152 Systemic Inflammation in Newborn Pigs with Meconium Aspiration Syndrome

Abstract

Background: Meconium may cause lung injury (meconium aspiration syndrome=MAS). Treatment is symptomatic by ventilatory support or in the worst cases extracorporal membrane oxygenation (ECMO). The pathophysiology is complex including a substantial inflammatory reaction in the lungs, but according to our results this inflammation may be systemic as well. We recently showed for the first time that meconium is a potent activator of complement (Castellheim A. et al. Pediatr. Res. 2004;55:310–318), leading us to hypothesize that complement activation is an essential part of the pathophysiology of MAS. Methods: MAS was induced by instillation of meconium into the lungs of newborn pigs (n=8). To mimic the asphyxia in clinical MAS, hypoxia was induced by supplying 8% oxygen in nitrogen until base excess reached -20 mmol/l. Anaesthesia was induced by Halothane and maintained intravenously by fentanyl and midazolam. Control animals (n=5) received saline under otherwise identical conditions for 7 hours. Hemo- and lung dynamics were recorded. Systemic complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines were measured in plasma samples by enzyme immunoassays. Granulocyte expression of CD18 and CD11b, as well as oxidative burst, were measured by flow cytometry. Results: Plasma TCC increased rapidly in the MAS animals (0.31±0.34 to 3.10±0.66) (AU7mL) (mean±2SEM), but decreased in the controls (0.55±0.88 to 0.28±0.10) (MAS vs controls: p<0.0005). The TCC concentration correlated closely with oxygenation- and ventilation indices (r=0.48 and 0.57, p=0.001 and <0.0005, respectively), and inversely with compliance (r=−0.63, p<0.0005); all thee reflecting severe deterioration in pulmonary function. Granulocyte oxidative burst declined significantly in the MAS animals compared with the controls (p=0.02) and correlated inversely with TCC (r=−0.37, p=0.02), probably reflecting a paralysis of granulocytes as part of a systemic inflammatory response. Finally, IL-6and IL-8 increased in MAS (IL-6: (26±3 to 188±80)(pg/mL) IL-8 (19±2 to 37±6)(pg/mL) animals compared to the controls (MAS vs controls: IL-6, p=0.002 and IL-8, p=0.001) Conclusion: We have for the first time demonstrated that complement is rapidly and systemically activated in experimental MAS. We suggest that this activation may induce secondary inflammatory reactions like cytokine production and oxidative burst, which contribute to the pathogenesis of MAS. Anti-complement therapy may be a rational for treatment of this disease.