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Federico Bianco - One of the best experts on this subject based on the ideXlab platform.
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Nebulization of High-Dose Poractant Alfa in Newborn Piglets on Nasal Continuous Positive Airway Pressure Yields Therapeutic Lung Doses of Phospholipids.
American journal of perinatology, 2020Co-Authors: Anders Nord, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Martin Schlun, Rikard Linner, Doris Cunha-goncalvesAbstract:Objective: It is not known how much surfactant must be nebulized to reach a lung dose of phospholipids equivalent to that obtained by the instillation of 200 mg/kg of surfactant. We aimed to assess the feasibility of nebulizing a high-dose of Poractant Alfa with the eFlow-Neos investigational vibrating-membrane nebulizer in newborn piglets on nasal continuous positive airway pressure (nCPAP) and to determine whether this intervention would yield therapeutic lung doses of phospholipids. Study Design: Twelve 1-day-old piglets on nCPAP received 600 mg/kg of Poractant Alfa admixed with technetium-99m via nebulization. Six piglets receiving 200 mg/kg of instilled synthetic surfactant served as controls. Lung deposition (percentage of the nominal dose) was determined by gamma scintigraphy, and the phospholipids' lung dose was calculated. Results: The lung dose of phospholipids (mean ± standard deviation [SD]) was 138 ± 96 mg/kg with nebulization, and 172 ± 24 mg/kg with instillation (p = 0.42). Nebulization took 58 ± 12 minutes. The arterial partial pressure of carbon dioxide increased from 6.7 ± 1.1 to 7.2 ± 1.1 kPa during nebulization (p = 0.04). Cerebral oximetry remained stable, and there was no hemodynamic instability. Conclusion: Nebulization was well tolerated, and the mean lung dose of phospholipids was above 100 mg/kg, that is, not different from the instillation group. These experimental findings suggest that it may be feasible to reach therapeutic lung doses of phospholipids by surfactant nebulization during nCPAP. Key Points It is not known if effective lung doses of surfactant can be delivered by nebulization. Nebulization of high-dose surfactant in newborn piglets on nCPAP was well tolerated. A high-dose of nebulized Poractant Alfa yielded therapeutic lung doses of phospholipids. (Less)
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Nebulized Poractant Alfa Reduces the Risk of Respiratory Failure at 72 Hours in Spontaneously Breathing Surfactant-Deficient Newborn Piglets.
Critical care medicine, 2020Co-Authors: Carmen Rey-santano, Fabrizio Salomone, Federico Bianco, Victoria E. Mielgo, Miguel Angel Gomez-solaetxe, B LoureiroAbstract:Objectives We have setup for the first time a long-term (72 hr) respiratory distress syndrome model in spontaneously breathing surfactant-deficient newborn piglets to investigate the continuous positive airway pressure failure rate with nebulized Poractant Alfa compared with that with the intubation surfactant extubation technique or continuous positive airway pressure only. Design Prospective randomized animal study. Setting Biocruces-Bizkaia Health Research Institute Animal Facility. Subjects-interventions Eighteen newborn piglets (n = 6/group) with surfactant-deficient respiratory distress syndrome were randomized to three continuous positive airway pressure-ventilated groups: 1) nebulized surfactant (Poractant Alfa 400 mg/kg) via a customized investigational eFlow-Neos vibrating membrane nebulizer system, 2) bolus administration using the Intubation Surfactant Extubation method (200 mg/kg), or 3) continuous positive airway pressure alone. Measurements and main results Pulmonary and hemodynamic variables were assessed at 6-hour intervals for 72 hours. Lung and brain histological analyses were performed. After bronchoalveolar lavages, piglets developed respiratory distress syndrome. Over the follow-up, both surfactant-treated groups had significantly better pulmonary outcomes than the continuous positive airway pressure alone group. Furthermore, unlike in the continuous positive airway pressure group, there were no cases of respiratory failure in either of the surfactant-treated groups. Conclusions In newborn piglets with respiratory distress syndrome, the nebulization of 400 mg/kg of Poractant Alfa using a customized investigational eFlow-Neos nebulizer was found to be safe and effective in reducing the risk of respiratory failure in the 72 hours after treatment.
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dose response study on surfactant nebulization therapy during nasal continuous positive airway pressure ventilation in spontaneously breathing surfactant deficient newborn piglets
Pediatric Critical Care Medicine, 2020Co-Authors: Carmen Reysantano, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Victoria E. Mielgo, Miguel Angel Gomezsolaetxe, B LoureiroAbstract:Objectives The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome-associated pathophysiology of the neonatal lungs. Design Prospective, randomized, animal model study. Setting An experimental laboratory. Subjects Thirty-six newborn piglets. Interventions Different doses (100, 200, 400, and 600 mg/kg) of Poractant Alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation-surfactant-extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets (n = 6/group) with bronchoalveolar lavage-induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). Measurements and main results Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized Poractant Alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. Conclusions In newborn piglets with severe bronchoalveolar lavage-induced respiratory distress syndrome, our results demonstrate that the administration of nebulized Poractant Alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.
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From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.
Respiratory research, 2019Co-Authors: Federico Bianco, Francesca Ricci, Xabier Murgia, Chiara Catozzi, M. Schlun, A. Bucholski, U. Hetzer, Sauro Bonelli, Marta Lombardini, Elena PasiniAbstract:Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (Poractant Alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. Particle size distribution of undiluted Poractant Alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100–600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized Poractant Alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized Poractant Alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted Poractant Alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016–004547-36).
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New Surfactant with SP-B and C Analogs Gives Survival Benefit after Inactivation in Preterm Lambs
2016Co-Authors: Matthias Seehase, Elke Kuypers, Daan R. M. G. Ophelders, Reint K. Jellema, Federico Bianco, Jennifer J. P. Collins, Olga L. Ospina, J. Perez-gil, Raffaella Garzia, Roberta RazzettiAbstract:Background: Respiratory distress syndrome in preterm babies is caused by a pulmonary surfactant deficiency, but also by its inactivation due to various conditions, including plasma protein leakage. Surfactant replacement therapy is well established, but clinical observations and in vitro experiments suggested that its efficacy may be impaired by inactivation. A new synthetic surfactant (CHF 5633), containing synthetic surfactant protein B and C analogs, has shown comparable effects on oxygenation in ventilated preterm rabbits versus Poractant Alfa, but superior resistance against inactivation in vitro. We hypothesized that CHF 5633 is also resistant to inactivation by serum albumin in vivo. Methodology/Principal Findings: Nineteen preterm lambs of 127 days gestational age (term=150 days) received CHF 5633 or Poractant Alfa and were ventilated for 48 hours. Ninety minutes after birth, the animals received albumin with CHF 5633 or Poractant Alfa. Animals received additional surfactant if PaO2 dropped below 100 mmHg. A pressure volume curve was done post mortem and markers of pulmonary inflammation, surfactant content and biophysiology, and lung histology were assessed. CHF 5633 treatment resulted in improved arterial pH, oxygenation and ventilation efficiency index. The survival rate was significantly higher after CHF 5633 treatment (5/7) than after Poractant Alfa (1/8) after 48 hours of ventilation. Biophysical examination of the surfactant recovered from bronchoalveolar lavages revealed that films formed by CHF 5633-treated animals reached low surface tensions in a wider range of compression rates than films from Poractant Alfa-treate
Fabrizio Salomone - One of the best experts on this subject based on the ideXlab platform.
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Nebulization of High-Dose Poractant Alfa in Newborn Piglets on Nasal Continuous Positive Airway Pressure Yields Therapeutic Lung Doses of Phospholipids.
American journal of perinatology, 2020Co-Authors: Anders Nord, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Martin Schlun, Rikard Linner, Doris Cunha-goncalvesAbstract:Objective: It is not known how much surfactant must be nebulized to reach a lung dose of phospholipids equivalent to that obtained by the instillation of 200 mg/kg of surfactant. We aimed to assess the feasibility of nebulizing a high-dose of Poractant Alfa with the eFlow-Neos investigational vibrating-membrane nebulizer in newborn piglets on nasal continuous positive airway pressure (nCPAP) and to determine whether this intervention would yield therapeutic lung doses of phospholipids. Study Design: Twelve 1-day-old piglets on nCPAP received 600 mg/kg of Poractant Alfa admixed with technetium-99m via nebulization. Six piglets receiving 200 mg/kg of instilled synthetic surfactant served as controls. Lung deposition (percentage of the nominal dose) was determined by gamma scintigraphy, and the phospholipids' lung dose was calculated. Results: The lung dose of phospholipids (mean ± standard deviation [SD]) was 138 ± 96 mg/kg with nebulization, and 172 ± 24 mg/kg with instillation (p = 0.42). Nebulization took 58 ± 12 minutes. The arterial partial pressure of carbon dioxide increased from 6.7 ± 1.1 to 7.2 ± 1.1 kPa during nebulization (p = 0.04). Cerebral oximetry remained stable, and there was no hemodynamic instability. Conclusion: Nebulization was well tolerated, and the mean lung dose of phospholipids was above 100 mg/kg, that is, not different from the instillation group. These experimental findings suggest that it may be feasible to reach therapeutic lung doses of phospholipids by surfactant nebulization during nCPAP. Key Points It is not known if effective lung doses of surfactant can be delivered by nebulization. Nebulization of high-dose surfactant in newborn piglets on nCPAP was well tolerated. A high-dose of nebulized Poractant Alfa yielded therapeutic lung doses of phospholipids. (Less)
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Nebulized Poractant Alfa Reduces the Risk of Respiratory Failure at 72 Hours in Spontaneously Breathing Surfactant-Deficient Newborn Piglets.
Critical care medicine, 2020Co-Authors: Carmen Rey-santano, Fabrizio Salomone, Federico Bianco, Victoria E. Mielgo, Miguel Angel Gomez-solaetxe, B LoureiroAbstract:Objectives We have setup for the first time a long-term (72 hr) respiratory distress syndrome model in spontaneously breathing surfactant-deficient newborn piglets to investigate the continuous positive airway pressure failure rate with nebulized Poractant Alfa compared with that with the intubation surfactant extubation technique or continuous positive airway pressure only. Design Prospective randomized animal study. Setting Biocruces-Bizkaia Health Research Institute Animal Facility. Subjects-interventions Eighteen newborn piglets (n = 6/group) with surfactant-deficient respiratory distress syndrome were randomized to three continuous positive airway pressure-ventilated groups: 1) nebulized surfactant (Poractant Alfa 400 mg/kg) via a customized investigational eFlow-Neos vibrating membrane nebulizer system, 2) bolus administration using the Intubation Surfactant Extubation method (200 mg/kg), or 3) continuous positive airway pressure alone. Measurements and main results Pulmonary and hemodynamic variables were assessed at 6-hour intervals for 72 hours. Lung and brain histological analyses were performed. After bronchoalveolar lavages, piglets developed respiratory distress syndrome. Over the follow-up, both surfactant-treated groups had significantly better pulmonary outcomes than the continuous positive airway pressure alone group. Furthermore, unlike in the continuous positive airway pressure group, there were no cases of respiratory failure in either of the surfactant-treated groups. Conclusions In newborn piglets with respiratory distress syndrome, the nebulization of 400 mg/kg of Poractant Alfa using a customized investigational eFlow-Neos nebulizer was found to be safe and effective in reducing the risk of respiratory failure in the 72 hours after treatment.
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dose response study on surfactant nebulization therapy during nasal continuous positive airway pressure ventilation in spontaneously breathing surfactant deficient newborn piglets
Pediatric Critical Care Medicine, 2020Co-Authors: Carmen Reysantano, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Victoria E. Mielgo, Miguel Angel Gomezsolaetxe, B LoureiroAbstract:Objectives The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome-associated pathophysiology of the neonatal lungs. Design Prospective, randomized, animal model study. Setting An experimental laboratory. Subjects Thirty-six newborn piglets. Interventions Different doses (100, 200, 400, and 600 mg/kg) of Poractant Alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation-surfactant-extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets (n = 6/group) with bronchoalveolar lavage-induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). Measurements and main results Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized Poractant Alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. Conclusions In newborn piglets with severe bronchoalveolar lavage-induced respiratory distress syndrome, our results demonstrate that the administration of nebulized Poractant Alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.
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metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice
Journal of Lipid Research, 2018Co-Authors: Jens Madsen, Nicola Pelizzi, Madhuriben Panchal, Rosemarie Mackay, Mercedes Echaide, Grielof Koster, Giancarlo Aquino, Jesus Perezgil, Fabrizio SalomoneAbstract:Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived Poractant Alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with Poractant Alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.
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estimating the contribution of surfactant replacement therapy to the alveolar pool an in vivo study based on 13 c natural abundance in rabbits
Journal of Mass Spectrometry, 2018Co-Authors: Sonia Giambelluca, Francesca Ricci, Fabrizio Salomone, M Simonato, Alessio Correani, Costanza Casiraghi, Matteo Storti, Paola Cogo, Virgilio P CarnielliAbstract:Variation of the isotopic abundance of selected nutrients and molecules has been used for pharmacological and kinetics studies under the premise that the administered molecule has a different isotopic enrichment from the isotopic background of the recipient subject. The aim of this study is to test the feasibility of assessing the contribution of exogenous surfactant phospholipids to the endogenous alveolar pool in vivo after exogenous surfactant replacement therapy in rabbits. The study consisted in measuring the consistency of 13 C/12 C ratio of disaturated-phosphatidylcholine palmitate (DSPC-PA) in 7 lots of Poractant Alfa, produced over a year, and among bronchoalveolar lavages of 20 rabbits fed with a standard chow. A pilot study was performed in a rabbit model of lavage-induced surfactant deficiency: 7 control rabbits and 4 treated with exogenous surfactant. The contribution of exogenous surfactant to the alveolar pool was assessed after intra-tracheal administration of 200 mg/kg of Poractant Alfa. The 13 C content of DSPC-PA was measured by isotope ratio mass spectrometry. The mean DSPC-PA 13 C/12 C ratio of the 7 lots of Poractant Alfa was -18.8‰ with a SD of 0.1‰ (range: -18.9‰; -18.6‰). The mean 13 C/12 C ratio of surfactant DSPC recovered from the lung lavage of 20 rabbits was -28.8 ± 1.2‰ (range: -31.7‰; -25.7‰). The contribution of exogenous surfactant to the total alveolar surfactant could be calculated in the treated rabbits, and it ranged from 83.9% to 89.6%. This pilot study describes a novel method to measure the contribution of the exogenous surfactant to the alveolar pool. This method is based on the natural variation of 13 C, and therefore it does not require the use of chemically synthetized tracers. This method could be useful in human research and especially in surfactant replacement studies in preterm infants.
Francesca Ricci - One of the best experts on this subject based on the ideXlab platform.
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Nebulization of High-Dose Poractant Alfa in Newborn Piglets on Nasal Continuous Positive Airway Pressure Yields Therapeutic Lung Doses of Phospholipids.
American journal of perinatology, 2020Co-Authors: Anders Nord, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Martin Schlun, Rikard Linner, Doris Cunha-goncalvesAbstract:Objective: It is not known how much surfactant must be nebulized to reach a lung dose of phospholipids equivalent to that obtained by the instillation of 200 mg/kg of surfactant. We aimed to assess the feasibility of nebulizing a high-dose of Poractant Alfa with the eFlow-Neos investigational vibrating-membrane nebulizer in newborn piglets on nasal continuous positive airway pressure (nCPAP) and to determine whether this intervention would yield therapeutic lung doses of phospholipids. Study Design: Twelve 1-day-old piglets on nCPAP received 600 mg/kg of Poractant Alfa admixed with technetium-99m via nebulization. Six piglets receiving 200 mg/kg of instilled synthetic surfactant served as controls. Lung deposition (percentage of the nominal dose) was determined by gamma scintigraphy, and the phospholipids' lung dose was calculated. Results: The lung dose of phospholipids (mean ± standard deviation [SD]) was 138 ± 96 mg/kg with nebulization, and 172 ± 24 mg/kg with instillation (p = 0.42). Nebulization took 58 ± 12 minutes. The arterial partial pressure of carbon dioxide increased from 6.7 ± 1.1 to 7.2 ± 1.1 kPa during nebulization (p = 0.04). Cerebral oximetry remained stable, and there was no hemodynamic instability. Conclusion: Nebulization was well tolerated, and the mean lung dose of phospholipids was above 100 mg/kg, that is, not different from the instillation group. These experimental findings suggest that it may be feasible to reach therapeutic lung doses of phospholipids by surfactant nebulization during nCPAP. Key Points It is not known if effective lung doses of surfactant can be delivered by nebulization. Nebulization of high-dose surfactant in newborn piglets on nCPAP was well tolerated. A high-dose of nebulized Poractant Alfa yielded therapeutic lung doses of phospholipids. (Less)
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dose response study on surfactant nebulization therapy during nasal continuous positive airway pressure ventilation in spontaneously breathing surfactant deficient newborn piglets
Pediatric Critical Care Medicine, 2020Co-Authors: Carmen Reysantano, Francesca Ricci, Fabrizio Salomone, Federico Bianco, Victoria E. Mielgo, Miguel Angel Gomezsolaetxe, B LoureiroAbstract:Objectives The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome-associated pathophysiology of the neonatal lungs. Design Prospective, randomized, animal model study. Setting An experimental laboratory. Subjects Thirty-six newborn piglets. Interventions Different doses (100, 200, 400, and 600 mg/kg) of Poractant Alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation-surfactant-extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets (n = 6/group) with bronchoalveolar lavage-induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). Measurements and main results Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized Poractant Alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. Conclusions In newborn piglets with severe bronchoalveolar lavage-induced respiratory distress syndrome, our results demonstrate that the administration of nebulized Poractant Alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.
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From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.
Respiratory research, 2019Co-Authors: Federico Bianco, Francesca Ricci, Xabier Murgia, Chiara Catozzi, M. Schlun, A. Bucholski, U. Hetzer, Sauro Bonelli, Marta Lombardini, Elena PasiniAbstract:Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (Poractant Alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. Particle size distribution of undiluted Poractant Alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100–600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized Poractant Alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized Poractant Alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted Poractant Alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016–004547-36).
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estimating the contribution of surfactant replacement therapy to the alveolar pool an in vivo study based on 13 c natural abundance in rabbits
Journal of Mass Spectrometry, 2018Co-Authors: Sonia Giambelluca, Francesca Ricci, Fabrizio Salomone, M Simonato, Alessio Correani, Costanza Casiraghi, Matteo Storti, Paola Cogo, Virgilio P CarnielliAbstract:Variation of the isotopic abundance of selected nutrients and molecules has been used for pharmacological and kinetics studies under the premise that the administered molecule has a different isotopic enrichment from the isotopic background of the recipient subject. The aim of this study is to test the feasibility of assessing the contribution of exogenous surfactant phospholipids to the endogenous alveolar pool in vivo after exogenous surfactant replacement therapy in rabbits. The study consisted in measuring the consistency of 13 C/12 C ratio of disaturated-phosphatidylcholine palmitate (DSPC-PA) in 7 lots of Poractant Alfa, produced over a year, and among bronchoalveolar lavages of 20 rabbits fed with a standard chow. A pilot study was performed in a rabbit model of lavage-induced surfactant deficiency: 7 control rabbits and 4 treated with exogenous surfactant. The contribution of exogenous surfactant to the alveolar pool was assessed after intra-tracheal administration of 200 mg/kg of Poractant Alfa. The 13 C content of DSPC-PA was measured by isotope ratio mass spectrometry. The mean DSPC-PA 13 C/12 C ratio of the 7 lots of Poractant Alfa was -18.8‰ with a SD of 0.1‰ (range: -18.9‰; -18.6‰). The mean 13 C/12 C ratio of surfactant DSPC recovered from the lung lavage of 20 rabbits was -28.8 ± 1.2‰ (range: -31.7‰; -25.7‰). The contribution of exogenous surfactant to the total alveolar surfactant could be calculated in the treated rabbits, and it ranged from 83.9% to 89.6%. This pilot study describes a novel method to measure the contribution of the exogenous surfactant to the alveolar pool. This method is based on the natural variation of 13 C, and therefore it does not require the use of chemically synthetized tracers. This method could be useful in human research and especially in surfactant replacement studies in preterm infants.
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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
Frontiers in pediatrics, 2017Co-Authors: Francesca Ricci, Xabier Murgia, Fabrizio Salomone, Elke Kuypers, Daan R. M. G. Ophelders, Maria Nikiforou, Monique G. M. Willems, Tobias Krieger, Matthias C. Hütten, Boris W. KramerAbstract:Background: Poractant 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. Objectives: comparing these two surfactant preparations in two different animal models of respiratory distress focusing on the short-term response to treatment. Methods: Poractant Alfa and Bovactant were administered in a 50-200 mg/kg dose-range to surfactant-depleted adult rabbits with Acute Respiratory Distress Syndrome (ARDS) 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 one hour in surfactant-depleted rabbits and for three hours in preterm lambs Results: Overall, 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. In 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 mg/kg or 200 mg/kg was associated with significantly higher lung gas volumes compared to Bovactant treatment with100 mg/kg. Conclusions: At 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.
Kristin Viswanathan - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis.
Pediatrics, 2011Co-Authors: Neetu Singh, Kristy L Hawley, Kristin ViswanathanAbstract:OBJECTIVE: To compare the efficacy of a porcine surfactant (Poractant Alfa) versus bovine surfactants (beractant and cAlfactant) with respect to clinical outcomes among preterm infants with respiratory distress syndrome. METHODS: A search of major electronic databases, including Medline (1980–2010) and the Cochrane Central Register of Controlled Trials, for randomized controlled trials that compared Poractant Alfa versus beractant and/or cAlfactant among preterm infants with respiratory distress syndrome who required intubation and surfactant treatment was performed. The primary outcome was oxygen requirement at a postmenstrual age of 36 weeks. RESULTS: Five randomized controlled trials involving 529 infants compared Poractant Alfa versus beractant for rescue treatment. No trials studied surfactant prophylaxis, and none compared Poractant Alfa versus cAlfactant. The incidences of oxygen dependence at a postmenstrual age of 36 weeks were similar for Poractant Alfa and beractant. Infants treated with Poractant Alfa at 100 mg/kg (low dose) or 200 mg/kg (high dose) exhibited statistically significant reductions in deaths (relative risk: 0.51 [95% confidence interval: 0.30–0.89]), the need for redosing (relative risk: 0.71 [95% confidence interval: 0.57–0.88]), oxygen requirements, duration of oxygen treatment, and duration of mechanical ventilation. The test of heterogeneity yielded positive results for the latter 2 outcomes. The difference remained statistically significant for deaths and the need for redosing with high-dose Poractant Alfa but not for low dose Poractant Alfa. CONCLUSIONS: There were significant reductions in deaths and the need for redosing with high-dose Poractant Alfa but not low-dose Poractant Alfa, compared with beractant.
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Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis.
Pediatrics, 2011Co-Authors: Neetu Singh, Kristy L Hawley, Kristin ViswanathanAbstract:To compare the efficacy of a porcine surfactant (Poractant Alfa) versus bovine surfactants (beractant and cAlfactant) with respect to clinical outcomes among preterm infants with respiratory distress syndrome. A search of major electronic databases, including Medline (1980-2010) and the Cochrane Central Register of Controlled Trials, for randomized controlled trials that compared Poractant Alfa versus beractant and/or cAlfactant among preterm infants with respiratory distress syndrome who required intubation and surfactant treatment was performed. The primary outcome was oxygen requirement at a postmenstrual age of 36 weeks. Five randomized controlled trials involving 529 infants compared Poractant Alfa versus beractant for rescue treatment. No trials studied surfactant prophylaxis, and none compared Poractant Alfa versus cAlfactant. The incidences of oxygen dependence at a postmenstrual age of 36 weeks were similar for Poractant Alfa and beractant. Infants treated with Poractant Alfa at 100 mg/kg (low dose) or 200 mg/kg (high dose) exhibited statistically significant reductions in deaths (relative risk: 0.51 [95% confidence interval: 0.30-0.89]), the need for redosing (relative risk: 0.71 [95% confidence interval: 0.57-0.88]), oxygen requirements, duration of oxygen treatment, and duration of mechanical ventilation. The test of heterogeneity yielded positive results for the latter 2 outcomes. The difference remained statistically significant for deaths and the need for redosing with high-dose Poractant Alfa but not for low dose Poractant Alfa. There were significant reductions in deaths and the need for redosing with high-dose Poractant Alfa but not low-dose Poractant Alfa, compared with beractant.
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Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.
The Journal of pediatrics, 2020Co-Authors: Rangasamy Ramanathan, Jatinder Bhatia, K C Sekar, Manoj Biniwale, Nazeeh Hanna, Sergio Golombek, Martha E. Naylor, Laura Fabbri, Guido Varoli, Debora SantoroAbstract:Objective To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, Poractant Alfa, for the treatment of respiratory distress syndrome in infants born preterm. Study design Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or Poractant Alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. Results Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and Poractant Alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P Conclusions Treatment with CHF5633 showed similar efficacy and safety as Poractant Alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. Trial registration ClinicalTrials.gov : NCT02452476 .
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mortality in preterm infants with respiratory distress syndrome treated with Poractant Alfa cAlfactant or beractant a retrospective study
Journal of Perinatology, 2013Co-Authors: Rangasamy Ramanathan, Jatinder Bhatia, K C Sekar, F R ErnstAbstract:Objective: The objective of this study is to compare all-cause in-hospital mortality in preterm infants with respiratory distress syndrome (RDS) treated with Poractant Alfa, cAlfactant or beractant. Study Design: A retrospective cohort study of 14173 preterm infants with RDS, treated with one of three surfactants between 2005 and 2009, using the Premier Database was done. Multilevel, multivariable logistic regression modeling, adjusting for patient- and hospital-level factors was performed. Result: CAlfactant treatment was associated with a 49.6% greater likelihood of death than Poractant Alfa (odds ratio (OR): 1.496, 95% confidence interval (CI): 1.014‐2.209, P ¼0.043). Beractant treatment was associated with a non-significant 37% increase in mortality, compared with Poractant Alfa (OR: 1.370, 95% CI: 0.996‐1.885, P ¼0.053). No differences in mortality were observed between cAlfactant and beractant treatment (OR: 1.092, 95% CI: 0.765‐1.559, P ¼0.626). Conclusion: Poractant Alfa treatment for RDS was associated with a
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a randomized multicenter masked comparison trial of Poractant Alfa curosurf versus beractant survanta in the treatment of respiratory distress syndrome in preterm infants
American Journal of Perinatology, 2004Co-Authors: Rangasamy Ramanathan, Maynard R Rasmussen, Dale R Gerstmann, Neil N Finer, Krishnamurthy SekarAbstract:We compared the onset of clinical response and safety of two surfactants, Poractant Alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n=293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of Poractant Alfa or 100 (n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (FIO 2 ) between 0 and 6 hours measured using the area under the curve (FIO 2 AUC 0 - 6 ); other outcomes were assessed for the entire cohort at 28 days and for infants born at ≤32 weeks gestation at 36 weeks postconceptional age. We found that the mean FIO 2 AUC 0 - 6 values for the 100 and 200 mg/kg Poractant Alfa groups were both significantly lower than the mean Floe AUC 0 - 6 values for the beractant group (p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at ≤32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg Poractant Alfa group than in either the beractant group (3% versus 11%;p = 0.034) or in the 100 mg/kg Poractant Alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg Poractant Alfa in comparison to the beractant-treated group (p < 0.002). Treatment with Poractant Alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality (p < 0.05) than either beractant or Poractant Alfa (100 mg/kg dosing) in infants ≤32 weeks gestation with RDS.
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a randomized multicenter masked comparison trial of Poractant Alfa curosurf versus beractant survanta in the treatment of respiratory distress syndrome in preterm infants
American Journal of Perinatology, 2004Co-Authors: Rangasamy Ramanathan, Dale R Gerstmann, Neil N Finer, Maynard Rasmussen, Krishnamurthy SekarAbstract:We compared the onset of clinical response and safety of two surfactants, Poractant Alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n = 293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of Poractant Alfa or 100 ( n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (F IO(2)) between 0 and 6 hours measured using the area under the curve (F IO(2) AUC (0-6)); other outcomes were assessed for the entire cohort at 28 days and for infants born at < or = 32 weeks gestation at 36 weeks postconceptional age. We found that the mean F IO(2) AUC (0-6) values for the 100 and 200 mg/kg Poractant Alfa groups were both significantly lower than the mean F IO(2) AUC (0-6) values for the beractant group ( p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at < or = 32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg Poractant Alfa group than in either the beractant group (3% versus 11%; p = 0.034) or in the 100 mg/kg Poractant Alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg Poractant Alfa in comparison to the beractant-treated group ( p < 0.002). Treatment with Poractant Alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality ( p <0.05) than either beractant or Poractant Alfa (100 mg/kg dosing) in infants < or =32 weeks gestation with RDS.
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A Cost Minimization Comparison of Two Surfactants-Beractant and Poractant Alfa-Based Upon Prospectively Designed, Comparative Clinical Trial Data.
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 2004Co-Authors: Wallace A. Marsh, Rangasamy Ramanathan, James E. Smeeding, John M. York, Krishnamurthy SekarAbstract:®® , DEY LP, Napa, CA) via a cost-minimization analysis. METHODS This analysis was based upon clinical data from two previously published studies (Speer C, et al. Arch Dis Child 1995;72: F8-13; and Ramanathan R, et al. Am J Perinatol 2004; 21:109-19) where investigators found significant differences in the number of doses required to achieve a similar clinical response. Our analyses employed several models based upon single-use or multiple-use of single-use vial scenarios, average wholesale pricing, and costs computed on a per-patient basis. Model 1 involved single-dose vials and mean weight of the infants (both trials). Models 2 and 3, based on individual patient weights, assessed single-dose and multiple-use of single-dose vials cost scenarios, respectively. Individual patient weights allowed for statistical evaluation in Models 2 and 3. RESULTS Model 1 savings with Poractant Alfa treatment was $949.67 (53%) based upon Speer and $617.90 (46%) based upon Ramanathan. Models 2 and 3 reported savings for Poractant Alfa of $220.50 (20%) (P 0.11) and $180 (20%) (P 0.018), respectively over beractant. CONCLUSIONS These analyses would suggest Poractant Alfa may offer a less costly, clinically-equivalent option. Savings may vary with vial usage and mix, patient weight distribution, and how surfactants are used in practice. Institutions utilizing surfactants may wish to examine usage patterns, dosing protocols, and patient mix to determine what potential savings may exist.