Less Invasive Surfactant Administration (LISA) Versus INSURE Method in Preterm Infants: a Retrospective Study.

Background: Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in preterm infants. Early nasal CPAP and selective administration of surfactant via the endotracheal tube are widely used in the treatment of RDS in preterm infants. Objective: The aim of this study was to compare the need for intubation and mechanical ventilation after surfactant delivery between LISA-treated and INSURE-treated premature infants with respiratory distress syndrome (RDS). Methods: Retrospective registry-based cohort study enrolled 36 newborns admitted to the neonatal intensive care unit of the "Santa Maria" Hospital of Terni between 2016 and 2023. As a primary outcome, we followed the need for intubation and mechanical ventilation within 72 hours of life, while the secondary outcomes were major neonatal morbidities and death before discharge. Results: The LISA group and the INSURE group included 13 and 23 newborns respectively. Demographic features showed no significant differences between the two groups. The need for mechanical ventilation in the first 72 hours of life was similar in both groups (p >0.99). There were no significant differences in morbidities. Conclusion: LISA and INSURE are equally effective modalities for surfactant administration for the treatment of RDS in preterm infants.

Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. METHODS AND FINDINGS: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. CONCLUSIONS: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

Nasal intermittent positive pressure ventilation during less invasive surfactant administration in preterm infants: An open-label randomized controlled study.

INTRODUCTION: Approximately half of very preterm infants with respiratory distress syndrome (RDS) fail treatment with nasal continuous positive airway pressure (NCPAP) and need mechanical ventilation (MV). OBJECTIVES: Our aim with this study was to evaluate if nasal intermittent positive pressure ventilation (NIPPV) during less invasive surfactant treatment (LISA) can improve respiratory outcome compared with NCPAP. MATERIALS AND METHODS: We carried out an open-label randomized controlled trial at tertiary neonatal intensive care units in which infants with RDS born at 25+0-31+6 weeks of gestation between December 1, 2020 and October 31, 2022 were supported with NCPAP before and after surfactant administration and received NIPPV or NCPAP during LISA. The primary endpoint was the need for a second dose of surfactant or MV in the first 72 h of life. Other endpoints were need and duration of invasive and noninvasive respiratory supports, changes in SpO2/FiO2 ratio after LISA, and adverse effect rate. RESULTS: We enrolled 101 infants in the NIPPV group and 99 in the NCPAP group. The unadjusted odds ratio for the composite primary outcome was 0.873 (95% confidence interval: 0.456-1.671; p = .681). We found that the SpO2/FiO2 ratio was transiently higher in the LISA plus NIPPV than in the LISA plus NCPAP group, while adverse effects of LISA had similar occurrence in the two arms. CONCLUSIONS: The application of NIPPV or NCPAP during LISA in very preterm infants supported with NCPAP before and after surfactant administration had similar effects on the short-term respiratory outcome and are both safe. Our study does not support the use of NIPPV during LISA.

Use of surfactant beyond respiratory distress syndrome, what is the evidence?

Surfactant replacement therapy is currently approved by the United States Food and Drug Administration (FDA) for premature infants with respiratory distress syndrome (RDS) caused by surfactant deficiency due to immaturity. There is strong evidence that surfactant decreases mortality and air leak syndromes in premature infants with RDS. However, surfactant is also used "off-label" for respiratory failure beyond classic RDS. This review discusses current evidence for the use of off-label surfactant therapy for (1) term infants with lung disease such as meconium aspiration syndrome (MAS), pneumonia/sepsis, and congenital diaphragmatic hernia (2) premature infants after 72 h for acute respiratory failure, and (3) the use of surfactant lavage. At last, we briefly describe the use of surfactants for drug delivery and the current evidence on evaluating infants for surfactant deficiency.

Creation of a rating scale to teach Less Invasive Surfactant Administration (LISA) in simulation.

BACKGROUND: Simulation-based training is gaining increasing prominence in neonatology training. The Less Invasive Surfactant Administration (LISA) method is starting to be taught in simulation. The aim of this educational study was to develop and validate a rating scale for teaching the LISA method in simulation. METHODS: The Downing framework was used to create this performance-rating scale. A first version of the scale was submitted to 12 French and Belgian experts to obtain their opinions. Consensus was reached using a modified Delphi method. The performance of 40 pediatricians was then evaluated with this scale on a preterm neonate manikin simulating a neonatal respiratory distress syndrome. Each run was evaluated using the scale by two independent observers based on video recordings. RESULTS: The Cronbach alpha score of the rating scale was 0.72. The intraclass correlation coefficient (ICC) was 0.91 and the scores between raters were not significantly different. Finally, this rating scale correctly distinguished the experienced from the inexperienced learners (p < 0.01). CONCLUSIONS: This rating scale is one of the first rating scales for the evaluation and teaching of the LISA method in simulation. This tool has ample potential for use in clinical practice to evaluate the performance of surfactant administration in preterm neonates.

A clinical study evaluating the combination of LISA and SNIPPV for the treatment of respiratory distress syndrome in preterm infants.

To compare the therapeutic effect of less invasive surfactant administration (LISA) followed by synchronized nasal intermittent positive pressure ventilation (SNIPPV) and traditional intubate-Surfactant-Extubate (InSurE) strategy for the treatment of neonatal respiratory distress syndrome (NRDS). A single-center, non-randomized and single- blinded study Tertiary neonatal intensive care unit 89 infants enrolled were preterm with gestational age < 366/7 weeks and clinically diagnosed with neonatal RDS (NRDS) Interventions: 32 infants were assigned to the LISA + SNIPPV group and 57 infants to the InSurE + nCPAP group. No statistically significant differences were noted in the baseline characteristics of the enrolled infants. A lower proportion of infants developed BPD in the LISA + SNIPPV group compared to the InSurE + CPAP group [10 (31.25%) vs. 21 (36.84%), P > 0.05]; however, there was no statistically significant difference. The number needed to treat (NNT) with LISA + SNIPPV to prevent BPD development is 18. The mortality rate was not significant between our study arms [1 (3.13%) vs 2 (3.51%), P > 0.05]. There were no statistically significant differences in the durations (days) of MV [(12.18 ± 13.89) vs. (11.35 ± 11.61), P > 0.05], oxygen therapy [(35.03 ± 19.13) vs. (39.75 ± 17.91), P > 0.05] and re-intubation rates [(0.19 ± 0.40) vs. (0.21 ± 0.45), P > 0.05] between the two study groups. In terms of complications, the incidence of patent ductus arteriosus (PDA) [24 (75.00%) vs. 27 (47.37%), P < 0.05] was higher and a lower rate of disturbed liver function [1 (3.23%) vs. 19 (33.33%), P < 0.05] were observed in the LISA + SNIPPV group. Acid-base imbalances were reportedly significantly higher in the InSurE group (P < 0.05). No significant differences in other complications were noted. In the interventional group, FiO2 requirements were significantly lower up until the 3rd week of treatment [FiO2 at day 0, (30.75 ± 4.78) vs. (34.66 ± 9.83), P < 0.05; FiO2 at day 21, (25.32 ± 3.74) vs. (29.11 ± 8.17), P < 0.05], as was RSS on days 2 [(0.77 ± 0.38) vs. (1.94 ± 0.75), P < 0.05] and 3 [(0.66 ± 0.33) vs. (1.89 ± 0.82), P < 0.05] after treatment. Additionally, infants in the standard group had a significantly prolonged hospital stay (days) [(45.97 ± 16.93) vs. (54.40 ± 16.26), P < 0.05]. The combination of LISA and SNIPPV for NRDS can potentially lower the rate of BPD, FiO2 demand and shorten the length of hospitalization.

External Validation of a Multivariate Model for Targeted Surfactant Replacement.

INTRODUCTION: Early targeted surfactant therapy for preterm infants is recommended but the best criteria to personalize treatment are unclear. We validate a previously published multivariate prognostic model based on gestational age (GA), lung ultrasound score (LUS), and oxygen saturation to inspire oxygen fraction ratio (SatO2/FiO2) using an independent data set. METHODS: Pragmatic, observational study in 10 Italian and Spanish NICUs, including preterm babies (250 and 336 weeks divided into 3 GA intervals) with clinical signs of respiratory distress syndrome and stabilized on CPAP. LUS and SatO2/FiO2 were collected soon after stabilization. Their prognostic accuracy was evaluated on the subsequent surfactant administration by a rigorously masked physician. RESULTS: One hundred seventy-five infants were included in the study. Surfactant was given to 74% infants born at 25-27 weeks, 38.5% at 28-30 weeks, and 26.5% at 31-33 weeks. The calibration curve comparing the validation and the development populations showed significant overlap with an intercept = 0.08, 95% CI (-0.34; 0.5) and a slope = 1.53, 95% CI (1.07-1.98). The validation cohort had a high predictive accuracy. Its ROC curve showed an AUC = 0.95, 95% CI (0.91-0.99) with sensitivity = 0.93, 95% CI (0.83-0.98), specificity = 0.81, 95% CI (0.73-0.88), PPV = 0.76, 95% CI (0.65-0.84), NPV = 0.95, 95% CI (0.88-0.98). LUS ≥9 demonstrated the highest sensitivity (0.91, 95% CI [0.82-0.97]) and specificity = 0.81, 95% CI (0.72-0.88) as individual predictor. LUS and SatO2/FiO2 prognostic performances varied with GA. CONCLUSION: We validated a prognostic model based on LUS and Sat/FiO2 to facilitate early, customized surfactant administration that may improve respiratory management of preterm neonates.

Less Invasive Surfactant Administration: A Viewpoint.

The standard of care in treating respiratory distress syndrome in preterm infants is respiratory support with nasal continuous positive airway pressure or a combination of continuous positive airway pressure and exogenous surfactant replacement. Endotracheal intubation, the conventional method for surfactant administration, is an invasive procedure associated with procedural and mechanical ventilation complications. The INSURE (intubation, surfactant administration, and extubation soon after) technique is an accepted method aimed at reducing the short-term complications and long-term morbidities related to mechanical ventilation but does not eliminate risks associated with endotracheal intubation and mechanical ventilation. Alternative methods of surfactant delivery that can overcome the problems associated with the INSURE technique are surfactant through a laryngeal mask, surfactant through a thin intratracheal catheter, and aerosolized surfactant delivered using nebulizers. The three alternative methods of surfactant delivery studied in the last two decades have advantages and limitations. More than a dozen randomized controlled trials have aimed to study the benefits of the three alternative techniques of surfactant delivery compared with INSURE as the control arm, with promising results in terms of reduction in mortality, need for mechanical ventilation, and bronchopulmonary dysplasia. The need to find a less invasive surfactant administration technique is a clinically relevant problem. Before broader adoption in routine clinical practice, the most beneficial technique among the three alternative strategies should be identified. This review aims to summarize the current evidence for using the three alternative techniques of surfactant administration in neonates, compare the three techniques, highlight the knowledge gaps, and suggest future directions. KEY POINTS: · The need to find a less invasive alternative method of surfactant delivery is a clinically relevant problem.. · Clinical trials that have studied alternative surfactant delivery methods have shown promising results but are inconclusive for broader adoption into clinical practice.. · Future studies should explore novel clinical trial methodologies and select clinically significant long term outcomes for comparison..

Prophylactic Oropharyngeal Surfactant for Preterm Newborns at Birth: A Randomized Clinical Trial.

Importance: Preterm newborns at risk of respiratory distress syndrome are supported with continuous positive airway pressure (CPAP). Many newborns worsen despite CPAP and are intubated for surfactant administration, an effective therapy for treatment of respiratory distress syndrome. Endotracheal intubation is associated with adverse effects. Pharyngeal administration of surfactant to preterm animals and humans has been reported as an alternative. Objective: To assess whether giving prophylactic oropharyngeal surfactant to preterm newborns at birth would reduce the rate of intubation for respiratory failure. Design, Setting, and Participants: This unblinded, parallel-group randomized clinical trial (Prophylactic Oropharyngeal Surfactant for Preterm Infants [POPART]) was conducted from December 17, 2017, to September 11, 2020, at 9 tertiary neonatal intensive care units in 6 European countries. Newborns born before 29 weeks of gestation without severe congenital anomalies, for whom intensive care was planned, were eligible for inclusion. The data were analyzed from July 27, 2022, to June 20, 2023. Intervention: Newborns were randomly assigned to receive oropharyngeal surfactant at birth in addition to CPAP or CPAP alone. Randomization was stratified by center and gestational age (GA). Main Outcomes and Measures: The primary outcome was intubation in the delivery room for bradycardia and/or apnea or in the neonatal intensive care unit for prespecified respiratory failure criteria within 120 hours of birth. Caregivers were not masked to group assignment. Results: Among 251 participants (mean [SD] GA, 26 [1.5] weeks) who were well matched at study entry, 126 (69 [54.8%] male) with a mean (SD) birth weight of 858 (261) grams were assigned to the oropharyngeal surfactant group, and 125 (63 [50.4%] male) with a mean (SD) birth weight of 829 (253) grams were assigned to the control group. The proportion of newborns intubated within 120 hours was not different between the groups (80 [63.5%) in the oropharyngeal surfactant group and 81 [64.8%] in the control group; relative risk, 0.98 [95% CI, 0.81-1.18]). More newborns assigned to the oropharyngeal surfactant group were diagnosed with and treated for pneumothorax (21 [16.6%] vs 8 [6.4%]; P = .04). Conclusions and Relevance: This randomized clinical trial found that administration of prophylactic oropharyngeal surfactant to newborns born before 29 weeks' GA did not reduce the rate of intubation in the first 120 hours of life. These findings suggest that administration of surfactant into the oropharynx immediately after birth in addition to CPAP should not be routinely used. Trial Registration: EudraCT: 2016-004198-41.

Analgosedation for less-invasive surfactant administration: Variations in practice.

BACKGROUND: Less-invasive surfactant administration (LISA) is widely used for surfactant delivery to spontaneously breathing preterm infants on nasal CPAP. However, the use of analgesia and/or sedation for the LISA procedure remains controversial. METHODS: We conducted a cross-sectional survey of all tertiary neonatal intensive care units (NICUs) in Austria, Germany, and Switzerland to assess current practices of analgosedation for LISA in preterm infants. RESULTS: Eighty-eight of 172 (51.2%) NICUs responded to the survey, of which 83 (94.3%) perform LISA. Analgosedation for LISA is used in 60 (72.3%) NICUs. Twenty-eight of those (46.7%) have unit protocols to guide analgosedation while 32 (53.3%) administer medication at the discretion of the attending physician. Ketamine (45.0% of NICUs), propofol (41.7%), fentanyl (21.7%), morphine (20.0%), and midazolam (20.0%) were most frequently used for analgosedation for LISA. Nine (10.7%) NICUs reported the use of pain or distress scores during LISA. CONCLUSION: LISA is well established among tertiary NICUs in the German-speaking countries. However, there are considerable variations regarding the use of analgosedation. More evidence is required to guide clinicians seeking to safely and effectively deliver surfactant via a thin catheter to spontaneously breathing preterm infants.

Neonatal surfactant therapy beyond respiratory distress syndrome.

Whilst exogenous surfactant therapy is central to the management of newborn infants with respiratory distress syndrome, its use in other neonatal lung diseases remains inconsistent and controversial. Here we discuss the evidence and experience in relation to surfactant therapy in newborns with other lung conditions in which surfactant may be deficient or dysfunctional, including meconium aspiration syndrome, pneumonia, congenital diaphragmatic hernia and pulmonary haemorrhage. We find that, for all of these diseases, administration of exogenous surfactant as bolus therapy is frequently associated with transient improvement in oxygenation, likely related to temporary mitigation of surfactant inhibition in the airspaces. However, for none of them is there a lasting clinical benefit of surfactant therapy. By virtue of interrupting disease pathogenesis, lavage therapy with dilute surfactant in MAS offers the greatest possibility of a more pronounced therapeutic effect, but this has yet to be definitively proven. Lavage therapy also involves a greater degree of procedural risk.

Surfactant as a drug carrier.

Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The inherent chemical properties of surfactant allows it to readily distribute throughout the respiratory system. Therapeutic agents delivered by surfactant can primarily confer additional benefits but have potential to improve surfactant function. It is critically important that additional agents do not interefere with the innate surface tension lowering function of surfactant. Systemic evaluation through benchtop, translational and human trials are required to translate this potential technique into clinical practice.

Alternative routes of surfactant application - An update.

Non-invasive modes of respiratory support have been shown to be the preferable way of primary respiratory support of preterm infants with respiratory distress syndrome (RDS). The avoidance of invasive mechanical ventilation can be beneficial for preterm infants in reduction of morbidity and even mortality. However, it is well-established that some infants managed with non-invasive respiratory support from the outset have symptomatic RDS to a degree that warrants surfactant administration. Infants for whom non-invasive respiratory support ultimately fails are prone to adverse outcomes, occurring at a frequency on par with the group intubated primarily. This raises the question how to combine non-invasive respiratory support with surfactant therapy. Several methods of less or minimally invasive surfactant therapy have been developed to address the dilemma between avoidance of mechanical ventilation and administration of surfactant. This paper describes the different methods of less invasive surfactant application, reports the existing evidence from clinical studies, discusses the limitations of each of the methods and the open and future research questions.

Surfactant delivery by aerosol inhalation - past, present, and future.

Surfactant replacement therapy (SRT) by nebulization to spontaneously breathing patients has been regarded as the Holy Grail since surfactant deficiency was first identified as the cause for neonatal respiratory distress syndrome. It avoids neonatal endotracheal intubation, a procedure that is often difficult and occasionally harmful. Unapproved alternatives to endotracheal tube placement for liquid surfactant instillation, such as LISA (thin catheter intubation) and SALSA (supraglottic airway insertion) have significant merit but are still invasive, leaving nebulized SRT as the only truly non-invasive method. In the past 60 years, we have learned much about the potential - and limitations - of nebulized SRT. In this review, we examine the promises and pitfalls of nebulized SRT, discuss what we know about neonatal aerosol drug delivery and recap some of the most recent randomized clinical trials of nebulized SRT. We conclude with a discussion of what is known and the next steps needed if this type of SRT is to become a regular part of clinical care.

Historical perspective on surfactant therapy: Transforming hyaline membrane disease to respiratory distress syndrome.

Lung surfactant is the first drug so far designed for the special needs of the newborn. In 1929, Von Neergard described lung hysteresis and proposed the role of surface forces. In 1955-1956, Pattle and Clements found direct evidence of lung surfactant. In 1959, Avery discovered that the airway's lining material was not surface-active in hyaline membrane disease (HMD). Patrick Bouvier Kennedy's death, among half-million other HMD-victims in 1963, stimulated surfactant research. The first large surfactant treatment trial failed in 1967, but by 1973, prediction of respiratory distress syndrome using surfactant biomarkers and promising data on experimental surfactant treatment were reported. After experimental studies on surfactant treatment provided insight in lung surfactant biology and pharmacodynamics, the first trials of surfactant treatment conducted in the 1980s showed a striking amelioration of severe HMD and its related deaths. In the 1990s, the first synthetic and natural surfactants were accepted for treatment of infants. Meta-analyses and further discoveries confirmed and extended these results. Surfactant development continues as a success-story of neonatal research.

Experience of less invasive surfactant administration with a 5F infant feeding tube in a tertiary center of low- and middle-income countries.

BACKGROUND: Less invasive surfactant administration (LISA) results in less need for mechanical ventilation and a reduction in death, bronchopulmonary dysplasia, and intraventricular hemorrhage as outcomes. This study aimed to evaluate the efficacy and short-term outcomes of surfactant administration by the LISA method using an 5F infant feeding tube in preterm infants. METHODS: During the period from May, 2019 to August, 2022, we carried out a prospective observational study that included all premature infants with respiratory distress syndrome who were admitted to our neonatal intensive care unit. The study involved collecting and analyzing data on the procedural efficacy of LISA, vital parameters, and short-term outcomes. RESULTS: Our study included a total of 110 infants with an average gestational age of 30.9 ± 1.9 weeks and a mean birthweight of 1347.5 ± 354.1 g. Of these infants, two required intubation during the LISA procedure, whereas 11 infants required intubation within 72 h after LISA. Infants with a higher pre-surfactant fraction of inspired oxygen (Fi O2 ) requirement, an elevated Score for Neonatal Acute Physiology with Perinatal Extension (SNAPPE), and the presence of sepsis were associated with the need for intubation within the first 72 h of life. Thirty-one infants also experienced a drop in saturation of peripheral oxygen (SpO2 ) below 80% for more than 1 min. CONCLUSIONS: Less invasive surfactant administration was feasible and safe to administer via an orotracheally introduced 5F infant feeding tube in non-invasive ventilation to support spontaneously breathing infants between 28+0 and 33+6 weeks of gestation.

Surfactant status assessment and personalized therapy for surfactant deficiency or dysfunction.

Surfactant is a pivotal neonatal drug used both for respiratory distress syndrome due to surfactant deficiency and for more complex surfactant dysfunctions (such as in case of neonatal acute respiratory distress syndrome). Despite its importance, indications for surfactant therapy are often based on oversimplified criteria. Lung biology and modern monitoring provide several diagnostic tools to assess the patient surfactant status and they can be used for a personalized surfactant therapy. This is desirable to improve the efficacy of surfactant treatment and reduce associated costs and side effects. In this review we will discuss these diagnostic tools from a pathophysiological and multi-disciplinary perspective, focusing on the quantitative or qualitative surfactant assays, lung mechanics or aeration measurements, and gas exchange metrics. Their biological and technical characteristics are described with practical information for clinicians. Finally, available evidence-based data are reviewed, and the diagnostic accuracy of the different tools is compared. Lung ultrasound seems the most suitable tool for assessing the surfactant status, while some other promising tests require further research and/or development.