NON-pharmacological Approach Less Invasive Surfactant Administration (NONA-LISA) trial: protocol for a randomised controlled trial.

INTRODUCTION: Using pre-procedure analgesia with the risk of apnoea may complicate the Less Invasive Surfactant Administration (LISA) procedure or reduce the effect of LISA. METHODS: The NONA-LISA trial (ClinicalTrials.gov, NCT05609877) is a multicentre, blinded, randomised controlled trial aiming at including 324 infants born before 30 gestational weeks, meeting the criteria for surfactant treatment by LISA. Infants will be randomised to LISA after administration of fentanyl 0.5-1 mcg/kg intravenously (fentanyl group) or isotonic saline solution intravenously (saline group). All infants will receive standardised non-pharmacological comfort care before and during the LISA procedure. Additional analgesics will be provided at the clinician's discretion. The primary outcome is the need for invasive ventilation, meaning mechanical or manual ventilation via an endotracheal tube, for at least 30 min (cumulated) within 24 h of the procedure. Secondary outcomes include the modified COMFORTneo score during the procedure, bronchopulmonary dysplasia at 36 weeks, and mortality at 36 weeks. DISCUSSION: The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice. IMPACT: Pre-procedure analgesia is associated with apnoea and may complicate procedures that rely on regular spontaneous breathing, such as Less Invasive Surfactant Administration (LISA). This randomised controlled trial addresses the effect of analgesic premedication in LISA by comparing fentanyl with a placebo (isotonic saline) in infants undergoing the LISA procedure. All infants will receive standardised non-pharmacological comfort. The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort or pain in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice regarding analgesic treatment associated with the LISA procedure.

Nordic survey showed wide variation in discharge practices for very preterm infants.

AIM: We aimed to describe clinical practices and criteria for discharge of very preterm infants in Nordic neonatal units. METHODS: Medical directors of all 89 level-2 and level-3 units in Denmark, Finland, Iceland, Norway and Sweden were invited by e-mail to complete a web-based multiple-choice survey with the option to make additional free-text comments. RESULTS: We received responses from 83/89 units (93%). In all responding units, discharge readiness was based mainly on clinical assessment with varying criteria. In addition, 36% used formal tests of cardiorespiratory stability and 59% used criteria related to infant weight or growth. For discharge with feeding tube, parental ability to speak the national language or English was mandatory in 45% of units, with large variation among countries. Post-discharge home visits and video-consultations were provided by 59% and 51%, respectively. In 54% of units, parental preparation for discharge were not initiated until the last two weeks of hospital stay. CONCLUSION: Discharge readiness was based mainly on clinical assessment, with criteria varying among units despite similar population characteristics and care structures. This variation indicates a lack of evidence base and may unnecessarily delay discharge; further studies of this matter are needed. Earlier parental preparation and use of interpreters might facilitate earlier discharge.

European consensus recommendations for neonatal and paediatric retrievals of positive or suspected COVID-19 patients.

BACKGROUND: The 2020 novel coronavirus (SARS-Cov-2) pandemic necessitates tailored recommendations addressing specific procedures for neonatal and paediatric transport of suspected or positive COVID-19 patients. The aim of this consensus statement is to define guidelines for safe clinical care for children needing inter-facility transport while making sure that the clinical teams involved are sufficiently protected from SARS-CoV-2. METHODS: A taskforce, composed of members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Transport section and the European Society for Paediatric Research (ESPR), reviewed the published literature and used a rapid, two-step modified Delphi process to formulate recommendations regarding safety and clinical management during transport of COVID-19 patients. RESULTS: The joint taskforce consisted of a panel of 12 experts who reached an agreement on a set of 17 recommendations specifying pertinent aspects on neonatal and paediatric COVID-19 patient transport. These included: case definition, personal protective equipment, airway management, equipment and strategies for invasive and non-invasive ventilation, special considerations for incubator and open stretcher transports, parents on transport and decontamination of transport vehicles. CONCLUSIONS: Our consensus recommendations aim to define current best-practice and should help guide transport teams dealing with infants and children with COVID-19 to work safely and effectively. IMPACT: We present European consensus recommendations on pertinent measures for transporting infants and children in times of the coronavirus (SARS-Cov-2 /COVID-19) pandemic. A panel of experts reviewed the evidence around transporting infants and children with proven or suspected COVID-19. Specific guidance on aspects of personal protective equipment, airway management and considerations for incubator and open stretcher transports is presented. Based on scant evidence, best-practice recommendations for neonatal and paediatric transport teams are presented, aiming for the protection of teams and patients. We highlight gaps in knowledge and areas of future research.

Bronchopulmonary dysplasia predicted at birth by artificial intelligence.

AIM: To develop a fast bedside test for prediction and early targeted intervention of bronchopulmonary dysplasia (BPD) to improve the outcome. METHODS: In a multicentre study of preterm infants with gestational age 24-31 weeks, clinical data present at birth were combined with spectral data of gastric aspirate samples taken at birth and analysed using artificial intelligence. The study was designed to develop an algorithm to predict development of BPD. The BPD definition used was the consensus definition of the US National Institutes of Health: Requirement of supplemental oxygen for at least 28 days with subsequent assessment at 36 weeks postmenstrual age. RESULTS: Twenty-six (43%) of the 61 included infants developed BPD. Spectral data analysis of the gastric aspirates identified the most important wave numbers for classification and surfactant treatment, and birth weight and gestational age were the most important predictive clinical data. By combining these data, the resulting algorithm for early diagnosis of BPD had a sensitivity of 88% and a specificity of 91%. CONCLUSION: A point-of-care test to predict subsequent development of BPD at birth has been developed using a new software algorithm allowing early targeted intervention of BPD which could improve the outcome.

Predicting respiratory distress syndrome at birth using a fast test based on spectroscopy of gastric aspirates: 2. Clinical part.

AIM: To evaluate the accuracy of our new rapid point-of-care (POC) test for lung maturity. The method as we describe in an accompanying article was developed with the purpose of improving the outcome from respiratory distress syndrome (RDS). The test enables the delivery of surfactant in infants with immature lungs already at birth and ensures that infants with mature lungs are not treated unnecessarily. METHODS: Fresh gastric aspirate (GAS) was sampled at birth in a cohort of preterm infants with gestational ages ranging between 24 and 31 completed weeks for lung surfactant measurement as lecithin-sphingomyelin ratio (L/S). L/S was prospectively compared with RDS development. The clinical outcome was blinded for the investigators of L/S. The time for analysis was <15 minutes. RESULTS: GAS was obtained from 72 infants. Forty-four (61%) developed RDS. The cut-off for L/S was 3.05; predicting RDS with a sensitivity of 91% and specificity of 79%. CONCLUSION: The new improved spectroscopic L/S method of lung maturity on GAS has high sensitivity. The method is designed for use as a POC test at birth, and a spectroscopic prototype has been developed for bedside use. Clinical trials with this new lung maturity test are planned.

Predicting respiratory distress syndrome at birth using fast test based on spectroscopy of gastric aspirates. 1. Biochemical part.

AIM: To develop a fast bedside lung maturity test. METHODS: Gastric aspirates obtained from premature infants contain lamellar bodies, carrying lung surfactant. To estimate lung maturity, we isolated lamellar bodies from fresh gastric aspirates by centrifugation. Erythrocytes and other cells were lysed by adding water and discarded subsequently with the supernatant. Mid-infrared spectroscopy was then performed to measure the lung maturity as lecithin-sphingomyelin ratio. Lecithin was determined as dipalmitoylphosphatidylcholine, the most surface-active phospholipid. Algorithms to measure lecithin and sphingomyelin concentrations in fresh gastric aspirates were developed on aspirates from 140 premature infants. Each gastric aspirate sample was divided into two samples: one for mass spectrometry as reference and one for spectroscopy. Development of the algorithm is described in detail in Appendix S1. RESULTS: Gastric aspirates stored at 4-5°C avoid flocculation of proteins and phospholipids in contrast to when the aspirates were frozen and thawed. Omission of freezing and concentration of the lung surfactant by centrifugation combined with diminished influence of proteins improves the spectroscopic measurement of lecithin-sphingomyelin ratio. Measurement of lecithin-sphingomyelin ratio by the new method was performed within 10-15 minutes. CONCLUSION: We present a new fast bedside lung maturity test on fresh gastric aspirate for early targeted surfactant treatment.

Survey shows large differences between the Nordic countries in the use of less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA), namely surfactant instillation through a thin catheter in the trachea during spontaneous breathing, is increasingly used for premature infants. We surveyed the use of this technique in the Nordic countries in autumn 2015. METHODS: A link to a web-based survey of surfactant administration methods was emailed to the directors of all neonatal units in the Nordic Region, apart from Finland, where only the five university-based departments were invited. RESULTS: Of the 73 units (85%) who responded, 23 (32%) said that they used LISA. The country rates were Iceland 100%, Norway 82%, Finland 60%, Denmark, including Faroe Island and Greenland, 11% and Sweden 9%. LISA was used in 62% of level three units, but only 14% of level two units and most commonly in babies with a gestational age of at least 26 weeks. Premedication was always or sometimes used by 78%. The main reasons for not using LISA were lack of familiarity with the technique (61%), no perceived benefit over other methods (22%) and concerns about patient discomfort (26%). CONCLUSION: Less invasive surfactant administration was used in 32% of Nordic neonatal units, most commonly in level three units. Premedication was used more often than previously reported.

Rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted respiratory distress syndrome with high sensitivity.

AIM: Respiratory distress syndrome (RDS) is a major cause of mortality and morbidity in premature infants. By the time symptoms appear, it may already be too late to prevent a severe course, with bronchopulmonary dysplasia or mortality. We aimed to develop a rapid test of lung maturity for targeting surfactant supplementation. METHODS: Concentrations of the most surface-active lung phospholipid dipalmitoylphosphatidylcholine and sphingomyelin in gastric aspirates from premature infants were measured by mass spectrometry and expressed as the lecithin/sphingomyelin ratio (L/S). The same aspirates were analysed with mid-infrared spectroscopy. Subsequently, L/S was measured in gastric aspirates and oropharyngeal secretions from another group of premature infants using spectroscopy and the results were compared with RDS development. The 10-minute analysis required 10 µL of aspirate. RESULTS: An L/S algorithm was developed based on 89 aspirates. Subsequently, gastric aspirates were sampled in 136 infants of 24-31 weeks of gestation and 61 (45%) developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92%, and specificity was 73%. In 59 cases, the oropharyngeal secretions had less valid L/S than gastric aspirate results. CONCLUSION: Our rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted RDS with high sensitivity.

Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research.

OBJECTIVE: Regarding the use of lung ultrasound (LU) in neonatal intensive care units (NICUs) across Europe, to assess how widely it is used, for what indications and how its implementation might be improved. DESIGN AND INTERVENTION: International online survey. RESULTS: Replies were received from 560 NICUs in 24 countries between January and May 2023. LU uptake varied considerably (20%-98% of NICUs) between countries. In 428 units (76%), LU was used for clinical indications, while 34 units (6%) only used it for research purposes. One-third of units had <2 years of experience, and only 71 units (13%) had >5 years of experience. LU was mainly performed by neonatologists. LU was most frequently used to diagnose respiratory diseases (68%), to evaluate an infant experiencing acute clinical deterioration (53%) and to guide surfactant treatment (39%). The main pathologies diagnosed by LU were pleural effusion, pneumothorax, transient tachypnoea of the newborn and respiratory distress syndrome. The main barriers for implementation were lack of experience with technical aspects and/or image interpretation. Most units indicated that specific courses and an international guideline on neonatal LU could promote uptake of this technique. CONCLUSIONS: Although LU has been adopted in neonatal care in most European countries, the uptake is highly variable. The main indications are diagnosis of lung disease, evaluation of acute clinical deterioration and guidance of surfactant. Implementation may be improved by developing courses and publishing an international guideline.

Red Blood Cell Transfusion in European Neonatal Intensive Care Units, 2022 to 2023.

Importance: Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown. Objective: To describe neonatal RBC transfusion practice in Europe. Design, Setting, and Participants: This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation. Exposure: Admission to the NICU. Main Outcomes and Measures: Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion. Results: A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration. Conclusions and Relevance: In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Point-of-care ultrasound in neonatal intensive care.

This review investigates how point-of-care ultrasound (POCUS) allows individualised treatment based on the patient's clinical and physiological state. Serial examinations enable timely adjustments of interventions, potentially fewer side effects, and less need for x-ray examinations. One of the main barriers to POCUS is the lack of systematic training and quality control. The next step toward more widespread use of neonatal POCUS is systematic theoretical and practical training and implementing standardized examination protocols.

Cerebral vascular effects of hypovolemia and dopamine infusions: a study in newborn piglets.

AIM: Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature. METHODS: In 12 piglets, cerebral perfusion (laser-Doppler flux) and oxygenation [near-infrared spectroscopy (NIRS)] were examined during dopamine (20-50 µg/kg per minute) and nonpharmacologically induced blood pressure (ABP) changes. Effect on cerebral perfusion and oxygenation was quantified as frequency gain between ABP and laser-Doppler flux (gain-LDF) and NIRS [gain-oxygenation index (OI)], respectively. Gain quantifies change in perfusion or oxygenation per ABP-change. CA was estimated as gain-LDF during nonpharmacologically induced ABP changes, that is, as degree of impairment. Dopamine's cerebrovascular effect was estimated by contrasting gain during dopamine- and nonpharmacologically induced ABP changes. Measurements were conducted during both normovolemia- and haemorrhage-induced hypovolemia. RESULTS: Hypovolemia elicited hypotension (p = 0.02) as well as increasing impairment of CA (p = 0.01). However, hypovolemia without hypotension did not affect CA significantly. Dopamine increased perfusion significantly compared to nonpharmacological challenges (mean difference: 1.5%/mmHg, 95% CI: 0.5-2.6, p = 0.007). Oxygenation was, however, similar (mean difference: 0.01 µmol/L per mmHg, 95% CI: -0.03 to 0.05, p = 0.7). CONCLUSION: Our findings do not support that hypovolemia alone impairs CA. Furthermore, dopamine seems to increase cerebral perfusion but not oxygenation.

Applicability of near-infrared spectroscopy to measure cerebral autoregulation noninvasively in neonates: a validation study in piglets.

Impaired cerebral autoregulation (CA) is common and is associated with brain damage in sick neonates. Frequency analysis using spontaneous changes in arterial blood pressure (ABP) and cerebral near-infrared spectroscopy (NIRS) has been used to measure CA in several clinical studies. Coherence of the NIRS and ABP signals (i.e. correlation in the frequency domain) detects impairment of CA, whereas gain (i.e. magnitude of ABP variability passing from systemic to cerebral circulation) estimates the degree of this impairment. So far, however, this method has not been validated. In 12 newborn piglets, we compared NIRS-derived measures of CA with a conventional measure of CA: cerebral blood flow was measured by laser Doppler flowmetry, and changes in ABP were induced by inflating a thoracic aorta balloon. CA capacity was calculated as %ΔCVR/%ΔABP (i.e. percentage of full autoregulatory capacity), where CVR (i.e. cerebral vascular resistance) was estimated as ABP/Doppler flux. Correlation between coherence and CA capacity (r = -0.34, n = 24, p > 0.05) and between gain and CA capacity (r = -0.11, n = 24, p > 0.05) was limited. As expected, however, gain was significantly associated with CA capacity in measurements with significant coherence (r = -0.55, n = 15, p = 0.03). In conclusion, our data validate frequency analysis for estimation of CA in clinical research. Low precision, however, hampers its clinical application.

[Surfactant therapy of respiratory distress syndrome].

This review gives a summary of the development of a method to measure lung surfactant on gastric aspirate at birth in premature infants with the purpose to threat respiratory distress syndrome early with targeted surfactant. Machine learning was used to create the algorithm, and a point-of-care spectrometer was constructed for use in the delivery room. The sensitivity was 91% and specificity 79% in a clinical trial. The same method was used to measure surfactant in tracheal fluid in patients with COVID-19 since lung surfactant may be diminished in these patients.

[Severe foetal anaemia caused by undetected alloimmunisation in a RhD-positive pregnant woman].

The incidence of haemolytic disease of the foetus or newborn (HDFN) has decreased considerably in Denmark since the introduction of routine administration of prophylactic anti-D immunoglobulin to RhD-negative pregnant women carrying a RhD-positive foetus. RhD-positive pregnant women are screened for irregular antibodies only in the first trimester of their pregnancy, as their risk of clinically relevant immunisation during pregnancy has been considered very low. This is a case report of severe undetected alloimmunisation causing fatal HDFN after the first trimester in a RhD-positive woman.

Fatal case of hospital-acquired hypernatraemia in a neonate: lessons learned from a tragic error.

A 3-week-old boy with viral gastroenteritis was by error given 200 mL 1 mmol/mL hypertonic saline intravenously instead of isotonic saline. His plasma sodium concentration (PNa) increased from 136 to 206 mmol/L. Extreme brain shrinkage and universal hypoperfusion despite arterial hypertension resulted. Treatment with glucose infusion induced severe hyperglycaemia. Acute haemodialysis decreased the PNa to 160 mmol/L with an episode of hypoperfusion. The infant developed intractable seizures, severe brain injury on magnetic resonance imaging and died. The most important lesson is to avoid recurrence of this tragic error. The case is unique because a known amount of sodium was given intravenously to a well-monitored infant. Therefore the findings give us valuable data on the effect of fluid shifts on the PNa, the circulation and the brain's response to salt intoxication and the role of dialysis in managing it. The acute salt intoxication increased PNa to a level predicted by the Edelman equation with no evidence of osmotic inactivation of sodium. Treatment with glucose in water caused severe hypervolaemia and hyperglycaemia; the resulting increase in urine volume exacerbated hypernatraemia despite the high urine sodium concentration, because electrolyte-free water clearance was positive. When applying dialysis, caution regarding circulatory instability is imperative and a treatment algorithm is proposed.