Background Information
Every 15 seconds, a U.S. citizen sustains a significant traumatic brain injury (TBI). Every five minutes, someone is permanently disabled as a consequence of TBI. Between 1.5 to 2 million Americans sustain a TBI each year. In addition to the 50,000 deaths and 235,000 hospitalizations caused by TBI each year, there are over 80,000 Americans disabled. Another 37,000 patients experience moderate disabilities. The CDC estimates that 5.3 million civilian Americans are living with some degree of disability from a traumatic brain injury. Survivors of severe brain injury (GCS 3-8) typically require 5 to 10 years of intensive therapy. The average per-person lifetime medical care costs of TBI are estimated as follows: moderate $80,800, severe $92,700, and very severe $324,400. However, the lifetime cost of care for a survivor of severe TBI can exceed $4 million. Aggregate annual cost of TBI in the United States approached $60 billion in 2000.
TBI has been labeled the signature wound of the Iraq war. The number of military personnel that fall victim to blunt TBI has risen dramatically due to an increase in concussive weapons as well as improved armor that has reduced penetrating injuries. In the Iraq/Afghan conflict, approximately 20% of combat personnel have suffered a TBI while in theater, a likely conservative figure due to lack of in-field screening. Despite the enormity of the problem, scientists have not identified an effective pharmacological agent that improves outcomes for TBI. Roberts et al. reviewed five treatments (hyperventilation, mannitol, CSF drainage, barbiturates, corticosteroids) for TBI and found that when studies had proper controls, none of these treatments was effective for reducing morbidity and mortality. In fact, no new pharmacological therapies have been implemented for acute TBI in over 30 years. Glucocorticoids, once considered a mainstay of TBI treatment, are now known to be ineffective or even harmful. This fact was recently underscored by the findings of the Corticosteroids After Significant Head Injury CRASH trial, which was prematurely halted due to an increased death rate in the treatment group. With no effective treatments to offer, clinicians adopt a supportive role, monitor for serious side effects (e.g., brain edema and expanding intracranial hematomas) and strive to prevent inter-current illnesses (e.g., pneumonia, ARDS, etc.). Intracranial monitoring is used to guide intensive therapy, but it has not been shown to improve outcome. Neurosurgical interventions, such as craniotomy for cerebral edema and evacuation of hematomas to ward off immediate deterioration, are largely supportive in nature. No agent has been shown to halt the deleterious secondary cascade of injury, much less improve functional outcome after an acute TBI.
Of the alternative therapies holding promise for use in TBI, none have produced definitively positive results when tested in humans.Results from a recently terminated clinical trial of magnesium were disappointing . A recent evaluation of albumin versus saline (SAFE study) for fluid resuscitation of acute TBI patients indicated a higher mortality for patients receiving albumin. Hypothermia has shown promise as a treatment for some forms of global ischemia, but there is still debate as to its effectiveness in TBI patients, especially those more than 45 years of age.
Why Progesterone?
Progesterone is a potent neurosteroid that is naturally synthesized in the CNS. A growing body of animal studies indicates that early administration of progesterone after experimental TBI reduces cerebral edema, neuronal loss, and limits behavioral deficits in laboratory animals. Certain properties of progesterone make it an ideal candidate for treatment of humans. First, in contrast to most drugs tested to date, progesterone rapidly enters the brain and reaches equilibrium with the plasma within an hour of administration. Second, unlike other candidate agents, progesterone has a long history of safe use in men and women. Third, the findings of our pilot clinical trial indicate that progesterone has consistent and predictable pharmacokinetic properties, is unlikely to produce harm, and may be efficacious for treating acute TBI in humans. Fourth, a more recently published human pilot clinical trial by Xiao et al. supports the ProTECTTM I findings; their study showed a decrease in mortality and an improvement in functional outcome at 6 months with progesterone treatment.