Failure of the competitive N-methyl-d-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two Phase III clinical trials

1999 ◽  
Vol 91 (5) ◽  
pp. 737-743 ◽  
Author(s):  
Gabrielle F. Morris ◽  
Ross Bullock ◽  
Sharon Bowers Marshall ◽  
Anthony Marmarou ◽  
Andrew Maas ◽  
...  
Keyword(s):  
Head Injury ◽  
Demographic Data ◽  
Phase Iii ◽  
Double Blind ◽  
Content Type ◽  
Treatment Groups ◽  
Severity Of Injury ◽  
Significant Difference ◽  
Cgs 19755 ◽  
Fine Print

Object. Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-d-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with postresuscitation Glasgow Coma Scale scores of 4 to 8.Methods. A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.Conclusions. Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

Comparative study of traumatic and spontaneous intracerebral hemorrhage

2002 ◽  
Vol 96 (1) ◽  
pp. 86-89 ◽  
Author(s):  
M. Shahid Siddique ◽  
Barbara A. Gregson ◽  
Helen M. Fernandes ◽  
Jane Barnes ◽  
Lynne Treadwell ◽  
...  
Keyword(s):  
Head Injury ◽  
Intracerebral Hemorrhage ◽  
Surgical Intervention ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Content Type ◽  
Younger Age ◽  
Severity Of Injury ◽  
Significant Difference ◽  
Gcs Score ◽  
Fine Print

Object. Spontaneous intracerebral hemorrhage (SICH) and traumatic intracerebral hemorrhage (TICH) are common disorders. The authors planned to study how these two types of hemorrhage behave pathologically and clinically to gain further insight into their causes, pathogeneses, indications for surgical intervention, and prognoses. Methods. Prospectively filled databases of demographic, clinical, radiological, and outcome details have been maintained for all patients admitted to the Regional Neurosciences Centre with head injury since 1987 and with SICH since 1993. Of the 5686 patients whose case information was included in the head-injury database, 90 were found to suffer from an isolated intracerebral hemorrhage (ICH) as the only major abnormality observed on computerized tomography scans (subdural and extradural hematomas were excluded). Case details on these 90 patients and the 440 patients from the SICH database were extracted and analyzed using a statistical software program. The median age of patients with TICH was lower than the median age of patients with SICH (51 years compared with 65 years, respectively), but it was much higher than the median age of the entire head-injury group (21 years). Among patients younger than 45 years of age, 0.8% of patients who experienced trauma suffered from an ICH compared with 4.3% of patients older than 45 years of age. Irrespective of intervention, much better outcomes were achieved by patients with TICH compared with those with SICH (67% favorable outcomes compared with 24% in patients with SICH). Following trauma, there was no significant relationship between the severity of injury and the development of ICH. At presentation the median Glasgow Coma Scale (GCS) score for both groups was 13. Younger age and higher GCS score at presentation were strongly related to a favorable outcome for both types of hemorrhage. There was no significant difference in patient age, presenting GCS score, or outcomes of patients who underwent surgery compared with those who did not for either type of hemorrhage. No conclusions can be drawn about the efficacy of surgery from such observational studies. Conclusions. On the basis of these data the authors suggest that TICH and SICH have different features: TICH affects a slightly younger age group and carries a much better prognosis compared with SICH. In addition, indications for surgical intervention are not well defined for either type of hemorrhage. Practice is subjective and inconsistent. The International Surgical Trial in Intracerebral Haemorrhage may resolve the dilemma for SICH. A similar trial in which surgery is compared with conservative management should be considered for cases of TICH.

Phenytoin and postoperative epilepsy

1983 ◽  
Vol 58 (5) ◽  
pp. 672-677 ◽  
Author(s):  
J. Brian North ◽  
Robert K. Penhall ◽  
Ahmad Hanieh ◽  
Derek B. Frewin ◽  
William B. Taylor
Keyword(s):  
Head Injury ◽  
High Risk ◽  
Seizure Control ◽  
Active Drug ◽  
Double Blind Trial ◽  
Double Blind ◽  
Content Type ◽  
Routine Prophylaxis ◽  
Risk Patients ◽  
Fine Print

✓ A double-blind trial of phenytoin therapy following craniotomy was performed to test the hypothesis that phenytoin is effective in reducing postoperative epilepsy. A significant reduction in the frequency of epilepsy was observed in the group receiving the active drug up to the 10th postoperative week. Half of the seizures occurred in the first 2 weeks and two-thirds within 1 month of cranial surgery. High rates of epilepsy were observed after surgery in patients with meningioma, metastasis, aneurysm, and head injury. Routine prophylaxis with phenytoin (in a dosage of 5 to 6 mg/kg/day) would seem to be indicated, particularly in high-risk patients and, where possible, this treatment should be started 1 week preoperatively. Seizure control is best when therapeutic levels of phenytoin are maintained.

The outcome of severe closed head injury

1991 ◽  
Vol 75 (Supplement) ◽  
pp. S28-S36 ◽  
Author(s):  
Lawrence F. Marshall ◽  
Theresa Gautille ◽  
Melville R. Klauber ◽  
Howard M. Eisenberg ◽  
John A. Jane ◽  
...  
Keyword(s):  
Head Injury ◽  
Mortality Rate ◽  
Severe Head Injury ◽  
Closed Head Injury ◽  
Data Bank ◽  
Content Type ◽  
Severity Of Injury ◽  
Gcs Score ◽  
Fine Print ◽  
Overall Mortality

✓ The outcome of severe head injury was prospectively studied in patients enrolled in the Traumatic Coma Data Bank (TCDB) during the 45-month period from January 1, 1984, through September 30, 1987. Data were collected on 1030 consecutive patients admitted with severe head injury (defined as a Glasgow Coma Scale (GCS) score of 8 or less following nonsurgical resuscitation). Of these, 284 either were brain-dead on admission or had a gunshot wound to the brain. Patients in these two groups were excluded, leaving 746 patients available for this analysis. The overall mortality rate for the 746 patients was 36%, determined at 6 months postinjury. As expected, the mortality rate progressively decreased from 76% in patients with a postresuscitation GCS score of 3 to approximately 18% for patients with a GCS score of 6, 7, or 8. Among the patients with nonsurgical lesions (overall mortality rate, 31%), the mortality rate was higher in those having an increased likelihood of elevated intracranial pressure as assessed by a new classification of head injury based on the computerized tomography findings. In the 276 patients undergoing craniotomy, the mortality rate was 39%. Half of the patients with acute subdural hematomas died — a substantial improvement over results in previous reports. Outcome differences between the four TCDB centers were small and were, in part, explicable by differences in patient age and the type and severity of injury. This study describes head injury outcome in four selected head-injury centers. It indicates that a mortality rate of approximately 35% is to be expected in such patients admitted to experienced neurosurgical units.

Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury

2000 ◽  
Vol 92 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Niels Juul ◽  
Gabrielle F. Morris ◽  
Sharon B. Marshall ◽  
_ _ ◽  
Lawrence F. Marshall
Keyword(s):  
Head Injury ◽  
Intracranial Hypertension ◽  
Cerebral Perfusion Pressure ◽  
Cerebral Perfusion ◽  
Severe Head Injury ◽  
Perfusion Pressure ◽  
Neurological Deterioration ◽  
Double Blind ◽  
Content Type ◽  
Fine Print

Object. Recently, a renewed emphasis has been placed on managing severe head injury by elevating cerebral perfusion pressure (CPP), which is defined as the mean arterial pressure minus the intracranial pressure (ICP). Some authors have suggested that CPP is more important in influencing outcome than is intracranial hypertension, a hypothesis that this study was designed to investigate.Methods. The authors examined the relative contribution of these two parameters to outcome in a series of 427 patients prospectively studied in an international, multicenter, randomized, double-blind trial of the N-methyl-d-aspartate antagonist Selfotel. Mortality rates rose from 9.6% in 292 patients who had no clinically defined episodes of neurological deterioration to 56.4% in 117 patients who suffered one or more of these episodes; 18 patients were lost to follow up. Correspondingly, favorable outcome, defined as good or moderate on the Glasgow Outcome Scale at 6 months, fell from 67.8% in patients without neurological deterioration to 29.1% in those with neurological deterioration. In patients who had clinical evidence of neurological deterioration, the relative influence of ICP and CPP on outcome was assessed. The most powerful predictor of neurological worsening was the presence of intracranial hypertension (ICP ≥ 20 mm Hg) either initially or during neurological deterioration. There was no correlation with the CPP as long as the CPP was greater than 60 mm Hg.Conclusions. Treatment protocols for the management of severe head injury should emphasize the immediate reduction of raised ICP to less than 20 mm Hg if possible. A CPP greater than 60 mm Hg appears to have little influence on the outcome of patients with severe head injury.

Low-dose aspirin prophylaxis and risk of intracranial hemorrhage in patients older than 60 years of age with mild or moderate head injury: a prospective study

2003 ◽  
Vol 99 (4) ◽  
pp. 661-665 ◽  
Author(s):  
Sergey Spektor ◽  
Samuel Agus ◽  
Vladimir Merkin ◽  
Shlomo Constantini
Keyword(s):  
Head Injury ◽  
Intracranial Hemorrhage ◽  
Ct Scanning ◽  
Treated Group ◽  
Control Group ◽  
Content Type ◽  
Significant Difference ◽  
Traumatic Intracranial Hemorrhage ◽  
Gcs Score ◽  
Fine Print

Object. The goal of this paper was to investigate a possible relationship between the consumption of low-dose aspirin (LDA) and traumatic intracranial hemorrhage in an attempt to determine whether older patients receiving prophylactic LDA require special treatment following an incidence of mild-to-moderate head trauma. Methods. Two hundred thirty-one patients older than 60 years of age, who arrived at the emergency department with a mild or moderate head injury (Glasgow Coma Scale [GCS] Scores 13–15 and 9–12, respectively), were included in the study. One hundred ten patients were receiving prophylactic LDA (100 mg/day) and these formed the aspirin-treated group. One hundred twenty-one patients were receiving no aspirin, and these formed the control group. There was no statistically significant difference between the two groups with respect to age, sex, mechanism of trauma, or GCS score on arrival at the emergency department. Most of the patients sustained the head injury from falls (88.2% of patients in the aspirin-treated group and 85.1% of patients in the control group), and had external signs of head trauma such as bruising or scalp laceration (80.9% of patients in the aspirin-treated group and 86.8% of patients in the control group). All patients underwent similar neurological examinations and computerized tomography (CT) scanning of the head. The CT scans revealed evidence of traumatic intracranial hemorrhage in 27 (24.5%) patients in the aspirin-treated group and in 31 patients (25.6%) in the control group. Surgical intervention was required for five patients in each group (4.5% of patients in the aspirin-treated group and 4.1% of patients in the control group). A surprising number of the patients who arrived with GCS Score 15 were found to have traumatic intracranial hemorrhage, as revealed by CT scanning (11.5% of patients in the aspirin-treated group and 16.5% of patients in the control group). Surgery, however, was not necessary for any of these patients. Conclusions. There was no statistically significant difference in the frequency or types of traumatic intracranial hemorrhage between patients who had received aspirin prophylaxis and those who had not. The authors conclude that LDA does not increase surgically relevant parenchymal or meningeal bleeding following moderate and minor head injury in patients older than 60 years of age.

Nimodipine treatment in poor-grade aneurysm patients

1988 ◽  
Vol 68 (4) ◽  
pp. 505-517 ◽  
Author(s):  
Kenneth C. Petruk ◽  
Michael West ◽  
Gerard Mohr ◽  
Bryce K. A. Weir ◽  
Brien G. Benoit ◽  
...  
Keyword(s):  
Outcome Analysis ◽  
Double Blind ◽  
Content Type ◽  
Poor Grade ◽  
Good Outcome ◽  
Significant Difference ◽  
Delayed Neurological Deterioration ◽  
Repeat Angiography ◽  
Grade 3 ◽  
Fine Print

✓ A multicenter, randomized placebo-controlled double-blind trial of nimodipine in poor-grade aneurysm patients was carried out in 17 Canadian hospitals. Of 188 patients enrolled in the trial, 32 were excluded for protocol violations and two were excluded due to statistical considerations, leaving 154 patients for valid outcome analysis. Nimodipine treatment was associated with a significantly better outcome (p < 0.001): 21 (29.2%) of 72 nimodipine-treated patients had a good outcome at 3 months after subarachnoid hemorrhage (SAH) compared to eight (9.8%) of 82 placebo-treated patients. Delayed ischemic deficits from vasospasm alone were significantly less frequent in the nimodipine group (p < 0.05) with permanent deficits occurring in five nimodipine-treated patients (6.9%) and in 22 placebo-treated patients (26.8%). Improvement in the good outcome rate and reduction in delayed ischemic deficits from vasospasm alone occurred in both Grade 3 and 4 patients, with no difference between nimodipine- and placebo-treated patients being found in Grade 5 patients. Repeat angiography after Day 4 was carried out in 124 patients. There was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients. The authors conclude that nimodipine treatment in poor-grade patients with SAH results in an increase in the number of good outcomes and a reduction in the incidence of delayed neurological deterioration due to vasospasm. This effect occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography.

Effect of THAM upon outcome in severe head injury: a randomized prospective clinical trial

1993 ◽  
Vol 78 (1) ◽  
pp. 54-59 ◽  
Author(s):  
Aizik L. Wolf ◽  
Lion Levi ◽  
Anthony Marmarou ◽  
John D. Ward ◽  
Paul J. Muizelaar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Head Injury ◽  
Adverse Effects ◽  
Glasgow Coma Scale ◽  
Severe Head Injury ◽  
Prospective Clinical Trial ◽  
Content Type ◽  
Coma Scale ◽  
Significant Difference ◽  
Fine Print

✓ Although mortality and morbidity rates from head injury have been reduced substantially by improved prehospital interventions, intensive care, and aggressive management of intracranial pressure (ICP), successful treatment of the primary brain injury has been elusive. In experimental models, tromethamine (THAM) has been effective in treating head injury; this drug acts by entering the cerebrospinal fluid compartment, reducing cerebral acidosis and ICP, and reversing the adverse effects of prophylactic hyperventilation on early recovery. In this randomized prospective clinical trial, THAM was studied to determine if it had beneficial effects in the early management of severe head injuries and if the adverse effects of hyperventilation could be prevented. A total of 149 patients with severe head injury (Glasgow Coma Scale scores of ≤ 8) were randomly assigned to either a control or a THAM group. Both groups of patients matched in terms of clinical parameters, including age, sex, number of surgical mass lesions, number in each Glasgow Coma Scale stratum, and first ICP measurement. All patients were treated by a standard management protocol, intubated, mechanically ventilated, and maintained in the pCO2 range of 32 to 35 mm Hg for 5 days. Tromethamine was administered as a 0.3-M solution in an initial loading dose (body weight × blood acidity deficit, average 4.27 cc/kg/hr) given over 2 hours, followed by a constant infusion of 1 ml/kg/hr for 5 days. Outcome was measured at 3, 6, and 12 months postinjury. Although analysis indicated no significant difference in outcome between these two groups at 3 months, 6 months, and 1 year, there was a difference regarding ICP. The time that ICP was above 20 mm Hg in the first 48 hours postinjury was less in patients treated with THAM (p < 0.05). Also, the number of patients requiring barbiturate coma was significantly less in the THAM group (5.48% vs. 18.4%, p < 0.05). The authors conclude that THAM ameliorates the deleterious effect of prolonged hyperventilation, may be beneficial in ICP control, and warrants further study as to the dosage and timing of administration.

Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study

1989 ◽  
Vol 70 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Juha Öhman ◽  
Olli Heiskanen
Keyword(s):  
Aneurysmal Subarachnoid Hemorrhage ◽  
Anterior Part ◽  
Controlled Trial ◽  
Randomized Study ◽  
Prospective Randomized Study ◽  
Double Blind ◽  
Content Type ◽  
Acute Surgery ◽  
Significant Difference ◽  
Fine Print

✓ A total of 216 patients with a ruptured aneurysm of the anterior part of the circle of Willis were enrolled into this prospective randomized study of timing of the operation after aneurysmal subarachnoid hemorrhage (SAH). Only patients in clinical Grades I to III (according to the classification of Hunt and Hess) who were admitted and randomly assigned to a treatment group within 72 hours after the SAH were included in the trial. The patients were randomly assigned to one of three operation groups: acute surgery (AS: 0 to 3 days after the SAH; day of SAH = Day 0), intermediate surgery (IS: 4 to 7 days after the SAH), or late surgery (LS: 8 days to an indefinite time after the SAH). Three patients (4.3%) in the IS group and six patients (8.6%) in the LS group died before surgery was undertaken. At 3 months post-SAH, 65 patients (91.5%) from the AS group were classified as independent compared to 55 (78.6%) from the IS group and 56 (80.0%) from the LS group. The management mortality rate in the AS group was 5.6% compared to 12.9% in the LS group. Of the 216 patients enrolled in the timing study, 159 were randomly assigned to an independent double-blind placebo-controlled trial of nimodipine in Grade I to III patients. A total of 79 patients received nimodipine and 80 placebo. When the nimodipine group and the no-nimodipine group (the 80 placebo-treated patients plus the 52 patients who were not entered into the nimodipine trial) were analyzed separately, a significant difference was seen in the outcome of the no-nimodipine group (dependent AS vs. dependent IS, p = 0.01). Nimodipine treatment was associated with a significant reduction of delayed ischemic deterioration (all operation groups combined, nimodipine vs. no nimodipine p = 0.01; LS with nimodipine vs. LS with no nimodipine, p = 0.03).

Treatment of head injuries in the American Civil War

1993 ◽  
Vol 78 (5) ◽  
pp. 838-845 ◽  
Author(s):  
Howard H. Kaufman
Keyword(s):  
Civil War ◽  
Head Injury ◽  
Head Injuries ◽  
Closed Head Injury ◽  
Gunshot Wounds ◽  
American Civil War ◽  
Content Type ◽  
Severity Of Injury ◽  
Surgical History ◽  
Fine Print

✓ At the time of the American Civil War (1861–1865), a great deal was known about closed head injury and gunshot wounds to the head. Compression was differentiated from concussion, but localization of lesions was not precise. Ether and especially chloroform were used to provide anesthesia. Failure to understand how to prevent infection discouraged physicians from aggressive surgery. Manuals written to educate inexperienced doctors at the onset of the war provide an overview of the advice given by senior surgeons. The Union experiences in the treatment of head injury in the Civil War were discussed in the three surgical volumes of The Medical and Surgical History of the War of the Rebellion. Wounds were divided into incised and puncture wounds, blunt injuries, and gunshot wounds, which were analyzed separately. Because the patients were not stratified by severity of injury and because there was no neuroimaging, it is difficult to understand the clinical problems and the effectiveness of surgery. Almost immediately after the war, increased knowledge about cerebral localization and the development of antisepsis (and then asepsis) permitted the development of modern neurosurgery.

A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

1998 ◽  
Vol 89 (4) ◽  
pp. 519-525 ◽  
Author(s):  
Lawrence F. Marshall ◽  
Andrew I. R. Maas ◽  
Sharon Bowers Marshall ◽  
Albino Bricolo ◽  
Michael Fearnside ◽  
...  
Keyword(s):  
Placebo Group ◽  
Head Injury ◽  
Severe Head Injury ◽  
Treated Group ◽  
Good Recovery ◽  
Content Type ◽  
Significant Difference ◽  
Tirilazad Mesylate ◽  
Gcs Score ◽  
Fine Print

Object. The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. Methods. A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4–8) and 15% (163) had sustained a moderate head injury (GCS score 9–12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p = 0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p = 0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p = 0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups. Conclusions. Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents.

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