In Vivo Evaluation of the Acute Pulmonary Response to Poractant Alfa and Bovactant Treatments in Lung-Lavaged Adult Rabbits and in Preterm Lambs with Respiratory Distress Syndrome

Abstract

BackgroundPoractant alfa (Curosurf®) and Bovactant (Alveofact®) are two animal-derived pulmonary surfactants preparations approved for the treatment of neonatal respiratory distress syndrome (nRDS). They differ in their source, composition, pharmaceutical form, and clinical dose. How much these differences affect the acute pulmonary response to treatment is unknown.ObjectivesComparing these two surfactant preparations in two different animal models of respiratory distress focusing on the short-term response to treatment.MethodsPoractant alfa and Bovactant were administered in a 50–200 mg/kg dose range to surfactant-depleted adult rabbits with acute respiratory distress syndrome induced by lavage and to preterm lambs (127–129 days gestational age) with nRDS induced by developmental immaturity. The acute impact of surfactant therapy on gas exchange and pulmonary mechanics was assessed for 1 h in surfactant-depleted rabbits and for 3 h in preterm lambs.ResultsOverall, treatment with Bovactant 50 mg/kg or Poractant alfa 50 mg/kg did not achieve full recovery of the rabbits’ respiratory conditions, as indicated by significantly lower arterial oxygenation and carbon dioxide values. By contrast, the two approved doses for clinical use of Poractant alfa (100 and 200 mg/kg) achieved a rapid and sustained recovery in both animal models. The comparison of the ventilation indices of the licensed doses of Bovactant (50 mg/kg) and Poractant alfa (100 mg/kg) showed a superior performance of the latter preparation in both animal models. At equal phospholipid doses, Poractant alfa was superior to Bovactant in terms of arterial oxygenation in both animal models. In preterm lambs, surfactant replacement therapy with Poractant alfa at either 100 or 200 mg/kg was associated with significantly higher lung gas volumes compared to Bovactant treatment with 100 mg/kg.ConclusionAt the licensed doses, the acute pulmonary response to Poractant alfa was significantly better than the one observed after Bovactant treatment, either at 50 or at 100 mg/kg dose, in two animal models of pulmonary failure.

Porcine vs bovine surfactant therapy for preterm neonates with RDS: systematic review with biological plausibility and pragmatic meta-analysis of respiratory outcomes

“…Hemodynamic troubles potentially leading to intracranial hemorrhage and other complications have already been described with usual doses of bovine surfactants [33]. For these reasons, also the more recent animal studies only investigated bovine surfactants at their licensed dose [67].…”

Generation of high concentrations of respirable solid-phase aerosols from viscous fluids

“…Adult patients with acute respiratory distress syndrome have both depleted and impaired surfactant (Dushianthan et al 2014) that contribute to their 40% mortality rate. In rabbit models, depletion of surfactant by repeated lavage or by acid challenge, the instillation of 100 or 200 mg/kg of surfactant at a concentration of 35 mg/ml into the tracheobronchial tree initiates a dramatic and early temporal improvement in arterial oxygen (PaO 2 ) (Walther et al 2014, Ricci et al 2017). Following 2 to 7 mg/kg of aerosol delivery of surfactant to pre-term lambs indicated some beneficial responses (Lewis et al 1991, Gordon et al 2003, Rahmel et al 2012).…”

Aerosol drug delivery to spontaneously-breathing preterm neonates: lessons learned

“…During the saccular phase, the alveolar ducts (defined as the last airway generation before the development of mature alveoli) start forming in the distal lung [55]. Also, the synthesis and secretion of pulmonary surfactant by the type II alveolar cells starts approximately at the 24th week of gestation and increases steadily until birth [56]. Surfactant in the alveolar space modulates the surface tension throughout the respiratory cycle, reducing it almost to zero at low gas volumes, preventing alveolar collapse at end-expiration [57].…”

“…The parameters are proposed by the authors as an example of an average patient and are not representative of the variability that can be observed in the heterogeneous premature infant population. V T , tidal volume; RR, respiratory rate; I:E ratio, inspiratory-expiratory ratio intratracheal instillation [56,[143][144][145][146], to test the efficacy of anti-inflammatory drugs [20,21,147,148], to gain insights onto the initial steps of the lung inflammatory process in the context of RDS [149,150], and to investigate the lung and cerebral effects of intravenouslydelivered drugs [151][152][153], among others. Interestingly, spontaneously-breathing premature lambs can be supported with NIV [81,154], monitored with NICU equipment, and allow the integration of nebulizer devices within the NIV circuit [155].…”