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Strickler SC, Farkas DR, Momin MAM, Vargas L, Aladwani G, Hindle M, Longest W. Development of an Infant Air-Jet Dry Powder Aerosol Delivery System (iDP-ADS) Including a New Multifunctional Bifurcating Two-Prong Nasal Interface. Pharm Res 2025; 42:365-384. [PMID: 39930310 PMCID: PMC11880044 DOI: 10.1007/s11095-024-03814-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/25/2024] [Indexed: 03/06/2025]
Abstract
PURPOSE To improve the quality of aerosol delivery to infants, the iDP-ADS was advanced to include dual-prong nose-to-lung aerosol administration with a bifurcating interface, consistently monitor lung pressures and control ventilatory parameters with a pressure monitoring and control (PMC) unit, and implement flexible nasal prongs for use across a range of subject sizes. METHODS Four bifurcating flow pathways were integrated into the iDP-ADS and tested in vitro with a full-term infant nose-throat (NT) model for comparison to the performance of a single-prong interface. After selecting the best-performing flow pathway, flexible prong designs were evaluated in the same model and chosen for additional testing. Realistic pulmonary mechanics (PM) and age-appropriate tidal volumes were used to simulate ventilation with the PMC unit and aerosol delivery in full-term and 34-week gestational age preterm NT models. RESULTS Three of the four bifurcating flow pathways matched the performance of the single-prong design (tracheal filter delivery of ~55%), and the FP4 design with co-flow was selected. A flexible prong version of FP4 produced similar performance to the rigid version. Measurements from the PMC unit demonstrated that consistent air volumes under safe operating pressures could be delivered with a PEEP between 4-6 cmH2O. Considering aerosol delivery, PM conditions resulted in ~4% decrease in filter deposition but high lung delivery efficiencies of ~45% and ~34% for the full-term and preterm models, respectively. CONCLUSIONS The best-performing interface with flexible prongs matched the lung delivery efficiency of a high-transmission single-prong interface and delivered high aerosol doses through late-preterm to full-term NT models.
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Affiliation(s)
- Sarah C Strickler
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, VA, 23284-3015, USA
| | - Dale R Farkas
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, VA, 23284-3015, USA
| | - Mohammad A M Momin
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Laura Vargas
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, VA, 23284-3015, USA
| | - Ghali Aladwani
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, VA, 23284-3015, USA
| | - Michael Hindle
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Worth Longest
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, VA, 23284-3015, USA.
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA.
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Jubaer H, Strickler S, Farkas D, Dalton C, Momin MAM, Dodson KM, Hindle M, Longest W. Development of CPAP Overlay Interfaces for Efficient Administration of Aerosol Surfactant Therapy to Preterm Infants. AAPS PharmSciTech 2025; 26:34. [PMID: 39821052 DOI: 10.1208/s12249-024-02987-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 10/30/2024] [Indexed: 01/19/2025] Open
Abstract
The administration of surfactant aerosol therapy to preterm infants receiving continuous positive airway pressure (CPAP) respiratory support is highly challenging due to small flow passages, relatively high ventilation flow rates, rapid breathing and small inhalation volumes. To overcome these challenges, the objective of this study was to implement a validated computational fluid dynamics (CFD) model and develop an overlay nasal prong interface design for use with CPAP respiratory support that enables high efficiency powder aerosol delivery to the lungs of preterm infants when needed (i.e., on-demand) and can remain in place without increasing the work of breathing compared with a baseline CPAP interface. Realistic in vitro experiments were first conducted to generate baseline validation data, and then the CFD model, once validated, was used to explore key design parameters across a range of preterm infant nose-throat geometries and aerosol delivery conditions. The most important factors for efficient aerosol delivery were shown to be (i) maintaining the aerosol delivery flow rate below the tracheal flow rate (to minimize CPAP line loss) and (ii) concentrating the aerosol within the first portion of the inhalation waveform. An optimized design was shown to deliver approximately 37-60% of the nominal dose through the system and to the lungs with low intersubject variability (1050-2200 g infants) across two modes of device actuation (automated and manual) with room for further improvement. Ergonomic curvatures and streamlining of the prong geometries were also found to reduce work of breathing and flow resistance compared with a commercial alternative.
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Affiliation(s)
- Hasan Jubaer
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Sarah Strickler
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Dale Farkas
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Caleb Dalton
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Mohammad A M Momin
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Kelley M Dodson
- Department of Otolaryngology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Michael Hindle
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Worth Longest
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, United States of America.
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, United States of America.
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Papoff P, D'Agostino B, Cicchetti R, Bitti A, Pennetta V, Caresta E. Bronchoscopic lung lavage and exogenous surfactant successfully reverse respiratory failure after severe chlorine exposure: A pediatric case report. Clin Case Rep 2025; 13:e9302. [PMID: 39810993 PMCID: PMC11732365 DOI: 10.1002/ccr3.9302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 07/01/2024] [Accepted: 07/25/2024] [Indexed: 01/16/2025] Open
Abstract
Key Clinical Message Although the symptoms of accidental chlorine inhalation are typically mild, severe exposure can result in acute respiratory distress syndrome (ARDS). We present a case of pediatric ARDS due to chlorine exposure in which lung lavage and exogenous surfactant were successful in avoiding more invasive and costly treatments. Abstract Chlorine inhalation as a result of swimming pool chlorination accidents is relatively common. Because symptoms are typically mild (cough and bronchospasm), complications such as severe acute respiratory distress syndrome (ARDS) are identified at a late stage, which places the patient's life at risk and necessitates highly invasive interventions. We present a case of severe ARDS in a 14-year-old boy following accidental exposure to chlorine powder. Upon arrival in the pediatric emergency department, the patient received oxygen administration, nebulized salbutamol, and intravenous steroids because of dyspnea and cyanosis. Despite this treatment, the patient's respiratory condition deteriorated. Early intubation and lung-protective ventilation transitorily improved hypoxemia. Given the underlying pathophysiology of chlorine lung injury characterized by surfactant dysfunction, the boy was treated with repeated bronchoscopic lung lavages followed by exogenous surfactant (Curosurf 30 mg/kg total), 1 h after intubation and subsequently after 6 and 12 h, when he achieved a significant and stable reduction in ventilatory requirements. This case study illustrates the beneficial effects of target therapy with bronchoscopic lung lavage followed by exogenous surfactant in chlorine related ARDS to prevent more invasive and costly treatments.
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Affiliation(s)
- Paola Papoff
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
| | - Benedetto D'Agostino
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
| | - Roberto Cicchetti
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
| | - Antonella Bitti
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
| | - Valentina Pennetta
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
| | - Elena Caresta
- Pediatric Intensive Care Unit, Department of Maternal and Child Health and Urological SciencesSapienza University of RomeRomeItaly
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DiBlasi RM, KenKnight H, Kontoudios N, Farkas D, Momin MAM, Hall F, Hindle M, Longest W. Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part II: In vivo Efficacy Testing in a Rabbit Surfactant Washout Model. Pharm Res 2024; 41:1827-1842. [PMID: 39237797 PMCID: PMC11436456 DOI: 10.1007/s11095-024-03754-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/26/2024] [Indexed: 09/07/2024]
Abstract
PURPOSE Surfactant therapy incorporates liquid bolus instillation via endotracheal tube catheter and a mechanical ventilator in preterm neonates with respiratory distress syndrome (RDS). Aerosolized surfactants have generated interest and conflicting data on the efficacy of phospholipid (PL) dose requirements. We developed and characterized a synthetic lung surfactant excipient enhanced growth (SLS-EEG) dry powder aerosol product. In this study, we compare the in vivo performance of the new aerosol product with standard-of-care liquid instillation. METHODS Juvenile rabbits were sedated, anesthetized, intubated, and ventilated. Endogenous surfactant was depleted via whole lung lavage. Animals received either a standard dose of liquid Curosurf (200 mg PL/kg) instilled via a tracheal catheter, SLS-EEG powder aerosol (60 mg device loaded dose; equivalent to 24 mg PL/kg), or sham control. Gas exchange, lung compliance, and indices of disease severity were recorded every 30 min for 3.5 h and macro- and microscopy images were acquired at necropsy. RESULTS While aerosol was administered at an approximately tenfold lower PL dose, both liquid-instilled and aerosol groups had similar, nearly complete recoveries of arterial oxygenation (PaO2; 96-100% recovery) and oxygenation index, and the aerosol group had superior recovery of compliance (P < 0.05). The SLS-EEG aerosol group showed less lung tissue injury, greater uniformity in lung aeration, and more homogenous surfactant distribution at the alveolar surfaces compared with liquid Curosurf. CONCLUSIONS The new dry powder aerosol SLS product (which includes the delivery strategy, formulation, and delivery system) has the potential to be a safe, effective, and economical alternative to the current clinical standard of liquid bolus surfactant instillation.
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Affiliation(s)
- Robert M DiBlasi
- Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, 1900 Ninth Ave, Seattle, WA, 98101, USA.
| | - Hattie KenKnight
- Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, 1900 Ninth Ave, Seattle, WA, 98101, USA
| | - Niko Kontoudios
- Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, 1900 Ninth Ave, Seattle, WA, 98101, USA
| | - Dale Farkas
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohammad A M Momin
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Felicia Hall
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Michael Hindle
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Worth Longest
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, USA
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Momin MAM, Farkas D, Hindle M, Hall F, DiBlasi RM, Longest W. Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part I: In Vitro Testing and Characterization. Pharm Res 2024; 41:1703-1723. [PMID: 39112775 PMCID: PMC11362531 DOI: 10.1007/s11095-024-03740-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/03/2024] [Indexed: 08/21/2024]
Abstract
PURPOSE Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments. METHODS A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals. RESULTS The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7-17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min. CONCLUSIONS A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.
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Affiliation(s)
- Mohammad A M Momin
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Dale Farkas
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, Virginia, 23284-3015, USA
| | - Michael Hindle
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Felicia Hall
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Robert M DiBlasi
- Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, Seattle, Washington, USA
| | - Worth Longest
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA.
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, Virginia, 23284-3015, USA.
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Qing Q, Zha P, Dai LY, Wang Y. Effect of different ventilation methods combined with pulmonary surfactant on neonatal acute respiratory distress syndrome. World J Clin Cases 2023; 11:5878-5886. [PMID: 37727476 PMCID: PMC10506026 DOI: 10.12998/wjcc.v11.i25.5878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/07/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Acute respiratory distress syndrome precipitates is widespread pulmonary injury in impacted individuals, the neonatal respiratory distress syndrome (NRDS), primarily observed in preterm infants, represents a prevalent critical condition in neonatal clinical settings. AIM To investigate the clinical efficacy of various ventilation strategies combined with pulmonary surfactant (PS) therapy in the treatment of NRDS. METHODS A total of 20 neonates diagnosed with respiratory distress syndrome, admitted between May 2021 and June 2022, were randomly assigned to either a research group or a control group. Neonates in the research group received treatment involving high-frequency oscillatory ventilation (HFOV) in conjunction with PS. In contrast, neonates in the control group were administered either controlled mechanical ventilation or synchronous intermittent mandatory ventilation, combined with PS. Arterial blood samples from the neonates in both groups were collected before treatment, as well as 6 h, 12 h, 24 h, and 48 h post-treatment. These samples underwent blood gas analysis, with measurements taken for pH value, partial pressures of oxygen (O2) and carbon dioxide. Concurrently, data was collected on the duration of ventilator use, length of hospitalization time, O2 treatment time, treatment outcomes, and complications of the ventilator. RESULTS From 6-48 h post-treatment, both groups demonstrated significant improvements in arterial blood pH and oxygen partial pressure, along with a significant decrease in carbon dioxide partial pressure compared to pre-treatment values (P < 0.05). Although these changes progressed over time, there were no significant differences between the two groups (P > 0.05). However, the research group had significantly lower X-ray scores, shorter hospitalization time, and less time on O2 therapy compared to the control group (P < 0.05). Mortality rates were similar between the two groups (P > 0.05), but the research group had a significantly lower incidence of complications (P < 0.05). CONCLUSION The integration of HFOV combine with PS has proven to effectively expedite the treatment duration, decrease the occurrence of complications, and secure the therapeutic efficacy in managing NRDS.
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Affiliation(s)
- Qing Qing
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Ping Zha
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei 230001, Anhui Province, China
| | - Li-Ying Dai
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei 230001, Anhui Province, China
| | - Yang Wang
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
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Bhandari V, Black R, Gandhi B, Hogue S, Kakkilaya V, Mikhael M, Moya F, Pezzano C, Read P, Roberts KD, Ryan RM, Stanford RH, Wright CJ. RDS-NExT workshop: consensus statements for the use of surfactant in preterm neonates with RDS. J Perinatol 2023; 43:982-990. [PMID: 37188774 PMCID: PMC10400415 DOI: 10.1038/s41372-023-01690-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/17/2023]
Abstract
OBJECTIVE To provide the best clinical practice guidance for surfactant use in preterm neonates with respiratory distress syndrome (RDS). The RDS-Neonatal Expert Taskforce (RDS-NExT) initiative was intended to add to existing evidence and clinical guidelines, where evidence is lacking, with input from an expert panel. STUDY DESIGN An expert panel of healthcare providers specializing in neonatal intensive care was convened and administered a survey questionnaire, followed by 3 virtual workshops. A modified Delphi method was used to obtain consensus around topics in surfactant use in neonatal RDS. RESULT Statements focused on establishing RDS diagnosis and indicators for surfactant administration, surfactant administration methods and techniques, and other considerations. After discussion and voting, consensus was achieved on 20 statements. CONCLUSION These consensus statements provide practical guidance for surfactant administration in preterm neonates with RDS, with a goal to contribute to improving the care of neonates and providing a stimulus for further investigation to bridge existing knowledge gaps.
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Affiliation(s)
- Vineet Bhandari
- The Children's Regional Hospital at Cooper/Cooper Medical School of Rowan University, Camden, NJ, USA.
| | | | - Bheru Gandhi
- Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | | | - Venkatakrishna Kakkilaya
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Fernando Moya
- Division of Wilmington Pediatric Subspecialists, Department of Pediatrics, UNC School of Medicine, Wilmington, NC, USA
| | - Chad Pezzano
- Department of Cardio-Respiratory Services Pediatric -Albany Medical Center, Albany, NY, USA
| | - Pam Read
- AESARA Inc., Chapel Hill, NC, USA
| | | | - Rita M Ryan
- UH Rainbow Babies and Children's Hospital -Case Western Reserve University, Cleveland, OH, USA
| | | | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO, USA
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Park SJ, Bae MH, Jeong MH, Jeong SH, Lee N, Byun SY, Park KH. Risk factors and clinical outcomes of extubation failure in very early preterm infants: a single-center cohort study. BMC Pediatr 2023; 23:36. [PMID: 36681822 PMCID: PMC9863082 DOI: 10.1186/s12887-023-03833-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 01/02/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Early extubation success (ES) in preterm infants may reduce various mechanical ventilation-associated complications; however, extubation failure (EF) can cause adverse short- and long-term outcomes. Therefore, the present study aimed to identify differences in risk factors and clinical outcomes between ES and EF in very early preterm infants. METHODS This retrospective study was conducted between January 2017 and December 2021. Premature infants born at 32 weeks' gestational age in whom extubation had failed at least once were assigned to the EF group. Successfully extubated patients with a similar gestational age and birth weight as those in the EF group were assigned to the ES group. EF was defined as the need for re-intubation within 120 h of extubation. Various variables were compared between groups. RESULTS The EF rate in this study was 18.6% (24/129), and approximately 80% of patients with EF required re-intubation within 90.17 h. In the ES group, there was less use of inotropes within 7 days of life (12 [63.2%] vs. 22 [91.7%], p = 0.022), a lower respiratory severity score (RSS) at 1 and 4 weeks (1.72 vs. 2.5, p = 0.026; 1.73 vs. 2.92, p = 0.010), and a faster time to reach full feeding (18.7 vs. 29.7, p = 0.020). There was a higher severity of bronchopulmonary dysplasia BPD (3 [15.8%] vs. 14 [58.3%], p = 0.018), longer duration of oxygen supply (66.5 vs. 92.9, p = 0.042), and higher corrected age at discharge (39.6 vs. 42.5, p = 0.043) in the EF group. The cutoff value, sensitivity, and specificity of the respiratory severity score (RSS) at 1 week were 1.98, 0.71, and 0.42, respectively, and the cutoff value, sensitivity, and specificity of RSS at 4 weeks were 2.22, 0.67, and 0.47, respectively. CONCLUSIONS EF caused adverse short-term outcomes such as a higher BPD severity and longer hospital stay. Therefore, extubation in very early preterm infants should be carefully evaluated. Using inotropes, feeding, and RSS at 1 week of age can help predict extubation success.
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Affiliation(s)
- Su Jeong Park
- Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Mi Hye Bae
- Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Mun Hui Jeong
- Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Seong Hee Jeong
- Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - NaRae Lee
- Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Shin Yun Byun
- Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Kyung Hee Park
- Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.
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Budh HP, Nimbalkar S. Surfactant Replacement Therapy: What’s the New Future? JOURNAL OF NEONATOLOGY 2022; 36:331-347. [DOI: 10.1177/09732179221136963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
Surfactant replacement therapy (SRT) can be lifesaving for preterm babies with respiratory distress because of surfactant deficiency. Attempts have been made over the last two decades to make surfactant administration as smooth and as nontraumatic as possible. Lesser invasive techniques, such as less invasive surfactant administration, minimally invasive surfactant therapy, intrapartum pharyngeal surfactant therapy, and the laryngeal mask airway, are preferred over invasive techniques like intubate surfactant extubation to reduce trauma and peridosing adverse effects. However, at present, aerosolized surfactant (AS) via nebulization remains the only truly noninvasive method of SRT. Many animal and human studies have shown promising results with the use of AS with similar clinical effects to an instilled surfactant with greater safety potential. But still AS has not been adapted to routine neonatal care. There is still scope for studies to further strengthen the role of AS. Also, SRT is a constantly changing field with new innovations revolutionizing and replacing old techniques.
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Affiliation(s)
- Hetal Pramod Budh
- Department of Neonatology, Pramukhswami Medical College, Bhaikaka University, Karamsad, Gujarat, India
| | - Somashekhar Nimbalkar
- Department of Neonatology, Pramukhswami Medical College, Bhaikaka University, Karamsad, Gujarat, India
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Y It Matters—Sex Differences in Fetal Lung Development. Biomolecules 2022; 12:biom12030437. [PMID: 35327629 PMCID: PMC8946560 DOI: 10.3390/biom12030437] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/01/2022] [Accepted: 03/09/2022] [Indexed: 02/01/2023] Open
Abstract
Within this review, sex-specific differences in alveolar epithelial functions are discussed with special focus on preterm infants and the respiratory disorders associated with premature birth. First, a short overview about fetal lung development, the challenges the lung faces during perinatal lung transition to air breathing and respiratory distress in preterm infants is given. Next, clinical observations concerning sex-specific differences in pulmonary morbidity of human preterm infants are noted. The second part discusses potential sex-specific causes of pulmonary complications, including pulmonary steroid receptors and local lung steroid metabolism. With regard to pulmonary steroid metabolism, it is important to highlight which steroidogenic enzymes are expressed at which stage during fetal lung development. Thereafter, we review the knowledge concerning sex-specific aspects of lung growth and maturation. Special focus is given to alveolar epithelial Na+ transport as a driver of perinatal lung transition and the sex differences that were noted in this process.
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Dell'Orto V, Nobile S, Correani A, Marchionni P, Giretti I, Rondina C, Burattini I, Palazzi ML, Carnielli VP. Early nasal continuous positive airway pressure failure prediction in preterm infants less than 32 weeks gestational age suffering from respiratory distress syndrome. Pediatr Pulmonol 2021; 56:3879-3886. [PMID: 34610212 DOI: 10.1002/ppul.25678] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 09/11/2021] [Accepted: 09/11/2021] [Indexed: 11/08/2022]
Abstract
BACKGROUND Early continuous positive airway pressure (CPAP) and surfactant replacement are effective treatments for neonatal respiratory distress syndrome (RDS). CPAP is the first line in preterm infants needing respiratory support, with surfactant replacement in case of CPAP failure (CPAP-F). OBJECTIVES To analyze incidence and factors associated with CPAP-F in preterm infants with RDS. DESIGN, SETTING AND PATIENTS Single-center retrospective database analysis (2004-2017) of inborn infants, gestational age (GA) 24 + 0/7-31 + 6/7 weeks, not intubated on admission to the neonatal intensive care unit, managed with CPAP. CPAP-F was defined as intubation and surfactant administration in the first 72 h of life; CPAP success (CPAP-S) was CPAP alone without need for additional RDS treatments. Demographic, respiratory, and clinical data associated with CPAP-F were studied using logistic regression analysis. RESULTS A total of 562 infants met the inclusion criteria: 252 (44.8%) were CPAP-F and 310 (55.2%) were CPAP-S. The CPAP-F, compared to CPAP-S group, had lower GA and birth weight, and were less likely to receive antenatal steroids or to be vaginal births. Logistic regression showed that the fraction of inspired oxygen (FiO2 ) ≥ 0.23 between 180 and 240 min of life (FiO2 180-240 min) was the strongest factor associated with CPAP-F (odds ratio: 16.01 [95% confidence interval: 10.34-24.81]). CONCLUSION FiO2 180-240 min was highly predictive of CPAP-F in preterm infants. With this model for surfactant administration/CPAP-F, 11.2% of infants would have unnecessarily received treatment, but importantly, 27.7% would have been treated much earlier, with a potential reduction in air leaks and duration of mechanical ventilation.
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Affiliation(s)
- Valentina Dell'Orto
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Stefano Nobile
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy.,Department of Mother, Child and Public Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Alessio Correani
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Paolo Marchionni
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Ilaria Giretti
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Clementina Rondina
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Ilaria Burattini
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Maria L Palazzi
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy
| | - Virgilio P Carnielli
- Division of Neonatology, Mother and Child Department, G. Salesi University Hospital, Ospedali Riuniti, Ancona, Italy.,Department of Odontostomatologic and Specialized Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
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12
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Physiologic Effects of Instilled and Aerosolized Surfactant Using a Breath-Synchronized Nebulizer on Surfactant-Deficient Rabbits. Pharmaceutics 2021; 13:pharmaceutics13101580. [PMID: 34683873 PMCID: PMC8540270 DOI: 10.3390/pharmaceutics13101580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/14/2021] [Accepted: 09/27/2021] [Indexed: 11/17/2022] Open
Abstract
Surfactant administration incorporates liquid bolus instillation via endotracheal tube catheter and use of a mechanical ventilator. Aerosolized surfactant has generated interest and conflicting data related to dose requirements and efficacy. We hypothesized that aerosolized surfactant with a novel breath-actuated vibrating mesh nebulizer would have similar efficacy and safety as instilled surfactant. Juvenile rabbits (1.50 ± 0.20 kg, n = 17) were sedated, anesthetized, intubated, and surfactant was depleted via lung lavage on mechanical ventilation. Subjects were randomized to receive standard dose liquid instillation via catheter (n = 5); low dose surfactant (n = 5) and standard dose surfactant (n = 5) via aerosol; and descriptive controls (no treatment, n = 2). Peridosing events, disease severity and gas exchange, were recorded every 30 min for 3 h following surfactant administration. Direct-Instillation group had higher incidence for peridosing events than aerosol. Standard dose liquid and aerosol groups had greater PaO2 from pre-treatment baseline following surfactant (p < 0.05) with greater ventilation efficiency with aerosol (p < 0.05). Our study showed similar improvement in oxygenation response with greater ventilation efficiency with aerosol than liquid bolus administration at the same dose with fewer peridosing events. Breath-synchronized aerosol via nebulizer has potential as a safe, effective, and economical alternative to bolus liquid surfactant instillation.
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13
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Zheng YR, Lei YQ, Liu JF, Wu HL, Xu N, Huang ST, Cao H, Chen Q. Effect of High-Frequency Oscillatory Ventilation Combined With Pulmonary Surfactant in the Treatment of Acute Respiratory Distress Syndrome After Cardiac Surgery: A Prospective Randomised Controlled Trial. Front Cardiovasc Med 2021; 8:675213. [PMID: 34368243 PMCID: PMC8339213 DOI: 10.3389/fcvm.2021.675213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/28/2021] [Indexed: 11/13/2022] Open
Abstract
Background: This study aimed to evaluate the effects of pulmonary surfactant (PS) combined with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) in infants with acute respiratory distress syndrome (ARDS) after congenital cardiac surgery. Methods: A total of 61 infants with ARDS were eligible and were randomised to the CMV + PS group (n = 30) or the HFOV + PS group (n = 31) between January 2020 and December 2020. The primary outcomes were the changes in arterial blood gas parameters. The duration of mechanical ventilation, length of hospitalisation and the incidence of complications were considered secondary outcomes. Results: A total of 61 infants completed the study. In the HFOV + PS group, the blood gas analysis results were significantly improved (P < 0.05), while the duration of mechanical ventilation and length of hospitalisation were shorter than the CMV + PS group (P < 0.05). However, the incidence of complications was not different between the two groups (P > 0.05). Conclusions: Compared with the CMV + PS group, the HFOV + PS group showed significantly improved ABG variables and had a shortened length of hospitalisation and mechanical ventilation in infants with ARDS after cardiac surgery. Clinical Trial Registration: Chinese Clinical Trial Registry; Number: ChiCTR2000039457.
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Affiliation(s)
- Yi-Rong Zheng
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Yu-Qing Lei
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Jian-Feng Liu
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Hong-Lin Wu
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Ning Xu
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Shu-Ting Huang
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Hua Cao
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
| | - Qiang Chen
- Department of Cardiac Surgery, Fujian Branch of Shanghai Children's Medical Center, Fuzhou, China.,Fujian Children's Hospital, Fuzhou, China.,Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital, Fuzhou, China
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14
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Boc S, Momin MAM, Farkas DR, Longest W, Hindle M. Development and Characterization of Excipient Enhanced Growth (EEG) Surfactant Powder Formulations for Treating Neonatal Respiratory Distress Syndrome. AAPS PharmSciTech 2021; 22:136. [PMID: 33860409 DOI: 10.1208/s12249-021-02001-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/22/2021] [Indexed: 12/18/2022] Open
Abstract
This study aimed to develop and characterize a spray-dried powder aerosol formulation of a commercially available surfactant formulation, Survanta® intratracheal suspension, using the excipient enhanced growth (EEG) approach. Survanta EEG powders were prepared by spray drying of the feed dispersions containing Survanta® (beractant) intratracheal suspension, hygroscopic excipients (mannitol and sodium chloride), and a dispersion enhancer (l-leucine or trileucine) in 5 or 20% v/v ethanol in water using the Buchi Nano Spray Dryer B-90 HP. Powders were characterized for primary particle size, morphology, phospholipid content, moisture content, thermal properties, moisture sorption, and surface activity. The aerosol performance of the powders was assessed using a novel low-volume dry powder inhaler (LV-DPI) device operated with 3-mL volume of dispersion air. At both ethanol concentrations, in comparison to trileucine, l-leucine significantly reduced the primary particle size and span and increased the fraction of submicrometer particles of the Survanta EEG powders. The l-leucine-containing Survanta EEG powders exhibited good aerosolization performance with ≥ 88% of the mass emitted (% nominal) after 3 actuations from the modified LV-DPI device. In addition, l-leucine-containing powders had a low moisture content (< 3% w/w) with transition temperatures close to the commercial surfactant formulation and retained their surface tension reducing activity after formulation processing. A Survanta EEG powder containing l-leucine was developed which showed efficient aerosol delivery from the modified LV-DPI device using a low dispersion air volume.
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15
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Patel P, Houck A, Fuentes D. Examining Variations in Surfactant Administration (ENVISION): A Neonatology Insights Pilot Project. CHILDREN-BASEL 2021; 8:children8040261. [PMID: 33800603 PMCID: PMC8065748 DOI: 10.3390/children8040261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/01/2022]
Abstract
Variability in neonatal clinical practice is well recognized. Respiratory management involves interdisciplinary care and often is protocol driven. The most recent published guidelines for management of respiratory distress syndrome and surfactant administration were published in 2014 and may not reflect current clinical practice in the United States. The goal of this project was to better understand variability in surfactant administration through conduct of health care provider (HCP) interviews. Questions focused on known practice variations included: use of premedication, decisions to treat, technique of surfactant administration and use of guidelines. Data were analyzed for trends and results were communicated with participants. A total of 54 HCPs participated from June to September 2020. In almost all settings, neonatologists or nurse practitioners intubated the infant and respiratory therapists administered surfactant. The INSURE (INtubation-SURrfactant-Extubation) technique was practiced by 83% of participants. Premedication prior to intubation was used by 76% of HCPs. An FiO2 ≥ 30% was the most common threshold for surfactant administration (48%). In conclusion, clinical practice variations exist in respiratory management and surfactant administration and do not seem to be specific to NICU level or institution type. It is unknown what effects the variability in clinical practice might have on clinical outcomes.
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Abstract
Objectives Effective treatment options for surfactant therapy in acute respiratory distress syndrome and coronavirus disease 2019 have not been established. To conduct preclinical studies in vitro and in vivo to evaluate efficiency, particle size, dosing, safety, and efficacy of inhaled surfactant using a breath-synchronized, nebulized delivery system in an established acute respiratory distress syndrome model. Design Preclinical study. Setting Research laboratory. Subjects Anesthetized pigs. Intervention In vitro analysis included particle size distribution and inhaled dose during simulated ventilation using a novel breath-synchronized nebulizer. Physiologic effects of inhaled aerosolized surfactant (treatment) were compared with aerosolized normal saline (control) in an adult porcine model (weight of 34.3 ± 0.6 kg) of severe acute respiratory distress syndrome (Pao2/Fio2 <100) with lung lavages and ventilator-induced lung injury during invasive ventilation. Measurements and Main Results Mass median aerosol diameter was 2.8 µm. In vitro dose delivered distal to the endotracheal tube during mechanical ventilation was 85% ± 5%. Nebulizers were functional up to 20 doses of 108 mg of surfactant. Surfactant-treated animals (n = 4) exhibited rapid improvement in oxygenation with nearly full recovery of Pao2/Fio2 (~300) and end-expiratory lung volumes with nominal dose less than 30 mg/kg of surfactant, whereas control subjects (n = 3) maintained Pao2/Fio2 less than 100 over 4.5 hours with reduced end-expiratory lung volume. There was notably greater surfactant phospholipid content and lower indicators of lung inflammation and pathologic lung injury in surfactant-treated pigs than controls. There were no peridosing complications associated with nebulized surfactant, but surfactant-treated animals had progressively higher airway resistance post treatment than controls with no differences in ventilation effects between the two groups. Conclusions Breath-synchronized, nebulized bovine surfactant appears to be a safe and feasible treatment option for use in coronavirus disease 2019 and other severe forms of acute respiratory distress syndrome.
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17
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何 明, 林 玉, 吴 琳, 沈 蔚, 唐 丽, 祝 垚, 黄 静, 林 新. [Safety of two ventilator weaning strategies after high-frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: a prospective randomized controlled trial]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2021; 23:18-24. [PMID: 33476532 PMCID: PMC7818152 DOI: 10.7499/j.issn.1008-8830.2010115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/18/2020] [Indexed: 06/12/2023]
Abstract
OBJECTIVE To study the safety of two ventilator weaning strategies after high-frequency oscillatory ventilation (HFOV) for the treatment of neonatal respiratory distress syndrome (NRDS) in preterm infants. METHODS A prospective randomized controlled trial was conducted for 101 preterm infants with NRDS, with a gestational age of ≤32+6 weeks or a birth weight of ≤1 500 g, who were admitted to the neonatal intensive care unit of Xiamen Maternal and Child Health Hospital from January 1, 2019 to June 30, 2020. The infants underwent HFOV as the preferred treatment. The infants were randomly divided into an observation group (50 infants with direct weaning from HFOV) and a control group (51 infants with weaning after HFOV was switched to conventional mechanical ventilation). The two groups were compared in terms of failure rate of ventilator weaning within 72 hours, changes in blood gas parameters at 2 hours before weaning and at 2 and 24 hours after weaning, respiratory support therapy, incidence rates of complications, and outcome at discharge. RESULTS There was no significant difference in the failure rate of ventilator weaning within 72 hours (8% vs 14%, P > 0.05). The observation group had a significantly shorter duration of mechanical ventilation than the control group [(64±39) hours vs (88±69) hours, P < 0.05]. There were no significant differences between the two groups in the duration of mechanical ventilation, total oxygen supply time, blood gas parameters before and after ventilator weaning, incidence rates of complications, and outcome at discharge (P > 0.05). CONCLUSIONS For preterm infants with NRDS, the strategy of weaning directly from HFOV is safe and reliable and can reduce the duration of invasive mechanical ventilation, and therefore, it holds promise for clinical application.
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Affiliation(s)
- 明嫄 何
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 玉聪 林
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 琳琳 吴
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 蔚 沈
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 丽霞 唐
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 垚 祝
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 静 黄
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
| | - 新祝 林
- />厦门大学附属妇女儿童医院/厦门市妇幼保健院新生儿科/厦门市围产-新生儿感染重点实验室, 福建厦门 361001Department of Neonatology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen Key Laboratory of Perinatal-Neonatal Infection, Xiamen, Fujian 361001, China
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Mikolka P, Curstedt T, Feinstein R, Larsson A, Grendar M, Rising A, Johansson J. Impact of synthetic surfactant CHF5633 with SP-B and SP-C analogues on lung function and inflammation in rabbit model of acute respiratory distress syndrome. Physiol Rep 2021; 9:e14700. [PMID: 33403805 PMCID: PMC7786196 DOI: 10.14814/phy2.14700] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/29/2020] [Accepted: 12/03/2020] [Indexed: 02/04/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is associated with diffuse inflammation, alveolar epithelial damage, and leakage of plasma proteins into the alveolar space, which together contribute to inactivation of pulmonary surfactant and respiratory failure. Exogenous surfactant delivery is therefore considered to hold potential for ARDS treatment, but clinical trials with natural derived surfactant or synthetic surfactant containing a surfactant protein C (SP-C) analogue have been negative. Synthetic surfactant CHF5633, containing analogues of SP-B and SP-C, may be effective against ARDS. The aim here was to compare treatment effects of CHF5633 and animal-derived surfactant poractant alfa in animal model of ARDS. ARDS was induced in adult New Zealand rabbits by mild lung lavages followed by injurious ventilation until respiratory failure (P/F ratio <26.7 kPa). The animals were then treated with intratracheal bolus of 200 mg/kg CHF5633 or poractant alfa (Curosurf® ), or air as control. The animals were subsequently ventilated for an additional 4 hr and respiratory parameters were recorded regularly. Postmortem, histological analysis, degree of lung edema, and levels of the cytokines TNFα, IL-6, and IL-8 in lung homogenates were evaluated. Both surfactant preparations improved lung function, reduced the levels of pro-inflammatory cytokines, and degree of lung edema to very similar degrees versus the controls. No significant differences in any of the analyzed parameters were observed between the CHF5633- and poractant alfa-treated groups. This study indicates that single dose of CHF5633 improves lung function and attenuates inflammation as effectively as poractant alfa in experimental ARDS caused by injurious ventilation.
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Affiliation(s)
- Pavol Mikolka
- Division for NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetHuddingeSweden
- Biomedical Center MartinJessenius Faculty of Medicine in MartinComenius University in BratislavaMartinSlovakia
- Department of PhysiologyJessenius Faculty of Medicine in MartinComenius University in BratislavaMartinSlovakia
| | - Tore Curstedt
- Department of Molecular Medicine and SurgeryKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Riccardo Feinstein
- Department of PathologyThe Swedish National Veterinary InstituteUppsalaSweden
| | - Anders Larsson
- Hedenstierna LaboratoryDepartment of Surgical SciencesUppsala UniversityUppsalaSweden
| | - Marian Grendar
- Biomedical Center MartinJessenius Faculty of Medicine in MartinComenius University in BratislavaMartinSlovakia
| | - Anna Rising
- Division for NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetHuddingeSweden
- Department of Anatomy, Physiology and BiochemistrySwedish University of Agricultural SciencesUppsalaSweden
| | - Jan Johansson
- Division for NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetHuddingeSweden
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19
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Obendorf J, Fabian C, Thome UH, Laube M. Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells. Stem Cell Res Ther 2020; 11:525. [PMID: 33298180 PMCID: PMC7724458 DOI: 10.1186/s13287-020-02028-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as bronchopulmonary dysplasia (BPD), the most common sequel of preterm birth. In these studies, cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD. Methods We aimed to determine if the conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na+ transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na+ transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants. Results MSC-CM strongly increased the activity of the epithelial Na+ channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’s actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na+ transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na+ transport. Conclusion The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of the fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus, MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.
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Affiliation(s)
- Janine Obendorf
- Center for Pediatric Research Leipzig, Department of Pediatrics, Division of Neonatology, University of Leipzig, Liebigstrasse 19, 04103, Leipzig, Germany
| | - Claire Fabian
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, 04103, Leipzig, Germany
| | - Ulrich H Thome
- Center for Pediatric Research Leipzig, Department of Pediatrics, Division of Neonatology, University of Leipzig, Liebigstrasse 19, 04103, Leipzig, Germany
| | - Mandy Laube
- Center for Pediatric Research Leipzig, Department of Pediatrics, Division of Neonatology, University of Leipzig, Liebigstrasse 19, 04103, Leipzig, Germany.
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Gregory TJ, Irshad H, Chand R, Kuehl PJ. Deposition of Aerosolized Lucinactant in Nonhuman Primates. J Aerosol Med Pulm Drug Deliv 2020; 33:21-33. [PMID: 31436493 PMCID: PMC7041326 DOI: 10.1089/jamp.2018.1505] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 07/08/2019] [Indexed: 11/29/2022] Open
Abstract
Background: Lucinactant for inhalation is an investigational noninvasive, aerosolized surfactant replacement therapy for treatment of preterm neonates with respiratory distress syndrome. Lucinactant for inhalation consists of lyophilized lucinactant and the Aerosurf® Delivery System (ADS). The objective of this study was to characterize the total and regional pulmonary deposition of lucinactant delivered by the ADS in nonhuman primates (NHPs). Methods: Lucinactant was radiolabeled by the addition of technetium-99m (99mTc)-sulfur colloid. The radiolabeled aerosol was characterized and validated using a Mercer cascade impactor. An in vivo deposition study was performed in three cynomolgus macaques. Radiolabeled lucinactant was aerosolized using the ADS and delivered via nasal cannula under 5 cm H2O nasal continuous positive airway pressure (nCPAP) for 5-9 minutes. A two-dimensional planar image was acquired immediately after aerosol administration, followed by a three-dimensional single-photon emission computed tomography (SPECT) image and a second planar image. The images were analyzed to determine the pulmonary (lungs) and extrapulmonary (nose + mouth, trachea, stomach) distribution. The SPECT data were used to determine regional deposition. Results: The radiolabed lucinactant aerosol had a mass median aerodynamic diameter = 2.91 μm, geometric standard deviation (GSD) = 1.81, and an activity median aerodynamic diameter = 2.92 μm, GSD = 2.06. Aerosolized lucinactant was observed to deposit in the lungs (11.4%), nose + mouth (79.9%), trachea (7.3%), and stomach (1.4%). Analysis of the SPECT image demonstrated that the regional deposition within the lung was generally homogeneous. Aerosolized lucinactant was deposited in both the central (52.8% ± 1.2%) and peripheral (47.2% ± 1.2%) regions of the lungs. Conclusion: Aerosolized lucinactant, delivered using the ADS via constant flow nCPAP, is deposited in all regions of the lungs demonstrating that surfactant can be aerosolized and delivered noninvasively to NHPs.
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Chen Z, Zhong M, Luo Y, Deng L, Hu Z, Song Y. Determination of rheology and surface tension of airway surface liquid: a review of clinical relevance and measurement techniques. Respir Res 2019; 20:274. [PMID: 31801520 PMCID: PMC6894196 DOI: 10.1186/s12931-019-1229-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 11/01/2019] [Indexed: 12/11/2022] Open
Abstract
By airway surface liquid, we mean a thin fluid continuum consisting of the airway lining layer and the alveolar lining layer, which not only serves as a protective barrier against foreign particles but also contributes to maintaining normal respiratory mechanics. In recent years, measurements of the rheological properties of airway surface liquid have attracted considerable clinical attention due to new advances in microrheology instruments and methods. This article reviews the clinical relevance of measurements of airway surface liquid viscoelasticity and surface tension from four main aspects: maintaining the stability of the airways and alveoli, preventing ventilator-induced lung injury, optimizing surfactant replacement therapy for respiratory syndrome distress, and characterizing the barrier properties of airway mucus to improve drug and gene delivery. Primary measuring techniques and methods suitable for determining the viscoelasticity and surface tension of airway surface liquid are then introduced with respect to principles, advantages and limitations. Cone and plate viscometers and particle tracking microrheometers are the most commonly used instruments for measuring the bulk viscosity and microviscosity of airway surface liquid, respectively, and pendant drop methods are particularly suitable for the measurement of airway surface liquid surface tension in vitro. Currently, in vivo and in situ measurements of the viscoelasticity and surface tension of the airway surface liquid in humans still presents many challenges.
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Affiliation(s)
- Zhenglong Chen
- School of Medical Instrumentation, Shanghai University of Medicine & Health Sciences, 257 Tianxiong Road, Shanghai, 201318 China
| | - Ming Zhong
- Department of Intensive Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032 China
| | - Yuzhou Luo
- School of Medical Instrumentation, Shanghai University of Medicine & Health Sciences, 257 Tianxiong Road, Shanghai, 201318 China
| | - Linhong Deng
- Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, 213164 Jiangsu China
| | - Zhaoyan Hu
- School of Medical Instrumentation, Shanghai University of Medicine & Health Sciences, 257 Tianxiong Road, Shanghai, 201318 China
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
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Looi K, Evans DJ, Garratt LW, Ang S, Hillas JK, Kicic A, Simpson SJ. Preterm birth: Born too soon for the developing airway epithelium? Paediatr Respir Rev 2019; 31:82-88. [PMID: 31103368 DOI: 10.1016/j.prrv.2018.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/31/2018] [Accepted: 11/23/2018] [Indexed: 12/17/2022]
Abstract
Birth prior to term interrupts the normal development of the respiratory system and consequently results in poor respiratory outcomes that persist throughout childhood. The mechanisms underpinning these poor respiratory outcomes are not well understood, but intrinsic abnormalities within the airway epithelium may be a contributing factor. Current evidence suggests that the airway epithelium is both structurally and functionally abnormal after preterm birth, with reports of epithelial thickening and goblet cell hyperplasia in addition to increased inflammation and apoptosis in the neonatal intensive care unit. However, studies focusing on the airway epithelium are limited and many questions remain unanswered; including whether abnormalities are a direct result of interrupted development, a consequence of exposure to inflammatory stimuli in the perinatal period or a combination of the two. In addition, the difficulty of accessing airway tissue has resulted in the majority of evidence being collected in the pre-surfactant era which may not reflect contemporary preterm birth. This review examines the consequences of preterm birth on the airway epithelium and explores the clinical relevance of currently available models whilst highlighting the need to develop a clinically relevant in vitro model to help further our understanding of the airway epithelium in preterm birth.
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Affiliation(s)
- Kevin Looi
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Denby J Evans
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Luke W Garratt
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Sherlynn Ang
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Jessica K Hillas
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Anthony Kicic
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia; Occupation and Environment, School of Public Health, Curtin University, Bentley 6845, Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, Nedlands 6009, Western Australia, Australia; Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands, WA 6009, Australia; UWA Centre for Child Health Research & School of Biomedical Sciences, Nedlands 6009, Western Australia, Australia
| | - Shannon J Simpson
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia.
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Qiu RX, Liu X, Wang JL, Cai C, Zeng JA, Liu HC, Cheng R, Li ZK, Liu J. [Clinical effect of exogenous pulmonary surfactant in the treatment of severe neonatal infectious pneumonia: a multicenter prospective clinical trial]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2019. [PMID: 31014423 DOI: 10.7499/j.issn.1008-8830.2019.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To study the clinical effect of calsurf, a domestic exogenous pulmonary surfactant, in the treatment of severe neonatal infectious pneumonia. METHODS A total of 208 neonates with severe infectious pneumonia who hospitalized in 5 hospitals of China were enrolled. According to their parents' wishes on admission, these neonates were administered with conventional treatment (control group; n=81) and calsurf treatment + conventional treatment (calsurf treatment group, n=127). The two groups were compared in terms of the degree of oxygen dependence on admission, blood gas parameters before and after treatment, lung ultrasound results, duration of mechanical ventilation, length of hospital stay, hospital costs, complications and prognosis. RESULTS Compared with the control group on admission, the calsurf treatment group had significantly higher inhaled oxygen concentration and partial pressure of carbon dioxide and significantly lower arterial partial pressure of oxygen and oxygenation index (P<0.01). After 1 hour of treatment, both groups had significant improvements in the above indices (P<0.05), and the improvements were more significant in the calsurf treatment group (P<0.05). After 4-6 hours of calsurf administration, there was a significant reduction in the degree of pulmonary consolidation. The calsurf treatment group had significantly shorter duration of mechanical ventilation and length of hospital stay than the control group, while there was no significant difference in the incidence rate of complications between the two groups. The neonates of both groups had a good prognosis. CONCLUSIONS In neonates with severe infectious pneumonia, calsurf treatment can significantly improve oxygenation, reduce the degree of pulmonary consolidation, and shorten the duration of mechanical ventilation and length of hospital stay. Therefore, it should be considered in neonates with severe infectious pneumonia.
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Affiliation(s)
- Ru-Xin Qiu
- Department of Neonatology, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing 100021, China.
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Gross I, Langer Y, Pasternak Y, Abu Ahmad W, Eventov-Friedman S, Koplewitz BZ. Questionnaire-based study showed that neonatal chest radiographs could be reliably interpreted using the WhatsApp messaging application. Acta Paediatr 2019; 108:94-100. [PMID: 29889988 DOI: 10.1111/apa.14444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 04/10/2018] [Accepted: 06/07/2018] [Indexed: 11/29/2022]
Abstract
AIM We surveyed whether clinicians used the WhatsApp messaging application to view neonatal chest radiographs and asked a sub-sample to compare them with computer screen viewings. METHODS The study was conducted at three university-affiliated medical centres in Israel from June-December 2016. Questionnaires on using smartphones for professional purposes were completed by 68/71 paediatric residents and 20/28 neonatologists. In addition, 11 neonatologists viewed 20 chest radiographs on a computer screen followed by a smartphone and 10 viewed the same radiographs in the opposite order, separated by a washout period of 2 months. After another 2 months, five from each group viewed the same radiographs on a computer screen. Different interpretations between viewing modes were assessed. RESULTS Most respondents used WhatsApp to send chest radiographs for consultation: 82% of the paediatric residents and 80% of the neonatologists. The mean number of inconsistencies in diagnosis was 3.7/20 between two computer views and 2.9/20 between computer and smartphone views (p = 0.88) and the disease severity means were 3.7/20 and 2.85/20, respectively (p = 0.94). Neonatologists using WhatsApp only determined umbilical line placement in 80% of cases. CONCLUSION WhatsApp was reliable for preliminary interpretation of neonatal chest radiographs, but caution was needed when assessing umbilical lines.
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Affiliation(s)
- Itai Gross
- Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yshia Langer
- Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Yehonatan Pasternak
- Department of Pediatrics A, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Wiessam Abu Ahmad
- Hebrew University--Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel
| | | | - Benjamin Z Koplewitz
- Department of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Ricci F, Casiraghi C, Storti M, D’Alò F, Catozzi C, Ciccimarra R, Ravanetti F, Cacchioli A, Villetti G, Civelli M, Murgia X, Carnielli V, Salomone F. Surfactant replacement therapy in combination with different non-invasive ventilation techniques in spontaneously-breathing, surfactant-depleted adult rabbits. PLoS One 2018; 13:e0200542. [PMID: 30001410 PMCID: PMC6042776 DOI: 10.1371/journal.pone.0200542] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 06/28/2018] [Indexed: 12/14/2022] Open
Abstract
Nasal intermittent positive pressure ventilation (NIPPV) holds great potential as a primary ventilation support method for Respiratory Distress Syndrome (RDS). The use of NIPPV may also be of great value combined with minimally invasive surfactant delivery. Our aim was to implement an in vivo model of RDS, which can be managed with different non-invasive ventilation (NIV) strategies, including non-synchronized NIPPV, synchronized NIPPV (SNIPPV), and nasal continuous positive airway pressure (NCPAP). Forty-two surfactant-depleted adult rabbits were allocated in six different groups: three groups of animals were treated with only NIV for three hours (NIPPV, SNIPPV, and NCPAP groups), while three other groups were treated with surfactant (SF) followed by NIV (NIPPV+SF, SNIPPV+SF, and NCPAP+SF groups). Arterial gas exchange, ventilation indices, and dynamic compliance were assessed. Post-mortem the lungs were sampled for histological evaluation. Surfactant depletion was successfully achieved by repeated broncho-alveolar lavages (BALs). After BALs, all animals developed a moderate respiratory distress, which could not be reverted by merely applying NIV. Conversely, surfactant administration followed by NIV induced a rapid improvement of arterial oxygenation in all surfactant-treated groups. Breath synchronization was associated with a significantly better response in terms of gas exchange and dynamic compliance compared to non-synchronized NIPPV, showing also the lowest injury scores after histological assessment. The proposed in vivo model of surfactant deficiency was successfully managed with NCPAP, NIPPV, or SNIPPV; this model resembles a moderate respiratory distress and it is suitable for the preclinical testing of less invasive surfactant administration techniques.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xabi Murgia
- Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany
| | - Virgilio Carnielli
- Division of Neonatology, Polytechnic University of Marche and Salesi Children’s Hospital, Ancona, Italy
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26
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In vitro and in vivo comparison between poractant alfa and the new generation synthetic surfactant CHF5633. Pediatr Res 2017; 81:369-375. [PMID: 27973472 DOI: 10.1038/pr.2016.231] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/30/2016] [Indexed: 11/08/2022]
Abstract
BACKGROUND CHF5633 is a new generation synthetic surfactant containing both SP-B and SP-C analogues developed for the treatment of respiratory distress syndrome. Here, the optimal dose and its performance in comparison to the animal-derived surfactant poractant alfa were investigated. METHODS In vitro surfactant activity was determined by means of the Wilhelmy balance and the capillary surfactometer. The dose-finding study was performed in preterm rabbits with severe surfactant deficiency. CHF5633 doses ranging from 50 to 300 mg/kg were used. Untreated animals and animals treated with 200 mg/kg of poractant alfa were included for comparison. RESULTS In vitro, minimum surface tension (γmin) was decreased from values above 70 to 0 mN/m by both surfactants, and they formed rapidly a film at the air-liquid interface. In vivo studies showed a clear dose-dependent improvement of lung function for CHF5633. The pulmonary effect of CHF5633 200 mg/kg dose was comparable to the pulmonary response elicited by 200 mg/kg of poractant alfa in preterm rabbits. CONCLUSION CHF5633 is as efficient as poractant alfa in our in vitro and in vivo settings. A clear dose-dependent improvement of lung function could be observed for CHF5633, with the dose of 200 mg/kg being the most efficient one.
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27
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Ricci F, Catozzi C, Murgia X, Rosa B, Amidani D, Lorenzini L, Bianco F, Rivetti C, Catinella S, Villetti G, Civelli M, Pioselli B, Dani C, Salomone F. Physiological, Biochemical, and Biophysical Characterization of the Lung-Lavaged Spontaneously-Breathing Rabbit as a Model for Respiratory Distress Syndrome. PLoS One 2017; 12:e0169190. [PMID: 28060859 PMCID: PMC5217971 DOI: 10.1371/journal.pone.0169190] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/13/2016] [Indexed: 12/01/2022] Open
Abstract
Nasal continuous positive airway pressure (nCPAP) is a widely accepted technique of non-invasive respiratory support in spontaneously-breathing premature infants with respiratory distress syndrome (RDS). Surfactant administration techniques compatible with nCPAP ventilation strategy are actively investigated. Our aim is to set up and validate a respiratory distress animal model that can be managed on nCPAP suitable for surfactant administration techniques studies. Surfactant depletion was induced by bronchoalveolar lavages (BALs) on 18 adult rabbits. Full depletion was assessed by surfactant component analysis on the BALs samples. Animals were randomized into two groups: Control group (nCPAP only) and InSurE group, consisting of a bolus of surfactant (Poractant alfa, 200 mg/kg) followed by nCPAP. Arterial blood gases were monitored until animal sacrifice, 3 hours post treatment. Lung mechanics were evaluated just before and after BALs, at the time of treatment, and at the end of the procedure. Surfactant phospholipids and protein analysis as well as surface tension measurements on sequential BALs confirmed the efficacy of the surfactant depletion procedure. The InSurE group showed a significant improvement of blood oxygenation and lung mechanics. On the contrary, no signs of recovery were appreciated in animals treated with just nCPAP. The surfactant-depleted adult rabbit RDS model proved to be a valuable and efficient preclinical tool for mimicking the clinical scenario of preterm infants affected by mild/moderate RDS who spontaneously breathe and do not require mechanical ventilation. This population is of particular interest as potential target for the non-invasive administration of surfactant.
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Affiliation(s)
| | | | - Xabier Murgia
- Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany
| | - Brenda Rosa
- Chiesi Farmaceutici, R&D Department, Parma, Italy
| | - Davide Amidani
- Department of Life Sciences, University of Parma, Parma, Italy
| | | | | | - Claudio Rivetti
- Department of Life Sciences, University of Parma, Parma, Italy
| | | | | | | | | | - Carlo Dani
- Department of Neurosciences, Psychology, Drug Research and Child Health, Careggi University Hospital of Florence, Florence, Italy
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Kong X, Cui Q, Hu Y, Huang W, Ju R, Li W, Wang R, Xia S, Yu J, Zhu T, Feng Z. Bovine Surfactant Replacement Therapy in Neonates of Less than 32 Weeks' Gestation: A Multicenter Controlled Trial of Prophylaxis versus Early Treatment in China--a Pilot Study. Pediatr Neonatol 2016; 57:19-26. [PMID: 26059103 DOI: 10.1016/j.pedneo.2015.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 01/31/2015] [Accepted: 03/05/2015] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND A domestic surfactant preparation has been used in China for a number of years. However, as for other surfactant preparations, there is debate among neonatologists regarding the optimal dose, mode of administration, and the best time of intervention. OBJECTIVE To evaluate whether prophylactic administration of surfactant is superior to early treatment in preterm infants < 32 weeks with a high risk of respiratory distress syndrome (RDS). METHODS We prospectively compared small premature infants (< 32 weeks) receiving 70 mg/kg bovine surfactant within 30 minutes after birth (prophylactic group, N = 116) with infants who received surfactant therapy for established RDS (early treatment group, N = 91). The primary outcome assessed was the incidence of RDS. The secondary outcomes assessed were severity of RDS, mortality, and bronchopulmonary dysplasia morbidity. RESULTS Compared with the early treatment group, the prophylactic group had a significantly better PaO2 (at 1 hour, 4 hours, and 12 hours postdose, respectively), better a/APO2 (at 1 hour, 4 hours, 12 hours, and 24 hours postdose, respectively), lower PaCO2 (at 1 hour postdose), and a significantly decreased need for mean airway pressure (MAP) and FiO2 on ventilation (p < 0.05). The prophylactic group had shorter durations for mechanical ventilation and supplemental oxygen compared with the early treatment group (p < 0.01 and p < 0.05, respectively). The incidence of RDS was comparable between the groups; however, the prophylactic group had a significantly lower incidence of severe RDS and significantly lower rate of repeated doses of surfactant than the early treatment group (p < 0.05). The incidences of bronchopulmonary dysplasia and patent ductus arteriosus were also lower in the prophylactic group than the early treatment group (p < 0.05). The two groups were comparable in mortality rate. CONCLUSION In preterm infants under 32 weeks' gestation, prophylactic use of a domestic surfactant preparation is better than early surfactant treatment in improving pulmonary status and in decreasing the incidence of severe RDS and duration on mechanical ventilation.
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Affiliation(s)
- Xiangyong Kong
- Newborn Care Center, Bayi Children's Hospital, the Military General Hospital of Beijing P.L.A., Beijing, China
| | - Qiliang Cui
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuhua Hu
- Department of Pediatrics, Jiangsu Province Hospital, Nanjing, China
| | - Weimin Huang
- Department of Pediatrics, Nanfang Hospital, Nanfang Medical University, Guangzhou, China
| | - Rong Ju
- Newborn Care Center, Chengdu Women's and Children's Central Hospital, Chengdu, China
| | - Wen Li
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Ruijuan Wang
- Newborn Care Center, Bayi Children's Hospital, the Military General Hospital of Beijing P.L.A., Beijing, China
| | - Shiwen Xia
- Department of Pediatrics, Hospital of Hubei Province, Wuhan, China
| | - Jialin Yu
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Tian Zhu
- Department of Neonatology, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Zhichun Feng
- Newborn Care Center, Bayi Children's Hospital, the Military General Hospital of Beijing P.L.A., Beijing, China.
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Takahashi A, Bartolák-Suki E, Majumdar A, Suki B. Changes in respiratory elastance after deep inspirations reflect surface film functionality in mice with acute lung injury. J Appl Physiol (1985) 2015; 119:258-65. [PMID: 26066828 DOI: 10.1152/japplphysiol.00476.2014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 05/13/2015] [Indexed: 01/11/2023] Open
Abstract
Pulmonary surfactant reduces surface tension in the lung and prevents alveolar collapse. Following a deep inspiration (DI), respiratory elastance first drops then gradually increases due to surface film and tissue viscoelasticity. In acute lung injury (ALI), this increase is faster and governed by alveolar collapse due to increased surface tension. We hypothesized that the rate of increase in elastance reflects the deficiency of surfactant in the lung. To test this, mice were ventilated before (baseline) and after saline lavage obtained by injecting 0.8 ml and withdrawing 0.7 ml fluid (severe ALI) or injecting 0.1 ml (mild ALI). After two DIs, elastance was tracked for 10 min followed by a full lavage to assess surfactant proteins B (SP-B) and C (SP-C) content. Following 2 DIs, the increases in elastance during 10 min ventilation (ΔH) were 3.60 ± 0.61, 5.35 ± 1.04, and 8.33 ± 0.84 cmH2O/ml in baseline mice and mice with mild and severe ALI, respectively (P < 0.0001). SP-B and SP-C in the lavage fluid dropped by 32.4% and 24.9% in the mild and 50.4% and 39.6% in the severe ALI, respectively. Furthermore, ΔH showed a strong negative correlation with both SP-B (r(2) = 0.801) and SP-C (r(2) = 0.810) content. The ΔH was, however, much smaller when the lavage fluid also contained exogeneous SP-B and SP-C. Thus ΔH can be interpreted as an organ level measure of surface film functionality in lavage-induced ALI in mice. This method could prove useful in clinical situations such as diagnosing surfactant problems, monitoring recovery from lung injury or the effectiveness of surfactant therapy.
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Affiliation(s)
- Ayuko Takahashi
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts
| | | | - Arnab Majumdar
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts
| | - Béla Suki
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts
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Curstedt T, Halliday HL, Speer CP. A unique story in neonatal research: the development of a porcine surfactant. Neonatology 2015; 107:321-9. [PMID: 26044099 DOI: 10.1159/000381117] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Surfactant deficiency was identified as the cause of respiratory distress syndrome (RDS) as long ago as 1959. Trials of surfactant replacement in the 1960s were unsuccessful because the preparations used contained only phospholipids and they were administered inefficiently by nebulization. In the 1970s Bengt Robertson and Göran Enhörning showed that natural surfactant, containing both phospholipids and proteins, could ameliorate the signs of RDS in immature rabbits. In the 1980s Bengt Robertson and Tore Curstedt developed a porcine surfactant, Curosurf (named after their surnames), which was effective in immature animals and was used in a pilot clinical trial beginning in 1983. Subsequent randomized clinical trials were planned a year later by Bengt Robertson, Tore Curstedt and Henry Halliday, and the first trial was begun in 1985. This showed that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS. A second trial, coordinated by Christian Speer, demonstrated that multiple doses of Curosurf were more effective than a single dose. Subsequent trials conducted by the Collaborative European Multicenter Study Group, which included among others Guilio Bevilacqua, Janna Koppe, Ola Saugstad, Nils Svenningsen and Jean-Pierre Relier, showed that early treatment was more effective than later administration and that infants treated at birth had similar neurodevelopmental status to untreated controls at a corrected age of 2 years. Members of the Collaborative European Multicenter Study Group in Denmark and Sweden performed studies to demonstrate the benefits of a combination of surfactant treatment and early continuous positive airway pressure. Curosurf has also been compared with several synthetic and natural surfactants, and at a dose of 200 mg/kg Curosurf has been shown to be superior to either Survanta or Curosurf used at a dose of 100 mg/kg. Recently, new-generation synthetic surfactants containing both phospholipids and proteins have been developed. After preclinical testing, CHF5633 (developed by Tore Curstedt and Jan Johansson in collaboration with Chiesi Farmaceutici) has undergone a preliminary first study in humans under the guidance of Christian Speer. If effective, this new surfactant preparation could revolutionize the treatment of preterm infants worldwide as it could be made consistently and safely in almost unlimited quantities. This story of a porcine surfactant preparation has been truly remarkable, and many thousands of preterm babies worldwide are now alive and well because of it.
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Affiliation(s)
- Tore Curstedt
- Section of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
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31
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Simulation training for surfactant replacement therapy: Implications for clinical practice. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.jnn.2014.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Goikoetxea E, Murgia X, Serna-Grande P, Valls-i-Soler A, Rey-Santano C, Rivas A, Antón R, Basterretxea FJ, Miñambres L, Méndez E, Lopez-Arraiza A, Larrabe-Barrena JL, Gomez-Solaetxe MA. In vitro surfactant and perfluorocarbon aerosol deposition in a neonatal physical model of the upper conducting airways. PLoS One 2014; 9:e106835. [PMID: 25211475 PMCID: PMC4161382 DOI: 10.1371/journal.pone.0106835] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 08/02/2014] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Aerosol delivery holds potential to release surfactant or perfluorocarbon (PFC) to the lungs of neonates with respiratory distress syndrome with minimal airway manipulation. Nevertheless, lung deposition in neonates tends to be very low due to extremely low lung volumes, narrow airways and high respiratory rates. In the present study, the feasibility of enhancing lung deposition by intracorporeal delivery of aerosols was investigated using a physical model of neonatal conducting airways. METHODS The main characteristics of the surfactant and PFC aerosols produced by a nebulization system, including the distal air pressure and air flow rate, liquid flow rate and mass median aerodynamic diameter (MMAD), were measured at different driving pressures (4-7 bar). Then, a three-dimensional model of the upper conducting airways of a neonate was manufactured by rapid prototyping and a deposition study was conducted. RESULTS The nebulization system produced relatively large amounts of aerosol ranging between 0.3±0.0 ml/min for surfactant at a driving pressure of 4 bar, and 2.0±0.1 ml/min for distilled water (H2Od) at 6 bar, with MMADs between 2.61±0.1 µm for PFD at 7 bar and 10.18±0.4 µm for FC-75 at 6 bar. The deposition study showed that for surfactant and H2Od aerosols, the highest percentage of the aerosolized mass (∼65%) was collected beyond the third generation of branching in the airway model. The use of this delivery system in combination with continuous positive airway pressure set at 5 cmH2O only increased total airway pressure by 1.59 cmH2O at the highest driving pressure (7 bar). CONCLUSION This aerosol generating system has the potential to deliver relatively large amounts of surfactant and PFC beyond the third generation of branching in a neonatal airway model with minimal alteration of pre-set respiratory support.
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Affiliation(s)
- Estibalitz Goikoetxea
- Research Unit for Experimental Neonatal Respiratory Physiology, Cruces University Hospital, Barakaldo, Bizkaia, Spain
- Thermal and Fluids Engineering Division, Mechanical Engineering Department, TECNUN, University of Navarra, San Sebastian, Gipuzkoa, Spain
| | - Xabier Murgia
- Research Unit for Experimental Neonatal Respiratory Physiology, Cruces University Hospital, Barakaldo, Bizkaia, Spain
| | - Pablo Serna-Grande
- Research Unit for Experimental Neonatal Respiratory Physiology, Cruces University Hospital, Barakaldo, Bizkaia, Spain
| | - Adolf Valls-i-Soler
- Neonatal Intensive Care Unit, Cruces University Hospital, Barakaldo, Bizkaia, Spain
| | - Carmen Rey-Santano
- Research Unit for Experimental Neonatal Respiratory Physiology, Cruces University Hospital, Barakaldo, Bizkaia, Spain
| | - Alejandro Rivas
- Thermal and Fluids Engineering Division, Mechanical Engineering Department, TECNUN, University of Navarra, San Sebastian, Gipuzkoa, Spain
| | - Raúl Antón
- Thermal and Fluids Engineering Division, Mechanical Engineering Department, TECNUN, University of Navarra, San Sebastian, Gipuzkoa, Spain
| | - Francisco J. Basterretxea
- Department of Physical Chemistry, Faculty of Science and Technology, University of the Basque Country, Leioa, Bizkaia, Spain
| | - Lorena Miñambres
- Department of Physical Chemistry, Faculty of Science and Technology, University of the Basque Country, Leioa, Bizkaia, Spain
| | - Estíbaliz Méndez
- Department of Physical Chemistry, Faculty of Science and Technology, University of the Basque Country, Leioa, Bizkaia, Spain
| | - Alberto Lopez-Arraiza
- Department of Electronics and Electrotechnics, High Technical School of Maritime Studies, University of the Basque Country, Bilbao, Bizkaia, Spain
| | - Juan Luis Larrabe-Barrena
- Department of Electronics and Electrotechnics, High Technical School of Maritime Studies, University of the Basque Country, Bilbao, Bizkaia, Spain
| | - Miguel Angel Gomez-Solaetxe
- Department of Electronics and Electrotechnics, High Technical School of Maritime Studies, University of the Basque Country, Bilbao, Bizkaia, Spain
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