It has been suggested that the increase in PO(2) observed with nitric oxide (NO) should be enhanced by the addition of a vasoconstrictor agent. The vasoconstrictor used in combination with NO should mimic or enhance hypoxic vasoconstriction. The aim of this study was to evaluate the respiratory and hemodynamic effects of norepinephrine (a nonspecific vasoconstrictor), almitrine bismesylate (a specific pulmonary vasoconstrictor), and inhaled NO, alone or together. During a 6-mo period, 16 patients presenting with ARDS were prospectively investigated. On inclusion, no patient was receiving cardiovasoactive drugs. The protocol consisted of seven consecutive phases: baseline, norepinephrine (in order to obtain a 3 mm Hg rise in mean pulmonary arterial pressure [Ppa]), almitrine bismesylate (16 micrograms/kg/min), inhaled NO (20 ppm delivered during inspiration), norepinephrine + inhaled NO, almitrine bismesylate + inhaled NO, almitrine bismesylate + norepinephrine + inhaled NO. General factorial analysis of variance showed that inhaled NO and almitrine bismesylate increased oxygenation (p < 0.0001). Norepinephrine had no effect on oxygenation. A synergistic effect between inhaled NO and almitrine bismesylate was found (p < 0.05), whereas norepinephrine did not affect the response to inhaled NO. Nitric oxide produced a significant decrease in Ppa and pulmonary vascular resistances (PVRI) (p < 0.0001). Both almitrine bismesylate and norepinephrine induced an increase in Ppa (p < 0.0001). Norepinephrine increased PVRI (p < 0.002), whereas almitrine bismesylate had no effect on PVRI. The present results support the hypothesis that a selective pulmonary vasoconstrictor enhances the increase in oxygenation induced by inhaled NO, whereas norepinephrine attenuates this effect.

Inhaled NO and almitrine bismesylate in patients with acute respiratory distress syndrome: effect of noradrenalin. L. Papazian, F. Bregeon, F. Gaillat, X. Thirion, A. Roch, E. Cortes, V. Fulachier, P. Saux, Y. Jammes, J-P. Auffray. #ERS Journals Ltd 1999. ABSTRACT: The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert pulmonary blood flow away from poorly ventilated toward well-ventilated areas. The aims of this prospective and comparative study were to: 1) confirm the beneficial effects on oxygenation of this association; 2) evaluate the haemodynamic effects of this association; and 3) evaluate the influence of noradrenaline (a nonspecific vasoconstrictor) on the modification of gas exchange related to inhaled NO and/or almitrine bismesylate.Forty-one sedated paralysed and ventilated patients were investigated. Haemodynamic and blood gas measurements were performed in a fixed order: baseline; inhalation of NO for 30 min.; intravenous infusion of almitrine bismesylate; and concomitant administration of inhaled NO and almitrine bismesylate.Inhaled NO and almitrine bismesylate increased arterial oxygen tension (Pa,O 2 )/ inspiratory oxygen fraction (FI,O 2 ) (p<0.001). The association of inhaled NO with almitrine bismesylate resulted in a dramatic improvement in Pa,O 2 /FI,O 2 (p<0.0001 versus almitrine bismesylate, p<0.05 versus inhaled NO). In patients receiving noradrenalin (n=19), almitrine bismesylate had no effect on oxygenation.The present study confirmed that the combination of inhaled NO with almitrine bismesylate improved oxygenation, and demonstrated that almitrine bismesylate has no effect on oxygenation in patients receiving noradrenalin. Eur Respir J 1999; 14: 1283±1289. Despite the use of new therapeutic agents, acute respiratory distress syndrome (ARDS)-related mortality remains high [1,2]. Inhaled nitric oxide has been widely used since the beginning of the 1990s but recent studies have been unable to demonstrate a significant decrease in mortality related to its use [3,4]. Certain methodological considerations could possibly explain, in part, this lack of positive impact on outcome. However, it could be useful to find some therapeutic associations that would enhance the beneficial effects of inhaled NO on oxygenation. It has been found that the association of the prone position with inhaled NO can enhance arterial oxygen tension Pa,O 2 [5]. A pharmacological approach consisting of diverting pulmonary blood flow away from poorly-ventilated toward well-ventilated areas in which inhaled NO can exert its vasodilating action would appear to be attractive. Several vasoactive agents have been proposed, i.e. the use of a systemic and pulmonary vasoconstrictor (phenylephrine) [6] or the use of a specific pulmonary vasoconstrictor (almitrine bismesylate) [7,8]. Noradrenalin (NA) is extensively used in the intensive care unit (ICU) [9], especially in septic shock, which is frequently associated with A...

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