Background Closed loop control mechanical ventilation has been reported to potentially reduce ventilator weaning time, burden on medicalcaregivers, and improve comfort during mechanical ventilation. However, the influence of closed loop control PEEP adjustment, on fluid requirements in the acute phase and cardiopulmonary dysfunction, remains unknown. The aim of this study was to investigate the impact of closed loop ventilation and PEEPFiO2 on decision support-based fluid resuscitation and respiratory mechanicsgas exchange using a clinically relevant ovine model of burn and smoke inhalation. Methods Adult female sheep 31-42kg were surgically prepared 5-7 days prior to the study. Sheep were then subjected to burn 3rd degree and 40 percent of body surface and smoke inhalation injury under anesthesia and analgesia. During the injury, a pulse-oximeter was placed on the ear to monitor SpO2. After the injury, sheep were randomly assigned into control group n5 which received adaptive support ventilation ASV and closed loop group n6 which received ASV with Intellivent, using the Hamilton S1 ventilator. Sheep were monitored for 48 hours in a conscious state. In the control group, FiO2 and Minute volume MV were adjusted according to PaO2 and PaCO2 values measured every 3 6 hours. The PEEP was fixed at 5 cmH2O. In the Intellivent group, FiO2, PEEP, and MV were automatically adjusted according to SpO2 and etCO2 changes. The initial fluid rate was 4 mLkg for 1 h, then the rate was adjusted hourly based on an algorithm using the hourly urinary output. The survival rate, total fluid in, urine output, net fluid balance, severity of pulmonary dysfunction, and hemodynamic changes, were monitored. Results All sheep survived in the closed loop group, while 2 out of 5 control group survived 48 hrs, p0.06. Because only 2 sheep survived in the control group, the data was summarized for first 24hrs.