Pitfalls and advances from the international tirilazad trial in moderate and severe head injury.

This manuscript reviews current experience with a large-scale clinical trial of the nonglucocorticoid 21-aminosteroid compound, tirilazad mesylate (U-74,006F). The trial itself now encompasses 15 countries with all central coordination conducted in the Data Coordinating Center at the University of California, San Diego. To date, the conduct of this trial has shown that diverse groups of clinicians in multiple countries have been able to work together to adhere to a tightly defined research protocol. Despite the success in initiating and conducting this trial, however, there have been several unanticipated problems that have complicated its progress. In this regard, difficulties have been associated with the use of mean Glasgow coma scores for data analysis. Similarly, a prospective identification of the risk variables was found necessary to preclude the potential for serious errors in data analysis. Lastly, a differential effect of the drug was noted in women compared to men in the European subarachnoid hemorrhage trial where a significant improvement in outcome was observed in males. This differential response appears to be linked to drug metabolism, but the problem may be further compounded by improper dosing because of failure to weigh many patients. Women appear to be routinely underdosed because their weights are routinely underestimated. Overall, this paper shows the feasibility of conducting such a large scale international trial, while also highlighting some of the potential pitfalls and problems that should be avoided in future trials of this nature.

The diagnosis of head injury requires a classification based on computed axial tomography.

The introduction of structural imaging of the brain by computed tomography (CT) scans and magnetic resonance imaging (MRI) has further refined classification of head injury for prognostic, diagnosis, and treatment purposes. We describe a new classification scheme to be used both as a research and a clinical tool in association with other predictors of neurologic status.

Neurological deterioration as a potential alternative endpoint in human clinical trials of experimental pharmacological agents for treatment of severe traumatic brain injuries. Executive Committee of the International Selfotel Trial.

OBJECTIVE: A recently improved understanding of the pathophysiological features of head injuries has led to the development of new drug therapies. Accurate human clinical trials remain necessary to document the efficacy and safety of new agents. It would be helpful to decrease the time from drug development to clinical use and general availability for drugs found to be effective. Conversely, ineffective agents could be abandoned in a timely fashion. RATIONALE: A new endpoint measure, defined as neuroworsening (NW), is an objective observable event that is identifiable during hospitalization. This may enable the efficacy of drugs to be demonstrated or disproved much earlier than with 6-month outcome assessments. The prospective, double-blind, multicenter trial of the N-methyl-D-aspartate receptor antagonist Selfotel was used to acquire data on the efficacy of NW in predicting neurological outcomes. The 6-month Glasgow Outcome Scale scores, which were the primary endpoints of that trial, were compared with the frequency of NW. NW was an observable event that could be objectively defined after head injuries. Patients who suffered one or more episodes of NW demonstrated significantly higher morbidity and mortality rates than did patients who did not. CONCLUSION: Future trials should consider the use of NW as an outcome measure that can be included with more traditional measures in the study design. If the strong correlation demonstrated between NW and 6-month Glasgow Outcome Scale scores can be prospectively demonstrated in a successful trial, the time to approval of future agents could be decreased.

Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial.

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 > or = 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.

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. The Selfotel Investigators.

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 post resuscitation 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.

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

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.

Neuromuscular blocking agents in neurointensive care.

INTRODUCTION: Intensive care treatment of patients with severe head injury is aimed at preventing secondary injury. One of the cornerstones in this treatment is sedation and ventilation. Use of Neuromuscular Blocking Agents (NBA) has gained widespread use as part of the protocol for maintaining normal intracranial pressure values, without class 1 evidence for the efficacy of the treatment. METHODS: We examined data of the use of NBA as infusion during ventilator treatment, and IntraCranial Pressure (ICP) measurements in the database from the international multicenter randomized double blind trial of the NMDA receptor antagonist Selfotel. No specific mode of sedation was recommended in the study protocol. RESULTS: Of the 427 patients enrolled in the study 326 had a full data set, 138 received NBA during their stay in the ICU. There were no statistical difference in demographic data between the two groups. During their stay in the ICU, patients who received NBA had a median of 13.5 hours with a recorded ICP above 20 mm Hg, patients who did not receive NBA had a median of 6.5 hours with ICP above 20 mm Hg (p < 0.05). CONCLUSION: Our data challenges the concept of using NBA as part of a routine sedation strategy in treatment of patients with severe head injury.

The frequency, antecedent events, and causal relationships of neurologic worsening following severe head injury. Executive Committee of the international Selfotel Trial.

Neurologic deterioration observed following head injury is recognized as having a deleterious effect on outcome. The present study examines this occurrence in detail to determine the frequency of these episodes, their antecedent events and causal relationships in order to identify patients who are at risk. Data was collected prospectively from a consecutive series of 427 patients entered into the international trial of the NMDA receptor antagonist Selfotel. Using a definition of neurologic worsening based upon objective criteria, 117 patients were identified who suffered 164 episodes of deterioration. The occurrence of a single episode of neurologic worsening increased mortality by more than five-fold and reduced favorable outcomes (good or moderate on the Glasgow Outcome Scale), by more than 50%. Increased intracranial volume resulting in intracranial hypertension was the single most frequent cause of neurologic worsening. This serves to emphasize the importance of more adequate treatments of intracranial hypertension in improving the outcome of patients with severe head injury.

The Traumatic Coma Data Bank: a nursing perspective, Part II.

The Traumatic Coma Data Bank (TCDB) was a collaborative project undertaken to study the nature and course of severe head injury. Evolution of nursing goals includes collection of data, communication, new clinical observations, designing future research projects, education and legislative impact. Management issues inherent in the collaborative research project are defining, collecting, entering, and analyzing and publishing results.

The Traumatic Coma Data Bank: a nursing perspective, Part I.

The Traumatic Coma Data Bank (TCDB) was a collaborative project undertaken to study the nature and causes of severe head injury, allowing patients similar in age, severity of insults and neurological and physical symptoms to be compared in terms of outcome. Systematic uniform data were collected during the prehospital, acute and rehabilitative phases on 581 patients from 6 centers during the pilot phase of the TCDB, June 1, 1979 through May 31, 1982. The pilot phase successfully determined that a collaborative approach to studying head injury was feasible and additional information gained was incorporated into the main phase April, 1983 through April, 1988. A description of the TCDB population as of this writing (730 patients) is included here.

Succession management: a model for developing nursing leaders.

Succession management is critical to all healthcare organizations as they respond to the cost-cutting initiatives brought about by the prospective payment era. This personnel management system ensures that motivated individuals enter and ascend the management hierarchy consistently. Such stabilization is reflected in turnover vacancy rates of < 12 percent and < 9 percent, respectively, at a time of unprecedented competition for professional nurses. This provides not only greater professional advancement but also stability for patient care delivery.

Pharmacologic therapy: promising clinical investigations.

The identification of ischemia as a central mechanism of cell injury within the nervous system has resulted in a commonality of interests of neurosurgeons, neurologists and basic scientists interested in head injury, subarachnoid hemorrhage and stroke. This, in turn, has led to a certain synergy between the development of new agents and the availability of interested and committed investigators so that these agents can be tested under appropriate clinical conditions. In head injury, major sources of focus have been the membrane damage resulting from the free-radical cascade and the disruption in cellular ionic homeostasis resulting from the excitotoxic effects of pathologic release of amino acid neurotransmitters. At present, the final analyses of phase III trials of the antagonism of the initiation and propagation of the free-radical cascade by tirilazad and polyethylene glycol-bound superoxide dismutase are nearing completion. Data on the efficacy of these agents in improving outcome from moderate and severe head injury should be available within the next 6 months. In addition, worldwide trials of glutamate antagonists are presently being initiated in severe head injury, with results anticipated in late 1997 or early 1998. In subarachnoid hemorrhage, calcium has been hypothesized to play a role in mediating vasospasm-induced ischemia as well as in promoting intracellular damage. Trials of calcium-channel blockade have demonstrated a reduction in mortality, but no improvement in the quality of survival over other methods of managing these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Health science library and information services in the hospital.

In an increasingly information-based society, hospitals need a variety of information for multiple purposes--direct patient care, staff development and training, continuing education, patient and community education, and administrative decision support. Health science library and information services play a key role in providing broad-based information support within the hospital. This guide identifies resources that will help administrators plan information services that are appropriate to their needs.

Early and late systemic hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in the Traumatic Coma Data Bank.

The outcome from severe head injury (GCS < or = 8 mmHg) was prospectively studied in patients from the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mmHg) occurring from injury through resuscitation (early hypotension; N = 717) or in the Intensive Care Unit [ICU] (late hypotension; N = 493). Early hypotension occurred in 248 patients (34.6%) and was associated with a doubling of mortality (55% vs. 27%). If shock was present on admission, the mortality was 65%. These effects were independent of age, admission GCS motor score, presence of hypoxia, or associated severe extracranial trauma, suggesting that the influence of multiple system trauma in head injured patients is primarily due to associated hypotension. Late hypotension occurred in 156 of 493 patients (32%) and was the only hypotensive episode in 117 (24%). For 117 patients whose only hypotensive episode occurred in the ICU, 66% either died or were vegetative survivors, compared to 17% of patients who never suffered an hypotensive episode. Logistic regression modelling suggested that early and late shock were the most powerful independent predictors of mortality in this group of patients. These data demonstrate that hypotension is a common and devastating secondary brain insult in severe head injury patients, occurring not only during transport and resuscitation but also "right under our noses" in the ICU. We suggest that vigorous attention to eliminate or minimize such insults has the potential of markedly improving outcome from severe head injury.

Marketing your nursing product line: reaping the benefits.

Survival in today's cost-conscious, competitive health care scene depends on strategic business skills, marketing, and product line management. As a major contributor to the delivery of health care, nursing practice must now include an orientation toward business with definable products. The authors discuss their success in developing a product line that results in professional growth, improved nurse recruitment and retention, and a greater competitive edge in the health care arena.