Pituitary function is rarely considered in the care of patients with traumatic brain injury (TBI). Yet, TBI poses significant risk to pituitary function given the gland's encasement within the sella, its delicate infundibular-hypothalamic structures and vulnerable vascular supply. Autopsy studies of fatal head injury victims confirm that up to one-third of patients sustain acute pituitary necrosis. The investigators and other investigators have documented chronic pituitary failure in long-term follow up studies of TBI subjects. The purpose of this study is to define acute post-traumatic changes in the hypothalamic-pituitary adrenocortical axis given that this hormonal axis is essential for survival, particularly in times of critical illness such as head injury. The major hypotheses to be tested in this study are: 1) a significant proportion of TBI victims suffer from unrecognized ASAI; 2) that ASAI results primarily from hypothalamic-pituitary hypoperfusion; 3) that the consequences of ASAI are systemic hypotension, increased vasopressor requirements and increased levels of serum and cerebrospinal fluid (CSF) proinflammatory cytokines; and 4) that treatment of individuals with ASAI with acute stress doses of glucocorticoids will improve blood pressure control, decrease CSF cytokine levels, shorten intensive care unit stay and improve neurological outcome. To test these hypotheses, they will first compare serial serum cortisol and ACTH levels over the first 10 days after injury in TBI versus matched non-TBI multiple trauma subjects to define ASAI. Next, TBI patients found to have inappropriately low cortisol levels that met criteria of ASAI, will be randomized to 48 hours of placebo or hydrocortisone therapy and changes in hemodynamics, cytokine levels, and neurological outcome will be measured. Pituitary/hypothalamic magnetic resonance imagings (MRIs) will be performed to assess for acute structural lesions and chronic pituitary volumetric changes. By diagnosing and treating acute traumatic neuroendocrine deficiency, this study may lead to dramatically improved management and neurological outcome of many future TBI patients. This proposal will help the candidate develop the theoretical and practical research skills necessary for an independent career in clinical investigation. The project will be done at two scientifically rich institutions supported by two GCRCs under the guidance of two experienced mentors from two different subspecialties appropriate for the study and the candidate's career development. Formal research instruction via the K30 Graduate Program at UCLA and courses at Harbor UCLA will complement the candidate's firm background in clinical medicine and endocrinology and enable him to successfully pursue a career as a clinical investigator in the field of neuroendocrinology.
