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Miracles, like London buses, just seem to come along. The truth is, there are no miracles, just lots of hard work behind the scenes, minds open to opportunity, serendipity, and possibly a little luck. In my time as a pediatric respiratory physician, I have borne witness to remarkable advances in treatment that have changed patients' fortunes overnight. Examples of these include artificial surfactant replacement for premature newborns, conjugate Haemophilus influenzae type b vaccination, propranolol for infants with subglottic haemangiomas, mandibular distraction for babies with micrognathia, cystic fibrosis transmembrane conductance regulator modulators therapy for patients with cystic fibrosis, and antisense oligonucleotide therapy for infants with spinal muscular atrophy. There are lessons to be learned from reflection upon these life-transforming treatments, and perhaps it is a good time just to pause and wonder.

Continuous positive airway pressure and surfactant represent the first- and second-line treatment for respiratory distress syndrome in preterm neonates, as European and American guidelines, since 2013 and 2014, respectively, started to recommend surfactant replacement only when continuous positive airway pressure fails. These recommendations, however, are not personalized to the individual physiopathology. Simple clinical algorithms may have improved the diffusion of neonatal care, but complex medical issues can hardly be addressed with simple solutions. The treatment of respiratory distress syndrome is a complex matter and can be only optimized with personalization. We performed a review of tools to individualize the management of respiratory distress syndrome based on physiopathology and actual patients’ need, according to precision medicine principles. Advanced oxygenation metrics, lung ultrasound, electrical impedance tomography, and both quantitative and qualitative surfactant assays were examined. When these techniques were investigated with diagnostic accuracy studies, reliability measures have been meta-analysed. Amongst all these tools, quantitative lung ultrasound seems the more developed for the widespread use and has a higher diagnostic accuracy (meta-analytical AUC = 0.952 [95% CI: 0.951–0.953]). Surfactant adsorption (AUC = 0.840 [95% CI: 0.824–0.856]) and stable microbubble test (AUC = 0.800 [95% CI: 0.788–0.812]) also have good reliability, but need further industrial development. We advocate for a more accurate characterization and a personalized approach of respiratory distress syndrome. With the above-described currently available tools, it should be possible to personalize the treatment of respiratory distress syndrome according to physiopathol­ogy.

Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in preterm infants due to primary surfactant deficiency. Surfactant replacement has greatly improved the short and long term prognosis of RDS but its administration criteria remain uncertain. Lung ultrasound has been recently shown as a non-invasive, repeatable, bedside tool to estimate parenchymal aeration using a semiquantitative score (LUS). The objective of this systematic review and meta-analysis is to evaluate the accuracy of LUS, assessed on the first day of life, to predict surfactant replacement. Methods will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines and the protocol has been registered in PROSPERO database (registration number: CRD42021247888). Primary outcome: in a population of preterm infants, LUS will be compared in neonates who received surfactant replacement versus those who did not. Secondary outcome will be the accuracy of lung ultrasound score to predict the need for ≥ 2 doses of surfactant.

Exogenous surfactant replacement is the most effective evidence-based therapy for respiratory distress syndrome in preterm infants. The mode of administration has evolved in the last decade towards less invasive techniques that aim to effectively provide an adequate dose of surfactant, while allowing spontaneous respiration to continue, and with the support of continuous positive airway pressure. Surfactant delivery via aerosolisation, pharyngeal instillation, and laryngeal mask are being actively pursued in research, but have not yet been adopted to any significant degree in clinical practice. Surfactant administration via thin catheter, on the other hand, is becoming more widely used in neonatal intensive care units worldwide and is now an acknowledged alternative to the standard mode of surfactant delivery. Different devices, including nasogastric tubes, vascular catheters, and purpose-built surfactant instillation catheters are used. We present here a contemporary review of surfactant administration via thin catheter, in a practical guide format that reflects the individual and collective scientific opinions of the clinicians who participated in formulating the guide.

Objective Semiquantitative lung ultrasound improves the timeliness of surfactant replacement, but its financial consequences are unknown. We aim to investigate if the ultrasound-guided surfactant administration influences the general costs of surfactant therapy for preterm neonates affected by respiratory distress syndrome. Study design This is a pharmacoeconomic, retrospective, and before-and-after study investigating the impact of ultrasound-guided surfactant replacement (echography-guided Surfactant THERapy [ESTHER]) on pharmaceutical expenditure within the ESTHER initiative. Data extracted from the institutional official database hosted by the hospital administration for financial management were used for the analysis. We analyzed the number of surfactant administrations in neonates of gestational age ≤326/7 weeks, and the number of surfactant vials used from January 1, 2014 to June 30, 2014 (i.e., during the period of standard surfactant administration policy) and from July 1, 2016 to December 31, 2018 (that is during ESTHER policy). Results ESTHER did not modify surfactant use, as proportion of treated neonates with RDS receiving at least one surfactant dose (Standard: 21.3% vs. ESTHER: 20.9%; p = 0.876) or as proportion of used vials over the total number of vials opened for neonates of any gestational age (Standard: 37% vs. ESTHER: 35%; p = 0.509). Conclusion Ultrasound-guided surfactant replacement using a semiquantitative lung ultrasound score in preterm infants with RDS does not change the global use of surfactant and the related expenditure. Key points · ESTHER is able to increase the timeliness of surfactant replacement.. · The ultrasound-guided surfactant administration does not increase the cost of surfactant therapy.. · The ultrasound-guided surfactant administration does not change the global surfactant utilization..

The reviews of this paper are available via the supplemental material section.

* Abbreviations: HMD: : hyaline membrane disease NIH: : National Institutes of Health UCLA: : University of California, Los Angeles Mary Ellen Avery, MD. Photograph kindly provided by Rosalind S. Brown, MD. How do the lungs of newborns support their first breaths, and why do some infants develop respiratory distress? This crucial research question emerged in the 1950s and was investigated by numerous physicians and scientists, including the American pediatrician Mary Ellen Avery, who devoted her career to the regulation of infant respiration. In a 1964 lecture, Avery drew a distinction between the intrauterine and extrauterine environments stating that “It is clearly at birth that regular rhythmic respiration begins. Something is turned on, something must be different just after birth from the way it was before, and this something must be essential to the regulation of respiration.”(1) Although Avery was a physician by training and not a scientist, research played a significant role in her career and led to her prominence as one of the investigational leaders of respiratory distress syndrome, which was known as hyaline membrane disease (HMD) during the time of Avery’s research. Avery focused on the role of surfactant, specifically its deficiency in HMD, challenging the accepted view at the time that HMD was caused by an obstruction in the lungs due to the aspiration of hyaline membranes. (2)(3)(4) Avery’s act of shifting the understanding of HMD from an obstructive disease to one of a biochemical deficiency was all the more striking given her role as a pediatrician and not a formally trained laboratory scientist. Biographers have estimated that her findings on HMD and their subsequent translation to treatment in the form of surfactant replacement have saved the lives of more than 800,000 infants. (2) The discovery of surfactant deficiency as the cause of HMD in 1959 not only challenged the accepted understanding of the disease at the time, but …

Variation of the isotopic abundance of selected nutrients and molecules has been used for pharmacological and kinetics studies under the premise that the administered molecule has a different isotopic enrichment from the isotopic background of the recipient subject. The aim of this study is to test the feasibility of assessing the contribution of exogenous surfactant phospholipids to the endogenous alveolar pool in vivo after exogenous surfactant replacement therapy in rabbits. The study consisted in measuring the consistency of 13 C/12 C ratio of disaturated-phosphatidylcholine palmitate (DSPC-PA) in 7 lots of poractant alfa, produced over a year, and among bronchoalveolar lavages of 20 rabbits fed with a standard chow. A pilot study was performed in a rabbit model of lavage-induced surfactant deficiency: 7 control rabbits and 4 treated with exogenous surfactant. The contribution of exogenous surfactant to the alveolar pool was assessed after intra-tracheal administration of 200 mg/kg of poractant alfa. The 13 C content of DSPC-PA was measured by isotope ratio mass spectrometry. The mean DSPC-PA 13 C/12 C ratio of the 7 lots of poractant alfa was -18.8‰ with a SD of 0.1‰ (range: -18.9‰; -18.6‰). The mean 13 C/12 C ratio of surfactant DSPC recovered from the lung lavage of 20 rabbits was -28.8 ± 1.2‰ (range: -31.7‰; -25.7‰). The contribution of exogenous surfactant to the total alveolar surfactant could be calculated in the treated rabbits, and it ranged from 83.9% to 89.6%. This pilot study describes a novel method to measure the contribution of the exogenous surfactant to the alveolar pool. This method is based on the natural variation of 13 C, and therefore it does not require the use of chemically synthetized tracers. This method could be useful in human research and especially in surfactant replacement studies in preterm infants.

Objective To improve time of surfactant administration with a surfactant replacement protocol based on semiquantitative lung ultrasound score (LUS) thresholds. Study design Quality improvement (QI), prospective, before-after, pilot study. In a 6-month period surfactant replacement was based only on inspired oxygen fraction (FiO2) thresholds. In the second 6-month period, surfactant was given when either the FiO2 or LUS exceeded the limits. The main QI measures were the proportion of neonates receiving surfactant within the first 3 hours of life and maximal FiO2 reached before surfactant replacement. Secondary QI measures were the duration of respiratory support and ventilator-free days. Data were also collected for 1 year after the study to verify sustainability. Results Echography-guided Surfactant THERapy (ESTHER) increased the proportion of neonates receiving surfactant within the first 3 hours of life (71.4%-90%; P Conclusions ESTHER improved the timeliness of surfactant administration and secondary QI indicators related to surfactant replacement.

Extracorporeal membrane oxygenation (ECMO) continues to be an important rescue therapy for newborns with a variety of causes of cardio-respiratory failure unresponsive to high-frequency ventilation, surfactant replacement, and inhaled nitric oxide. There are approximately 800 neonatal respiratory ECMO cases reported annually to the Extracorporeal Life Support Organization; venoarterial ECMO has been used in approximately 72% with a cumulative survival of 71% and venovenous has been used in 28% with a survival of 84%. Congenital diaphragmatic hernia is now the most common indication for ECMO. This article reviews the development of the two types of extracorporeal support, venoarterial and venovenous ECMO, and discusses the advantages of each method, the current selection criteria, the procedure, and the clinical management of neonates on ECMO.

In this study, a simple yet effective protein detection method was established by using bimetallic Au@Ag core-shell nanobrick as SERS active building blocks. The Au@Ag core-shell nanobrick is synthesized by well-defined ‘two-step’ growing method, enabling uniform and controllable silver shell growth on the surface of the gold nanorods induced by surfactant replacement. The thickness of the silver shell can be programmably adjusted by controlling the amount of silver nitrate in the system, which in turn realized the controllable adjustment of the optical properties of Au@Ag core-shell nanobrick. We selected bovine serum albumin as a model protein and established a highly-sensitive assay for label-free SERS detection of protein. The detection limit can reach to as low as 0.5 μg/mL, enabling promising avenue for its clinical application in ultrasensitive biomarker detection.

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report updated recommendations of a European Panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007 and 2010. This second update of the guidelines is based upon published evidence up to the end of 2012. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is still not clear if the benefit of repeated courses on respiratory outcomes outweighs the risk of adverse outcomes in the short and long term. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not completely clear. In addition, use of very early continuous positive airway pressure (CPAP) has altered the indications for prophylactic surfactant administration. Respiratory support in the form of mechanical ventilation may be lifesaving but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using non-invasive respiratory support such as CPAP. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of normal body temperature, proper fluid management, good nutritional support, appropriate management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion. Copyright (c) 2013 S. Karger AG, Basel

Despite remarkable improvements in survival of extremely premature infants, the burden of BPD among survivors remains a frustrating problem for parents and caregivers. Advances, such as antenatal steroids and surfactant replacement, which have dramatically improved survival, have not reduced BPD among survivors. Other advances that have significantly improved the combined outcome of death or BPD, such as vitamin A and avoidance of mechanical ventilation, have had smaller magnitude effects on the outcome of BPD alone. Postnatal steroids have a clear beneficial effect on BPD, but the optimal preparation, dose, and timing for maximizing benefit and minimizing harm have yet to be determined. This persistent burden of BPD among the most immature survivors remains a challenge for the NRN and other researchers in neonatal medicine.

Surfactant deficiency was identified as the cause of respiratory distress syndrome (RDS) as long ago as 1959. Trials of surfactant replacement in the 1960s were unsuccessful because the preparations used contained only phospholipids and they were administered inefficiently by nebulization. In the 1970s Bengt Robertson and Göran Enhörning showed that natural surfactant, containing both phospholipids and proteins, could ameliorate the signs of RDS in immature rabbits. In the 1980s Bengt Robertson and Tore Curstedt developed a porcine surfactant, Curosurf® (named after their surnames), which was effective in immature animals and was used in a pilot clinical trial beginning in 1983. Subsequent randomized clinical trials were planned a year later by Bengt Robertson, Tore Curstedt and Henry Halliday, and the first trial was begun in 1985. This showed that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS. A second trial, coordinated by Christian Speer, demonstrated that multiple doses of Curosurf were more effective than a single dose. Subsequent trials conducted by the Collaborative European Multicenter Study Group, which included among others Guilio Bevilacqua, Janna Koppe, Ola Saugstad, Nils Svenningsen and Jean-Pierre Relier, showed that early treatment was more effective than later administration and that infants treated at birth had similar neurodevelopmental status to untreated controls at a corrected age of 2 years. Members of the Collaborative European Multicenter Study Group in Denmark and Sweden performed studies to demonstrate the benefits of a combination of surfactant treatment and early continuous positive airway pressure. Curosurf has also been compared with several synthetic and natural surfactants, and at a dose of 200 mg/kg Curosurf has been shown to be superior to either Survanta® or Curosurf used at a dose of 100 mg/kg. Recently, new-generation synthetic surfactants containing both phospholipids and proteins have been developed. After preclinical testing, CHF5633 (developed by Tore Curstedt and Jan Johansson in collaboration with Chiesi Farmaceutici) has undergone a preliminary first study in humans under the guidance of Christian Speer. If effective, this new surfactant preparation could revolutionize the treatment of preterm infants worldwide as it could be made consistently and safely in almost unlimited quantities. This story of a porcine surfactant preparation has been truly remarkable, and many thousands of preterm babies worldwide are now alive and well because of it.

The respiratory surface in the mammalian lung is stabilized by pulmonary surfactant, a membrane-based system composed of multiple lipids and specific proteins, the primary function of which is to minimize the surface tension at the alveolar air-liquid interface, optimizing the mechanics of breathing and avoiding alveolar collapse, especially at the end of expiration. The goal of the present review is to summarize current knowledge regarding the structure, lipid-protein interactions and mechanical features of surfactant membranes and films and how these properties correlate with surfactant biological function inside the lungs. Surfactant mechanical properties can be severely compromised by different agents, which lead to surfactant inhibition and ultimately contributes to the development of pulmonary disorders and pathologies in newborns, children and adults. A detailed comprehension of the unique mechanical and rheological properties of surfactant layers is crucial for the diagnostics and treatment of lung diseases, either by analyzing the contribution of surfactant impairment to the pathophysiology or by improving the formulations in surfactant replacement therapies. Finally, a short review is also included on the most relevant experimental techniques currently employed to evaluate lung surfactant mechanics, rheology, and inhibition and reactivation processes.