Timothy J. Gregory

Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS

Background:Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants.Methods:Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination.Results:SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant.Conclusion:These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant.

Aerosolized KL4 surfactant improves short-term survival and gas exchange in spontaneously breathing newborn pigs with hydrochloric acid-induced acute lung injury.

Surfactant therapy may be beneficial in acute lung injury (ALI). In spontaneously breathing newborn pigs with ALI supported with continuous positive airway pressure (CPAP), we evaluated the hypothesis that aerosolized KL4 surfactant (AERO KL4S) would provide a similar therapeutic effect as intratracheal KL4 surfactant (ETT KL4S) when compared to controls.

Pulmonary Distribution of Lucinactant and Poractant Alfa and Their Peridosing Hemodynamic Effects in a Preterm Lamb Model of Respiratory Distress Syndrome

Tracheal instillation of surfactant to premature newborns improves their survivability but may transiently obstruct airways resulting in undesirable acute effects on cerebral blood flow (CBF) and oxygenation. The acute peridosing hemodynamic effects of surfactant administration may be avoided by minimizing the volume of surfactant administered, but smaller surfactant volumes may also result in less even distribution of surfactant throughout the lung. These experiments were undertaken to compare responses to two surfactants with different dose volumes (porcine-derived poractant alfa, 2.5 mL/kg vs peptide-based synthetic lucinactant, 5.8 mL/kg) given to newly delivered lambs at 85% gestation. Both surfactants resulted in similar improvements in blood gas values, a doubling of dynamic compliance, increases in brain tissue oxygen tension, and stable blood pressure with no significant change in CBF. Distribution of surfactant throughout the lungs was more uniform with lucinactant than poractant alfa when assessed by labeled microspheres. We conclude that improvements in lung mechanics, gas exchange, and changes in CBF are comparable for a porcine-derived and peptide-containing synthetic surfactant, despite instilled volumes differing by 2-fold. Intrapulmonary distribution of surfactant is more uniform after a larger volume is instilled.

comparison of poractant alfa and lyophilized lucinactant in a preterm lamb model of acute respiratory distress

Introduction:A lyophilized formulation of lucinactant has been developed to simplify preparation and dosing. Endotracheal administration of surfactant can be associated with potentially harmful transient hemodynamic changes including decreases in cerebral blood flow and delivery of O2 to the brain. Efficacy and peri-dosing effects of poractant alfa and a lyophilized form of lucinactant were compared in this study.Methods:Premature lambs (126–129 d gestation) were delivered by c-section, tracheostomized, ventilated, and instrumented with cerebral laser Doppler flowmetry and tissue PO2 probes. Pulmonary compliance and tidal volumes were monitored continuously and surfactant lung distribution was assessed. Lambs received either poractant alfa or lyophilized lucinactant and were monitored for 3 h after treatment.Results:Both groups showed significant improvements in arterial pCO2, pH, pulmonary compliance, and tidal volume (all P < 0.01), a similar intra-pulmonary distribution profile, and no significant changes in arterial blood pressure or cerebral blood flow. Administration of poractant alfa was associated with higher mean airway pressures from 75 min post-dosing and transiently decreased heart rate and increased brain tissue PO2 during the first 30 min after treatment.Discussion:In this newborn lamb model of respiratory distress, lyophilized lucinactant results in improved lung function as compared with poractant alfa.