Progesterone Improves Head Injury Recovery
HANGZHOU, China, April 30 -- Head injury patients treated with injections of progesterone in an investigational protocol had improved survival and better function after six months in a small randomized trial, researchers here said.
Six-month mortality among severely brain-injured patients treated with progesterone was 18%, versus 32% in patients receiving placebo (P=0.039), reported Guomin Xiao, M.D., of Zhejiang University, and colleagues, online in Critical Care.
Progesterone appeared to have little or no other effect during the acute phase. The main effect of progesterone was seen during recovery after discharge.
Significantly more patients given progesterone were judged to have good recovery or moderate disability at six months as measured by the Glasgow Outcome Scale, Dr. Xiao and colleagues said.
Progesterone-treated patients also showed more normal overall function according to modified Functional Independence Measure scores.
A previous phase II trial conducted in the U.S., reported last year by David Wright, M.D., of Emory University, and colleagues, found a benefit for progesterone in 30-day mortality).
"The present trial showed for the first time that progesterone administration had a longer-term efficacy on clinical outcomes in acute traumatic brain injury patients," Dr. Xiao and colleagues wrote.
The Chinese study involved 159 adult patients admitted for acute, severe traumatic brain injury with Glasgow Coma Scale scores of 8 or less over three years. Most patients were injured in motor vehicle accidents, with falls and assaults accounting for some 7%.
Exclusion criteria included use of estrogen or progesterone drugs in the previous month, severe anoxic intracerebral damage or brain death, unstable clinical condition, pregnancy, lactation, and any possibility that a patient's neurological status resulted from spinal cord injury rather than brain injury.
Patients were randomized to placebo or 1 mg/kg of progesterone by intramuscular injection beginning no more than eight hours after the injury. Injections were repeated twice daily for five days.
All patients received standard care for acute brain injury according to published guidelines.
Some 70% of the 40 deaths in the study occurred in the first week after injury, Dr. Xiao and colleagues said. All deaths were considered related to head injury, and all but three occurred during patients' hospitalization.
There were no differences between treatment groups in intracranial pressure, Glasgow Coma Scale scores, body temperature, heart and respiration rates, blood pressure, blood oxygen saturation, or laboratory findings during the first two weeks after injury.
Progesterone treatment was associated with a significantly higher rate of favorable outcomes at six months, as defined by Glasgow Outcome Scale scores indicating good recovery or moderate disability.
About 58% of progesterone-treated patients had favorable outcomes at six months, compared with 42% of the placebo group (P=0.048).
There was also a significant difference at six months in modified Functional Independence Measure scores. Progesterone-treated patients had mean scores of 9.87 (SD 1.17) compared with 8.95 (SD 1.05) in the placebo group (P<0.01).
The benefit appeared to be largely confined to patients with less severe injury at baseline. There was no significant advantage for progesterone in patients with initial Glasgow Coma Scale scores of 3 to 5, whereas significantly more progesterone-treated patients with coma scale scores of 6 to 8 had favorable outcomes.
Dr. Xiao and colleagues found no adverse effects related to progesterone treatment.
The researchers offered no definitive mechanism for progesterone's apparent neuroprotective effect. No statistically significant difference was found in intracranial pressure monitoring between the groups given progesterone or placebo.
Other research has found that the hormone aids in neuronal development and protects brain function in animal experiments.
Dr. Wright at Emory applauded the Chinese study in an interview. "Overall I thought it was well done," he said.
"It's certainly very interesting and confirms all the work we've been doing at Emory," Dr. Wright said. "I'm delighted to see it."
However, he said one finding in the study was difficult to understand. In the subgroup analysis of patients with coma scale scores of 3 to 5 versus those with scores of 6 to 8, the patients with better neurological function at baseline had lower rates of favorable outcome at six months than the study sample as a whole.
For example, 58% of the entire progesterone group and 42% of the placebo group had favorable six-month outcomes. But among the subgroup with coma scale scores of 6 to 8, only 42% of those receiving progesterone and 28% of those receiving placebo had favorable outcomes.
"It does need to be clarified," Dr. Wright said.
He pointed out that it was a small study for this type of research. "I would call it a pilot," he said.
Dr. Wright said he and his colleagues were seeking funding for a multicenter trial of progesterone, with a planned enrollment of 1,140 patients and evaluations at six months.
Although neither his study nor the Chinese trial found any evidence of adverse effects, he said it's still premature to recommend progesterone clinically for traumatic brain injury, even on a compassionate basis.
As an emergency physician who treats head injuries, Dr. Wright said he would not prescribe it for his own patients before the larger trial is completed.
The study was supported by the Scientific Research Fund of Zhejiang Provincial Education Department, China.