CPAP Versus NIPPV Postextubation in Preterm Neonates: A Comparative-Effectiveness Study.

BACKGROUND AND OBJECTIVES: Nasal intermittent positive pressure ventilation (NIPPV) has been shown to be superior to nasal continuous positive airway pressure (CPAP) postextubation in preterm neonates. However, studies have not permitted high CPAP pressures or rescue with other modes. We hypothesized that if CPAP pressures >8 cmH2O and rescue with other modes were permitted, CPAP would be noninferior to NIPPV. METHODS: We conducted a pragmatic, comparative-effectiveness, noninferiority study utilizing network-based real-world data from 22 Canadian NICUs. Centers self-selected CPAP or NIPPV as their standard postextubation mode for preterm neonates <29 weeks' gestation. The primary outcome was failure of the initial mode ≤72 hours. Secondary outcomes included failure ≤7 days, and reintubation ≤72 hours and ≤7 days. Groups were compared using a noninferiority adjusted risk-difference (aRD) margin of 0.05, and margin of no difference. RESULTS: A total of 843 infants extubated to CPAP and 974 extubated to NIPPV were included. CPAP was not noninferior (and inferior) to NIPPV for failure of the initial mode ≤72 hours (33.0% vs 26.3%; aRD 0.07 [0.03 to 0.12], Pnoninferiority(NI) = .86), and ≤7 days (40.7% vs 35.8%; aRD 0.09 [0.05 to 0.13], PNI = 0.97). However, CPAP was noninferior (and equivalent) to NIPPV for reintubation ≤72 hours (13.2% vs 16.1%; aRD 0.01 [-0.05 to 0.02], PNI < .01), and noninferior (and superior) for reintubation ≤7 days (16.4% vs 22.8%; aRD -0.04 [-0.07 to -0.001], PNI < .01). CONCLUSIONS: CPAP was not noninferior to NIPPV for failure ≤72 hours postextubation; however, it was noninferior to NIPPV for reintubation ≤72 hours and ≤7 days. This suggests CPAP may be a reasonable initial postextubation mode if alternate rescue strategies are available.

Association between immediate oxygenation response and survival in preterm infants receiving rescue inhaled nitric oxide therapy for hypoxemia from pulmonary hypertension: A systematic review and meta-analysis.

PURPOSE: To investigate whether immediate response to inhaled nitric oxide (iNO) therapy is associated with reduced mortality in preterm infants with hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH). METHODS: A systematic review and meta-analysis of observational studies was conducted to examine the association between immediate response (improved oxygenation ≤6 h) compared to non-response, and all-cause mortality among preterm infants <34 weeks gestational age without congenital anomalies or genetic disorders who received iNO treatment. Adjusted and unadjusted odds ratio, were pooled using a random effects meta-analysis Hartung-Knapp-Sidik-Jonkman approach. Subgroup analyses were planned for infants with preterm premature rupture of membranes (PPROM) and those treated within 72 h after birth. RESULTS: The primary analysis included 5 eligible studies, a total of 400 infants (196 responders; 204 non-responders). The studies were rated as low to moderate risk of bias based on the Quality in Prognostic Studies tool. Immediate iNO responsiveness was associated with reduced odds of mortality [odds ratio (OR) 0.22, 95 % confidence interval (95 % CI) (0.10-0.49)]. Although there was insufficient data for a subgroup analysis of infants with PPROM, infants treated with iNO within 72 h demonstrated consistent findings of reduced mortality [OR 0.21 95 % CI (0.13-0.36)]. Based on the GRADE approach, considering the risk of bias of included studies, the overall strength of evidence was rated as moderate. CONCLUSION: There is evidence to suggest that immediate improvement in oxygenation following iNO therapy is associated with reduced odds of mortality before discharge in preterm infants with HRF and clinically suspected or confirmed PH.

Cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension.

OBJECTIVE: Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH). STUDY DESIGN: Retrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH. RESULTS: Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05). CONCLUSION: Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.

Organ dysfunction and mortality in preterm neonates with late-onset bloodstream infection.

BACKGROUND: Organ dysfunction (ODF) in late-onset bloodstream infection (LBSI) is associated with increased risk of adverse outcomes. However, no established definition of ODF exists among preterm neonates. Our objective was to describe an outcome-based ODF definition for preterm infants, and assess factors associated with mortality. METHODS: This is a six-year retrospective study of neonates <35 weeks gestational age, >72 h of age, with non-CONS bacterial/fungal LBSI. Discriminatory ability of each parameter for mortality was evaluated: base deficit ≤-8 mmol/L (BD8), renal dysfunction (urine output <1 cc/kg/h or creatinine ≥100 µmol/L), hypoxic respiratory failure (HRF, ventilated, FiO2 = 1.0), or vasopressor/inotrope use (V/I). Multivariable logistic regression analysis was performed to derive a mortality score. RESULTS: One hundred and forty-eight infants had LBSI. BD8 had the highest individual predictive ability for mortality (AUROC = 0.78). The combination BD8 + HRF + V/I was used to define ODF (AUROC = 0.84). Fifty-seven (39%) infants developed ODF, among which 28 (49%) died. Mortality increased inversely relative to GA at LBSI-onset (aOR 0.81 [0.67, 0.98]) and directly relative to ODF occurrence (12.15 [4.48, 33.92]). Compared to no-ODF, ODF infants had lower GA and age at illness, and higher frequency of Gram-negative pathogen. CONCLUSIONS: Among preterm neonates with LBSI, significant metabolic acidosis, HRF, and vasopressor/inotrope use may identify infants high risk for mortality. These criteria could help identify patients for future studies of adjunctive therapies. IMPACT: Sepsis-related organ dysfunction is associated with increased risk of adverse outcomes. Among preterm neonates, significant metabolic acidosis, use of vasopressors/inotropes, and hypoxic respiratory failure may identify high-risk infants. This can be used to target research and quality improvement efforts toward the most vulnerable infants.

Clinical impact of less invasive surfactant administration using video laryngoscopy in extremely preterm infants.

BACKGROUND: Examine the real-world clinical impact of adopting less invasive surfactant administration (LISA) as the primary surfactant administration method in extremely preterm infants. METHODS: Single-center pre-post cohort study conducted over a 4-year period comparing outcomes of spontaneously breathing inborn infants 24+0-28+6 weeks gestational age (GA) receiving surfactant via endotracheal tube (pre-cohort, n = 154) or LISA via thin catheter (post-cohort, n = 70). Primary outcome was need for invasive mechanical ventilation (IMV, ≥2 h) ≤72 h of age. Secondary outcomes were a composite of mortality, bronchopulmonary dysplasia, intraventricular hemorrhage ≥grade 3 or necrotizing enterocolitis, and its individual components. Groups were compared using propensity score methods, including covariates: GA, birth weight, sex, small for GA, SNAP II ≥20, premature rupture of membranes, maternal hypertension/diabetes, and C-section. RESULTS: GA and birth weight were 27.1 (26, 28.1) weeks and 914 (230) g, and 27.1 (26.1, 28.1) weeks and 920 (236) g for pre- and post-cohorts, respectively. Pre-cohort had higher C-section rates, (67% vs. 51%, p = 0.03). After adjustment for covariates, LISA was associated with reduced IMV exposure [AOR (95% CI) 0.07 (0.04, 0.11)], lower odds of the composite clinical outcome [0.49 (0.33, 0.73)], and most of its individual components. CONCLUSION: Real-world experience favors LISA as the primary method in extremely preterm infants with established spontaneous respiration. IMPACT: Less invasive surfactant administration (LISA) is associated with a reduction in respiratory morbidity, but real-world data of routine use among extremely preterm infants are limited. LISA is associated with reduced frequency of exposure to and duration of IMV in both ≤72 h after birth and during hospital stay. LISA is associated with a reduction in mortality, and most other major morbidities including bronchopulmonary dysplasia, and interventricular hemorrhage. Data from a large North American center providing real-world clinical outcomes following LISA as the primary method of surfactant administration.

Accuracy of lung and diaphragm ultrasound in predicting successful extubation in extremely preterm infants: A prospective observational study.

OBJECTIVE: Chest ultrasound has emerged as a promising tool in predicting extubation readiness in adults and children, yet its utility in preterm infants is lacking. Our aim was to assess the utility of lung ultrasound severity score (LUSS) and diaphragmatic function in predicting extubation readiness in extremely preterm infants. STUDY DESIGN: In this prospective cohort study, preterm infants < 28 weeks gestational age (GA) who received invasive mechanical ventilation for ≥12 h were enrolled. Chest ultrasound was performed before extubation. The primary outcome was lung ultrasound accuracy for predicting successful extubation at 3 days. Descriptive statistics and logistic regression were done using SPSS version 22. RESULTS: We enrolled 45 infants, of whom 36 (80%) were successfully extubated. GA and postmenstrual age (PMA) at extubation were significantly higher in the successful group. The LUSS was significantly lower in the successful group compared to failed group (11.9 ± 3.2 vs. 19.1 ± 3.1 p < 0.001). The two groups had no statistically significant difference in diaphragmatic excursion or diaphragmatic thickness fraction. Logistic regression analysis controlling for GA and PMA at extubation showed LUSS was an independent predictor for successful extubation (odd ratio 0.46, 95% confidence interval [0.23-0.9], p = 0.02). The area under the receiver operating characteristic curve was 0.95 (p ˂ 0.001) for LUSS, and a cut-off value of ≥15 had 95% sensitivity and 85% specificity in detecting extubation failure. CONCLUSION: In extremely preterm infants, lung ultrasound has good accuracy for predicting successful extubation. However, diaphragmatic measurements were not reliable predictors.

Dopamine or norepinephrine for sepsis-related hypotension in preterm infants: a retrospective cohort study.

The purpose of this study is to compare the clinical effectiveness of dopamine (DA) versus norepinephrine (NE) as first-line therapy for sepsis-related hypotension in preterm infants. This is a retrospective cohort study over 10 years at two tertiary neonatal units. Preterm infants born < 35 weeks post-menstrual age (PMA), who received DA or NE as primary therapy for hypotension during sepsis, defined as culture-positive or culture-negative infections or necrotizing enterocolitis (NEC), were included. Episode-related mortality (< 7 days from treatment), pre-discharge mortality, and major morbidities among survivors were compared between two groups. Analyses were adjusted using the inverse probability of treatment weighting estimated by propensity score (PS). A total of 156 infants were included, 113 received DA and 43 NE. The mean ± SD PMA at birth and at treatment for the DA and NE groups were 25.8 ± 2.3 vs. 25.2 ± 2.0 weeks and 27.7 ± 3.0 vs. 27.1 ± 2.6 weeks, respectively (p > 0.05). Pre-treatment, the NE group had higher mean airway pressure (14 ± 4 vs. 12 ± 4 cmH2O), heart rate (185 ± 17 vs. 175 ± 17 beats per minute), and median (IQR) fraction of inspired oxygen [0.67 (0.42, 1.0) vs. 0.52 (0.32, 0.82)] (p < 0.05 for all). After PS adjustment, NE was associated with lower episode-related mortality [adjusted odds ratio (95% CI) 0.55 (0.33, 0.92)], pre-discharge mortality [0.60 (0.37, 0.97)], post-illness new diagnosis of significant neurologic injury [0.32 (0.13, 0.82)], and subsequent occurrence of NEC/sepsis among the survivors [0.34, (0.18, 0.65)]. CONCLUSION: NE may be more effective than DA for management of sepsis-related hypotension among preterm infants. These data provide a rationale for prospective evaluation of these commonly used agents. WHAT IS KNOWN: •Dopamine is the commonest vasoactive agent used to support blood pressure among preterm infants. •For adult patients, norepinephrine is recommended as the preferred therapy over dopamine for septic shock. WHAT IS NEW: •This is the first study examining the relative clinical effectiveness of dopamine and norepinephrine as first-line pharmacotherapy for sepsis-related hypotension among preterm infants. •Norepinephrine use may be associated with lower mortality and morbidity than dopamine in preterm infants with sepsis.

Validity of the vasoactive-inotropic score in preterm neonates receiving cardioactive therapies.

BACKGROUND: Vasoactive-Inotropic Score (VIS) is a weighted sum of various vasopressors and inotropes; its utility among preterm neonates is understudied. OBJECTIVE: To investigate the association between maximum VIS (VISmax) during the first 12, 24 and 48 h of treatment among preterm neonates who received vasopressors/inotropes, and the composite outcome of death/severe neuroinjury (sNI). METHODS: Retrospective cohort study, over 6-years, including neonates <35 weeks gestational age (GA). Infants who met the primary composite outcome of death or sNI (defined as new intraventricular hemorrhage ≥grade 3 or periventricular leukomalacia) were compared to those who survived without sNI. Maximum VIS was categorized as <10, 10-19 or ≥ 20 for comparison. RESULTS: 192 infants (mean GA and birth weight 26.8 ± 3.3 weeks and 952 ± 528 g, respectively) were included. The most common primary diagnosis was sepsis/necrotizing enterocolitis (69 %). Median VIS for the entire cohort was 10. Death/sNI was associated with lower GA at birth and treatment, as well as higher frequency of VISmax of 10-19 or ≥20, compared to <10, during each time period (all p < 0.01). Multivariable regression revealed GA at treatment and VISmax ≥ 20 [not 10-19, referenced to <10] were associated death/sNI; adjusted odds ratio (95 % CI) for VISmax ≥ 20 within 12, 24, and 48 h were 4.2 (1.6-11.0), 4.9 (1.9-12.3), and 6.7 (2.7-16.7), respectively. CONCLUSIONS: Vasoactive-Inotropic Score may be a valid measure to quantify cardiovascular support in preterm infants needing hemodynamic support. Maximum VIS ≥20 within 48 h of treatment initiation may identify patients at high risk of adverse outcomes.

Blood pressure, organ dysfunction, and mortality in preterm neonates with late-onset sepsis.

BACKGROUND: The objective of this study was to investigate the association between systolic, diastolic, and mean blood pressures (SBP, DBP, and MBP) and adverse outcomes in preterm neonates with late-onset sepsis (LOS). METHODS: This is a two-center retrospective study over 6 years. Neonates <35 weeks gestational age (GA) with blood ± cerebrospinal fluid culture positive for organisms other than coagulase-negative Staphylococcus at >72 h age were included. Outcome measures were organ dysfunction (ODF) using the predefined criteria and post-ODF mortality (≤7 days from LOS onset). The lowest noninvasive blood pressures (BPs) recorded at baseline (24-48 h pre-LOS) and 0-12, 13-24, 25-36, and 37-48 h post LOS were analyzed. RESULTS: Of 147 neonates, ODF occurred in 70 (48%), of which 20 (29%) died. ODF was associated with a drop in all BP components, starting 0-12 h post-LOS onset (p < 0.01 for all); BPs remained unchanged in the non-ODF group. Mortality was associated with a greater reduction in SBP [-13 (-19, -8) vs. -4 (-8, 0); p < 0.01] and MBP [-9 (-13, -5) vs. +1 (-1, +4); p = 0.03] 0-12 h post-LOS onset. SBP had a higher area under the curve for mortality than MBP and DBP (0.83, 0.81, and 0.78, respectively). An inverse relation may exist between corrected GA and percentage reduction in SBP from baseline for equivalent risk of death. CONCLUSIONS: Reduction in BPs early in illness may identify preterm neonates at the highest risk of ODF and mortality from LOS. IMPACT: Drop in BPs from baseline starting in the immediate post-illness onset period may identify preterm neonates at the highest risk of developing ODF and mortality in LOS. Lowest systolic followed by mean BP measured during the first 12 h of illness provided the highest discriminating ability for LOS-related mortality. Absolute BPs recorded during the first 12 h of illness performed better than relative change from baseline for identifying neonates at risk of LOS-related mortality. The specific BP thresholds identified in this study may inform future therapeutic trials.

Bloodstream Infections in Preterm Neonates and Mortality-Associated Risk Factors.

OBJECTIVE: To investigate the association of early (±4 hours after onset of bloodstream infection) clinical and laboratory variables with episode-related mortality (<7 days). STUDY DESIGN: This 2-site retrospective study included 142 neonates born at <35 weeks of gestational age with positive blood/cerebrospinal fluid (CSF) culture at >72 hours of age from organisms other than coagulase-negative Staphylococcus. Early variables were compared between those with bloodstream infection-related mortality and survivors. Multivariable analysis was conducted for the primary outcome, and the area under the curve (AUC) was estimated for relevant variables. RESULTS: The neonates who died were of lower gestational age at disease onset. After adjusting for relevant variables, lowest mean blood pressure (MBP) (aOR, 0.10; 95% CI, 1.02-1.19) and highest base deficit (aOR, 1.18; 95% CI, 1.06-1.32) were independently associated with mortality. The AUC was 0.87 (95% CI, 0.78-0.96) for base deficit, increasing to 0.91 (95% CI, 0.83-0.99) with the addition of MBP. CONCLUSION: Low MBP and high base deficit within ±4 hours of bloodstream infection onset identify preterm neonates at risk of mortality.

Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease.

INTRODUCTION: Although chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers. METHODS AND ANALYSIS: In this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest. ETHICS AND DISSEMINATION: Ethics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children's and Women's REB (H19-02738), and is under review at Boston Children's Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals. TRAIL REGISTRATION NUMBER: NCT04402645.

Short and long-term outcomes of chronic pulmonary hypertension in preterm infants managed using a standardized algorithm.

BACKGROUND: There is limited data on management strategies for chronic pulmonary hypertension (cPH) in chronic lung disease (CLD) of prematurity. Our objective was to evaluate clinical outcomes following a standardized policy, wherein only cPH with right-ventricular (RV) dilatation was treated and diuretics were employed as first-line therapy; cPH without RV-dilatation was managed expectantly. METHOD: In this retrospective cohort study, all infants with CLD were categorized as "CLD-only" or "CLD-cPH," using echocardiography at ≥36 weeks postmenstrual age. Intergroup comparison was performed. Regression analysis examined the association between cPH and primary outcome of death or disability at 18-24 months. RESULTS: Of 128 CLD infants, 48 (38%) had cPH, of which 29 (60%) received diuretics. Symptomatic improvement within 1-week was recorded in 90%. Although CLD-cPH had worse in-hospital respiratory course than CLD-only, all post-discharge respiratory and neurodevelopmental outcomes were similar. cPH was not associated with death or disability (adjusted odds ratio, 1.02; 95% confidence interval, 0.32-3.27). Disease progression treated with sildenafil occurred in 2 (4%) cases. There was no death from respiratory or RV failure. CONCLUSION: Primary treatment of CLD-cPH with diuretics using RV-dilatation as therapeutic threshold, may result in symptomatic improvement, disease stabilization and post-discharge outcomes comparable to infants without cPH.

Combined Multimodal Cerebral Monitoring and Focused Hemodynamic Assessment in the First 72 h in Extremely Low Gestational Age Infants.

BACKGROUND: Characteristic changes in cerebral saturation (CrSO2), amplitude-integrated electroencephalography (aEEG), and echocardiography (ECHO) may be associated with intraventricular hemorrhage (IVH); however, the feasibility of their combined application is not known. OBJECTIVE: The aim of this work was to investigate the feasibility and safety of combined multimodal cerebral and hemodynamic monitoring in extremely low gestational age (ELGA) infants in the first 72 h after birth. METHODS: In this prospective -observational study of 50 infants born between 23 + 0 and 27 + 6 weeks gestation, we measured CrSO2 and aEEG, starting <8 h until 72 h of age. Sequential echocardiography and head ultrasound were performed at 4-8, 12-18, 24-30, and 48-60 h of age. The primary outcome was feasibility of multimodal monitoring, defined as >75% of the subjects satisfying at least 3/4 criteria: (a) CrSO2 and (b) aEEG monitoring each for >75% of the time, and (c) at least 2 out of 4 ECHO and (d) head ultrasounds (at least one by age 24 h). Adverse reactions to sensors, desaturation, and bradycardia during ultrasound studies were recorded. RESULTS: Fifty infants were enrolled over 14 months. Multimodal monitoring was feasible in 49 (98%) infants. Forty-one (82%) infants fulfilled all 4 criteria. Mild erythema below CrSO2 sensors lasting 3-8 h without skin breakdown was noted in 8/50 subjects (16%). Desaturation was noted during 17/197 (8.6%) of the ultrasound studies. In total, 26/50 (52%) infants developed IVH (grade I/II, n = 22; grade III/IV, n = 4). CONCLUSION: Multimodal monitoring is feasible, safe, and well tolerated in ELGA infants in the first 72 h after birth.

Survey of practices in relation to chronic pulmonary hypertension in neonates in the Canadian Neonatal Network and the National Institute of Child Health and Human Development Neonatal Research Network.

Current knowledge gaps pertaining to diagnosis and management of neonatal chronic pulmonary hypertension (cPH) may result in significant variability in clinical practice. The objective of the study is to understand cPH management practices in neonatal intensive care units affiliated with the Canadian Neonatal Network (CNN) and National Institute of Child Health and Human Development Neonatal Research Network (NRN). A 32-question survey seeking practice details for cPH evaluation, diagnostic criteria, conservative measures, pharmacotherapeutics, and follow-up was e-mailed to a designated physician at each center. Responses were described as frequency (percentage) and compared between CNN and NRN, where appropriate. Overall response rate was 67% (CNN 20/28 (71%), NRN 9/15 (60%)). While 8 (28%) centers had standardized management protocols, 17 (59%) routinely evaluate high-risk patients; moderate-severe chronic lung disease being the commonest indication. While interventricular septal flattening on echocardiography was the commonest listed diagnostic criterion, several adjunctive indices were also identified. Asymptomatic neonates with cPH were managed expectantly (routine care) in 50% of sites, and using various conservative measures in others. Pulmonary vasodilators were prescribed for symptomatic cases, with 60% of sites using them early (86% reporting any use). Seventy-five percent of sites use inhaled nitric oxide and sildenafil citrate as first- and second-line agents, respectively. Use of standard protocols, cardiac catheterization, and conservative measures for asymptomatic cases was more common in NRN units (p < 0.05). While there is relative homogeneity in patient identification and diagnostic criteria used for neonatal cPH, significant interunit inconsistencies still exists in routine evaluation, use of additional investigations, management of asymptomatic cases, frequency and type of conservative measures, and choice of pulmonary vasodilators.

Clinical and echocardiography predictors of response to inhaled nitric oxide in hypoxic preterm neonates.

AIM: To evaluate the clinical and echocardiography modulators of treatment response in hypoxemic preterm infants exposed to inhaled nitric oxide (iNO). METHODS: In this multicentre retrospective study, clinical parameters, including oxygenation, ventilation and haemodynamics, were collected for preterm infants <36 weeks gestation before and 2 h after initiation of iNO for acute hypoxemia. Comprehensive echocardiography, performed near the time iNO initiation, was analysed by experts blind to the clinical course. Multiple logistic regression analysis was used to identify factors associated with iNO response as defined by a reduction in the fraction of inspired oxygen by >0.20. RESULTS: A total of 213 infants met eligibility criteria, of which 73 had echocardiography data available and formed the study cohort. Response to iNO was demonstrated in 56% of patients. Younger post-natal age (odds ratio (OR) 0.94; 95% confidence interval (CI) 0.89, 0.99) and the presence of pulmonary hypertension (PH) (OR 4.47; 95% CI 1.23-11.9) were independently predictive of iNO response regardless of gestational age. Among neonates <72 h old with documented PH, iNO response was seen in 82%. The onset of a new diagnosis of severe (grade III/IV) intraventricular haemorrhage (IVH) after iNO treatment was seen in 6 of 40 patients <28 weeks' gestational age, with a greater frequency in responders (32 vs. 0%, P = 0.02). CONCLUSIONS: Positive response to iNO is greatest in the first 3 days of life and in patients with echo-confirmed PH, independent of gestational age. The association between critical illness, iNO administration and IVH in extremely premature infants may merit prospective delineation.

Patent ductus arteriosus: The physiology of transition.

The transition from intrauterine to extrauterine life represents a critical phase of physiological adaptation which impacts many organ systems, most notably the heart and the lungs. The majority of term neonates complete this transition without complications; however, dysregulation of normal postnatal adaptation may lead to acute cardiopulmonary instability, necessitating advanced intensive care support. Although not as well appreciated as changes in vascular resistances, the shunt across the DA plays a crucial physiologic role in the adaptive processes related to normal transitional circulation. Further, we describe key differences in the behavior of the ductal shunt during transition in preterm neonates and we postulate mechanisms through which the DA may modulate major hemodynamic complications during this vulnerable period. Finally, we describe the conditions in which preservation of ductal patency is a desired clinical goal and we discuss clinical factors that may determine adequate balance between pulmonary and systemic circulation.

Outcomes of hypoxic respiratory failure at birth associated with previable rupture of membranes.

OBJECTIVE: To characterize clinical outcomes of infants born after previable rupture of membranes (pROM, < 23 weeks gestation and latency period ≥ 2 weeks) in relation to refractory hypoxic respiratory failure (rHRF). STUDY DESIGN: pROM neonates categorized as rHRF (FiO2 > 0.6 for ≥ 2 h) and treated (high frequency ventilation + inhaled nitric oxide) were compared with no rHRF group. Primary outcome was survival until discharge. Factors associated with rHRF and mortality were identified. RESULT: Overall, mortality and disability rates were 28% and 22%, respectively. Treated rHRF group (n = 32) had longer period of ROM, mortality was (31% vs. 14%; p = 0.20), with similar survival-without-disability (54% vs. 47%; p = 0.67). Higher gestational age at birth [1.57 (1.03,2.39)] and cesarean delivery [12.6 (1.22,125)] were associated with increased survival. CONCLUSION: Birth after pROM is associated with high rates of adverse outcomes, independent of latency period. Following treatment, rHRF infants may have similar long-term outcomes as those without rHRF.

Short-term and long-term outcomes of preterm neonates with acute severe pulmonary hypertension following rescue treatment with inhaled nitric oxide.

OBJECTIVE: To describe short-term and long-term outcomes of preterm neonates with severe acute pulmonary hypertension (aPHT) in relation to response to rescue inhaled nitric oxide (iNO) therapy. DESIGN: Retrospective cohort studyover a 6 year period. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 89 neonates <35 weeks gestational age (GA) who received rescue iNO for aPHT, including 62 treated at ≤3 days of age (early aPHT). INTERVENTIONS: iNO ≥ 1 hour. MAIN OUTCOME MEASURES: Positive responders (reduction in fraction of inspired oxygen (FiO2) ≥0.20 within 1 hour of iNO) were compared with non-responders. Primary outcome was survival without moderate-to-severe disability at 18 months of age. RESULTS: Mean (SD) GA and birth weight was 27.7 (3.0) weeks and 1077 (473) gm, respectively. Median (IQR) pre-iNO FiO2 was 1.0 (1.0, 1.0). Positive response rate to iNO was 46%. Responders showed improved survival without disability (51% vs 15%; p<0.01), lower mortality (34% vs 71%; p<0.01) and disability among survivors (17% vs 50%; p=0.06). Higher GA (adjusted OR: 1.44 (95% CI 1.10 to 1.89)), aPHT in context of preterm prolonged rupture of membranes (6.26 (95% CI 1.44 to 27.20)) and positive response to rescue iNO (5.81 (95% CI 1.29 to, 26.18)) were independently associated with the primary outcome. Compared with late cases (>3 days of age), early aPHT had a higher response rate to iNO (61% vs 11%; p<0.01) and lower mortality (43% vs 78%; p<0.01). CONCLUSION: A positive response to rescue iNO in preterm infants with aPHT is associated with survival benefit, which is not offset by long-term disability.