Pharmacotherapy of acute lung injury and acute respiratory distress syndrome.
ABSTRACT Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.
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ABSTRACT: To determine the incidence of late pulmonary hypertension (late PH) in congenital diaphragmatic hernia (CDH) and whether prolonged treatment with noninvasive inhaled NO therapy delivered through a nasal cannula (NC) would sustain pulmonary vasodilation during a period of transition from mechanical ventilation to spontaneous breathing. We collected data on all patients with a diagnosis of CDH admitted to the Children's Hospital, Denver, from January 1996 through December 2001. Patients who had suprasystemic pulmonary hypertension when inhaled NO was discontinued before extubation were treated with inhaled NO delivered with the nasal cannula. Newborn infants (n = 47) with CDH were treated during this time period. Short-term (<3 months) and long-term (>1 year) survival was 85% and 75%, respectively; 30 newborn infants were treated with inhaled NO (64%). Inhaled NO was successfully discontinued in 16 patients before extubation, and 10 (21%) were treated with inhaled NO through NC after extubation because of pulmonary hypertension and marked hypoxemia when trials off inhaled NO were performed. Nasopharyngeal NO concentrations were 5.4 +/- 0.5 ppm and 2.4 +/- 0.4 ppm with inhaled NO measured proximally in the delivery device at 10 and 5 ppm, respectively. Late PH occurs in a significant subset of newborn infants with CDH. Noninvasive inhaled NO treatment may reduce the duration of mechanical ventilation while safely treating late PH.Journal of Pediatrics 04/2003; 142(4):397-401. · 4.04 Impact Factor
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ABSTRACT: Inhaled nitric oxide is a potent and selective pulmonary artery vasodilator. We studied the effects of nitric oxide inhalation in neonatal and pediatric acute respiratory distress syndrome (ARDS) patients with respect to dosage, prolonged inhalation, and weaning. Prospective, open-label study. Neonatal and pediatric intensive care units of a level three university hospital. Seventeen patients with severe ARDS (1 day to 6 yrs of age [mean 1.75]; oxygenation index of > 20 cm H2O/torr) were enrolled. To identify the optimal dosage for continuous nitric oxide inhalation, doses between 1 and 80 parts per million (ppm) of nitric oxide were tested after the patients had stabilized. Daily withdrawals of nitric oxide were made, according to predetermined criteria. Nine neonatal and eight pediatric ARDS patients (mean Pediatric Risk of Mortality score 28.4 +/- 6.1; mortality risk 54 +/- 15%) were studied. The following variables changed within 24 hrs of nitric oxide inhalation: mean oxygenation index decreased by 56% (from 34 +/- 12 to 15 +/- 7 cm H2O/torr, p = .0004); alveolar-arterial O2 gradient decreased by 31% (from 579 +/- 71 to 399 +/- 102 torr (77.2 +/- 9.5 to 53.2 +/- 13.6 kPa), p = .0004); and mean systemic arterial pressure increased by 15% (from 49 +/- 10 to 57 +/- 12 mm Hg, p = .0029). The optimal dose of nitric oxide was 20 ppm in neonates (with additional persistent pulmonary hypertension of the newborn) and 10 ppm in pediatric patients. Prolonged inhalation (4 to 21 days) was associated with continuous improvement of oxygenation. An oxygenation index of < 5 cm H2O/torr predicted successful withdrawal, with a sensitivity of 75% and a specificity of 89%. None of the patients had to be rescued with extracorporeal membrane oxygenation and 16 of the 17 patients survived. Inhaled nitric oxide enhances pulmonary gas exchange, with concomitant hemodynamic stabilization, in neonatal and pediatric ARDS. Best effective doses were 10 ppm of nitric oxide in pediatric ARDS and 20 ppm in neonates. Treatment should be continued until an oxygenation index of < or = 5 cm H2O/torr is achieved. Effects on outcome need verification in larger controlled trials.Critical Care Medicine 11/1996; 24(11):1913-9. · 6.12 Impact Factor
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ABSTRACT: The effects of two surfactant preparations on lung mechanics have been studied on 24 ventilated premature infants with respiratory distress syndrome (RDS): 13 were given artificial surfactant (Exosurf Neonatal, Burroughs-Wellcome) and 11 natural porcine surfactant (Curosurf, Laboratoire Serono France). Measurements of respiratory system compliance (Cdyn, Crs) and resistance (Rrs) were performed immediately before surfactant administration and repeated 6, 18, 24, 48, and 72 hours later. With Exosurf treatment, 6 hours after surfactant administration inhaled O2 concentration (FlO2) could be lowered from (0.72 +/- 0.20, to 0.62 +/- 0.33; P < 0.05), whereas Crs did not change (0.37 mL/cmH2O/kg, +/- 0.14 vs. 0.39 +/- 0.12, NS). After 24 hours and during the following days a significant increase in Crs occurred (24 hours post-Exosurf: 0.51 +/- 0.18, P < 0.05). With Curosurf treatment, the improvement in oxygenation was greater and FlO2 could be lowered much more after 6 hours (from FlO2, 0.78 +/- 0.23 to 0.34 +/- 0.11, P < 0.01). This was associated with an increase in Crs (from 0.39 +/- 0.09 to 0.59 +/- 0.17, P < 0.05). During the following days, Crs was significantly higher in the group treated with Curosurf. Resistance was not altered by the type of surfactant preparation used except after 72 hours, when Rrs increased in the group treated with Exosurf. In conclusion, Curosurf appears to be more effective than Exosurf with regard to immediate pulmonary changes in ventilator treated premature infants with RDS. A rapid increase in Crs after Curosurf treatment indicates that recruitment of new functional areas of the lung is likely to be associated with a stabilization of small airways and alveolar units.Pediatric Pulmonology 12/1994; 18(5):273-8. · 2.38 Impact Factor