Impact of airway closure and lung collapse on inhaled nitric oxide effect in acute lung injury: an experimental study

Background

Efficacy of inhaled therapy such as Nitric Oxide (iNO) during mechanical ventilation may depend on airway patency. We hypothesized that airway closure and lung collapse, countered by positive end-expiratory pressure (PEEP), influence iNO efficacy. This could support the role of an adequate PEEP titration for inhalation therapy. The main aim of this study was to assess the effect of iNO with PEEP set above or below the airway opening pressure (AOP) generated by airway closure, on hemodynamics and gas exchange in swine models of acute respiratory distress syndrome. Fourteen pigs randomly underwent either bilateral or asymmetrical two-hit model of lung injury. Airway closure and lung collapse were measured with electrical impedance tomography as well as ventilation/perfusion ratio (V/Q). After AOP detection, the effect of iNO (10ppm) was studied with PEEP set randomly above or below regional AOP. Respiratory mechanics, hemodynamics, and gas-exchange were recorded.

Results

All pigs presented airway closure (AOP > 0.5cmH₂O) after injury. In bilateral injury, iNO was associated with an improved mean pulmonary pressure from 49 ± 8 to 42 ± 7mmHg; (p = 0.003), and ventilation/perfusion matching, caused by a reduction in pixels with low V/Q and shunt from 16%[IQR:13–19] to 9%[IQR:4–12] (p = 0.03) only at PEEP set above AOP. iNO had no effect on hemodynamics or gas exchange for PEEP below AOP (low V/Q 25%[IQR:16–30] to 23%[IQR:14–27]; p = 0.68). In asymmetrical injury, iNO improved pulmonary hemodynamics and ventilation/perfusion matching independently from the PEEP set. iNO was associated with improved oxygenation in all cases.

Conclusions

In an animal model of bilateral lung injury, PEEP level relative to AOP markedly influences iNO efficacy on pulmonary hemodynamics and ventilation/perfusion match, independently of oxygenation.

Key Points

1. Airway Closure in ARDS: Airway closure was present in all experimental models following lung injury, contributing to ventilation-perfusion (V/Q) mismatch and impaired gas exchange. This phenomenon is a significant factor in ARDS and must be accounted for in therapeutic strategies.
2. Effect of iNO on Pulmonary Hemodynamics: Inhaled nitric oxide improved mean pulmonary artery pressure (mPAP) and V/Q matching, but these benefits were only observed when PEEP was set above AOP in cases of bilateral lung injury.
3. PEEP and Airway Patency: Setting PEEP above AOP prevented repeated airway closure and reopening, maintaining airway patency and optimizing the delivery of iNO. PEEP levels below AOP negated the hemodynamic benefits of iNO in bilateral lung injury.
4. Asymmetrical vs. Bilateral Injury: The response to iNO differed between bilateral and asymmetrical lung injuries. In asymmetrical injury, iNO improved pulmonary hemodynamics and V/Q matching regardless of PEEP settings, likely due to the presence of a relatively healthier lung.
5. Gas Exchange Improvements: Oxygenation improved with iNO across all experimental conditions, independent of PEEP levels, reinforcing its role in enhancing oxygen delivery despite its limited impact on survival in clinical studies.
6. Influence on Ventilation/Perfusion Ratios: In bilateral lung injury, iNO effectively reduced dead space and shunt, improving the proportion of lung regions with normal V/Q only when PEEP was set above AOP. This effect was maintained in asymmetrical injury regardless of PEEP settings.
7. Reduction of Pulmonary Vascular Resistance: The study demonstrated a decrease in pulmonary vascular resistance (PVR) when iNO was administered at appropriate PEEP levels, further supporting its role in optimizing hemodynamics in ARDS.
8. Carbon Dioxide Clearance: iNO administration was associated with reduced arterial carbon dioxide levels (PaCO₂), likely due to improved V/Q matching and reduced dead space ventilation.
9. Clinical Implications for iNO Therapy: These findings suggest that iNO’s effectiveness in ARDS depends on airway patency, and clinicians should optimize PEEP settings above AOP to maximize its hemodynamic and gas exchange benefits.
10. Future Research and Translation to Clinical Practice: The study underscores the need for further clinical validation of these findings, emphasizing the importance of individualized PEEP titration in ARDS patients receiving iNO therapy.