lucinactant and Disease-Models--Animal

Today, in meconium aspiration syndrome, treatment focuses on bronchoalveolar lavage, because it removes meconium and proinflammatory factors from airways. This technique might be more effective if different solutions were used such as saline solution, a protein-free surfactant, or a perfluorocarbon, because these would be less inhibited by meconium proteins.. Pulmonary physiology research unit, Cruces Hospital.. Prospective, randomized study.. We studied 24 lambs (<6 days) on mechanical ventilation for 180 mins. Catheters were placed and femoral and pulmonary arteries pressures registered (systemic and pulmonary arterial pressures).. Lambs were instilled with 20% meconium (3-5 mL/Kg) and were randomly assigned to one of the following groups (n = 6): control: only continuous mechanical ventilation; saline bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of saline solution; dilute surfactant bronchoalveolar lavage: bronchoalveolar lavage with 32 mL/kg of diluted surfactant (lucinactant, 10 mg/mL); or perfluorocarbon bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of perfluorocarbon.. Blood gases, cardiovascular parameters, and pulmonary mechanics were assessed. Meconium instillation produced severe hypoxia, hypercapnia, acidosis, and pulmonary hypertension with impairment of pulmonary mechanics (p < .05). Lung lavage with dilute surfactant resulted in the resolution of pulmonary hypertension as well as better gas exchange and pulmonary mechanics than the control group (p < .05). Bronchoalveolar lavage with perfluorocarbon produced a transient improvement in gas exchange and ventilatory indices in comparison with control and saline bronchoalveolar lavage groups.. In lambs with meconium aspiration syndrome, bronchoalveolar lavage with diluted lucinactant is an effective therapy producing significant improvements in gas exchange, pulmonary hypertension, and pulmonary mechanics. In addition, bronchoalveolar lavage with perfluorocarbon appears to confer some advantages over lavage with equal volumes of saline or no lavage.

Topics: Animals; Bronchoalveolar Lavage; Disease Models, Animal; Drug Combinations; Fatty Alcohols; Fluorocarbons; Humans; Infant, Newborn; Meconium Aspiration Syndrome; Phosphatidylglycerols; Proteins; Pulmonary Surfactants; Random Allocation; Respiration, Artificial; Sheep; Sodium Chloride; Treatment Outcome

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.. 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.. 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.. In this newborn lamb model of respiratory distress, lyophilized lucinactant results in improved lung function as compared with poractant alfa.

Topics: Animals; Animals, Newborn; Biological Products; Blood Gas Analysis; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Combinations; Fatty Alcohols; Freeze Drying; Gestational Age; Lung; Phosphatidylglycerols; Phospholipids; Premature Birth; Proteins; Pulmonary Surfactants; Recovery of Function; Respiration; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Respiratory Function Tests; Sheep; Time Factors; Tissue Distribution

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.. 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.. 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.. 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.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Biomarkers; Disease Models, Animal; Drug Combinations; Fatty Alcohols; Gestational Age; Inflammation Mediators; Lung; Lung Compliance; Phosphatidylglycerols; Phospholipids; Pneumonia; Proteins; Pulmonary Gas Exchange; Pulmonary Surfactants; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Sheep; Time Factors; Ventilator-Induced Lung Injury

This study was designed to study effects of lung lavage versus the classical bolus instillation with a peptide-based synthetic surfactant (lucinactant) in a model of Meconium Aspiration Syndrome (MAS). Eighteen newborn lambs received meconium and were randomized to: the experimental meconium installation (eMAS) group-lambs with eMAS kept on conventional mechanical ventilation (control); the SF-Bolus group-eMAS receiving a lucinactant bolus (30 mg/ml); or the D-SF-Lavage group-eMAS treated with dilute lucinactant bronchoalveolar lavage (10 mg/ml). Systemic and pulmonary arterial pressures, blood gases, and pulmonary mechanics were recorded for 180 min. In addition, the intrapulmonary distribution of the lucinactant was determined using dye-labeled microspheres. Following meconium instillation, severe hypoxia, hypercapnia, acidosis, and pulmonary hypertension developed, and dynamic compliance decreased (50% from baseline). After lung lavage with dilute lucinactant, gas exchange significantly improved versus bolus instillation (P < 0.05). Further, only in the lavage group did pulmonary arterial pressure return to basal values and dynamic compliance significantly increased. Both lung lavage and bolus techniques for the administration of lucinactant resulted in a non-uniform lung distribution. In conclusion, in newborn lambs with respiratory failure and pulmonary hypertension induced by meconium, lung lavage with dilute lucinactant seems to be an effective and safe alternative for treatment for MAS.

Topics: Animals; Animals, Newborn; Blood Pressure; Bronchoalveolar Lavage; Disease Models, Animal; Drug Combinations; Fatty Alcohols; Humans; Infant, Newborn; Meconium Aspiration Syndrome; Phosphatidylglycerols; Proteins; Pulmonary Surfactants; Respiratory Function Tests; Sheep

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.

Topics: Analysis of Variance; Animals; Biological Products; Blood Gas Analysis; Blood Pressure; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Fatty Alcohols; Humans; Infant, Newborn; Lung; Microspheres; Oxygen; Phosphatidylglycerols; Phospholipids; Proteins; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Sheep