Patients with isolated severe head injury must recover from both the primary brain injury and secondary central and peripheral sequelae. Extensive efforts to control elevated intracranial pressure and prevent the systemic complications associated with head injury have improved mortality. Secondary insults, such as metabolic effects, are major contributors to poor outcome. Recent results from basic research and clinical trials demonstrate that damaged nerve cells can regain function. Neurotrophic factors such as insulin-like energy substrates available to the brain, and prevent the detrimental systemic sequelae of brain injury. The metabolic response to brain injury is linked to increased levels of cytokines and catabolic hormones and immunocompetence, altered vascular permeability, and altered gastrointestinal function. Head-injured patients have increased cytokines/catabolic hormones and decreased cytokines/catabolic hormones and decreased IGF-1 may lead to many of the secondary consequences of head injury. Recent studies suggest that providing early adequate nutritional support improves rate of recovery and lessens mortality from head injury. In a preliminary study of 33 patients with severe closed head injury, recombinant IGF-1 was infused for 14 days post-injury at a rate of 0.001 mg/Kg/hr. Favorable trends were observed in treated (IGF-1) versus control groups (saline) for sepsis, rate, nitrogen balance, neurological outcome, and mortality rate. In this clinical project we will study the efficacy of a promising new therapeutic modality, IGF-1 combined with GH. This clinical trial will identify whether or not IGF-1 infusion and subcutaneous GH injection in humans with head injury can significantly whether decrease mortality and improve neurologic outcome. Mechanisms of improvement will also be explored. We hypothesize that intravenous IGF-1 combined with GH may improve outcome of patients with severe head injury through several possible mechanisms: 1) enhanced neural repair or reorganization; 2) altered systemic hyperglycemia and decreased brain lactic acidosis; 3) preservation of normal ratios of amino acid substrates available to brain after injury; 4) decreased infection rate; and 5) decreased gut permeability, cytokine release, and lessened acute-phase and hypercatabolic responses to injury. Basic experiments in project 2,3,4, and 5 will help to identify the mechanisms of the combination IGF-1/GH actions.
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