Nebulized Prostacyclin:A Replacement for Nitric Oxide?
Abstract & Commentary
Synopsis: Nine patients with severe ARDS were treated with continuous aerosolized prostacyclin (AP). All of them demonstrated a dose-response improvement in oxygenation ratio and alveolar-arterial oxygen tension difference. There was no effect on systemic or pulmonary arterial pressures or on platelet function over the dosage range tested (10-50 mcg/kg/min). AP may be an effective selective pulmonary vasodilator similar to inhaled nitric oxide.
Source: van Heerden PV, et al. Chest 2000;117:819-827.
The short clinical half-life and selective nature of prostacyclin makes it a potential candidate to improve the hypoxia of the acute respiratory distress syndrome (ARDS), if this agent can be shown to improve shunt and not cause significant side effects. By delivering the agent only to ventilated lung units, it is theoretically possible to achieve this improvement without affecting systemic hemodynamics, in much the same way as with nitric oxide.
Nine patients with severe ARDS, having a lung injury score of at least 2.5, were studied. All of them were intubated, on at least 50% oxygen, and ventilated with approximately 8 mL/kg per breath at a rate sufficient to maintain normal pH and partial pressure of carbon dioxide (PCO2) during the experiment. All patients were treated with continuous aerosolized prostacyclin (AP) for 30 minutes prior to obtaining measurements. An increasing dose scheme was used, with an additional 10 mcg/kg/min added for each subsequent 30-minute trial. After the final, 50-mcg/kg/min dose was tested, patients were returned to baseline in order to document reversibility. In addition to the hemodynamic variables, the major metabolite of prostacyclin, 6-ketoPGF1a, was determined, and platelet function was determined in an aggregometer.
Increasing doses of AP produced a dose-response increase in oxygenation ratio from 184 to 210 at the highest dose and a reduction in alveolar-to-arterial oxygen tension difference (A-a gradient) from 290 to 270 mm Hg. There was a linear increase in 6-ketoPGF1a, and no effect on platelet aggregation. Right-to-left shunt was less at all doses, but there was no dose-response effect. There was no significant change in pulmonary artery pressures, although none of the patients had significantly high pressures to begin with. No change in systemic hemodynamics was seen, although there was a trend to a slight increase in cardiac index at the highest dose.
COMMENT BY CHARLES G. DURBIN, Jr., MD, FCCM
This is an important preliminary study demonstrating a simple way to deliver a selective, short-acting pulmonary vasodilator. It may be a less expensive alternative to inhaled nitric oxide. Since delivery is limited to only those ventilated alveoli, prostacyclin may enhance arterial oxygenation by improving ventilation/perfusion ratios. No toxicity was identified in this study. However, further testing would be required to identify longer term effects, possible toxicities or side effects, and the appropriate dose range.
The magnitude of the improvement in oxygenation in this study was quite modest. The effects of AP must be compared with those of nitric oxide. While no long-term improvement in outcome has been shown for adult patients treated with nitric oxide, short-term improvements in oxygenation have allowed reduced exposure to high, possibly toxic, levels of oxygen in some patients as well as decreases in elevated pulmonary artery pressure. If AP is effective in improving oxygenation on a short-term basis, an improvement in patient outcome should be sought during additional evaluations.
A substantial problem with nebulization is inefficiency. Most of the drug fails to reach the alveolus, and "rain-out" in the tubing and larger airways limits therapeutic effects. This problem can be overcome by using larger amounts or concentrations of the agent, although with this strategy side effects will likely increase as well. Since the price of nitric oxide has recently been raised to unacceptable levels, a more economical equivalent product is needed. Although additional research is needed, this simple solution appears promising.
The primary effect of inhaled nebulized prostacycin is:
a. reduced platelet thrombi in the lung.
b. improved oxygenation.
c. reduced pulmonary pressures.
d. increased bronchospasm.
e. fewer pneumonias in intubated patients.
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