An animal model of response and nonresponse to inhaled nitric oxide in endotoxin-induced lung injury

Study objective: Oxygenation may be improved in 40 to 60% of ARDS patients by inhalation of nitric oxide (NO). We have studied the response to inhaled NO in porcine acute lung injury 4 h and 6 h after onset of a 2-h endotoxin infusion (30 mug/kg/h), hypothesizing that a responder may change to a nonresponder over time and with progression of lung injury. Design; Animal study. Setting: Experimental laboratory in a university hospital. Interventions and measurements: We studied eight pigs under general anesthesia (mean weight, 26.2 kg) receiving mechanical ventilation adjusted to normocapnia, with a fraction of inspired oxygen (FIo(2)) of 0.5 to 1.0. Blood gases, endotoxin concentration, and central hemodynamics were measured hourly, and ventilation-perfusion ((V) over dot/(Q) over dot) relationships were assessed by multiple inert gas elimination technique before and after inhalation of NO. NO was delivered at 40 ppm for 10 min at 4 h and 6 h of endotoxin exposure. Results: Seven of eight pigs were responders to NO at 4 h, defined as a greater than or equal to 20% increase in oxygenation index (Pao(2)/FIO2) [223 +/- 43 to 330 +/- 56 mm Hg; p = 0.001]. The same pigs exhibited a a: 20% fall in mean pulmonary artery pressure (39.4 +/- 2.2 to 30.0 +/- 2.1 mm Hg; p < 0.001). The response correlated to the perfusion to "normal (V) over dot /(Q) over dot" regions (r = - 0.82) and negatively to shunt and dead space ventilation (r = 0.76 and r = 0.87, respectively). At 6 h, seven of eight pigs were nonresponders, despite unaltered hemodynamics and gas exchange. Correlations at 4 h between physiologic variables and response to NO were abolished. The logarithmic SDs of the perfusion distribution, a measure of the degree of (V) over dot/(Q) over dot mismatch, increased significantly from 4 to 6 h (p = 0.04). Conclusion: Response to inhaled NO is abolished over time in endotoxin-induced ARDS pig lungs. The response seems to be related to the degree of (V) over dot/(Q) over dot mismatch, which may indicate an important role of hypoxic pulmonary vasoconstriction.