Effects of Erythropoietin on Cerebral Vascular Dysfunction and Anemia in Traumatic Brain Injury

Traumatic brain injury (TBI) causes a spectrum of cerebrovascular dysfunction, ranging from
impaired pressure autoregulation to severe global ischemia (inadequate blood flow).
Pressure autoregulation is the ability of an organ to maintain a constant blood flow despite
changes in perfusion pressure. Impaired pressure autoregulation causes TBI patients to be
more vulnerable to secondary ischemic attacks.

Erythropoietin (Epo) is a substance that is normally made by the kidneys and stimulates the
production of red blood cells. It is usually given to patients to treat anemia. Scientists
recently discovered that Epo also is made in the brain after injury. In animal models of
TBI, the brain's production of Epo has numerous protective effects, including reducing
inflammation in the brain, reducing death of brain cells, and improving blood flow to the
brain. In the laboratory, the effects of this naturally-occurring, protective agent can be
enhanced by giving additional amounts intravenously. Because Epo may have beneficial
effects for both the injured brain and anemia, scientists are studying the effects of giving
Epo to patients with severe TBI.

The primary objective of this randomized, placebo-controlled study is to determine the
effect of early administration of recombinant human Epo (rhEpo), on long-term neurological
outcome in patients with severe TBI. The researchers also will examine the effects of rhEpo
administration on the cerebrovascular system, hemoglobin concentration, brain oxygenation,
the need for blood transfusion, and on systemic complications.

This study consists of 2 parts: 1) a treatment phase, and 2) a monitoring phase. In the
treatment phase, participants will be randomly assigned to 1 of 4 groups: a low or high
dose rhEPO treatment group or low or high dose placebo group (control group). All other
aspects of treatment during the acute post-injury phase will follow the standard treatment
protocol for individuals with severe TBI. Generally the treatment phase lasts 1-2 weeks or
the amount of time that is required for patients to receive treatment of their TBIs in the
ICU (intensive care unit). The monitoring part of the study (which includes recording
information from tests performed as part of the standard TBI treatment, as well as some
additional tests performed especially for the study) lasts for up to 6 months after the TBI.

Information learned in this study may lead to knowledge about whether rhEpo improves
outcomes after TBI and about the optimal hemoglobin concentration to maintain in patients
with TBI.

Inclusion Criteria:

- Blunt trauma mechanism of brain injury

- Glasgow Coma Score - motor component ≤ 5 (not following commands) on the
post-resuscitation neurologic exam

- Available for enrollment and administration of study drug within 6 hours of injury

Exclusion Criteria:

- Penetrating trauma (i.e. gun shot wounds)

- Glasgow Coma Score = 3 and bilateral fixed and dilated pupils

- Abbreviated Injury Scale score > 5 for any body part except brain

- Severe pre-existing chronic disease

- Uncontrolled hypertension, defined as mean arterial pressure > 130mmHg despite
antihypertensive treatment

- Known hypersensitivity to mammalian cell-derived products or human albumin

- Currently taking anticoagulants