Regional pulmonary vasoreactivity, with special reference to nitric oxide, prostacyclin and body posture

Abstract

The primary aim of the study was to investigate possible mechanisms behind the improved arterial oxygenation in ventilator-treated patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) when turned into prone position. A secondary aim was to discover new knowledge of possible importance for treatment of patients with oxygenation problems in intensive care and during anesthesia.

Previous work have described a dominant blood flow in dorsal lung regions regardless of posture and a better matching of ventilation (V) and perfusion (Q) in prone vs supine posture. Perfusion and also V/Q ratios are more homogeneous in prone than in supine position. The hypothesis of the study was that differences in regional pulmonary vasoreactivity to the endogenous vasodilators nitric oxide (NO) and prostacyclin (PGI2) may explain the improved gas exchange in severe lung disease during ventilator treatment in prone position.

Regional pulmonary vasoreactivity to NO and PGI2, as well as effects of posture on distribution of regional pulmonary blood flow, were investigated in isolated human and porcine lung tissue and pulmonary arteries in vitro and in volunteers and patients in vivo. Presently it was shown that expression of mRNA for endothelial NO synthase (eNOS) was higher in dorsal compared to ventral human lung regions. Ca2+-dependent NOS activity was higher in dorsal than in ventral regions of both human and porcine lungs. Relaxation of porcine pulmonary arteries in vitro by acetylcholine and bradykinin, endothelial-dependent vasodilators, acting via the NO / cGMP pathway was more potent in vessels from dorsal than from ventral lung regions. Furthermore, NOS inhibition by infusion of NG-monomethyl-L-arginine (L-NMMA) redistributed blood flow from dorsal to ventral lung regions in healthy volunteers in supine position. Altogether these results strongly suggest a role for endogenous NO in regulation of regional pulmonary perfusion.

Inhalation of iloprost, a synthetic PGI2 analogue, decreased arterial oxygen tension in healthy volunteers. Pulmonary perfusion was redistributed towards dependent lung regions in both supine and prone, whereas ventilation was redirected towards non-dependent lung regions in supine position, indicating increased mismatch of ventilation and perfusion. Prostaglandin synthesis inhibition by the non-selective cyclooxygenase (COX) inhibitor diclofenac did not affect pulmonary perfusion distribution or oxygenation in healthy subjects.

Patients subjected to left side thoracic surgery in lateral decubitus position with one-lung ventilation (OLV) were treated with non-selective COX-inhibition by diclofenac infusion. They had significantly lower shunt and better oxygenation as measured by alveolo-arterial oxygen difference than patients receiving placebo. The results suggest that a COX-related arachidonic acid metabolite attenuates pulmonary hypoxic vasoconstriction.

In conclusion the results strongly suggest a role for endogenous NO in regulation of regional pulmonary perfusion. PGI2 is likely not involved in regulation of regional pulmonary perfusion during normoxia whereas it may be of importance during hypoxia. The present results may become of importance for patients with oxygenation problems in intensive care as well as during one-lung ventilation for thoracic surgery.