Gabrielle F. Morris

Neurological Deterioration as a Potential Alternative Endpoint in Human Clinical Trials of Experimental Pharmacological Agents for Treatment of Severe Traumatic Brain Injuries

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.

Effect of surgical cricothyrotomy on the unstable cervical spine in a cadaver model of intubation.

Cricothyrotomy is indicated for patients who require an immediate airway and in whom orotracheal or nasotracheal intubation is unsuccessful or contraindicated. Cricothyrotomy is considered safe with cervical spine (c-spine) injury; however, the amount of c-spine movement that occurs during the procedure has not been determined. In this experimental study, an established cadaver model of c-spine injury was used to quantify movement during cricothyrotomy. A complete C5--6 transection was performed by using an osteotome on 13 fresh-frozen cadavers. Standard open cricothyrotomy was performed on each cadaver, with c-spine images recorded in real time on fluoroscopy, then transferred to video and Kodachrome still images. Outcome measures included movement across the C5--6 site with regard to angulation expressed in degrees of rotation and linear measures of axial distraction and anterior-posterior (AP) displacement expressed as a proportion of C5 body width. Data were analyzed by using descriptive statistics to determine mean change from baseline in each of three planes of movement. Significance was assumed if 95% confidence intervals did not include zero. A significant amount of movement was observed with regard to AP displacement (6.3% of C5 width) and axial distraction (-4.5% of C5 width, indicating narrowing of the intervertebral space). These correspond to 1--2 mm AP displacement and less than 1 mm axial compression. No significant angular displacement was observed. In conclusion, cricothyrotomy results in a small but significant amount of movement across an unstable c-spine injury in a cadaver model. This degree of movement is less than the threshold for clinical significance.

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

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.