Combined Surfactant Therapy and Inhaled Nitric Oxide in Rabbits with Oleic Acid-induced Acute Respiratory Distress Syndrome

Abstract

Intratracheal administration of surfactant and inhaled nitric oxide (INO) have had variable effects in clinical trials on patients with acute respiratory distress syndrome (ARDS). We hypothesized that combined treatment with exogenous surfactant and INO may have effects in experimental ARDS. After intravenous infusion of oleic acid in adult rabbits and 4-6 h of ventilation, there was more than a 40% reduction in both dynamic compliance (Cdyn) of the respiratory system and functional residual capacity (FRC), a 50% increment of respiratory resistance (Rrs), a 70% reduction in PaO2 /FIO2, and an increase in intrapulmonary shunting (Q S/Q T) from 4.4 to 33.5%. The animals were then allocated to groups receiving (1) neither surfactant nor INO (control), (2) 100 mg/kg of surfactant (S) administered intratracheally, (3) 20 ppm INO (NO), or (4) 100 mg/kg of surfactant and 20 ppm INO (SNO), and subsequently ventilated for 6 h. After the period of ventilation, the animal lungs were used for analysis of disaturated phosphatidylcholine (DSPC) and total proteins (TP) in bronchoalveolar lavage fluid (BALF), and for determination of alveolar volume density (VV). The animals in the control group had the lowest survival rate, and no improvement in lung mechanics and blood oxygenation, whereas those in the S group had a modest but statistically significant improvement in Cdyn, Rrs, PaO2 and FRC, reduced Q S/Q T, lowered minimum surface tension (gammamin) of BALF, and increased DSPC/ TP and alveolar VV. The NO group had increased PaO2 and reduced Q S/Q T. The SNO group showed improved Cdyn, Rrs, FRC, DSPC/TP, alveolar VV, and gammamin of BALF comparable to the S group, but there was a further increase in survival rate and PaO2, and additional reduction in Q S/Q T and TP in BALF. These results indicate that, in this animal model of ARDS, a combination of surfactant therapy and INO is more effective than either treatment alone.

The Effect of N^G-Nitro-<i>L</i>-Arginine Methyl Ester, a Nitric Oxide Synthase Inhibitor, on Respiratory Mechanics in Rats

“…The present results are in contrast with some data previously reported, but in the experiments by Dahm et al [4] and Zhu et al [6], the absence of effects of NO inhalation on respiratory system resistance was evaluated in endotoxin- or oleic acid-induced lung injury, respectively, and Zhang et al [5]simply reported that NO inhalation did not adversely affect basal respiratory system resistance. In the experiments by Kips et al [11] and Maniscalco et al [12], no significant effect of L -NAME was detected on basal respiratory system resistance in healthy rats or humans, respectively, but the L -NAME dosages were much lower than the dosage presently used.…”

“…The same result has been also confirmed by data obtained by Zhu et al [6] on a rabbit experimental model of oleic acid-induced respiratory distress syndrome: no effect of isolated NO inhalation on the bronchoalveolar lavage fluid content of tensioactive desaturated phosphatidylcholine was detected. In contrast, Storme et al [17] reported increased hysteresis areas as an effect of NO inhalation, but their data were probably influenced by the confounding effects of long-lasting 100% oxygen inhalation.…”

“…Some investigators have, however, failed to demonstrate that NO inhalation reduces airway resistance in a porcine model of septic shock [4], in mechanically ventilated healthy piglets [5] and in rabbits with oleic acid-induced respiratory distress syndrome [6]. …”

The Future of Exogenous Surfactant Therapy

“…148,149 In contrast, animal models of indirect lung injury generally respond less well to surfactant administration. Injury from oleic acid infusion via the pulmonary artery shows almost no improvement with surfactant, 150 although many would argue that this is a lethal injury with substantial cellular disruption 151 that is unlikely to respond to any therapy. A porcine sepsis model that used intravenous lipopolysaccharide infusion showed some oxygenation improvement following surfactant administration, 152,153 but the response was less striking than in the surfactant-treated animals injured with intratracheal lipopolysaccharide above.…”

Use of Surfactant-BL in Adult Patients with Acute Respiratory Distress Syndrome

“…Дополнитель ными факторами повреждения лёгочной ткани и сурфактантной системы являются волюмотравма, баротравма и токсическое действие высоких концен траций О 2 . В эксперименте был продемонстрирован синергизм действия иNO и экзогенного сурфактанта на артериальную оксигенацию [16]. Усиление дейст вия иNO объясняют, прежде всего, рекрутирующим и стабилизирующим действием экзогенного сурфак танта, приводящим к увеличению числа альвеол, до ступных для поступления лечебного газа [6].…”