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Pediatrics and Neonatology Feb 2021Respiratory distress syndrome (RDS) was recognized to be caused by primary surfactant deficiency almost 70 years ago and continuous positive airway pressure was... (Review)
Review
Respiratory distress syndrome (RDS) was recognized to be caused by primary surfactant deficiency almost 70 years ago and continuous positive airway pressure was introduced approximately 50 years ago. Since then, there have been many developments in neonatology; we know many things but others are still controversial. The more we know, the more questions arise. However, this review aims to indicate what is more needed to understand and how should be the modern approach to RDS in the era of precision medicine. The review is divided between new concepts and new tools. We will explain the interaction between steroids, CPAP and surfactant, as well as the surfactant catabolism and the diagnosis of NARDS; lung ultrasound and new tools to optimize CPAP will also be covered. How these concepts are integrated in the author's personal experience is also illustrated.
Topics: Continuous Positive Airway Pressure; Critical Care; Humans; Infant, Newborn; Infant, Premature; Lung; Precision Medicine; Pulmonary Surfactants; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Ultrasonography
PubMed: 33358440
DOI: 10.1016/j.pedneo.2020.11.005 -
Archives of Disease in Childhood. Fetal... Nov 2019Non-invasive ventilation and especially the application of continuous positive airway pressure (CPAP) has become standard for the treatment of premature infants with... (Review)
Review
Non-invasive ventilation and especially the application of continuous positive airway pressure (CPAP) has become standard for the treatment of premature infants with respiratory problems. However, CPAP failure may occur due to respiratory distress syndrome, that is, surfactant deficiency. Less invasive surfactant administration (LISA) aims to provide an adequate dose of surfactant while the infant is breathing spontaneously, thus avoiding positive pressure ventilation support. Using a thin catheter for surfactant application allows infants to maintain function of the glottis and continue spontaneous breathing, whereas the INtubate-SURfactant-Extubate (INSURE) procedure is connected with sedation/analgesia, regular intubation and a (brief) period of positive pressure ventilation. Individual studies and meta-analyses summarised in this review point in the direction that LISA is more effective than standard treatment or INSURE both in terms of short-term (avoidance of mechanical ventilation) and long-term (intracerebral haemorrhage and bronchopulmonary dysplasia) outcomes. Open questions include exact treatment thresholds for different gestational ages, the usefulness of devices/catheters that have recently been purpose-built for the LISA technique and especially the question of analgesia/sedation during the procedure. The current technology still demands laryngoscopy with all its unpleasant effects for infants. Therefore, studies with pharyngeal surfactant deposition immediately after delivery, the use of laryngeal airways for surfactant administration and attempts to nebulise surfactant are under way. Finally, LISA is not simply an isolated technical procedure for surfactant delivery but rather part of a comprehensive non-invasive approach supporting the concept of a gentle transition to the extrauterine world enabling preterm infants to benefit from the advantages of spontaneous breathing.
Topics: Gestational Age; Humans; Infant, Newborn; Infant, Premature; Noninvasive Ventilation; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn
PubMed: 31296694
DOI: 10.1136/archdischild-2018-316557 -
Science (New York, N.Y.) Feb 2020Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)-biomimetic liposomes encapsulating 2',3'-cyclic...
Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)-biomimetic liposomes encapsulating 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine-induced humoral and CD8 T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP-adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8 T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked or gap junctions were blocked, PS-GAMP-mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.
Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Biomimetic Materials; CD8-Positive T-Lymphocytes; Ferrets; Immunologic Memory; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza Vaccines; Liposomes; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Nanoparticles; Nucleotides, Cyclic; Orthomyxoviridae Infections; Pulmonary Surfactants; Vaccination
PubMed: 32079747
DOI: 10.1126/science.aau0810 -
Pediatric Research Apr 2023The harmful effects of mechanical ventilation (MV) on the preterm lung are well established. Avoiding MV at birth and stabilization on continuous positive airway... (Review)
Review
The harmful effects of mechanical ventilation (MV) on the preterm lung are well established. Avoiding MV at birth and stabilization on continuous positive airway pressure (CPAP) decreases the composite outcome of death or bronchopulmonary dysplasia. Although preterm infants are increasingly being admitted to the neonatal intensive care unit on CPAP, centers differ in the ability to manage infants primarily on CPAP. Over the last decade, less invasive surfactant administration (LISA), a method of administering surfactant with a thin catheter, has been devised and has been shown to decrease the need for MV and improve outcomes compared to surfactant administration via an endotracheal tube following intubation. While LISA has been widely adopted in Europe and other countries, its use is not widespread in the United States. This article provides a summary of the existing evidence on LISA, and practical guidance for US units choosing to implement a change of practice incorporating optimization of CPAP and LISA. IMPACT: The accumulated body of evidence for less invasive surfactant administration (LISA), a widespread practice in other countries, justifies its use as an alternative to intubation and surfactant administration in US neonatal units. This article summarizes the current evidence for LISA, identifies gaps in knowledge, and offers practical tips for the implementation of LISA as part of a comprehensive non-invasive respiratory support strategy. This article will help neonatal units in the US develop guidelines for LISA, provide optimal respiratory support for infants with respiratory distress syndrome, improve short- and long-term outcomes of preterm infants, and potentially decrease costs of NICU care.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Surface-Active Agents; Pulmonary Surfactants; Respiration, Artificial; Continuous Positive Airway Pressure; Respiratory Distress Syndrome, Newborn; Lipoproteins; Intubation, Intratracheal
PubMed: 35986148
DOI: 10.1038/s41390-022-02265-8 -
Paediatric Anaesthesia Feb 2022Extremely preterm infants commonly suffer from respiratory distress syndrome. Ventilatory management of these infants starts from birth and includes decisions such as... (Review)
Review
Extremely preterm infants commonly suffer from respiratory distress syndrome. Ventilatory management of these infants starts from birth and includes decisions such as timing of respiratory support in relation to umbilical cord management, oxygenation targets, and options of positive pressure support. The approach of early intubation and surfactant administration through an endotracheal tube has been challenged in recent years by primary noninvasive respiratory support and newer methods of surfactant administration via thin catheters. Available data comparing the thin catheter method to endotracheal tube and delayed extubation in extremely preterm infants born before 28 weeks of gestation did not show differences in survival free of bronchopulmonary dysplasia. Data from numerous randomized trials comparing conventional ventilation with high-frequency oscillatory ventilation did not show differences in meaningful outcomes. Among conventional modes of ventilation, there is good evidence to favor volume-targeted ventilation over pressure-limited ventilation. The former reduces the combined risk of bronchopulmonary dysplasia or death and several important secondary outcomes without an increase in adverse events. There are no evidence-based guidelines to set positive end-expiratory pressure in ventilated preterm infants. Recent research suggests that the forced oscillation technique may help to find the lowest positive end-expiratory pressure at which lung recruitment is optimal. Benefits and risks of the various modes of noninvasive ventilation depend on the clinical setting, degree of prematurity, severity of lung disease, and competency of staff in treating associated complications. Respiratory care after discharge includes home oxygen therapy, lung function monitoring, weaning from medication started in the neonatal unit, and treatment of asthma-like symptoms.
Topics: Humans; Infant, Extremely Premature; Infant, Newborn; Intensive Care Units, Neonatal; Pulmonary Surfactants; Respiration, Artificial; Respiratory Distress Syndrome, Newborn
PubMed: 34878697
DOI: 10.1111/pan.14369 -
JAMA Dec 2021The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are... (Comparative Study)
Comparative Study Randomized Controlled Trial
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.
Topics: Biological Products; Bronchopulmonary Dysplasia; Continuous Positive Airway Pressure; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Phospholipids; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Single-Blind Method
PubMed: 34902013
DOI: 10.1001/jama.2021.21892 -
The Cochrane Database of Systematic... Oct 2020Respiratory distress, particularly respiratory distress syndrome (RDS), is the single most important cause of morbidity and mortality in preterm infants. In infants with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Respiratory distress, particularly respiratory distress syndrome (RDS), is the single most important cause of morbidity and mortality in preterm infants. In infants with progressive respiratory insufficiency, intermittent positive pressure ventilation (IPPV) with surfactant has been the usual treatment, but it is invasive, potentially resulting in airway and lung injury. Continuous positive airway pressure (CPAP) has been used for the prevention and treatment of respiratory distress, as well as for the prevention of apnoea, and in weaning from IPPV. Its use in the treatment of RDS might reduce the need for IPPV and its sequelae.
OBJECTIVES
To determine the effect of continuous distending pressure in the form of CPAP on the need for IPPV and associated morbidity in spontaneously breathing preterm infants with respiratory distress.
SEARCH METHODS
We used the standard strategy of Cochrane Neonatal to search CENTRAL (2020, Issue 6); Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions; and CINAHL on 30 June 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.
SELECTION CRITERIA
All randomised or quasi-randomised trials of preterm infants with respiratory distress were eligible. Interventions were CPAP by mask, nasal prong, nasopharyngeal tube or endotracheal tube, compared with spontaneous breathing with supplemental oxygen as necessary.
DATA COLLECTION AND ANALYSIS
We used standard methods of Cochrane and its Neonatal Review Group, including independent assessment of risk of bias and extraction of data by two review authors. We used the GRADE approach to assess the certainty of evidence. Subgroup analyses were planned on the basis of birth weight (greater than or less than 1000 g or 1500 g), gestational age (groups divided at about 28 weeks and 32 weeks), timing of application (early versus late in the course of respiratory distress), pressure applied (high versus low) and trial setting (tertiary compared with non-tertiary hospitals; high income compared with low income) MAIN RESULTS: We included five studies involving 322 infants; two studies used face mask CPAP, two studies used nasal CPAP and one study used endotracheal CPAP and continuing negative pressure for a small number of less ill babies. For this update, we included one new trial. CPAP was associated with lower risk of treatment failure (death or use of assisted ventilation) (typical risk ratio (RR) 0.64, 95% confidence interval (CI) 0.50 to 0.82; typical risk difference (RD) -0.19, 95% CI -0.28 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 4 to 11; I = 50%; 5 studies, 322 infants; very low-certainty evidence), lower use of ventilatory assistance (typical RR 0.72, 95% CI 0.54 to 0.96; typical RD -0.13, 95% CI -0.25 to -0.02; NNTB 8, 95% CI 4 to 50; I = 55%; very low-certainty evidence) and lower overall mortality (typical RR 0.53, 95% CI 0.34 to 0.83; typical RD -0.11, 95% CI -0.18 to -0.04; NNTB 9, 95% CI 2 to 13; I = 0%; 5 studies, 322 infants; moderate-certainty evidence). CPAP was associated with increased risk of pneumothorax (typical RR 2.48, 95% CI 1.16 to 5.30; typical RD 0.09, 95% CI 0.02 to 0.16; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 7 to 50; I = 0%; 4 studies, 274 infants; low-certainty evidence). There was no evidence of a difference in bronchopulmonary dysplasia, defined as oxygen dependency at 28 days (RR 1.04, 95% CI 0.35 to 3.13; I = 0%; 2 studies, 209 infants; very low-certainty evidence). The trials did not report use of surfactant, intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis and neurodevelopment outcomes in childhood.
AUTHORS' CONCLUSIONS
In preterm infants with respiratory distress, the application of CPAP is associated with reduced respiratory failure, use of mechanical ventilation and mortality and an increased rate of pneumothorax compared to spontaneous breathing with supplemental oxygen as necessary. Three out of five of these trials were conducted in the 1970s. Therefore, the applicability of these results to current practice is unclear. Further studies in resource-poor settings should be considered and research to determine the most appropriate pressure level needs to be considered.
Topics: Bronchopulmonary Dysplasia; Continuous Positive Airway Pressure; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Intermittent Positive-Pressure Ventilation; Outcome Assessment, Health Care; Pneumothorax; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Selection Bias; Treatment Failure
PubMed: 33058208
DOI: 10.1002/14651858.CD002271.pub3 -
Jornal de Pediatria 2024To compare LISA with INSURE technique for surfactant administration in preterm with gestational age (GA) < 36 weeks with RDS in respect to the incidence of pneumothorax,... (Meta-Analysis)
Meta-Analysis Review
Less invasive surfactant administration versus intubation-surfactant-extubation in the treatment of neonatal respiratory distress syndrome: a systematic review and meta-analyses.
OBJECTIVES
To compare LISA with INSURE technique for surfactant administration in preterm with gestational age (GA) < 36 weeks with RDS in respect to the incidence of pneumothorax, bronchopulmonary dysplasia (BPD), need for mechanical ventilation (MV), regional cerebral oxygen saturation (rSO2), peri‑intraventricular hemorrhage (PIVH) and mortality.
METHODS
A systematic search in PubMed, Embase, Lilacs, CINAHL, SciELO databases, Brazilian Registry of Randomized Clinical Trials (ReBEC), Clinicaltrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) was performed. RCTs evaluating the effects of the LISA technique versus INSURE in preterm infants with gestational age < 36 weeks and that had as outcomes evaluation of the rates of pneumothorax, BPD, need for MV, rSO2, PIVH, and mortality were included in the meta-analysis. Random effects and hazard ratio models were used to combine all study results. Inter-study heterogeneity was assessed using Cochrane Q statistics and Higgin's I2 statistics.
RESULTS
Sixteen RCTs published between 2012 and 2020 met the inclusion criteria, a total of 1,944 preterms. Eleven studies showed a shorter duration of MV and CPAP in the LISA group than in INSURE group. Two studies evaluated rSO2 and suggested that LISA and INSURE transiently affect brain autoregulation during surfactant administration. INSURE group had a higher risk for MV in the first 72 h of life, pneumothorax, PIVH and mortality in comparison to the LISA group.
CONCLUSION
This systematic review and meta-analyses provided evidence for the benefits of the LISA technique in the treatment of RDS, decreasing CPAP time, need for MV, BPD, pneumothorax, PIVH, and mortality when compared to INSURE.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Surface-Active Agents; Airway Extubation; Pneumothorax; Pulmonary Surfactants; Intubation; Respiratory Distress Syndrome, Newborn; Cerebral Hemorrhage
PubMed: 37353207
DOI: 10.1016/j.jped.2023.05.008 -
JCI Insight Aug 2023Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are...
Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.
Topics: Animals; Mice; Fatty Acid Synthase, Type II; Pulmonary Disease, Chronic Obstructive; Fatty Acid Synthases; Pulmonary Surfactants; Surface-Active Agents; Epithelial Cells; Homeostasis; Lipids
PubMed: 37606038
DOI: 10.1172/jci.insight.163403 -
Seminars in Fetal & Neonatal Medicine Dec 2023Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The... (Review)
Review
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.
Topics: Humans; Infant, Newborn; Surface-Active Agents; Drug Carriers; Pulmonary Surfactants; Drug Delivery Systems; Lipoproteins; Respiratory Distress Syndrome, Newborn
PubMed: 38040583
DOI: 10.1016/j.siny.2023.101499