The pulmonary and haematological toxicity of inhaled aerosolised prostacyclin

Inhaled aerosolised prostacyclin (IAP) has gained prominence as a selective pulmonary vasodilator (SPV), which may be used for the treatment of pulmonary hypertension and severe hypoxaemia, as may occur in conditions such as ARDS [1, 2]. Prostacyclin (Epoprostenol™, GlaxoWellcome, Boronia, Victoria, Australia) is diluted in an alkaline (pH 10.5) buffer prior to nebulisation. The current study was devised to determine the toxic effects on respiratory mucosa of the alkaline buffer as well as any antiplatelet effect of high dose IAP.

Methods

Five piglets weighing 10–20 kg were anaesthetized with halothane in oxygen-enriched air (FiO₂-0.4) and pentobarbitone (8 mg/kg/h) and exposed to one of three aerosolised treatments via a jet nebuliser (MMD = 5.44 μm) as follows. Two piglets acted as controls – one received nebulised normal saline and one received no inhaled therapy, was killed and the lungs immediately harvested. Two piglets received nebulised glycine diluent and two piglets received IAP at a dose of 200 ng/kg/min. All the nebulised therapies were delivered at the same volume as would be required to deliver 200 ng/kg/min of IAP. This therapy was continued for 6–8 h.

Monitoring included invasive BP, rectal temperature and HR. Hourly thromboelastograph (TEG) measurements were carried out to determine any reduction in the maximum amplitude (MA), as a marker of platelet inhibition. At the end of the study period the lungs were harvested and sectioned. Multiple sections were examined histologically for the presence of polymorphonuclear leucocytes as evidence of acute inflammation. A ventilation scan using nebulised radiolabelled DTPA dissolved in the glycine diluent was carried out on one additional piglet to ensure widespread deposition of the nebulised therapy in the lungs of the study piglets.

Results

All piglets receiving either glycine diluent or IAP (prostacyclin in glycine diluent) showed evidence of acute inflammation, which was worse in the trachea and major bronchi than in the lower airways and lung parenchyma. Also, the changes were more marked on the luminal surface of the airways. The two piglets receiving IAP showed evidence of platelet inhibition as determined by a reduction in MA from baseline. The nuclear medicine ventilation scan confirmed widespread and distal deposition of the aerosol droplets.

Conclusion

Prolonged exposure (6–8 h) to nebulised glycine diluent in which IAP is delivered is associated with mild inflammation of the respiratory mucosa in the piglet. Also, high dose IAP results in the systemic absorption of prostacyclin with a resultant antiplatelet aggregation effect as determined by TEG. These findings differ somewhat from a previous animal model where no evidence of pulmonary inflammation could be found after response to IAP [3]. The current study employed higher doses of IAP (200 ng/kg/min) and the testing for inflammation was more specific, which may account for the difference in findings.