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An Animal Model of Response and Nonresponse to Inhaled Nitric Oxide in Endotoxin-Induced Lung Injury^*

^* From the Department of Clinical Physiology (Drs. Maurenbrecher and Hedenstierna), University Hospital, Uppsala, Sweden; Department of Anesthesia and Intensive Care (Drs. Lamy and Deby-Dupont), University Hospital, Liège, Belgium; and Department of Anesthesiology (Dr. Frascarolo), University Hospital, Lausanne, Switzerland.

Correspondence to: Göran Hedenstierna, MD, Department of Clinical Physiology, University Hospital, S-75185 Uppsala, Sweden

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 µg/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 (FIO₂) of 0.5 to 1.0. Blood gases, endotoxin concentration, and central hemodynamics were measured hourly, and ventilation-perfusion (/) 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 20% increase in oxygenation index (PaO₂/FIO₂) [223 ± 43 to 330 ± 56 mm Hg; p = 0.001]. The same pigs exhibited 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 /" 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 / 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 / mismatch, which may indicate an important role of hypoxic pulmonary vasoconstriction.

Key Words: endotoxin • lung injury • nitric oxide • pig

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