The increasing rate of hospital-acquired infection and antibiotic resistance are major causes of prolonged ICU stay and death in hospitalized patients. The enormous impact of ICU-related infection demands the need for cost-effective therapies that can be rapidly implemented to improve patient immune response to control infection. Unfortunately, little high-quality comparative effectiveness research has been performed on micronutrient treatment regimens as methods to decrease hospital-acquired infection in critically ill patients. Critically ill medical and surgical patients have an extremely high prevalence of vitamin D insufficiency. We will perform a rigorous, double-blind, randomized, controlled, pilot clinical trial in ventilator-dependent ICU patients to test the clinical/metabolic safety and efficacy of two doses of oral high-dose vitamin D3 therapy versus standard therapy (no supplemental vitamin D). The primary endpoint is to test whether high-dose regimens \[either 50,000 or 100,000 international units (IU) of enteral vitamin D3 given daily for 5 consecutive days (total dose = 250,000 or 500,000 IU, respectively) increase plasma 25(OH)D concentrations into a desirable range (\> 30 ng/mL).

1. We will evaluate, over 12 weeks, the safety and efficacy of two high-dose vitamin D3 regimens in severely ill ICU patients. Vitamin D or placebo ( depending on study arm) will be given sequentially in divided doses for 5 days 2. We will explore whether these vitamin D regimens are capable of increasing the production of key antimicrobial peptides LL-37 and hBD-2 ( substances produced by our bodies to fight infections), in both the blood and in lung. 3. We will determine whether a higher vitamin D level in the blood is associated with a decrease in hospital infection rates and other complications in high-risk ICU patients with respiratory failure. Study Design: Enrollment goal is 36 patients. Once consent is obtained subjects will be randomly assigned to one of three study groups. Each group consists of 12 patients with enteral access ; a placebo arm, an arm where subjects receive 50,000 IU of Vitamin D for 5 days, and a third arm where subjects receive 100,000 IU of Vitamin D for 5 days. Methods: Baseline blood samples (25-hydroxyvitamin D, vitamin D binding protein, ionized calcium, LL-37,and hBD-2) will be taken on study day 7,14,21,28,84 days. On study day 1 and 8, LL-37, hBD-2, cathelicidin from BAL fluid will also be analyzed. Patients will be given either placebo, Vitamin D3 50,000 IU x 5 days (total 250,000 IU) or Vitamin D3 100,000 IU x 5 days (total 500,000 IU) with an intention to treat model. Baseline data on the patients including demographic, laboratory, documented infections, severity illness score (APACHE II) and organ dysfunction score (SOFA) will be collected. ELISA assay on the serum and BAL will be performed.