Lung UltrasouNd Guided surfactant therapy in preterm infants: an international multicenter randomized control trial (LUNG study).

BACKGROUND: The management of respiratory distress syndrome (RDS) in premature newborns is based on different types of non-invasive respiratory support and on surfactant replacement therapy (SRT) to avoid mechanical ventilation as it may eventually result in lung damage. European guidelines currently recommend SRT only when the fraction of inspired oxygen (FiO2) exceeds 0.30. The literature describes that early SRT decreases the risk of bronchopulmonary dysplasia (BPD) and mortality. Lung ultrasound score (LUS) in preterm infants affected by RDS has proven to be able to predict the need for SRT and different single-center studies have shown that LUS may increase the proportion of infants that received early SRT. Therefore, the aim of this study is to determine if the use of LUS as a decision tool for SRT in preterm infants affected by RDS allows for the reduction of the incidence of BPD or death in the study group. METHODS/DESIGN: In this study, 668 spontaneously-breathing preterm infants, born at 25+0 to 29+6 weeks' gestation, in nasal continuous positive airway pressure (nCPAP) will be randomized to receive SRT only when the FiO2 cut-off exceeds 0.3 (control group) or if the LUS score is higher than 8 or the FiO2 requirements exceed 0.3 (study group) (334 infants per arm). The primary outcome will be the difference in proportion of infants with BPD or death in the study group managed compared to the control group. DISCUSSION: Based on previous published studies, it seems that LUS may decrease the time to administer surfactant therapy. It is known that early surfactant administration decreases BPD and mortality. Therefore, there is rationale for hypothesizing a reduction in BPD or death in the group of patients in which the decision to administer exogenous surfactant is based on lung ultrasound scores. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05198375 . Registered on 20 January 2022.

Reply to the comment on "Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey".

The Authors Chang Liu B.S and Yuan Shi commented our paper on Fluid restriction in management of patent ductus arteriosus (PDA) in Italy. With our study, we conducted a prospective cross-sectional survey among all Italian Neonatal Intensive Care Units (NICUs) to address conservative management of patent ductus arteriosus (PDA) in preterm infants below 29 weeks' gestational age (GA), with specific regard to fluid restriction (FR). The Authors wondered if the heterogeneity of use of fluid restriction both as a prophylactic tool and as a conservative tool when a hemodynamically significant PDA is diagnosed, was due to economic disparities among areas of the included centers. Conducting a secondary analysis of our data, we observed that if we separately consider the responses of two areas, northern and central-southern Italy, FR is slightly more frequently applied in Central and Southern regions (82%) as compared to Northern regions (78%), although this finding does not reach statistical significance. No correlation between the likelihood to adopt conservative measures and the amount of allowed fluid intake was found. The hypothesis that "less fluid intake resulted in milder clinical and echocardiographic presentations of PDA, and thus a lower rate of pharmacological treatment" cannot be supported by our current study design and might deserve future investigations.

Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey.

We aimed at establishing the state of the art in fluid restriction practice in our national setting and providing a foundation for future research efforts. A prospective cross-sectional survey was conducted among all 114 Italian Neonatal Units in order to address conservative management of patent ductus arteriosus (PDA) in preterm infants below 29 weeks' gestational age (GA), with specific regard to fluid restriction. Response rate was 80%. Conservative measures for PDA management are provided in the majority of NICUs and 80% of centers reduce fluid intake in neonates with PDA. No relationship can be found among pharmacologically or surgically treated patients per year and the approach to fluid restriction. The minimum intake administered at regimen when fluid restriction is applied is associated to the ratio between the maximum number of neonates managed pharmacologically and number of admitted < 29 weeks' GA newborns. CONCLUSION: Our survey shows an extreme variability among centers in terms of use of fluid restriction as a prophylactic tool but also in terms of its use (both opportunity and modality) when a hemodynamically significant PDA is diagnosed. This variability, that can be also found in randomized trials and observational studies, suggests that further evidence is needed to better understand its potential beneficial effects and its potential harms such as dehydration, hypotension, decreased end-organ perfusion, and reduced caloric intake. WHAT IS KNOWN: • The lack of demonstrable improvement following the treatment of patent ductus arteriosus has recently paved the way to a more conservative approach. • Fluid restriction is the most commonly applied conservative treatment of PDA. WHAT IS NEW: • Among Italian NICUs an extreme variability in terms of indications, timing and modalities of application of Fluid restriction can be found. • This variability reflects the lack of standardization of this practice and the contrasting evidence on its efficacy.

Lung ultrasound score follows the chronic pulmonary insufficiency of prematurity trajectory in early infancy.

Extremely preterm birth is associated with a high risk of chronic pulmonary insufficiency of prematurity (CPIP). Lung ultrasound score (LUS) proved capable to characterise CPIP progression beyond the acute setting, but still, post-discharge data remain lacking. We hypothesised a priori that LUS in both BPD and no-BPD infants declines with postnatal age from birth through early infancy. This observational retrospective cohort study included preterm infants < 32 gestational weeks, who underwent the follow-up for CPIP. LUS was assessed from birth to 8 months postnatal age, over antero-lateral (LUS) and posterior (pLUS) pulmonary areas, placing the transducer longitudinally over the midclavicular and midaxillary lines and medial to the scapular line respectively. Extended LUS (eLUS) including LUS and pLUS was calculated. The primary outcome was LUS time course. Secondary outcomes included the correlation between LUS and pLUS. Sixty-two infants were included: 22 (35.5%) in the BPD group and 40 (64.5%) in the no-BPD group. BPD group infants were smaller (weight 841 g (± 228) vs 1226 (± 328), p < 0.001) and younger (26.8 weeks (± 2.0) vs 28.9 (± 1.9), p < 0.001). LUS declined over time in the entire population (ß = - 1.75, p < 0.001) and in both no-BPD and BPD groups (ß = - 1.64, p < 0.001 and ß = - 1.93, p < 0.001, respectively). eLUS declined correspondingly (p < 0.001). LUS and likewise eLUS were significantly different between BPD and no-BPD groups over time (p < 0.001).  Conclusion: LUS trajectory progressively decreased from birth to early infancy. BPD cohort tracked higher, implying a worse respiratory status. pLUS had a similar timepoint course, adding no further information to LUS. To the best of our knowledge, this is the first study that describes preterm LUS time course after discharge. LUS may help track the CPIP progression. What is Known: • Extremely preterm birth is associated with high risk of chronic pulmonary insufficiency of prematurity (CPIP). • Several studies investigated the ability of lung ultrasound score (LUS) to characterize CPIP progression beyond the acute setting, still post-discharge data remain lacking. What is New: • LUS trajectory progressively decreases from birth to early infancy; BPD cohort tracks higher, implying a worse respiratory status. pLUS has similar timepoint course, adding no further information to LUS. • The use of LUS may contribute to better characterising and monitoring CPIP in BPD and no-BPD infants.

Lung ultrasound in Italian neonatal intensive care units: A national survey.

INTRODUCTION: Lung ultrasound (LU) is a noninvasive, bedside imaging technique that is attracting growing interest in the evaluation of neonatal respiratory diseases. We conducted a nationwide survey of LU usage in Italian neonatal intensive care units (NICUs). METHODS: A structured questionnaire was developed and sent online to 114 Italian NICUs from June to September 2021. RESULTS: The response rate was 79%. In the past 4 years (range: 2-6), LU has been adopted in 82% of Italian NICUs. It is the first-choice diagnostic test in 23% of the centers surveyed. The main LU diagnostic applications reported were: pneumothorax (95%), respiratory distress syndrome (89%), transient tachypnea of the newborn (89%), plural effusion (88%), atelectasis (66%), pneumonia (64%), bronchopulmonary dysplasia (43%), congenital pulmonary airway malformation (41%), and congenital diaphragmatic hernia (34%). Thirty percent of participating centers calculated LU score routinely, but only seven units used it to predict the need for surfactant replacement. Sixty-six percent of respondents learned the LU technique via a self-training process, while 34% of them visited an expert in the field for one-to-one tuition. CONCLUSIONS: LU has a widespread use in Italian NICUs. However, the use of LU is extremely heterogeneous among centers. There is an urgent need to ensure standardization of clinical practice guidelines and to design and implement a formalized and accredited training program.

Lung ultrasound score parallels trends in systemic haemodynamics after PDA ligation: a case series.

B-lines in lung ultrasound (LU) are non-specific but highly informative sign of interstitial pulmonary oedema (iPE). Sustained exposure to a high-volume left-to-right patent ductus arteriosus (PDA) shunt is associated with iPE. Cardiorespiratory deterioration, named post-ligation cardiac syndrome (PLCS), may follow surgical ligation between 6 and 12 h post-operatively. We conducted a pilot longitudinal evaluation of peri-procedural LU score change. Infants < 32-week gestational age or < 1500-g birthweight undergoing PDA ligation, where pre-, 1 h and 6-12 h LU were performed, were included. Two independent raters evaluated LU score (LUS). Neonatologist performed echocardiography (NPE) was performed concurrently to appraise changes in left ventricular output (LVO). Milrinone was initiated if LVO was < 200 mL/kg/min 1 h after surgery, to prevent PLCS. The primary outcome was peri-procedural LUS change. Secondary outcomes included PLCS. Five infants were included (birthweight 787(88) g; gestational age 25.6(0.7) weeks). Postnatal age and weight at the intervention were 41(14) days and 1175(295) g. All infants, but one, received milrinone prophylaxis. None of the patients developed PLCS or required rescue HFOV. Post-interventional LUS were lower compared to pre-operative LUS (p = 0.041 vs 1 h, p = 0.042 vs 6-12 h). A concurrent fall post-operative LVO was noted (p < 0.05 vs pre-operative). CONCLUSION: A sustained fall in LUS after PDA ligation was identified, which most likely reflects reduction in pulmonary blood flow and interstitial edema. Changes in LUS paralleled changes in LVO, suggesting physiologic linkage. These data suggest that LU may be a useful tool to guide monitoring the biologic nature of pulmonary disease after PDA ligation. WHAT IS KNOWN: • Sustained exposure to a high-volume left-to-right patent ductus arteriosus (PDA) shunt is associated with interstitial pulmonary oedema. • In the most immature patients, cardiorespiratory deterioration, named post-ligation cardiac syndrome, presents 6-12 h post-operatively. WHAT IS NEW: • An early and sustained fall in lung ultrasound score (LUS) after PDA ligation most likely reflects reduction in pulmonary blood flow and interstitial oedema. LUS changes parallel changes in left ventricular output, suggesting linkage. • LU is a promising adjunctive tool in the post-operative management of PDA ligation.

Neonatal Lung Ultrasound and Surfactant Administration: A Pragmatic, Multicenter Study.

BACKGROUND: Previous research shows that a lung ultrasound score (LUS) can anticipate CPAP failure in neonatal respiratory distress syndrome. RESEARCH QUESTION: Can LUS also predict the need for surfactant replacement? STUDY DESIGN AND METHODS: Multicenter, pragmatic study of preterm neonates who underwent lung ultrasound at birth and those given surfactant by masked physicians, who also were scanned within 24 h from administration. Clinical data and respiratory support variables were recorded. Accuracy of LUS, oxygen saturation to Fio2 ratio, Fio2, and Silverman score for surfactant administration were evaluated using receiver operating characteristic curves. The simultaneous prognostic values of LUS and oxygen saturation to Fio2 ratio for surfactant administration, adjusting for gestational age (GA), were analyzed through a logistic regression model. RESULTS: Two hundred forty infants were enrolled. One hundred eight received at least one dose of surfactant. LUS predicted the first surfactant administration with an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI, 0.81-0.91), cut off of 9, sensitivity of 0.79 (95% CI, 0.70-0.86), specificity of 0.83 (95% CI, 0.76-0.89), positive predictive value of 0.79 (95% CI, 0.71-0.87), negative predictive value of 0.82 (95% CI, 0.75-0.89), positive likelihood ratio of 4.65 (95% CI, 3.14-6.89), and negative likelihood ratio of 0.26 (95% CI, 0.18-0.37). No significant difference was shown among different GA groups: 25 to 27 weeks' GA (AUC, 0.91; 95% CI, 0.84-0.99), 28 to 30 weeks' GA (AUC, 0.81; 95% CI, 0.72-0.91), and 31 to 33 weeks' GA (AUC, 0.88; 95% CI, 0.79-0.95), respectively. LUS declined significantly within 24 h in infants receiving one surfactant dose. When comparing Fio2, oxygen saturation to Fio2 ratio, LUS, and Silverman scores as criteria for surfactant administration, only the latter showed a significantly poorer performance. The combination of oxygen saturation to Fio2 ratio and LUS showed the highest predictive power, with an AUC of 0.93 (95% CI, 0.89-0.97), regardless of the GA interval. INTERPRETATION: LUS is a reliable criterion to administer the first surfactant dose regardless of GA. Its association with oxygen saturation to Fio2 ratio significantly improves the prediction power for surfactant need.

Lung Ultrasound Score Progress in Neonatal Respiratory Distress Syndrome.

BACKGROUND AND OBJECTIVES: The utility of a lung ultrasound score (LUS) has been described in the early phases of neonatal respiratory distress syndrome (RDS). We investigated lung ultrasound as a tool to monitor respiratory status in preterm neonates throughout the course of RDS. METHODS: Preterm neonates, stratified in 3 gestational age cohorts (25-27, 28-30, and 31-33 weeks), underwent lung ultrasound at weekly intervals from birth. Clinical data, respiratory support variables, and major complications (sepsis, patent ductus arteriosus, pneumothorax, and persistent pulmonary hypertension of the neonate) were also recorded. RESULTS: We enrolled 240 infants in total. The 3 gestational age intervals had significantly different LUS patterns. There was a significant correlation between LUS and the ratio of oxygen saturation to inspired oxygen throughout the admission, increasing with gestational age (b = -0.002 [P < .001] at 25-27 weeks; b = -0.006 [P < .001] at 28-30 weeks; b = -0.012 [P < .001] at 31-33 weeks). Infants with complications had a higher LUS already at birth (12 interquartile range 13-8 vs 8 interquartile range 12-4 control group; P = .001). In infants 25 to 30 weeks' gestation, the LUS at 7 days of life predicted bronchopulmonary dysplasia with an area under the curve of 0.82 (95% confidence interval 0.71 to 93). CONCLUSIONS: In preterm neonates affected by RDS, the LUS trajectory is gestational age dependent, significantly correlates with the oxygenation status, and predicts bronchopulmonary dysplasia. In this population, LUS is a useful, bedside, noninvasive tool to monitor the respiratory status.

Pulmonary hypertension in a neonatologist-performed echocardiographic follow-up of bronchopulmonary dysplasia.

Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation, including pulmonary hypertension (PH). PH may complicate bronchopulmonary dysplasia (BPD) course. Aims of this retrospective study were to assess the feasibility of NPE follow-up of infants with BPD and to describe the course of PH of infants with moderate/severe BPD. Preterm infants <32 gestational weeks or birthweight ≤1500 g with moderate/severe BPD underwent NPE follow-up, from 36 weeks postmenstrual age up to 8 months postnatal age. Twenty-three preemies were included (birth weight 840 (213) g, gestational age 26.8 (2.3) weeks); 12/23 developed mild PH, 2/12 after discharge. PH resolved at 8.9 (3.9) months. Clinical and echocardiographic variables did not differ between infants with and without PH, except pulmonary artery acceleration time (PAAT) and PAAT/right ventricle ejection time (RVET) ratio (PAAT: 36 weeks, 68.9 (11.9) vs 52.0 (19.1), p = 0.0443; 6 months: 83.9 (38.9) vs 74.8 (16.9), p = 0.0372). No deaths or admissions for PH were reported. Neonatologist's Image Quality Assessment score attributed by the cardiologist assumed as gold standard was adequate or optimal (9.5/14 total score); inter-rater agreement was excellent (ICC 0.974).Conclusions: NPE follow-up seems to be feasible and safe in both intensive care and outpatient clinic. Mild PH is frequently detected in moderate/severe BPD, with good prognosis. What is Known: • Preterm infants with bronchopulmonary dysplasia (BPD) may develop pulmonary hypertension (PH) and have a late diagnosis. • Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation of the neonate. What is New: • To our knowledge this is the first study of NPE follow-up of moderate/severe BPD, describing the course of mild PH from diagnosis to its resolution. • NPE follow-up of BPD seems to be safe and practicable, in both intensive care and outpatient clinic, as long as neonatologists maintain a sound collaboration with pediatric cardiologists.

Survey of PDA management in very low birth weight infants across Italy.

BACKGROUND: The optimal management of PDA in very low birth weight (VLBW) infants is still controversial. Aim of our study was to investigate the management of PDA in the Italian neonatal intensive care units (NICU). METHODS: We conducted an on-line survey study from June to September 2017. A 50-items questionnaire was developed by the Italian Neonatal Cardiology Study Group and was sent to Italian NICUs. RESULTS: The overall response rate was 72%. Diagnosis of PDA was done by neonatologists, cardiologists or both (62, 12 and 28% respectively). PDA significance was assessed by a comprehensive approach in all centers, although we found a heterogeneous combination of parameters and cut-offs used. None used prophylactic treatment. 19% of centers treated PDA in the first 24 h, 60% after the first 24 h, following screening echocardiography or clinical symptoms, 18% after the first 72 h and 2% after the first week. In the first course of treatment ibuprofen, indomethacin and paracetamol were used in 87, 6 and 7% of centers respectively. Median of surgical ligation was 3% (1-6%). CONCLUSIONS: Significant variations exist in the management of PDA in Italy. Conservative strategy and targeted treatment to infants older than 24 h with echocardiographic signs of hemodynamic significance seemed to be the most adopted approach.

Neonatologist performed echocardiography (NPE) in Italian neonatal intensive care units: a national survey.

BACKGROUND: Neonatologist performed echocardiography (NPE) has increasingly been used to assess the hemodynamic status in neonates. Aim of this survey was to investigate the utilization of NPE in Italian neonatal intensive care units (NICUs). METHODS: We conducted an on-line survey from June to September 2017. A questionnaire was developed by the Italian neonatal cardiology study group and was sent to each Italian NICU. RESULTS: The response rate was 77%. In 94% of Italian NICUs functional echocardiography was used by neonatologists, cardiologists or both (57, 15 and 28% respectively). All the respondents used NPE in neonates with patent ductus arteriosus and persistent pulmonary hypertension, 93% in neonates with hypotension or shock, 85% in neonates with perinatal asphyxia, 78% in suspicion of cardiac tamponade, and 73% for line positioning. In 30% of center, there was no NPE protocol. Structural echocardiography in stable and critically ill neonates was performed exclusively by neonatologists in 46 and 36% of center respectively. CONCLUSIONS: NPE is widely used in Italian NICUs by neonatologists. Structural echocardiography is frequently performed by neonatologists. Institutional protocols for NPE are lacking. There is an urgent need of a formal training process and accreditation to standardize the use of NPE.

Application of NPE in the assessment of a patent ductus arteriosus.

In many preterm infants, the ductus arteriosus remains patent beyond the first few days of life. This prolonged patency is associated with numerous adverse outcomes, but the extent to which these adverse outcomes are attributable to the hemodynamic consequences of ductal patency, if at all, has not been established. Different treatment strategies have failed to improve short-term outcomes, with a paucity of data on the correct diagnostic and pathophysiological assessment of the patent ductus arteriosus (PDA) in association with long-term outcomes. Echocardiography is the selected method of choice for detecting a PDA, assessing the impact on the preterm circulation and monitoring treatment response. PDA in a preterm infant can result in pulmonary overcirculation and systemic hypoperfusion, Therefore, echocardiographic assessment should include evaluation of PDA characteristics, indices of pulmonary overcirculation with left heart loading conditions, and indices of systemic hypoperfusion. In this review, we provide an evidence-based overview of the current and emerging ultrasound measurements available to identify and monitor a PDA in the preterm infant. We offer indications and limitations for using Neonatologist Performed Echocardiography to optimize the management of a neonate with a PDA.

Application of Neonatologist Performed Echocardiography in the assessment and management of persistent pulmonary hypertension of the newborn.

Pulmonary hypertension contributes to morbidity and mortality in both the term newborn infant, referred to as persistent pulmonary hypertension of the newborn (PPHN), and the premature infant, in the setting of abnormal pulmonary vasculature development and arrested growth. In the term infant, PPHN is characterized by the failure of the physiological postnatal decrease in pulmonary vascular resistance that results in impaired oxygenation, right ventricular failure, and pulmonary-to-systemic shunting. The pulmonary vasculature is either maladapted, maldeveloped, or underdeveloped. In the premature infant, the mechanisms are similar in that the early onset pulmonary hypertension (PH) is due to pulmonary vascular immaturity and its underdevelopment, while late onset PH is due to the maladaptation of the pulmonary circulation that is seen with severe bronchopulmonary dysplasia. This may lead to cor-pulmonale if left undiagnosed and untreated. Neonatologist performed echocardiography (NPE) should be considered in any preterm or term neonate that presents with risk factors suggesting PPHN. In this review, we discuss the risk factors for PPHN in term and preterm infants, the etiologies, and the pathophysiological mechanisms as they relate to growth and development of the pulmonary vasculature. We explore the applications of NPE techniques that aid in the correct diagnostic and pathophysiological assessment of the most common neonatal etiologies of PPHN and provide guidelines for using these techniques to optimize the management of the neonate with PPHN.

Neonatal Lung Sonography: Interobserver Agreement Between Physician Interpreters With Varying Levels of Experience.

OBJECTIVES: To assess the reliability of lung sonography in neonates between physician interpreters with different degrees of experience. METHODS: We retrospectively reviewed lung sonograms from neonates admitted to a neonatal intensive care unit with respiratory distress in the first 24 hours of life. The first scans were selected; only patients with available video clips documenting both hemithoraxes were included. The clips were independently examined by 4 different experienced observers blinded to clinical data. The interpreting physicians made a codified sonographic diagnosis, and the Cohen κ coefficient was used to measure the reliability between a proven experienced main interpreter and expert (κ1), intermediate (κ2), and beginner (κ3) control interpreters. We also calculated the specific agreement on respiratory distress syndrome and transient tachypnea of the neonate. RESULTS: Four hundred sixty-five clips were taken from 114 neonates examined over a 16-month period. The patients' median gestational age (range) was 34 weeks (25-41 weeks), and the median birth weight (range) was 2085 g (608-4134 g). Eighty-eight percent of examinations were performed within 24 hours after birth. The overall κ coefficients (95% confidence intervals) were κ1 = 0.94 (0.88-1.00); κ2 = 0.72 (0.61-0.83); and κ3 = 0.81 (0.71-0.90). For respiratory distress syndrome, κ1 = 0.94 (0.87-1.00); κ2 = 0.90 (0.81-0.99); and κ3 = 0.87 (0.78-0.97). For transient tachypnea of the neonate, κ1 = 0.95 (0.89-1.00); κ2 = 0.76 (0.64-0.88); and κ3 = 0.81 (0.70-0.91). CONCLUSIONS: In neonates with early respiratory distress, lung sonography has high interobserver agreement even between interpreters with varying levels of experience.

Correlation between plasma and urinary caffeine levels in preterm infants.

BACKGROUND: We hypothesize that urine levels might be reliable to assess the therapeutic range of caffeine. OBJECTIVES: We correlated plasma and urinary levels of caffeine in preterm infants treated with this drug for apnea of prematurity. METHODS: Infants (n=56) were given a loading dose of caffeine citrate (10 mg/kg, per os) and 24 h later a maintenance dose (2 mg/kg, per os, once a day). Plasma and urinary levels of caffeine were determined 24 h after the loading dose (before administration of the maintenance dose) and then weekly. RESULTS: Plasma and urinary levels correlate at all examined ages: 29 weeks (r=0.92, P<0.001), 30 weeks (r=0.97, P<0.001), 31 weeks (r=0.82, P<0.001), 32 weeks (r=0.92, P<0.001), 33 weeks (r=0.87, P<0.001), 34 weeks (r=0.81, P<0.001). CONCLUSION: Urinary levels of caffeine might be a useful means to assess therapeutic ranges.