Surfactant administration methods for premature newborns: LISA vs. INSURE comparative analysis.

INTRODUCTION: Respiratory Distress Syndrome (RDS) is the most common respiratory disorder among premature infants. The use of surfactant has significantly reduced respiratory complications and mortality. There are two conventional methods for administering surfactant: Intubate-Surfactant-Extubate (INSURE) and Less Invasive Surfactant Administration (LISA). This study aims to compare the effects of surfactant administration using these two methods on the treatment outcomes of premature newborns. MATERIALS AND METHODS: In this retrospective cohort study, we included 100 premature newborns with RDS and spontaneous breathing who were admitted to the Neonatal Intensive Care Unit of Besat Hospital in Sanandaj city in 2021. Exclusion criteria comprised congenital anomalies and the needing for intubation for resuscitation at birth. The outcomes of epmericaly trated with two methods were compared: the LISA (50 neonates) and the INSURE (50 neonates). Our interesting outcomes were needing for mechanical ventilation, duration of ventilation, pneumothorax, pulmonary hemorrhage, severe retinopathy, CPAP duration, and bronchopulmonary dysplasia. Finally, we entered the data into STATA-14 statistical software and analyzed it using chi-square and t-tests. RESULTS: In this study, 69% of the neonates were boys. The LISA group exhibited significantly lower rates of need for mechanical ventilation (P = 0.003) and ventilation duration (P < 0.001) compared to the INSURE group. Conversely, there were no significant differences between the two groups (P > 0.05) in terms of pneumothorax, pulmonary hemorrhage, severe retinopathy, CPAP duration, and bronchopulmonary dysplasia rates. CONCLUSION: The results of this study suggest that the LISA method is a safe and non-invasive approach for surfactant administration. Notably, it resulted in a reduced need for mechanical ventilation and decreased ventilation duration compared to the INSURE method.

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OBJECTIVES: To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. METHODS: A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. RESULTS: The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). CONCLUSIONS: The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

[Efficacy and safety of inhalation of pulmonary surfactant using vibrating mesh nebulizers combined with nasal continuous positive airway pressure in the treatment of neonatal respiratory distress syndrome].

OBJECTIVE: To investigate the efficacy and safety of nasal continuous positive airway pressure (NCPAP) combined with inhalation of pulmonary surfactant (PS) using vibrating mesh nebulizers in the treatment of neonatal respiratory distress syndrome (RDS). METHODS: A prospective study was performed on premature infants with RDS admitted to the First Affiliated Hospital of Bengbu Medical College between December 2020 and June 2021. They were randomly assigned into vibrating mesh atomization technology group and intubation-surfactant-extubation (INSURE) technology group. The two groups were treated with NCPAP combined with PS. PS in the vibrating mesh atomization technology group was inhaled into the lungs by the new vibrating mesh atomization technology, while PS in the INSURE group was injected into the lungs by endotracheal tube. The pH value, arterial partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), mechanical ventilation via endotracheal tube (MVET) demand rate, duration of respiratory support, secondary use of PS, complications, and hospital mortality were compared between the two groups. The occurrences of adverse events in the two groups were recorded. RESULTS: A total of 42 preterm infants were finally enrolled, including 20 cases in the vibrating mesh atomization technology group and 22 cases in the INSURE technology group. There were no significant differences in blood gas analysis and PaO2/FiO2 before PS administration between the two groups. One hour after PS administration, blood gas analysis and PaO2/FiO2 were significantly improved in both groups. Compared with the INSURE technology group, the improvement of PaO2/FiO2 was more obvious in the vibrating mesh atomization technology group [mmHg (1 mmHg≈0.133 kPa): 198±34 vs. 173±39, P < 0.05], but no significant difference in pH value or PaCO2 was found between the two groups. The duration of respiratory support in the vibrating mesh atomization technology group was significantly shorter than that in the INSURE technology group (hours: 96±13 vs. 120±18, P < 0.01), but there was no statistical difference in MVET demand rate [5.0% (1/20) vs. 13.6% (3/22), P > 0.05]. The incidence of periventricular-intraventricular hemorrhage (PVH-IVH) in the vibrating mesh atomization technology group was less than that in the INSURE technology group [0% (0/20) vs. 18.2% (4/22)], but no statistical difference was found (P > 0.05). No significant differences in the secondary use rate of PS and incidence of bronchopulmonary dysplasia (BPD) or other complications were found between the vibrating mesh atomization technology group and the INSURE technology group [5.0% (1/20) vs. 9.1% (2/22), 5.0% (1/20) vs. 4.5% (1/22), both P > 0.05]. There were no deaths or serious adverse events such as pneumothorax, pulmonary hemorrhage, periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC) in both groups. CONCLUSIONS: Compared with the INSURE technique, NCPAP combined with vibrating mesh atomization technology was also effective and safe in the treatment of RDS, which could significantly improve PaO2/FiO2 and shorten the duration of respiratory support. Thus, it was worthy of clinical popularization and application.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

The possible effect of pentoxifylline on development and severity of retinopathy of prematurity.

BACKGROUND AND AIM: Retinopathy of prematurity (ROP) is the major ocular problem of preterm infants that occurs with abnormal proliferation of immature retinal vessels. Although pentoxifylline (PTX) was reported to inhibit vasculogenesis and neovascularization in experimental studies, there is no clinical data about the effects of PTX treatment on the development and severity of ROP. This clinical study aimed to investigate the possible effects of PTX on the development of ROP. MATERIALS AND METHODS: A single-centre retrospective study was conducted including preterm infants who were hospitalised in the neonatal intensive care unit between 2015-2017 years. Infants were divided into two groups in terms of PTX administration for adjuvant therapy, as PTX and non-PTX groups. RESULTS: A total of 211 infants were included in the study [gestational age 29 (27-31) weeks, birth weight 1140 (960-1340) g]. From these, 97 infants (46%) were given PTX treatment. The two groups were similar in terms of demographic data and baseline clinical characteristics. Any stage of ROP was detected in 47.4% of infants in the PTX group, which was significantly higher than those in the non-PTX group (27.2%) (p = 0.002). The incidence of advanced-stage ROP in the PTX group (10.3%) was also higher than in the non-PTX group (2.6%) (p = 0.021). Repeated usage of PTX was not found to be related to the development of ROP (p = 0.059). The time of PTX administration was similar between the ROP and no-ROP groups (median; one vs one week, p = 0.825). Surfactant therapy, duration of hospital stay, and PTX treatment were found as significant risk factors for ROP in the logistic regression analysis. CONCLUSIONS: In contrast to the experimental studies and also promising results of PTX treatment in some neonatal morbidities, it may be associated with increased incidence and stage of ROP.

Bi-level Nasal Positive Airway Pressure (BiPAP) versus Nasal Continuous Positive Airway Pressure (CPAP) for Preterm Infants with Birth Weight Less Than 1500 g and Respiratory Distress Syndrome Following INSURE Treatment: A Two-center Randomized Controlled Trial.

The present study aimed to examine the effectiveness of bi-level positive airway pressure (BiPAP) versus continuous positive airway pressure (CPAP) in preterm infants with birth weight less than 1500 g and respiratory distress syndrome (RDS) following intubation-surfactant-extubation (INSURE) treatment. A two-center randomized control trial was performed. The primary outcome was the reintubation rate of infants within 72 h of age after INSURE. Secondary outcomes included bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP) and incidences of adverse events. Lung function at one year of corrected age was also compared between the two groups. There were 140 cases in the CPAP group and 144 in the BiPAP group. After INSURE, the reintubation rates of infants within 72 h of age were 15% and 11.1% in the CPAP group and the BiPAP group, respectively (P>0.05). Neonates in the BiPAP group was on positive airway pressure (PAP) therapy three days less than in the CPAP group (12.6 d and 15.3 d, respectively, P<0.05), and on oxygen six days less than in the CPAP group (20.6 d and 26.9 d, respectively, P<0.05). Other outcomes such as BPD, NEC, ROP and feeding intolerance were not significantly different between the two groups (P>0.05). There was no difference in lung function at one year of age between the two groups (P>0.05). In conclusion, after INSURE, the reintubation rate of infants within 72 h of age was comparable between the BiPAP group and the CPAP group. BiPAP was superior to CPAP in terms of shorter durations (days) on PAP support and oxygen supplementation. There were no differences in the incidences of BPD and ROP, and lung function at one year of age between the two ventilation methods.

Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia.

OBJECTIVE: To test the hypothesis that lung ultrasound (LUS) performed in the first week of life would predict bronchopulmonary dysplasia (BPD). Secondary outcomes included the utility of LUS in predicting interim respiratory interventions. DESIGN: A prospective observational cohort study in preterm infants born <28 weeks' gestation in the single tertiary statewide neonatal intensive care unit in Western Australia. METHODS: A rigorous protocol for LUS acquisition on day 1, day 3-4, day 7, day 28 and 36 weeks' postmenstrual age (PMA) was implemented with blinded analysis using a modified, previously validated LUS score. BPD was defined by both recent National Institute of Child Health and Human Development categorical criteria and a continuous physiological variable using a modified Shift test. RESULTS: Of the 100 infants studies, primary outcome data were available for the 96 infants, surviving to 36 weeks' PMA. In a univariate logistic regression analysis, LUS on days 3-4 and day 7 accurately predicted BPD (day 3-4 OR (95% CI)=1.54 (1.03 to 2.42), p=0.044; day 7 OR (95% CI)=1.66 (1.07 to 2.70), p=0.031). The predictive value of LUS was insignificant in a multivariate model in which gestational age was the dominant predictor. LUS accurately predicted interim respiratory outcomes including surfactant administration, duration of intubation and extubation to non-invasive support at 48 hours. CONCLUSIONS: LUS in the first week of life predicted BPD. However, LUS offers little additive accuracy to current gestational age-based models. TRIAL REGISTRATION NUMBER: ACTRN12617000208303.

Proposal of selective wedge instillation of pulmonary surfactant for COVID-19 pneumonia based on computational fluid dynamics simulation.

BACKGROUND: The most important target cell of SARS-CoV-2 is Type II pneumocyte which produces and secretes pulmonary surfactant (PS) that prevents alveolar collapse. PS instillation therapy is dramatically effective for infant respiratory distress syndrome but has been clinically ineffective for ARDS. Nowadays, ARDS is regarded as non-cardiogenic pulmonary edema with vascular hyper-permeability regardless of direct relation to PS dysfunction. However, there is a possibility that this ineffectiveness of PS instillation for ARDS is caused by insufficient delivery. Then, we performed PS instillation simulation with realistic human airway models by the use of computational fluid dynamics, and investigated how instilled PS would move in the liquid layer covering the airway wall and reach to alveolar regions. METHODS: Two types of 3D human airway models were prepared: one was from the trachea to the lobular bronchi and the other was from a subsegmental bronchus to respiratory bronchioles. The thickness of the liquid layer covering the airway was assigned as 14 % of the inner radius of the airway segment. The liquid layer was assumed to be replaced by an instilled PS. The flow rate of the instilled PS was assigned a constant value, which was determined by the total amount and instillation time in clinical use. The PS concentration of the liquid layer during instillation was computed by solving the advective-diffusion equation. RESULTS: The driving pressure from the trachea to respiratory bronchioles was calculated at 317 cmH2O, which is about 20 times of a standard value in conventional PS instillation method where the driving pressure was given by difference between inspiratory and end-expiratory pressures of a ventilator. It means that almost all PS does not reach the alveolar regions but moves to and fro within the airway according to the change in ventilator pressure. The driving pressure from subsegmental bronchus was calculated at 273 cm H2O, that is clinically possible by wedge instillation under bronchoscopic observation. CONCLUSIONS: The simulation study has revealed that selective wedge instillation under bronchoscopic observation should be tried for COVID-19 pneumonia before the onset of ARDS. It will be also useful for preventing secondary lung fibrosis.

Effectiveness of Pulmonary Surfactant in the Treatment of Corneal Edema.

Purpose: To compare the effectiveness of topical surfactant and 3% sodium chloride (NaCl) in the treatment of corneal edema occurring after cataract surgery. Methods: Ninety eyes of 90 patients with no corneal disease who underwent cataract surgery were included in the study. Thirty eyes without corneal edema comprised group 1. Patients with corneal edema were divided into two groups: those treated with 3% NaCl (group 2, 30 eyes) and those treated with surfactant drop (group 3, 30 eyes). Results: The mean age was 70.8 ± 6.6 years, with no significant age difference between the groups. Preoperatively, there was no significant difference in mean central corneal thickness (CCT) or mean endothelial cell count (ECC) among the groups (P = 0.999). On postoperative day 1, CCT was significantly lower in group 1 (P < 0.001) but did not differ between groups 2 and 3 (P = 0.999). There was no significant difference between groups in terms of ECC (P > 0.05). At postoperative day 7 and 14, CCT differed significantly between groups 1 and 2 (P < 0.001) and between groups 2 and 3 (P = 0.001), with no significant difference between groups 1 and 3 (P = 0.474). ECC was significantly higher in group 1 (P < 0.05), whereas there was no significant difference between groups 2 and 3 (P > 0.05). Conclusion: Topical pulmonary surfactant may be a more effective treatment option than 3% hypertonic NaCl for the treatment of corneal edema that develops after cataract surgery.

Comparative efficacy of methods for surfactant administration: a network meta-analysis.

OBJECTIVES: To compare surfactant administration via thin catheters, laryngeal mask, nebulisation, pharyngeal instillation, intubation and surfactant administration followed by immediate extubation (InSurE) and no surfactant administration. DESIGN: Network meta-analysis. SETTING: Medline, Scopus, CENTRAL, Web of Science, Google-scholar and Clinicaltrials.gov databases were systematically searched from inception to 15 February 2020. PATIENTS: Preterm neonates with respiratory distress syndrome. INTERVENTIONS: Less invasive surfactant administration. MAIN OUTCOME MEASURES: The primary outcomes were mortality, mechanical ventilation and bronchopulmonary dysplasia. RESULTS: Overall, 16 randomised controlled trials (RCTs) and 20 observational studies were included (N=13 234). For the InSurE group, the median risk of mortality, mechanical ventilation and bronchopulmonary dysplasia were 7.8%, 42.1% and 10%, respectively. Compared with InSurE, administration via thin catheter was associated with significantly lower rates of mortality (OR: 0.64, 95% CI: 0.54 to 0.76), mechanical ventilation (OR: 0.43, 95% CI: 0.29 to 0.63), bronchopulmonary dysplasia (OR: 0.57, 95% CI: 0.44 to 0.73), periventricular leukomalacia (OR: 0.66, 95% CI: 0.53 to 0.82) with moderate quality of evidence and necrotising enterocolitis (OR: 0.67, 95% CI: 0.41 to 0.9, low quality of evidence). No significant differences were observed by comparing InSurE with administration via laryngeal mask, nebulisation or pharyngeal instillation. In RCTs, thin catheter administration lowered the rates of mechanical ventilation (OR: 0.39, 95% CI: 0.26 to 0.60) but not the incidence of the remaining outcomes. CONCLUSION: Among preterm infants, surfactant administration via thin catheters was associated with lower likelihood of mortality, need for mechanical ventilation and bronchopulmonary dysplasia compared with InSurE. Further research is needed to reach firm conclusions about the efficacy of alternative minimally invasive techniques of surfactant administration.

Surfactant therapy for COVID-19 related ARDS: a retrospective case-control pilot study.

BACKGROUND: COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. METHODS: We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. RESULTS: Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. CONCLUSIONS: Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.

Restoration of surfactant activity by polymyxin B in lipopolysaccharide-potentiated injury of immature rabbit lungs.

During postnatal adaptation pulmonary surfactant may be inactivated by lipopolysaccharide (LPS). We evaluated the effect of surfactant therapy in combination with antibiotic polymyxin B (PxB) in double-hit model of neonatal lung injury. Surfactant (poractant alfa, Curosurf) was exposed to smooth (S) LPS without/with PxB and tested in captive bubble surfactometer. Preterm rabbits received intratracheally saline (control) or S-LPS and were ventilated with 100% oxygen. After 30 min, LPS-treated animals received no treatment, or surfactant (200 mg/kg) without/with 3% PxB; controls received the same dose of surfactant. Animals were ventilated for further 2 h. In vitro, addition of 5% S-LPS to surfactant increased minimum surface tension (γmin) and addition of 1-3% PxB to surfactant/S-LPS mixture restored γmin to low values. Animals only given S-LPS had lower lung compliance and lung gas volume (LGV) compared to surfactant groups. Treatment with surfactant/PxB, but not with surfactant only, restored LGV. Addition of PxB to the surfactant increased the alveolar expansion. S-LPS interferes with surface activity of the pulmonary surfactant and PxB improves the resistance of surfactant to LPS-induced inactivation. In our neonatal model of respiratory distress syndrome surfactant gives positive response even in simultaneous exposure to S-LPS, when enriched with PxB.

Clinical evaluation of an application aid for less-invasive surfactant administration (LISA).

BACKGROUND: Less-invasive surfactant administration (LISA) is increasingly used. We investigated the feasibility of a new LISA-device (Neofact®) in neonates. DESIGN: Prospective observational pilot study with open-label LISA in two tertiary neonatal intensive care units. PATIENTS: 20 infants with a gestational age of ≥26+0/7 weeks and an indication for LISA (Respiratory Severity Score (RSS)≥5 or fraction of inspired oxygen (FiO2) ≥0.30). Infants with respiratory tract malformations or unavailability of an instructed neonatologist were excluded. MAIN OUTCOME MEASURES: Success of LISA, defined as laryngoscopy-confirmed intratracheal catheter position or a decrease in FiO2 by ≥0.05 or to 0.21, accompanied by an RSS decrease of ≥2; number of attempts needed for tracheal catheterisation. RESULTS: 20/57 screened infants were enrolled. Successful application occurred in 19/20 (95%). One application failed after three attempts. No device-related adverse events occurred. The median number of attempts was 2, success rate per attempt 19/31 (61%). CONCLUSION: LISA via Neofact® appears feasible.

Retratamento com surfactante em prematuros de muito baixo peso: preditores de risco e sua influência nos resultados neonatais / Retreatment with surfactant in very low birth weight preterm infants: risk predictors and their influence on neonatal outcomes

ABSTRACT Objective: To assess clinical predictors and outcomes associated to the need for surfactant retreatment in preterm infants. Methods: Retrospective cohort study, including very low birth weight preterm infants from January 2006 to December 2015 who underwent surfactant replacement therapy. Beractant was used (100 mg/kg), repeated every six hours if FiO2 ≥0.40. The subjects were classified into two groups: single surfactant dose; and more than one dose (retreatment). We evaluated maternal and neonatal predictors for the need of retreatment and neonatal outcomes associated to retreatment. Results: A total of 605 patients (44.5%) received surfactant; 410 (67.8%) one dose, and 195 (32.2%) more than one dose: 163 (83.5%) two doses and 32 (16.4%) three doses. We could not find clinical predictors for surfactant retreatment. Retreatment was associated to a greater chance of BPD in infants >1000 g (RR 1.78; 95%CI 1.30‒2.45) and ≤1000 g (RR 1.33; 95%CI 1.04‒1.70), in infants with gestational age<28 weeks (RR 1.56; 95%CI 1.12‒2.18) and ≥28 weeks (RR 1.50; 95%CI 1.17‒1.92), in neonates with early sepsis (RR 1.48; 95%CI 1.20‒1.81), and in infants not exposed to antenatal corticosteroids (RR 1.62; 95%CI 1.20‒2.17) Conclusions: We could not find predictor factors associated to surfactant retreatment. The need for two or more doses of surfactant was significantly related to bronchopulmonary dysplasia.

RESUMO Objetivo: Avaliar preditores clínicos e resultados associados à necessidade de retratamento com surfactante. Métodos: Coorte retrospectiva com prematuros de muito baixo peso, no período de janeiro de 2006 a dezembro de 2015, em uso de terapia de reposição de surfactante. O surfactante utilizado foi beractante (100 mg/kg), repetido a cada seis horas se FiO2≥0.40. Foram analisados dois grupos: dose única de surfactante e mais de uma dose (retratamento). Foram avaliados preditores maternos e neonatais para retratamento e resultados neonatais. Resultados: 605 pacientes (44,5%) receberam surfactante; 410 (67,8%) uma dose e 195 (32,2%) mais de uma dose: 163 (83,5%) duas doses e 32 (16.4%) três doses. Não foram encontrados fatores associados ao retratamento com surfactante. A displasia broncopulmonar (DBP) foi associada ao retratamento (p<0.01). A presença de retratamento aumentou a chance de ocorrência de DBP em neonatos >1000 g (RR 1,78; IC95% 1,30‒2,45) e ≤1000 g (RR 1,33; IC95% 1,04‒1,70), em recém-nascidos com idade gestacional <28 semanas (RR 1,56; IC95% 1,12‒218) e ≥28 semanas (RR 1,50; IC95% 1,17‒1,92), naqueles com sepse precoce (RR 1,48; IC95% 1,20‒1,81), e nos que não foram expostos ao corticoide antenatal (RR 1,62; IC95% 1,20‒2,17). Conclusões: Não encontramos fatores preditores associados à necessidade de retratamento. A necessidade de duas ou mais doses de surfactante está associada à displasia broncopulmonar.

RETREATMENT WITH SURFACTANT IN VERY LOW BIRTH WEIGHT PRETERM INFANTS: RISK PREDICTORS AND THEIR INFLUENCE ON NEONATAL OUTCOMES.

OBJECTIVE: To assess clinical predictors and outcomes associated to the need for surfactant retreatment in preterm infants. METHODS: Retrospective cohort study, including very low birth weight preterm infants from January 2006 to December 2015 who underwent surfactant replacement therapy. Beractant was used (100 mg/kg), repeated every six hours if FiO2 ≥0.40. The subjects were classified into two groups: single surfactant dose; and more than one dose (retreatment). We evaluated maternal and neonatal predictors for the need of retreatment and neonatal outcomes associated to retreatment. RESULTS: A total of 605 patients (44.5%) received surfactant; 410 (67.8%) one dose, and 195 (32.2%) more than one dose: 163 (83.5%) two doses and 32 (16.4%) three doses. We could not find clinical predictors for surfactant retreatment. Retreatment was associated to a greater chance of BPD in infants >1000 g (RR 1.78; 95%CI 1.30‒2.45) and ≤1000 g (RR 1.33; 95%CI 1.04‒1.70), in infants with gestational age<28 weeks (RR 1.56; 95%CI 1.12‒2.18) and ≥28 weeks (RR 1.50; 95%CI 1.17‒1.92), in neonates with early sepsis (RR 1.48; 95%CI 1.20‒1.81), and in infants not exposed to antenatal corticosteroids (RR 1.62; 95%CI 1.20‒2.17). CONCLUSIONS: We could not find predictor factors associated to surfactant retreatment. The need for two or more doses of surfactant was significantly related to bronchopulmonary dysplasia.

Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy.

RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be activated by cytosolic delivery of small interfering RNA (siRNA), inducing sequence-specific gene knockdown on the post-transcriptional level. Although siRNA drugs hold many advantages over currently applied therapies, their clinical translation is hampered by inefficient delivery across cellular membranes. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel core (nanogel) coated with Curosurf®, a clinically used pulmonary surfactant (PS). The latter enhances both particle stability as well as intracellular siRNA delivery, which was shown to be governed by the PS-associated surfactant protein B (SP-B). Despite having a proven in vitro and in vivo siRNA delivery potential when prepared ex novo, clinical translation of this liquid nanoparticle suspension requires the identification of a long-term preservation strategy that maintains nanoparticle stability and potency. In addition, to achieve optimal pulmonary deposition of the nanocomposite, its compatibility with state-of-the-art pulmonary administration techniques should be evaluated. Here, we demonstrate that PS-coated nanogels can be lyophilized, reconstituted and subsequently nebulized via a vibrating mesh nebulizer. The particles retain their physicochemical integrity and their ability to deliver siRNA in a human lung epithelial cell line. The latter result suggests that the functional integrity of SP-B in the PS coat towards siRNA delivery might be preserved as well. Of note, successful lyophilization was achieved without the need for stabilizing lyo- or cryoprotectants. Our results demonstrate that PS-coated siRNA-loaded nanogels can be lyophilized, which offers the prospect of long-term storage. In addition, the formulation was demonstrated to be suitable for local administration with a state-of-the-art nebulizer for human use upon reconstitution. Hence, the data presented in this study represent an important step towards clinical application of such nanocomposites for treatment of pulmonary disease.

DMBT1 is upregulated in lung epithelial cells after hypoxia and changes surfactant ultrastructure.

BACKGROUND: Hypoxia and asphyxia are known to induce surfactant inactivation in newborns. Deleted in Malignant Brain Tumors 1 (DMBT1) is an innate immunity protein with functions in epithelial differentiation and angiogenesis. It was detected in hyaline membranes of infants with respiratory distress syndrome. Human recombinant DMBT1 is able to increase the surface tension of exogenous surfactant preparations in a dose-dependent manner. METHODS: Immunohistochemistry was performed on lung sections of infants who died due to pre-, peri- or postnatal hypoxia. The lung epithelial cell line A549 was stably transfected with a DMBT1 (DMBT1+ cells) expression plasmid or with an empty plasmid (DMBT1- cells). The cells were cultured in normoxic or hypoxic conditions, and then DMBT1 as well as HIF-1α RNA expression were analyzed by using real-time-polymerase chain reaction. Human recombinant DMBT1 was added to the modified porcine natural surfactant Curosurf to examine the effect of DMBT1 on surfactant ultrastructure with electron microscopy. RESULTS: DMBT1 expression was upregulated in human lung tissue after fetal/peri-/postnatal hypoxia. In addition, in vitro experiments showed increased DMBT1 RNA expression in A549 cells after hypoxia. HIF-1α was upregulated in both DMBT1+ and DMBT1- cells in response to hypoxia. The addition of human recombinant DMBT1 to Curosurf caused an impaired surfactant ultrastructure. CONCLUSIONS: DMBT1 is upregulated in response to hypoxia and there seems to be a link between hypoxia and surfactant inactivation.

Effect of low-dose exogenous surfactant on infants with acute respiratory distress syndrome after cardiac surgery: a retrospective analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) in infants undergoing cardiac surgery is associated with significant mortality and prolonged ventilation; surfactant administration may be a useful therapy. The purpose of this study is to evaluate the effect of low-dose exogenous surfactant therapy on infants suffering ARDS after cardiac surgery. METHODS: We conducted a case-control study of infants diagnosed with moderate-to-severe ARDS (PaO2/FiO2 < 150) after cardiac surgery. A case was defined as a patient that received surfactant and standard therapy, while a control was defined as a patient that underwent standard therapy. The primary endpoint was the improvement in oxygenation index (OI) after 24-h of surfactant treatment; and secondary endpoints were the ventilator time and PICU time. RESULTS: Twenty-two infants treated with surfactant were matched with 22 controls. Early low-dose (20 mg/kg) surfactant treatment was associated with improved outcomes. After surfactant administration for 24-h, the surfactant group was much better compared with the control group at the 24-h in OI (difference in average change from baseline, - 6.7 [95% CI, - 9.3 to - 4.1]) (P < 0.01) and ventilation index (VI, mean difference, - 11.9 [95% CI, - 18.1 to - 5.7]) (P < 0.01). Ventilation time and PICU time were significantly shorter in the surfactant group compared with the control group (133.6 h ± 27.2 vs 218.4 h ± 28.7, P < 0.01; 10.7d ± 5.1 vs 17.5d ± 6.8, P < 0.01). Infants in the surfactant group under 3 months benefit more from OI and VI than the infants over 3 months in a preliminary exploratory analysis. CONCLUSIONS: In infants with moderate-to-severe ARDS after cardiac surgery, early low-dose exogenous surfactant treatment could prominently improve oxygenation and reduce mechanical ventilation time and PICU time. Infants younger than 3 months may get more benefit of oxygenation than the older ones. Randomized controlled trials are needed to explore the effect of surfactant to ARDS of cardiac surgical infants.