ATLANTA -- Giving progesterone to adults with traumatic brain injury can cut their risk of near-term death in half and may improve chances for recovery in patients with less severe injuries.
ATLANTA, Oct. 3 -- Giving progesterone to adults with traumatic brain injury can cut their risk of near-term death in half and may improve chances for recovery in patients with less severe injuries, according to researchers here.
Despite the improvement in mortality, survivors who received the hormone and those who received placebo in a randomized phase II clinical trial had generally poor neurologic outcomes at 30 days, they reported in the online edition of Annals of Emergency Medicine.
But progesterone did appear to have a modest neuroprotective effect in patients with moderate traumatic brain injury (Glasgow score 9-12), reported David Wright, M.D., of Emory, and colleagues at Morehouse School of Medicine and Grady Memorial Hospital here.
"We found encouraging evidence that progesterone is safe in the setting of traumatic brain injury, with no evidence of side effects or serious harmful events," said Dr. Wright. "In addition, we found a 50% reduction in the rate of death in the progesterone-treated group. Furthermore, we found a significant improvement in the functional outcome and level of disability among patients who were enrolled with a moderate brain injury."
In animal studies, progesterone administered shortly after traumatic brain injury reduced cerebral edema, prevented neuronal loss, and improved functional outcomes, but this study marks the first time that the hormone's effects on injured human brains has been put to the test, according to the authors.
"Progesterone offers a number of advantages over other experimental treatments for traumatic brain injury," they wrote. "Because it is lipid soluble, it rapidly crosses the blood-brain barrier and reaches equilibrium with the plasma within an hour of administration. It has a long history of safe use in men and women. The intravenous formulation we used can be easily administered by peripheral line. Because the agent is widely available in generic forms, it is inexpensive."
The three-year phase II pilot study, dubbed ProTECT (for Progesterone for Traumatic brain injury -- Experimental Clinical Treatment), involved 100 patients who presented at Grady Memorial (Atlanta's only Level I trauma center), with a traumatic brain injury less than 11 hours old.
The patients all had blunt injuries and an initial Glasgow Coma Scale score ranging from 4-12. Health care proxies were asked to provide consent for the patients.
The patients were randomized on a 4:1 basis to receive intravenous progesterone (77) or placebo (23). Progesterone was delivered at a loading dose of 0.71 mg/kg at 14 mL/hour for the first hour. The infusion was then reduced to 10 mL/hour to deliver 0.5 mg/kg per hour for the next 11 hours. Five additional 12-hour maintenance infusions were delivered at the standard rate of 10mL/hour, for a total of three days of treatment.
Observers blinded to the type of therapy assessed the patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcomes were assessed 30 days after the initial injury.
The primary safety outcomes were differences in adverse event rates and 30-day mortality. The primary efficacy outcome was the dichotomized Glasgow Outcome Scale-Extended 30 days after the injury.
The majority of patients (71) were male, and 34 were black. The mean patient age was 36. More than 80% of the injuries were due to car crashes or falls.
At the time of presentation, 72 patients had an index Glasgow Coma Scale score of 4-8, indicating severe traumatic brain injury; the remaining 28 patients had moderate injuries, indicated by a Glasgow score of 9-12.
Treatment was initiated at a mean of 6.3 hours (955% confidence interval, 5.9 to 6.8 hours) in the progesterone group and 6.2 hours (95% CI, 5.9 to 6.6 hours) in the placebo group. The delays in treatment were largely due to problems locating and obtaining consent from proxies, the authors noted.
There were no serious adverse events attributable to progesterone, and rates of adverse and serious adverse events were similar between the groups in all respects, except for the mortality rate.
The investigators found that patients who received progesterone had significantly lower risk of dying within 30 days compared with controls, but because the number of participants in the study was relatively small, the confidence interval around this estimate approaches 1 (relative risk 0.43, 95% CI, 0.18 to 0.99. P value not given).
"Thirty days post-injury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores," the authors wrote. "However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo."
On the Dichotomized Glasgow Outcome Score-Extended scale, 55.6% of patients who received progesterone and who had moderate initial brain injury had moderate to good scores at 30 days, compared with none of the placebo patients (no risk ratio estimate possible; P=0.0202).
The investigators plan a phase III trial pitting progesterone against placebo in 1,000 adults with traumatic brain injury. They noted that the effects of progesterone in children with traumatic brain injury are unknown, and will require separate study.