Previous studies have demonstrated that if isotonic amino acid infusions were administered at a rate that approximated normal daily protein requirements, a leftward shift of the minute ventilation · PaCO2relationship occurred. This study examined the effect of the administration of parenteral nutrition, at a fixed caloric intake and two levels of nitrogen (N) intake, on the ventilatory response to CO2in nutritionally depleted patients. The intent was to determine whether increasing protein intake from normal to twice normal requirements would result in a further enhancement of the ventilatory response to CO2.Eight patients with nutritional depletion (greater than 10% weight loss) were studied. The resting energy expenditure (REE) was measured during administration of 5% dextrose, using principles of indirect calorimetry. Each patient received parenteral nutrition for a 2-week period. Two diets were examined for a 1-week period each: 1) a high N intake—15 mg nitrogen per kcal REE (approximately 21 g/day), or b) a low N intake—7.5 mg nitrogen per kcal REE (approximately 11 g/day). The initial diet was assigned randomly. Total energy intake was set at 1.35 X REE as measured during administration of 5% dextrose solution. Nonprotein calories were administered as 50% glucose and 50% fat. Breathing patterns at rest and during inhalations of 2 and 4% CO2were analyzed using a canopy-computer-spirometer system.With an increased nitrogen intake there was a significant reduction in resting arterial PaCO2from 39.9 to 37.6 mmHg (P< 0.05) with no significant change inpH. The relationship between VEand PaCO2observed during inhalation of CO2showed a marked leftward shift (P< 0.01), indicating an increased ventilatory sensitivity to CO2.These data indicate that increasing the protein component of a fixed caloric intake will enhance the ventilatory response to carbon dioxide.