Global and regional heterogeneity of lung aeration in neonates with different respiratory disorders: a physiological, observational study.

BACKGROUND.: Aeration heterogeneity affects lung stress and influences outcomes in adults with acute respiratory distress syndrome (ARDS). We hypothesize that aeration heterogeneity may differ between neonatal respiratory disorders and is associated with oxygenation, so its evaluation may be relevant in managing respiratory support. METHODS.: Observational, prospective study. Neonates with respiratory distress syndrome (RDS), transient tachypnea (TTN), evolving bronchopulmonary dysplasia (BPD) and neonatal ARDS (NARDS) were enrolled. Quantitative lung ultrasound and transcutaneous blood gas measurements were simultaneously performed. Global aeration heterogeneity (with its intra- and inter-patient components) and regional aeration heterogeneity were primary outcomes; oxygenation metrics were the secondary outcomes. RESULTS.: 230 (50 RDS, TTN or evolving BPD and 80 NARDS) patients were studied. Intra-patient aeration heterogeneity was higher in TTN (mean: 61% [standard deviation: 33%]) and evolving BPD (mean: 57% [standard deviation: 20%], p<0.001), with distinctive aeration distributions. Inter-patient aeration heterogeneity was high for all disorders (Gini-Simpson index: between 0.6 and 0.72) except RDS (Gini-Simpson index: 0.5) whose heterogeneity was significantly lower than all others (p<0.001). NARDS and evolving BPD had the most diffuse injury and worst gas exchange metrics. Regional aeration heterogeneity was mostly localized in upper anterior and posterior zones. Aeration heterogeneity and total lung aeration had an exponential relationship (p<0.001; adj-R 2=0.62). Aeration heterogeneity is associated with greater total lung aeration (i.e., higher heterogeneity means a relatively higher proportion of normally aerated lung zones, thus greater aeration; p<0.001; adj-R 2=0.83) and better oxygenation metrics upon multivariable analyses. CONCLUSIONS.: Global aeration heterogeneity and regional aeration heterogeneity differ amongst neonatal respiratory disorders. TTN and evolving BPD have the highest intra-patient aeration heterogeneity. TTN, evolving BPD and NARDS have the highest inter-patient aeration heterogeneity, but the latter two have the most diffuse injury and worst gas exchange. Higher aeration heterogeneity is associated with better total lung aeration and oxygenation.

Ultrasound-assessed lung aeration, oxygenation and respiratory care in neonatal bile acid pneumonia: A nested case-control study.

AIM: Neonatal bile acid pneumonia (NBAP) occurs in neonates following obstetric cholestasis. We aimed to study the lung aeration and respiratory support of NBAP. METHODS: Nested, case/control study enrolling age-matched neonates with NBAP, respiratory distress syndrome (RDS) or transient tachypnoea (TTN). Lung aeration and oxygenation were assessed with lung ultrasound score, oxygenation index and SpO2 /FiO2 . RESULTS: Nineteen, 22 and 25 neonates with NBAP, RDS and TTN, respectively were studied (mean gestational age = 33 (2.2) weeks, 30 (45.5%) males). Upon admission, RDS patients had the worst lung ultrasound score (p = 0.022) and oxygenation index (p = 0.001), while NBAP and TTN neonates had similar values. At the worst time-point, NBAP and RDS patients showed similar oxygenation index (NBAP: 4.6 [2], RDS: 5.7 [3]) and SpO2 /FiO2 (NBAP: 3.1 [1.1], RDS: 2.7 [1]) which were worse than those of TTN patients (oxygenation index: p = 0.015, SpO2 /FiO2 : p = 0.001). RDS neonates needed the longest continuous positive airway pressure and highest mean airway pressure, but NBAP neonates needed invasive ventilation (26.3%, p = 0.01) and surfactant (31.6%, p = 0.003) more often than TTN patients who never needed these. CONCLUSION: NBAP was a mild disorder in the first hours of life but subsequently worsened and became similar to RDS.

Ultra-high frequency lung ultrasound in preterm neonates: a test validation study on interpretation agreement and reliability.

OBJECTIVE: To verify if increasing frequency, through the use of ultra-high frequency transducers, has an impact on lung ultrasound pattern recognition. DESIGN: Test validation study. SETTING: Tertiary academic referral neonatal intensive care unit. PATIENTS: Neonates admitted with respiratory distress signs. INTERVENTIONS: Lung ultrasound performed with four micro-linear probes (10, 15, 20 and 22 MHz), in random order. Anonymised images (600 dpi) were randomly included in a pictorial database: physicians with different lung ultrasound experience (beginners (n=7), competents (n=6), experts (n=5)) blindly assessed it. Conformity and reliability of interpretation were analysed using intraclass correlation coefficient (ICC), area under the curve (AUC) of the multi-class ROC analysis, correlation and multivariate linear regressions (adjusting for frequency, expertise and their interaction). OUTCOME MEASURES: A (0-3) score based on classical lung ultrasound semiology was given to each image as done in the clinical routine. RESULTS: ICC (0.902 (95% CI: 0.862 to 0.936), p<0.001) and AUC (0.948, p<0.001) on the whole pictorial database (48 images acquired on 12 neonates), and irrespective of the frequency and physicians' expertise, were excellent. Physicians detected more B-lines with increasing frequency: there was a positive correlation between score and frequency (ρ=0.117, p=0.001); multivariate analysis confirmed the score to be higher using 22 MHz-probes (ß=0.36 (0.02-0.7), p=0.041). CONCLUSION: Overall conformity and reliability of interpretations of lung ultrasound patterns were excellent. There were differences in the identification of the B-patterns and severe B-patterns as increasing probe frequency is associated with higher score given to these patterns.

Continuous Venovenous Hemofiltration Performed by Neonatologists With Cardio-Renal Pediatric Dialysis Emergency Machine to Treat Fluid Overload During Multiple Organ Dysfunction Syndrome: A Case Series.

OBJECTIVES: A new device is available for neonates needing extracorporeal renal replacement therapy. We reviewed the use of this device (in continuous venovenous hemofiltration [CVVH] mode) in term or preterm neonates affected by multiple organ dysfunction syndrome (MODS) with fluid overload. DESIGN: Case series. SETTING: Academic specialized referral neonatal ICU (NICU) with expertise on advanced life support and monitoring. PATIENTS: Neonates with MODS and fluid overload despite conventional treatments and receiving at least one CVVH session. INTERVENTION: CVVH with the Cardio-Renal Pediatric Dialysis Emergency Machine. MEASUREMENTS AND MAIN RESULTS: Ten (three preterm) neonates were treated using 18 consecutive CVVH sessions. All patients were in life-threatening conditions and successfully completed the CVVH treatments, which almost always lasted 24 hr/session, without major side effects. Three neonates survived and were successfully discharged from hospital with normal follow-up. CVVH reduced fluid overload (before versus after represented as a weight percentage: 23.5% [12-34%] vs 14.6% [8.2-24.1%]; p = 0.006) and lactate (before versus after: 4.6 [2.9-12.1] vs 2.9 mmol/L [2.3-5.5 mmol/L]; p = 0.001). CVVH also improved the Pa o2 to Fio2 (before vs after: 188 mm Hg [118-253 mm Hg] vs 240 mm Hg [161-309 mm Hg]; p = 0.003) and oxygenation index (before vs after: 5.9 [3.8-14.6] vs 4 [2.9-11]; p = 0.002). The average cost of CVVH in these patients was minor (≈3%) in comparison with the median total cost of NICU care per patient. CONCLUSIONS: We have provided CVVH to critically ill term and preterm neonates with MODS. CVVH improved fluid overload and oxygenation. The cost of CVVH was minimal compared with the overall cost of neonatal intensive care.

CARPEDIEM® for continuous kidney replacement therapy in neonates and small infants: a French multicenter retrospective study.

BACKGROUND: The Cardio-Renal Pediatric Dialysis Emergency Machine (CA.R.P.E.D.I.E.M.®) device is a continuous kidney replacement therapy (CKRT) equipment dedicated to neonates and small infants. This study aimed to assess the effectiveness, feasibility, outcomes, and technical considerations relating to CARPEDIEM® use. METHODS: This retrospective multicenter study included 19 newborns and six infants receiving CARPEDIEM® in five French pediatric and neonatal intensive care units. Laboratory parameters were collected at the initiation and end of the first CARPEDIEM® session. Results are presented as median [IQR] (range). RESULTS: At initiation, age was 4 days [2-13] (1-1134) with a body weight of 3.3 kg [2.5-4] (1.3-11.1). Overall, 131 sessions and 2125 h of treatment were performed. Treatment duration per patient was 42 h [24-91] (8-557). Continuous veno-venous hemofiltration (CVVH) was performed in 20 children. Blood flow rate was 8 mL/kg/min [6-9] (3-16). The effluent flow rate for CVVH was 74 mL/kg/h [43-99] (28-125) and net ultrafiltration (UF) 6 mL/kg/h [2-8] (1-12). In the five children treated by hemodialysis, the blood and dialysate flow rates were 6 mL/kg/min [5-7] (4-7) and 600 mL/h [300-600] (120-600), respectively, while session duration was 8 h [6-12] (2-24). Most infants required a catheter between 4.5 and 6.5 French. Hemodynamic instability with a need for volume replacement occurred in 31 sessions (23%). Thrombocytopenia was observed in 29 sessions (22%). No hemorrhage occurred; all the patients survived the sessions, but only eight patients (32%) were alive at hospital discharge. CONCLUSIONS: These data confirm that the use of CARPEDIEM® is safe and effective in critically ill neonates and infants. A higher resolution version of the Graphical abstract is available as Supplementary information.

Respiratory and haemodynamic effects of 6h-pronation in neonates recovering from respiratory distress syndrome, or affected by acute respiratory distress syndrome or evolving bronchopulmonary dysplasia: a prospective, physiological, crossover, controlled cohort study.

Background: Pronation ameliorates oxygenation in adults with acute respiratory distress syndrome (ARDS); the effect in neonates with ARDS or other types of respiratory failure is unknown. We aimed to verify if pronation has similar respiratory and haemodynamic effects in three common types of neonatal respiratory failure. Methods: Prospective, physiologic, crossover, quasi-randomised, controlled cohort study performed in a tertiary academic neonatal intensive care unit. We enrolled neonates with: 1) recovering respiratory distress syndrome (RDS, mild restrictive pattern); 2) neonatal ARDS (NARDS, severe restrictive pattern); or 3) evolving bronchopulmonary dysplasia (BPD), that is chronic pulmonary insufficiency of prematurity (mixed restrictive/obstructive pattern). Neonates with other lung disorders, malformations or haemodynamic impairment were excluded. Patients were started prone or supine and then shifted to the alternate position for 6h; measurements were performed after 30' of "wash out" from the positioning and at the end of 6h period. Primary outcomes were respiratory (PtcCO2, modified ventilatory index, PtcO2/FiO2, SpO2/FiO2, oxygenation index, ultrasound-assessed lung aeration) and haemodynamic (perfusion index, heart rate, arterial pressure, cardiac output) parameters. Findings: Between May 1st, 2019, and May 31st, 2021, 161 participants were enrolled in this study, and included in the final analysis. Pronation improved gas exchange and lung aeration (p always <0.01) and these effects were overturned in the alternate position, except for lung aeration in NARDS where the improvement persisted. The effects were greater in patients recovering from RDS than in those with evolving BPD than in those with NARDS, in this order (p always <0.01). Pronation produced a net recruitment as lung ultrasound score decreased in patients shifted from supine (16.9 (standard deviation: 5.8)) to prone (14.1 (standard deviation: 3.3), p < 0.01) and this reduction correlated with oxygenation improvement. Haemodynamic parameters remained within normal ranges. Interpretation: 6h-pronation can be used to improve gas exchange and lung aeration in neonates with recovering RDS, evolving BPD or NARDS without relevant haemodynamic effects. Funding: None.

Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections.

OBJECTIVE: This study aimed to describe the characteristics of fetal demise after SARS-CoV-2 infections and clarify whether it is associated with clinical severity, placental lesions, or malformations or due to actual fetal infections. DATA SOURCES: PubMed and Web of Science databases were searched between December 1, 2019, and April 30, 2022. STUDY ELIGIBILITY CRITERIA: Cohort, cross-sectional, and case-control studies and case series or case reports describing stillbirths or late miscarriages (ie, pregnancy loss occurring between 14 and 22 weeks of gestation, before and after the onset of labor) from mothers with SARS-CoV-2 infection during pregnancy (demonstrated by at least 1 positive real-time reverse transcription-polymerase chain reaction from nasopharyngeal swabs and/or SARS-CoV-2 placental infection). No language restriction was applied; cases with other causes possibly explaining the fetal demise were excluded. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines were followed. The quality of the case series and case reports was evaluated using the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data and placental and fetal virology and histology findings were collected. Data were summarized with descriptive statistics using the World Health Organization criteria to classify disease severity and fetal-neonatal infections. RESULTS: Data from 184 mothers and 190 fetuses were analyzed. No clear link to maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demise cases occurred during the second and third trimesters of pregnancy, approximately 6 to 13 days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms. Most placentas (88%) were positive for SARS-CoV-2 or presented the histologic features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (85%-91%). Of note, 11 fetuses (5.8%) had a confirmed in utero transmitted SARS-CoV-2 infection, and 114 fetuses (60%) had a possible in utero transmitted SARS-CoV-2 infection. CONCLUSION: The synthesis of available data showed that fetal demise generally occurs a few days after the infection with histologic placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

Evolution of Ultrasound-Assessed Lung Aeration and Gas Exchange in Respiratory Distress Syndrome and Transient Tachypnea of the Neonate.

OBJECTIVE: To use clinical, lung ultrasound, and gas exchange data to clarify the evolution of lung aeration and function in neonates with respiratory distress syndrome (RDS) and transient tachypnea of the neonate (TTN), the most common types of neonatal respiratory failure. STUDY DESIGN: In this prospective observational cohort study, lung aeration and function were measured with a semiquantitative lung ultrasound score (LUS) and transcutaneous blood gas measurement performed at 1 hour (time point 0), 6 hours (time point 1), 12 hours (time point 2), 24 hours (time point 3) and 72 hours (time point 4) of life. Endogenous surfactant was estimated using lamellar body count (LBC). LUS, oxygenation index (OI), oxygen saturation index (OSI), and transcutaneous pressure of carbon dioxide (PtcCO2) were the primary outcomes. All results were adjusted for gestational age. RESULTS: Sixty-nine neonates were enrolled in the RDS cohort, and 58 neonates were enrolled in the TTN cohort. LUS improved over time (within-subjects, P < .001) but was worse for the RDS cohort than for the TTN cohort at all time points (between-subjects, P < .001). Oxygenation improved over time (within-subjects, P = .011 for OI, P < .001 for OSI) but was worse for the RDS cohort than for the TTN cohort at all time points (between-subjects, P < .001 for OI and OSI). PtcCO2 improved over time (within-subjects, P < .001) and was similar in the RDS and TTN cohorts at all time points. Results were unchanged after adjustment for gestational age. LBC was associated with RDS (ß = -0.2 [95% CI, -0.004 to -0.0001]; P = .037) and LUS (ß = -3 [95% CI, -5.5 to -0.5]; P = .019). CONCLUSIONS: For the first 72 hours of life, the RDS cohort had worse lung aeration and oxygenation compared with the TTN cohort at all time points. CO2 clearance did not differ between the cohorts, whereas both lung aeration and function improved in the first 72 hours of life.

Enhanced INSURE (ENSURE): an updated and standardised reference for surfactant administration.

There is no firm consensus about the optimal technique for the administration of exogenous surfactant in preterm neonates, and different techniques may be equally effective. The intubation-surfactant-extubation (INSURE) procedure has not been fully described, and important details, such as duration and mode of ventilation, remain unclear, leading to significant clinical practice variations and influencing its suitability and feasibility. Since the first INSURE description, our knowledge in respiratory care has largely progressed, but the technique has not been updated according to current evidence-based practice. Thus, our aim is to formally describe a modern way to perform INSURE, based on the current knowledge and technology, to increase its feasibility and patients' safety. We offer ENSURE (Enhanced INSURE) as an updated and standardised technique for surfactant administration, clarifying crucial issues of the original method by applying current state-of-the-art concepts of respiratory care. We performed a cross-sectional observational study enrolling 57 preterm neonates describing ENSURE feasibility and safety.   Conclusion: ENSURE can be used as a reference technique in clinical practice, teaching and research. What is Known: • There is no consensus about the optimal method for surfactant administration. INSURE technique has been originally described many years ago without considering modern principles of neonatal respiratory care and the available state-of-the-art technology. What is New: • We here describe a modern way to perform INSURE, based on the current knowledge and technology. We called it ENSURE (Enhanced INSURE) and clarified crucial points of the original technique, in light of the current knowledge. We verified feasibility and safety of ENSURE in a cross-sectional observational study enrolling 57 preterm neonates.

Effect of inspired gas temperature on lung mechanics and gas exchange in neonates in normothermia or therapeutic hypothermia.

BACKGROUND: Respiratory critical care guidelines suggest heating the air/oxygen mixture but do not recommend a specific temperature target. We aimed to clarify if the inspired gas temperature influences lung mechanics and gas exchange in intubated patients treated with whole body hypothermia (WBH) or normothermia (NT). METHODS: Prospective cohort study enrolling neonates ventilated for perinatal asphyxia resuscitation (no lung disease) or acute hypoxemic respiratory failure. Patients were divided between those ventilated in NT or WBH. Compliance (Cdyn), airway resistances (Raw), oxygenation index (OI), PaO2/FiO2, A-a gradient, a/A ratio, estimated alveolar dead space (VDalv), ventilatory index (VI) and CO2 production (VCO2) were registered at the study beginning (inspired gas at 37°C). Then, gas temperature was decreased (32 °C) and variables were recorded again after 1 and 3 h. Data were analysed with univariate and multivariate repeated measures-ANOVA. RESULTS: Cdyn, Raw, OI, PaO2/FiO2, A-a gradient, a/A ratio, VDalv, VI and VCO2 are similar between WBH and NT at any timepoint (between-subjects effect); these results do not change adjusting for the presence of respiratory failure. When this is considered in multivariate ANOVA (within-subjects effect), Cdyn (p = 0.016), Raw (p = 0.034) and VDalv (p < 0.001) were worse in patients with respiratory failure than in those without lung disease. CONCLUSIONS: Decreasing the gas temperature from 37 °C to 32 °C for 3 h does not change lung mechanics and gas exchange, neither in neonates with, nor in those without respiratory failure and in those treated in NT or WBH. These findings fill a knowledge gap regarding the effect of inspired gas temperature during WBH: they may inform future respiratory critical care guidelines.

Refractive Outcome in Preterm Newborns With ROP After Propranolol Treatment. A Retrospective Observational Cohort Study.

Background: Recent explorative studies suggest that propranolol reduces retinopathy of prematurity (ROP) progression, but the short-term effects of propranolol treatment at 1 year of corrected age have not been extensively evaluated. Methods: A multi-center retrospective observational cohort study was conducted to assess the physical development and the refractive outcome of infants with prior ROP treated with propranolol. Forty-nine infants treated with propranolol were compared with an equal number of patients who did not receive any propranolol therapy and represent the control group, with comparable anthropometrical characteristics and stages of ROP. Results: The weight, length, and head circumference at 1 year of corrected age were similar between infants who had been treated, or not, with propranolol, without any statistically significant differences. Refractive evaluation at 1 year showed spherical equivalent values decreasing with the progression of ROP toward more severe stages of the disease, together with an increasing number of infants with severe myopia. On the contrary, no differences were observed between infants who had been treated with propranolol and those who had not. Conclusion: This study confirms that the progression of ROP induces an increase of refractive errors and suggests that propranolol itself does not affect the refractive outcome. Therefore, if the efficacy of propranolol in counteracting ROP progression is confirmed by further clinical trials, the conclusion will be that propranolol might indirectly improve the visual outcome, reducing the progression of ROP.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.