MedicalResearch.com Interview with: Dr. Brett E. Skolnick PhD Department of Neurosurgery Cushing Neuroscience Institute Hofstra North Shore–LIJ School of Medicine, Manhasset, NY Medical Research: What is the background for this study? What are the main findings? Dr. Skolnick: The experimental evidence for a role of progesterone is based on extensive non-clinical studies in non-primate species (4 animal species such as rat, mice) the majority of which indicate that progesterone has a variety of neuroprotective properties. The animal models of injury in traumatic brain injury (TBI) have included models of blunt trauma, fluid percussion injury, cortical aspiration but similar effects have been seen stroke models and models of spinal cord injury. In these experiments progesterone has been shown to reduce cerebral edema thus limiting the effects or preventing intracranial pressure increases which can lead to secondary injury. Progesterone has also been shown to exert anti-inflammatory, anti-apopotic and perhaps even anti-oxidant effects. All of these effect are postulated to work synergistically to prevent cell death which could result in improved functional outcomes. Two small single center clinical trials provided the support in traumatic brain injury patients that progesterone could have impact on functional outcomes in larger, properly powered trials.  The results of which are summarized in the NEJM article. In the current trial evaluated the Glasgow Outcome Scale and the extended version of the Glasgow Outcome scale at 6 months following injury. These scales are well validated scales that are used to determine the degree of recovery in terms of disability and handicap due to TBI rather than the degree of impairment. The GOS has 5 levels: death, vegetative state, severe disability, moderate disability and good recovery with death and vegetative state typically collapsed because they are considered equally undesirable. The Extended GOS takes the three best levels of recovery and subdivides these into a upper and lower category to increase the granularity of the outcome measure. Progesterone was administered within 8 hour of injury (loading dose followed by continuous infusions) for a total of 120 hours.  Careful assessments were performed to ensure optimal patient management during the trial to provide the best background to evaluate the impact of the addition of progesterone or placebo (1  to 1 randomization).  No effect was seen on the GOS or the extended GOS. In addition a fairly new approach of categorizing patients based on prognostic factors known at time of randomization (such as Age, baseline GCS, pupillary response, hypoxia, hypotension, Marshall Classification or presence/absence of subarachnoid hemorrhage) as developed by Hukkelhoven and colleagues was used. This was expected to tease out improvements, if they existed in subgroups of patients where perhaps progesterone could work better in the most severe or less severe traumatic brain injury patients. But again no effects were seen. The unfavorable outcomes (see NEJM paper for details) were essentially identical between progesterone and placebo groups whether they had the worst prognosis or the best prognosis.