Premedication for less invasive surfactant administration: a narrative review.

Less invasive surfactant administration (LISA) is an increasingly popular technique to deliver surfactant to spontaneously breathing preterm infants with respiratory distress syndrome. The optimal method of alleviating the pain and discomfort associated with LISA, either pharmacological or non-pharmacological, while maintaining spontaneous respiration remains unclear. There is limited evidence to guide clinicians, resulting in wide variations in practice. The aim of this article is to summarise the current knowledge and evidence gaps regarding the use of premedication prior to LISA.

Non-invasive versus invasive respiratory support in preterm infants.

Respiratory insufficiency is almost ubiquitous in infants born preterm, with its incidence increasing with lower gestational age. A wide range of respiratory support management strategies are available for these infants, separable into non-invasive and invasive forms of respiratory support. Here we review the history and evolution of respiratory care for the preterm infant and then examine evidence that has emerged to support a non-invasive approach to respiratory management where able. Continuous positive airway pressure (CPAP) is the non-invasive respiratory support mode currently with the most evidence for benefit. CPAP can be delivered safely and effectively and can commence in the delivery room. Particularly in early life, time spent on non-invasive respiratory support, avoiding intubation and mechanical ventilation, affords benefit for the preterm infant by virtue of a lessening of lung injury and hence a reduction in incidence of bronchopulmonary dysplasia. In recent years, enthusiasm for application of non-invasive support has been further bolstered by new techniques for administration of exogenous surfactant. Methods of less invasive surfactant delivery, in particular with a thin catheter, have allowed neonatologists to administer surfactant without resort to endotracheal intubation. The benefits of this approach appear to be sustained, even in those infants subsequently requiring mechanical ventilation. This cements the notion that any reduction in exposure to mechanical ventilation leads to alleviation of injury to the vulnerable preterm lung, with a long-lasting effect. Despite the clear advantages of non-invasive respiratory support, there will continue to be a role for intubation and mechanical ventilation in some preterm infants, particularly for those born <25 weeks' gestation. It is currently unclear what role early non-invasive support has in this special population, with more studies required.

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.

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.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). STATISTICAL ANALYSIS PLAN: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.

Surfactant delivery strategies to prevent bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most devastating morbidities of preterm infants. Antenatal factors like growth restriction and inflammation are risk factors for its development. Use of oxygen and positive pressure ventilation, which are often necessary to treat respiratory distress syndrome (RDS), increase the risk for development of BPD. Continuous positive airway pressure (CPAP) as primary respiratory support allows for avoidance of positive pressure ventilation in many cases but may lead to a delay of surfactant administration which is a proven therapy for RDS. Several alternative surfactant delivery strategies, including nebulization of surfactant, pharyngeal instillation of surfactant, delivery of surfactant via supraglottic airway device or surfactant delivery via a thin endotracheal catheter have been described which allow for the benefit of surfactant therapy while on CPAP. This review reports available data and discusses the existing evidence of their value in preventing BPD as well as further research directions.

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.

Apnoea-triggered increase in fraction of inspired oxygen in preterm infants: a randomised cross-over study.

OBJECTIVES: To investigate the impact of a pre-emptive apnoea triggered oxygen response on oxygen saturation (SpO2) targeting following central apnoea in preterm infants. DESIGN: Interventional crossover study of a 12-hour period of automated oxygen control with an apnoea response (AR) module, nested within a crossover study of a 24-hour period of automated oxygen control compared with aggregated data from two flanking 12-hour periods of manual control. SETTING: Neonatal intensive care unit PATIENTS: Preterm infants receiving non-invasive respiratory support and supplemental oxygen; median (IQR) birth gestation 27 (26-28) weeks, postnatal age 17 (12-23) days. INTERVENTION: Automated oxygen titration with an automated control algorithm modified to include an AR module. Alterations to inspired oxygen concentration (FiO2) were actuated by a motorised blender. Desired SpO2 range was 90-94%. Apnoea detection was by capsule pneumography. MAIN OUTCOME MEASURES: Duration, magnitude and area under the curve (AUC) of SpO2 deviations following apnoea; frequency and duration of apnoeic events. Comparisons between periods of manual, automated and automated control with AR module. RESULTS: In 60 studies in 35 infants, inclusion of the AR module significantly reduced AUC for SpO2 deviations below baseline compared with both automated and manual control (manual: 87.1%±107.6% s, automated: 84.6%±102.8% s, AR module: 79.4%±102.7% s). However, there was a coincident increase in SpO2 overshoot (AUC (SpO2>SpO2(onset)); manual: 44.3±99.9% s, automated: 54.7%±103.4% s, AR module: 65.7%±126.2% s). CONCLUSION: Automated control with a pre-emptive apnoea-triggered FiO2 boost resulted in a modest reduction in post-apnoea hypoxaemia, but was followed by a greater SpO2 overshoot. TRIAL REGISTRATION NUMBER: ACTRN12616000300471.

Curriculum and assessment tool for less invasive surfactant administration: an international Delphi consensus study.

BACKGROUND: Training and assessment of operator competence for the less invasive surfactant administration (LISA) procedure vary. This study aimed to obtain international expert consensus on LISA training (LISA curriculum (LISA-CUR)) and assessment (LISA assessment tool (LISA-AT)). METHODS: From February to July 2022, an international three-round Delphi process gathered opinions from LISA experts (researchers, curriculum developers, and clinical educators) on a list of items to be included in a LISA-CUR and LISA-AT (Round 1). The experts rated the importance of each item (Round 2). Items supported by more than 80% consensus were included. All experts were asked to approve or reject the final LISA-CUR and LISA-AT (Round 3). RESULTS: A total of 153 experts from 14 countries participated in Round 1, and the response rate for Rounds 2 and 3 was >80%. Round 1 identified 44 items for LISA-CUR and 22 for LISA-AT. Round 2 excluded 15 items for the LISA-CUR and 7 items for the LISA-AT. Round 3 resulted in a strong consensus (99-100%) for the final 29 items for the LISA-CUR and 15 items for the LISA-AT. CONCLUSIONS: This Delphi process established an international consensus on a training curriculum and content evidence for the assessment of LISA competence. IMPACT: This international consensus-based expert statement provides content on a curriculum for the less invasive surfactant administration procedure (LISA-CUR) that may be partnered with existing evidence-based strategies to optimize and standardize LISA training in the future. This international consensus-based expert statement also provides content on an assessment tool for the LISA procedure (LISA-AT) that can help to evaluate competence in LISA operators. The proposed LISA-AT enables standardized, continuous feedback and assessment until achieving proficiency.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). DISCUSSION: Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017.

Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.

BACKGROUND: Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. METHODS: To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. RESULTS: From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. CONCLUSION: Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.

Detection of respiratory activity in newborn infants using a noncontact vision-based monitor.

OBJECTIVE: To examine the effectiveness of a noncontact vision-based infrared respiratory monitor (IRM) in the detection of authentic respiratory motion in newborn infants. STUDY DESIGN: Observational study in a neonatal intensive care unit. METHODS: Eligible infants lay supine with torso exposed under the IRM's infrared depth-map camera and torso images were recorded at 30 frames/s. Respiratory motion waveforms were subsequently derived from upper (IRMupper ) and lower (IRMlower ) torso region images and compared with contemporaneous impedance pneumography (IP) and capsule pneumography (CP). Waveforms, in 15 s investigative epochs, were scanned with an 8 s sliding window for authentic respiratory waveform (spectral purity index [SPI] ≥ 0.75, minimum five complete breaths). Maximum SPI and frequency of occurrence of authentic respiratory waveform in 15 s epochs were compared between monitoring modalities in pooled and per patient data (Friedman ANOVA). RESULTS: Recordings comprised 532 min of images from 35 infants, yielding 2131 investigative epochs, with authentic respiratory motion detected in all infants. For CP, IP, IRMupper , and IRMlower , the proportion of epochs containing authentic respiratory motion in pooled data were 65%, 50%, 36%, and 48%, with median SPImax of 0.79, 0.75, 0.70, and 0.74, respectively. Per-patient average SPImax was 0.79, 0.75, 0.69, and 0.74 for CP, IP, IRMupper , and IRMlower with proportion of authentic respiratory motion being 64%, 50%, 29%, and 49%, respectively. CONCLUSION: An IRM focused on the lower torso detected authentic respiratory motion with comparable performance to IP in newborn infants in intensive care and deserves further investigation.

Impact of probiotic administration on the incidence of necrotising enterocolitis: A single-centre cohort study.

AIM: To examine the effect of probiotic administration on the incidence of necrotising enterocolitis (NEC) in preterm infants. METHODS: We conducted a retrospective study examining the incidence of NEC in a cohort of infants that received probiotics compared to those that had not, over an 18-year period in a single centre. Infants were included if they were born <32 weeks' gestation with birthweight <1500 g and survived beyond 72 h. Infants in the probiotic group received either ABC Dophilus or Infloran. The primary outcome was the rate of NEC. The main secondary outcomes were late-onset sepsis and mortality. Differences in these outcomes between cohorts were examined in univariate and multivariate analyses, taking account of confounding variables, reporting adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: 805 infants were included in the study. Infants receiving probiotics had a lower risk of developing NEC compared with those that did not (32/419 (7.6%) vs. 14/386 (3.6%); aOR 0.37 (95% CI 0.18-0.74)). There was also a reduction in the late-onset sepsis rate (22.4% vs. 14.2%, aOR 0.52, 95% CI 0.35-0.77) and mortality rate (9.5% vs. 4.6%, aOR 0.35, 95% CI 0.17-0.73). CONCLUSION: The administration of a multi-organism probiotic formulation, including Bifidobacteria, to very preterm infants in our unit was associated with a reduced incidence of NEC, late-onset sepsis and mortality.

Comparison of two automated oxygen controllers in oxygen targeting in preterm infants during admission: an observational study.

OBJECTIVE: To compare the effect of two different automated oxygen control devices on time preterm infants spent in different oxygen saturation (SpO2) ranges during their entire stay in the neonatal intensive care unit (NICU). DESIGN: Retrospective cohort study of prospectively collected data. SETTING: Tertiary level neonatal unit in the Netherlands. PATIENTS: Preterm infants (OxyGenie 75 infants, CLiO2 111 infants) born at 24-29 weeks' gestation receiving at least 72 hours of respiratory support between October 2015 and November 2020. INTERVENTIONS: Inspired oxygen concentration was titrated by the OxyGenie controller (SLE6000 ventilator) between February 2019 and November 2020 and the CLiO2 controller (AVEA ventilator) between October 2015 and December 2018 as standard of care. MAIN OUTCOME MEASURES: Time spent within SpO2 target range (TR, 91-95% for either epoch) and other SpO2 ranges. RESULTS: Time spent within the SpO2 TR when receiving supplemental oxygen was higher during OxyGenie control (median 71.5 [IQR 64.6-77.0]% vs 51.3 [47.3-58.5]%, p<0.001). Infants under OxyGenie control spent less time in hypoxic and hyperoxic ranges (SpO2<80%: 0.7 [0.4-1.4]% vs 1.2 [0.7-2.3]%, p<0.001; SpO2>98%: 1.0 [0.5-2.4]% vs 4.0 [2.0-7.9]%, p<0.001). Both groups received a similar FiO2 (29.5 [28.0-33.2]% vs 29.6 [27.7-32.1]%, p=not significant). CONCLUSIONS: Oxygen saturation targeting was significantly different in the OxyGenie epoch in preterm infants, with less time in hypoxic and hyperoxic SpO2 ranges during their stay in the NICU.

Comparing Descriptive Statistics for Retrospective Studies From One-per-Minute and One-per-Second Data.

Background: Large amounts of data are collected in neonatal intensive care units, which could be used for research. It is unclear whether these data, usually sampled at a lower frequency, are sufficient for retrospective studies. We investigated what to expect when using one-per-minute data for descriptive statistics. Methods: One-per-second inspiratory oxygen and saturation were processed to one-per-minute data and compared, on average, standard deviation, target range time, hypoxia, days of supplemental oxygen, and missing signal. Results: Outcomes calculated from data recordings (one-per-minute = 92, one-per-second = 92) showed very little to no difference. Sub analyses of recordings under 100 and 200 h showed no difference. Conclusion: In our study, descriptive statistics of one-per-minute data were comparable to one-per-second and could be used for retrospective analyses. Comparable routinely collected one-per-minute data could be used to develop algorithms or find associations, retrospectively.