Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.

Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome. Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation. Because endotoxin is a potent and clinically important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure, we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin. We studied the effects of protective (tidal volume [VT] 5 ml. kg(-)(1), positive end-expiratory pressure [PEEP] 10 to 12.5 cm H(2)O) versus nonprotective (VT 12 ml. kg(-)(1), PEEP zero) ventilatory strategy on translocation of endotracheally instilled endotoxin. Anesthetized New Zealand White rabbits were subjected to saline lung lavage, and 32 were randomized to one of four groups: PS (protective ventilation + instilled saline); PE (protective ventilation + instilled endotoxin); NS (nonprotective ventilation + instilled saline); NE (nonprotective ventilation + instilled endotoxin), and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group, and remained low and unchanged in the other groups. Peak levels of plasma tumor necrosis factor-alpha (TNF-alpha) were higher in NE versus other groups. Pa(O(2)) and mean arterial pressure (Pa) were lowest, and requirement for pressor and bicarbonate support greatest, in the NE group. Finally, plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors. These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin. This translocation depends on ventilatory strategy, and suggests a pathophysiologic link between ventilatory strategy and outcome.