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Dose–Response Characteristics during Long-Term Inhalation of Nitric Oxide in Patients with Severe Acute Respiratory Distress Syndrome

A Prospective, Randomized, Controlled Study

Departments of Anesthesiology and Critical Care Medicine, Vivantes–Klinikum Neukoelln, Berlin; University Hospital Charité-Virchow, Berlin; Ernst-von-Bergmann Hospital, Potsdam; and University Hospital of the Rheinisch-Westfaelische Technische Hochschule, Aachen; Mundipharma GmbH, Limburg, Germany

Correspondence and requests for reprints should be addressed to Prof. Dr. Herwig Gerlach, Vivantes–Klinikum Neukoelln, Klinik für Anaesthesie, Operative Intensivmedizin und Schmerztherapie, Rudower Strasse 48, D-12313 Berlin, Germany. E-mail: herwig.gerlach{at}knk-berlin.de

Inhaled nitric oxide (NO) improves systemic oxygenation (Pa_O2/FI_O2) in adult patients with acute respiratory distress syndrome (ARDS). However, individual response varies, and previous trials demonstrated no outcome benefit. This prospective, randomized study in 40 ARDS patients analyzed dose–response (DR) characteristics during long-term inhaled NO. Patients were randomized for conventional therapy (control) or continuous treatment with 10 parts per million (ppm) inhaled NO until weaning was initiated. We measured DR curves of Pa_O2/FI_O2 versus the inhaled NO dose at regular intervals. Before treatment (Day 0), peak improvement in Pa_O2/FI_O2 was achieved at 10 ppm for both control and NO-treated patients. After 4 days, the DR curve of the NO-treated patients was left shifted with a peak response at 1 ppm. At higher doses (10 and 100 ppm), oxygenation deteriorated, and the response to inhaled NO disappeared in several patients. This effect was not observed in the control group. There was no effect of inhaled NO on duration of mechanical ventilation or stay at the intensive care unit. In conclusion, long-term inhaled NO with constant doses of 10 ppm leads to enhanced sensitivity after several days and does do not allow reduction of ventilation parameters. Hence, previous trials on therapy with inhaled NO in ARDS should be carefully interpreted, as they used constant NO concentrations, which may have become overdoses leading to deterioration of oxygenation after several days.

Key Words: nitric oxide • respiratory distress syndrome, adult • acute respiratory distress syndrome • inhalation drug administration • dose–response relationship, drug

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