Hypotension = systolic blood pressure < 90 mm Hg ll Patients who died within 6 months of injury were autopsied whenever possible by the Dallas County Medical Examiner's Office. The brains were cut after formalin fixation by a neuropathologist (J.K.) in the presence of one of the other authors (P.R.C. or S.M.). When possible the plane of sectioning was adjusted to the orientation of the CT scan. The drug codes were not broken until autopsy data were reported or until the 6-month assessment of outcome was made. During the first 8 months of the study 97 patients had been entered, but 2 patients who are still alive have not yet reached 6 months from the time of injury. Data were analyzed only for the 76 patients who died or were followed for 6 months. The salient clinical features of the patient series are listed in Table. Results lnfluence of Dexamethasone on Outcome Table 2 relates outcome to steroid dosage and admission coma grade. The number of patients in each subset is small; therefore, for statistical analysis we analyzed outcome as "good" or "bad": patients with good recovery or moderate disability had "good" results, and those with severe disability, persistent vegetative state, or who died had "bad" results. The total number of patients with "good" and "bad" outcomes in each treatment group are presented in Table 3. The proportion of patients with "good" outcomes did not differ significantly among the three treatment groups. Patients on the high-dosage regimen did slightly worse than patients on the low-dose regimen or placebo, but the difference was not statistically significant. There were no significant differences among treatment groups when outcomes were considered separately for each coma grade. In this series, patients were judged to have a focal or diffuse injury on the basis of CT scan or angiogram performed on admission. There is, however, an inherent inaccuracy in making this distinction at the time of admission. In patients with the admitting diagnosis of focal injury, subsequent CT scans often showed the appearance of hemorrhagic lesions consistent with diffuse injury. Autopsies in some patients thought to have focal injury on admission showed lesions consistent with diffuse injury. The outcome for patients with diffuse injury was better than that for patients with focal injury (Table ). There were significantly more patients with focal injuries in the high-dose group than the placebo group (Table ; chi-square =., p < 0.05). However, the relative ordering of the treatment groups with respect to proportion of "good" outcomes was the same among patients with focal injuries as among patients with diffuse injuries. Therefore, the differences in outcome among the treatment groups cannot be attributed to differences in the proportion of patients with focal injuries. Relationship of Outcome to Admission Parameters Table 5 shows that outcome had a significant relationship to admission coma grade and the status of.pupillary and oculocephalic reflexes. There was no J. Neurosurg. / Volume 5 / September,

4 P. R. Cooper, et al. TABLE 2 Admission coma grade, treatment, and outcome Grady Outcome* Coma Grade Treatment GR MD SD PVS Died Total 3 placebo low dose high dose total placebo low dose 3 I 2 high dose total placebo low dose high dose total all placebo low dose high dose total *GR = good recovery; MD = moderate disability; SD = severe disability; PVS = persistent vegetative state. association of outcome with the presence of systemic injuries. Systemic hypotension was significantly associated with "bad" outcome (p < 0.05 using a onetail test). Relationship of Outcome to Age Table 6 shows the relationship between outcome and age. Patients 0 years old or less had significantly better outcomes than older patients (chi-square = TABLE 3 Outcome summarized according to treatment Treatment Good Outcome Bad Outcome No. Percent No. Percent placebo low dose 56 high dose total , p < 0.05); 3% of the patients were 0 years of age or less. Outcomes did not differ significantly among other age groups. The outcomes of patients over 0 years of age were almost identical in the three treatment groups. Relationship of Steroid Dose to Change in Neurological Status The influence of steroid administration on the rate of neurological improvement during the first 2 weeks of hospitalization was examined. Glasgow Coma scores were used to provide a semi-quantitative assessment of neurological function (Table 7). If a patient was discharged or transferred to another hospital before all examinations could be completed, the Glasgow Coma score for subsequent days was considered to be the same as the last examination before discharge. If a patient died, his Glasgow Coma score was considered to be 3 for all subsequent examination days. TABLE Outcome as a function of steroid dose and type of injury* Treatment Good Diffuse Injury Bad No. Percent No. Percent Total placebo low dose high dose total *Determination of diffuse or focal injury made on admission. Good Focal Injury Bad No. Percent No. Percent Total J. Neurosurg. / Volume 5 / September, 979

5 Dexamethasone and severe head injury In interpreting Glasgow Coma scores, it must be kept in mind that they are qualitative, and not quantitative. That is, a score of 6 is "better" than a score of 5, which is "better" than a score of, but the difference in neurological status implied by a change from a score of 5 to 6 may not be quantitatively the same as that implied by a change from to 5. Glasgow Coma scores must be regarded as categories for analytical purposes. Table 7 illustrates that the median neurological status remained about the same in the placebo group, improved in the low-dose group, and deteriorated in the high-dose group during the first 2 weeks following the injury. There is no significant difference among treatment groups except at Day when the median Glasgow Coma score was significantly better in the low-dose compared to the high-dose group (p < 0.05; analysis performed according to the method of Klotz). 9 Intracranial Pressure, Steroid Dose, and Outcome ntracranial pressure was measured in 5 patients. The relationship between ICP and steroid dosage is seen in Table 8. There was no significant difference in ICP patterns when the three treatment groups were compared. The ICP patterns did have a significant correlation with survival (Table 9). No patient with uncontrolled elevations of ICP survived, whereas seven of 7 patients (%) with elevated but controlled ICP survived. Patients who had normal ICP at all times did better than those whose ICP was elevated but controlled, but this difference did not reach statistical significance. Complications and Steroid Dosage Significant gastrointestinal bleeding occurred in only one patient, and he was receiving placebo. Two TABLE 5 Outcome related to various admission parameters Admission Good Bad Signif- Parameters Outcome Outcome icance coma Grade 3 22 coma Grades and p <0.00 impaired pupillary reflexes 35 intact pupillary reflexes 7 3 p <0.0 normal oculocephalic reflexes 5 0 impaired oculocephalic reflexes 3 38 p <0.0 normotensive hypotensive 0 p <0.05* systemic injury 25 no systemic injury 23 *One-tail test; chi-square tests for statistical significance used elsewhere. patients developed diabetes mellitus requiring insulin during the course of their hospitalization; one received high-dose steroids and the other received placebo. Infectious complications were frequent in all treatment groups. Three types of complications were considered for statistical analysis: pulmonary infections (pneumonia, lung abscess, empyema), septicemia, and infections of the central nervous system (wound infection, meningitis, brain abscess). Virtually all patients had urethral catheters and bacteriuria so this problem was not analyzed. Analysis of the data (Table 0) shows no significant difference in infection rates within any one coma grade when patients on the various drug regimens are compared. Infectious com- NS Decade of Age > 30 all patients > 0 years Outcome good bad total good bad total good bad total good bad total good bad total TABLE 6 Outcome in each treatment group by decade of age Placebo Low Dose High Dose Total No. Percent No. Percent No. Percent No. Percent J. Neurosurg. / Volume5 / September, 979 3

6 P. R. Cooper, et al. TABLE 7 Glasgow Coma score distributions in each treatment group on each day Day Treatment Median Score placebo 5 low dose 6 high dose 5/6 3 placebo 5 low dose 6 high dose 5 7 placebo 5 low dose 6 high dose /5 placebo 6 low dose 7 high dose 3/* *Significantly lower scores in high-dose group than in lowdose group (p < 0.05). Treatment TABLE 8 Intracranial pressure and steroid dosage Normal No. Percent Elevated Controlled* Elevated Uncontrolledt Total No. Percent No. Percent placebo low dose high dose *Elevations above 20 mm Hg; controlled below 20 mm Hg with medical therapy. televations above 20 mm Hg; uncontrolled with medical therapy. TABLE 9 Intracranial pressure (ICP) and outcome Good Bad ICP Results Results Total normal 3 I0 23 elevated; controlled elevated; uncontrolled TABLE 0 Infectious complications as a function of coma grade and steroid dose* Grady Placebo Low Dose High Dose Coma Grade No. Percent No. Percent No. Percent 3 5/2 2 6/ 55 6/0 60 /2 33 8/ 73 5/ 5 5 2/3 67 2/3 67 I/3 33 total /27 6/25 6 2/2 50 *Numerator represents number of patients with infections and denominator is number of patients at risk. plications were least frequent in the placebo-treated patients and highest in low-dose treated patients; this difference is not significant (chi-square = 2.8, p > 0.). When infections in the high- and low-dose steroid-treated patients are pooled and compared with placebo-treated patients, the difference is not significant (chi-square =.87, p > 0.). Sixteen of the 76 patients had more than one infectious complication (Table ). The proportion of patients with more than one infectious complication did not differ significantly among the treatment groups. Cause of Death or Disability Thirty-nine patients died within 6 months of injury, 27 of them within the first 2 weeks. Postmortem examinations were obtained in 32 patients (82%). In patients not having postmortem examination an assessment of cause of death was made from knowledge of their hospital course and CT scans. The cause of death (Table 2) was assigned to one of five categories: Diffuse Brain Injury. Most of the deaths (72%) were caused by diffuse brain injury. Diffuse brain injury was defined according to the criteria of Adams, et al. In all cases the patients were unconscious immediately after impact. Gross pathological examination showed varying combinations of avulsion and hemorrhages of the superior cerebellar peduncles and corpus callosum, multiple hemorrhagic lesions of the brain stem, or hemorrhages of the deep white and gray matter. While many of these lesions were seen in patients who had elevations of ICP, the work of Adams, et al., showed that these lesions result from initial impact injury and not from elevations of ICP. Figure 2 shows typical lesions in two patients with diffuse brain injuries. The CT scans of patients remaining severely disabled or vegetative were reviewed to identify lesions that might explain poor outcome. Table 3 shows that five of nine such patients had CT evidence of hemorrhages located deep within cerebral parenchyma consistent with a diagnosis of diffuse brain injury. It is posible that the four patients who did not have deep hemorrhages identifiable on CT had diffuse lesions that could not be resolved by CT scanning but would have been identified at autopsy. Uncontrolled Elevations of lntracranial Pressure. Twelve patients had uncontrolled elevations of ICP. Eight of those patients also had diffuse brain injury such that even without uncontrolled ICP they would probably not have had a good outcome. These eight patients are listed among those who died of diffuse brain injury. The remaining four patients had elevated and uncontrolled ICP without gross evidence of diffuse brain injury, and are the only patients included in this category. Medical Complications. One patient died of meningitis and two of septicemia. There was one noninjury related death (myeloproliferative disorder). 32 J. Neurosurg. / Volume5 / September, 979

7 Dexamethasone and severe head injury TABLE Analysis of number of infectious complications per patient Grady No. of Complications Median No. Coma Treatment Total Comp/Case Grade placebo low dose high dose total , 5 placebo low dose 5 high dose total all placebo low dose high dose total Cases with no Comp (%) Inadequate Surgery. Two patients had recurrent intracranial hematomas which were directly responsible for their deaths. Systemic Injury. One patient died of severe pulmonary and abdominal injuries after being crushed beneath a motor vehicle. Discussion A common assumption regarding the beneficial effects of corticosteroids for patients with severe head injury is that they reduce brain edema. This, theoretically, should result in a decrease in ICP and FIG. 2. Left: Brain of patient with diffuse brain injury cut in CT plane. Arrow points to region of avulsion of corpus callosum. Right: Coronal section of brain of a patient who died of diffuse brain injury. Multiple small hemorrhages are seen in the thalamus and deep white matter. J. Neurosurg. / Volume 5 / September, 979 3]3

8 P. R. Cooper, et al. TABLE 2 Cause of death in 39 patients Cause No. of Cases diffuse brain injury 28* avulsion/hemorrhage corpus callosum 8 avulsion cerebellar peduncle 3 multiple hemorrhages deep gray matter 3 primary brain-stem hemorrhages 2 diffuse contusions 2 multiple hemorrhages deep white matter 2 avulsion cerebral peduncle hypothalamic contusion uncontrolled elevation of intracranial pressure medical complications sepsis 2 meningitis myeloproliferative disorder (unrelated to trauma) recurrent intracranial hematoma 2 systemic injury *Several patients with diffuse brain injury had lesions in more than one anatomical location. improvement in outcome. Data obtained from animals are difficult to extrapolate to humans; nevertheless, Long, et al., 2~ provided incontrovertible morphological evidence of a decrease in experimental cold injury edema with corticosteroid treatment. Kobrine and Kempe 2~ showed that corticosteroid administration produced a decrease in cerebral edema and ICP leading to improved outcome in dogs sustaining mechanical head injuries. In humans, Faupel, et al., 9 and Gobiet, et al., Is showed an improvement in mortality rate with large-dose dexamethasone treatment. In this study all patients were treated within 6 hours of injury. One group was treated with "low-dose" dexamethasone and a second group with "high-dose" dexamethasone for 6 days. Examination of the data shows that dexamethasone in either high or low doses had no statistically significant effect on outcome. It is possible that study of additional patients might result in a demonstration of "low dose" efficacy but this seems unlikely. Application of Bayesian analysis to the outcomes shows that there is only a one in 33 chance of showing the high dosage leading to an out- No. of Cases TABLE 3 CT findings in nine patients surviving in persistent vegetative state or with severe disability CT Findings 3 multiple bilateral superficial contusions/hematomas 2 corpus callosum hemorrhage* 2 hemorrhage deep white/gray matter* primary brain-stem hemorrhage* normal CT scan *Lesions consistent with diffuse brain injury. come superior to the low dosage, ~ if the study were to be continued. The ineffectiveness of steroids in this study can be explained by examining the causes of death and anatomical findings in the autopsied patients. A mortality analysis of this kind has not been performed in previous studies investigating steroid treatment of human head injury. Twenty-nine patients (7% of those who died) had diffuse brain injuries with gross anatomical disruption or hemorrhage deep within cerebral parenchyma. These injuries aresimilar to those identified by Adams, et al., resulting from immediate impact injury. They would not be affected by corticosteroid administration. Patients with recurrent hematomas or fatal systemic injuries would not be affected benefic ally by corticosteroids. Three patients who died of infectious comp/ications might have been adversely affected by steroid administration, although this cannot be proven. The outcome of the 35 patients described above (90% of those who died) should probably not have been affected by steroids. Five of nine patients who remained vegetative or severely disabled had CT evidence of diffuse and/or deeply located hemorrhages and tissue disruption that would not be beneficially affected by corticosteroids. Adams, et al., in an anatomical study and Zimmerman, et al.? e in a CT study showed that patients with lesions such as cerebellar peduncular tears, and corpus callosal tears, die or at best survive in a vegetative fashion. Four patients died of uncontrolled elevations of ICP. Eight other patients who died had uncontrolled elevations of ICP but also had diffuse brain injury. Control of ICP was probably not relevant to this group's ultimate outcome. This in no way detracts from the conclusion of Miller, et al., 2~ regarding the importance of controlling ICP in reducing mortality from head injury. Vigorous means were used to control ICP, and it remained normal or was controlled in 39 of 5 patients in whom it was measured. This probably contributed to improved outcome. When ICP cannot be controlled, severe diffuse brain injury usually coexists. Patients were classified on admission as having a diffuse or focal injury according to findings on CT scan or angiography, or at operation. Postmortem examinations showed that many patients thought clinically to have focal lesions (such as subdural hematomas or unilateral hemispheric injuries) actually had diffuse lesions. This finding has been commented on previously ~ and points out the difficulty in distinguishing between diffuse and focal injuries on clinical data alone. Human head injury is a more complex process than that produced in most experimental models. Analysis of this series shows that a bad outcome was usually due to diffuse injury sustained at the time of impact. Severe cerebral edema with uncontrolled ICP elevations almost always co-existed with irreparable 3 J. Neurosurg. / Volume5 / September, 979

9 Dexamethasone and severe head injury injury of immediate impact type. The decreased mortality in head-injured dogs treated with corticosteroids by Kobrine and Kempe ~~ probably occurred because the brain injury produced focal edema, but did not result in diffuse anatomical disruption of tissues. Steroids did control the associated elevations of ICP, but probably would not have if the impact produced diffuse tissue disruptions and more severe, diffuse edema. Gobiet, et al., ~ reported a decrease in mortality in patients treated with high-dose dexamethasone compared to placebo-treated patients. Analysis of their data shows that the mortality difference between the two groups is not statistically significant. No specific data were given as to type of outcome for survivors. Moreover, the study was not "blinded" and was performed in sequential fashion over 3 years; that is, all patients in any year received the same treatment. Observer bias and management changes might have favorably influenced outcome making it appear that corticosteroid therapy was efficacious. Faupel, et al.,9 concluded that dexamethasone improved outcome in severe head injury. They pooled the high-dose and low-dose treatment groups and found a mortality rate of 2% in steroid-treated patients and 57% in placebotreated patients, a difference that is statistically significant. However, it would appear that many patients who might have died were converted to vegetative survivors as there was a marked increase in patients remaining vegetative in the dexamethasone group (25.%) when compared to placebo (3.6%). A more meaningful way of evaluating outcome would be to look at "good" results versus "bad" results. When this is done, their data show that good results were achieved in nine of 28 patients receiving placebo and 26 of 67 patients receiving steroids. The difference in good outcome between the steroid- and placebotreated groups is now not statistically significant. Analysis of our data shows that the factors associated with improved outcome are: age under 0 years, lighter depth of coma, and presence of intact brain-stem reflexes upon admission. This is similar to the findings of Becker, et al? Admission blood gas abnormalities had no effect on outcome. Systemic hypotension on admission was significantly associated with poor outcome. Infectious complications were more frequent in steroid-treated patients, but the difference was not statistically significant. In almost 60% of the cases meningitis or septicemia occurred after the patients were no longer receiving corticosteroids. The reason for this is not clear, but it is possible that the immune system remained suppressed for a period of time following cessation of corticosteroid therapy. Three patients died from infections; although all were dexamethasone-treated, this is not statistically significant. No significant gastrointestinal bleeding occurred in patients receiving corticosteroids. Marshall, et al.?2 found a similar lack of relationship between gastroin- testinal bleeding and corticosteroid administration. In our series, 57% of the patients were decorticate or flaccid upon admission. This is over 20% higher than that reported by Becker, et al? The reason for this is not clear but may be due to an emergency medical care system which rapidly transports to the hospital patients who might otherwise have died at the site of injury. To compare this series with others having less ill patients, the following index had been used: e Percentage of patients dead, vegetative or with severe disability/percentage of patients admitted decerebrate or flaccid -- 63%/57% =.. The lower the outcome index the better are the results. This outcome index compares quite favorably with other large series2 Summary No previous study has shown a significant improvement in outcome following severe head injury as a result of treatment with corticosteroids. A decrease in mortality rate achieved by increasing the number of vegetative survivors is not a desirable result. Our resuits show no difference in outcome when either highor low-dose corticosteroid treatment is compared with placebo. This series shows that most patients do not survive because of "diffuse injuries" and other causes of death not amenable to steroid treatment. Addendum Since this report was submitted for publication 6- month-outcome data have become available for 2 patients in addition to the 76 reported in Table 2. Analysis of outcome in 97 patients shows: for placebo, 3 (39%) had a good outcome and 20 (6%) a poor outcome; for low-dose therapy, 5 (8%) had a good outcome and 6 (52%) a poor outcome; for high-dose therapy, 2 (36%) had a good outcome and 2 (6%) a poor outcome. Acknowledgment The authors gratefully acknowledge the assistance of Ms. Christine Capuano in the preparation of the manuscript. References. Adams JH, Mitchell DE, Graham DI, et al: Diffuse brain damage of immediate impact type. Its relationship to 'primary brain-stem damage' in head injury. Brain 00:89-502, Alexander E Jr: Medical management of closed head injuries. Clin Neurosurg 9:20-250, Becker DP, Miller JD, Ward JD, et al: The outcome from severe head injury with early diagnosis and intensive management. J Neurosurg 7:9-502, 977. Beks JWF, Doorenbos H, Walstra GJM: Clinical experiences with steroids in neurosurgical patients, in Reulen H J, Schtirmann K (eds): Steroids and Brain Edema. 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A practical scale. Lancet 2:8-8, Thomas LM, Gurdjian ES: Cerebral contusion in closed head injury and nonoperative management of head injury, in Youmans JR (ed): Neurological Surgery. Philadelphia/London/Toronto: WB Saunders, 973, Vol 3, pp Tornheim PA, McLaurin RL: Effect of dexamethasone on cerebral edema from cranial impact in the cat. J Neurosurg 8: , Zimmerman RA, Bilaniuk LT, Genneralli T: Computed tomography of shearing injuries of the cerebral white matter. Radiology 27: , 978 This study was supported in part by Biomedical Research Support NIH 5-S07-RR0526-6, and by a grant from the Merck, Sharp and Dohme Company. Address reprint requests to: Paul R. Cooper, M.D., Department of Neurosurgery, State University of New York, Downstate Medical Center, 50 Clarkson Avenue, Brooklyn, New York J.Neurosurg. / Volume5 / September, 979