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Background: PPHN is a common cause of neonatal respiratory failure and is still a serious condition and associated with high mortality., Objectives: To compare the demographic variables, clinical characteristics, and treatment outcomes in neonates with PHHN who underwent ECMO and survived compared to neonates with PHHN who underwent ECMO and died., Methods: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and searched ProQuest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature for studies on the development of PPHN in neonates who underwent ECMO, published from January 1, 2010 to May 31, 2023, with English language restriction., Results: Of the 5689 papers that were identified, 134 articles were included in the systematic review. Studies involving 1814 neonates with PPHN who were placed on ECMO were analyzed (1218 survived and 594 died). Neonates in the PPHN group who died had lower proportion of normal spontaneous vaginal delivery (6.4% vs 1.8%; p value > 0.05) and lower Apgar scores at 1 min and 5 min [i.e., low Apgar score: 1.5% vs 0.5%, moderately abnormal Apgar score: 10.3% vs 1.2% and reassuring Apgar score: 4% vs 2.3%; p value = 0.039] compared to those who survived. Neonates who had PPHN and died had higher proportion of medical comorbidities such as omphalocele (0.7% vs 4.7%), systemic hypotension (1% vs 2.5%), infection with Herpes simplex virus (0.4% vs 2.2%) or Bordetella pertussis (0.7% vs 2%); p = 0.042. Neonates with PPHN in the death group were more likely to present due to congenital diaphragmatic hernia (25.5% vs 47.3%), neonatal respiratory distress syndrome (4.2% vs 13.5%), meconium aspiration syndrome (8% vs 12.1%), pneumonia (1.6% vs 8.4%), sepsis (1.5% vs 8.2%) and alveolar capillary dysplasia with misalignment of pulmonary veins (0.1% vs 4.4%); p = 0.019. Neonates with PPHN who died needed a longer median time of mechanical ventilation (15 days, IQR 10 to 27 vs. 10 days, IQR 7 to 28; p = 0.024) and ECMO use (9.2 days, IQR 3.9 to 13.5 vs. 6 days, IQR 3 to 12.5; p = 0.033), and a shorter median duration of hospital stay (23 days, IQR 12.5 to 46 vs. 58.5 days, IQR 28.2 to 60.7; p = 0.000) compared to the neonates with PPHN who survived. ECMO-related complications such as chylothorax (1% vs 2.7%), intracranial bleeding (1.2% vs 1.7%) and catheter-related infections (0% vs 0.3%) were more frequent in the group of neonates with PPHN who died (p = 0.031)., Conclusion: ECMO in the neonates with PPHN who failed supportive cardiorespiratory care and conventional therapies has been successfully utilized with a neonatal survival rate of 67.1%. Mortality in neonates with PPHN who underwent ECMO was highest in cases born via the caesarean delivery mode or neonates who had lower Apgar scores at birth. Fatality rate in neonates with PPHN who underwent ECMO was the highest in patients with higher rate of specific medical comorbidities (omphalocele, systemic hypotension and infection with Herpes simplex virus or Bordetella pertussis) or cases who had PPHN due to higher rate of specific etiologies (congenital diaphragmatic hernia, neonatal respiratory distress syndrome and meconium aspiration syndrome). Neonates with PPHN who died may need a longer time of mechanical ventilation and ECMO use and a shorter duration of hospital stay; and may experience higher frequency of ECMO-related complications (chylothorax, intracranial bleeding and catheter-related infections) in comparison with the neonates with PPHN who survived., (© 2024. The Author(s).)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis., Competing Interests: Conflicts of Interest No conflict of interest to all authors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To review our experience with Extra-Corporeal Membrane Oxygenation (ECMO) for respiratory support in neonates. From 1989 to 2018 2114 patients underwent respiratory ECMO support, with 764 (36%) neonates. Veno-Venous (V-V) cannulation was used in 428 (56%) neonates and Veno-Arterial (V-A) in 336 (44%). Historically V-V ECMO was our preferred modality, but due to lack of suitable cannula in the last 7 years V-A was used in 209/228 (92%) neonates. Mean and inter-quartile range of ECMO duration was 117 hours (inter-quartile range 90 to 164 hours). Overall 724 (95%) neonates survived to ECMO decannulation, with 640 (84%) hospital discharge. Survival varied with underlying diagnosis: meconium aspiration 98% (354/362), persistent pulmonary hypertension 80% (120/151), congenital diaphragmatic hernia 66% (82/124), sepsis 59% (35/59), pneumonia 86% (6/7), other 71% (43/61). Survival was 86% with V-V and 80% with V-A cannulation, better than ELSO Registry with 77% V-V and 63% V-A. Major complications: cerebral infarction/hemorrhage in 4.7% (31.1% survival to discharge), renal replacement therapy in 17.6% (58.1% survival to discharge), new infection in 2.9%, with negative impact on survival (30%). Following a circuit design modification and subsequent reduction in heparin requirement, intracerebral hemorrhage decreased to 9/299 (3.0%) radiologically proven cerebral infarction/hemorrhage. We concluded (1) outcomes from neonatal ECMO in our large case series were excellent, with better survival and lower complication rate than reported in ELSO registry. (2) These results highlight the benefits of ECMO service in high volume units. (3) The similar survival rate seen in neonates with V-A and V-V cannulation differs from the ELSO register; this may reflect the change in cannulation enforced by lack of suitable V-V cannula and all neonates undergoing V-A cannulation., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Objectives: To explore the incidence, etiologies, diagnostic methods, treatment options and outcomes in neonates with persistent pulmonary hypertension of the newborn (PPHN) and to identify mortality risk factors in a study from six Asian countries. Methods: A retrospective chart review of patients with documented PPHN from seven centers in six Asian countries (Japan, Kuwait, India, Pakistan, Singapore, and Thailand) between 1 January, 2014 and 31 December, 2016, was performed. Results: A total of 369 PPHN infants were identified. The incidence of PPHN ranged from 1.2 to 4.6 per 1000 live births. The all-cause mortality rate was 20.6% (76 of 369). Meconium aspiration syndrome was the primary cause of PPHN (24.1%). In most cases (84.8%) echocardiography was used to establish the diagnosis of PPHN. Sildenafil was the most commonly used pulmonary vasodilator (51.2%). Multivariate multiple regression analysis indicated gestational age <34 weeks (adjusted odds ratio (OR) = 3.27; 95% CI 1.56-6.74), congenital diaphragmatic hernia (CDH)/lung hypoplasia (LH) (adjusted OR = 6.13 (95% CI 2.28-16.42)), treatment with high frequency oscillation ventilation (HFOV) with or without inhaled nitric oxide (iNO) (adjusted OR = 3.11 (95% CI 1.52-6.34)), and inotropic agents (adjusted OR = 9.43 (95% CI 2.71-32.83)) were independently associated with increased risk of death. Conclusions: The incidence of PPHN in the current study was higher than in western settings. Birth weight, gestational age, CDH/LH, HFOV/iNO, and inotropic agents were significant mortality risk factors.

Objective: To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies and severities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverse clinical outcomes., Study Design: This was a population-based study using an administrative dataset linking birth and death certificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants ≥34 weeks' gestational age with International Classification of Diseases,9th edition, codes consistent with PPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first year of life. Crude and adjusted risk ratio (aRR) with 95% CIs were calculated to quantify the risk for the primary outcome and to identify risk factors., Results: Infants with PPHN (n = 7847) had an aRR of 3.5 (95% CI, 3.3-3.7) for the primary outcome compared with infants without PPHN (n = 3 974 536), and infants with only mild PPHN (n = 2477) had an aRR of 2.2 (95% CI, 2.0-2.5). Infants with congenital diaphragmatic hernia as the etiology for PPHN had an aRR of 8.2 (95% CI, 6.7-10.2) and infants with meconium aspiration syndrome had an aRR of 4.2 (95% CI, 3.7-4.6) compared with infants without PPHN. Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primary outcome., Conclusions: The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infants with mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable. These data could inform counseling of parents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective:  This study aims to determine the risk factors and outcome of persistent pulmonary hypertension of the newborn (PPHN)-associated acute kidney injury (AKI)., Study Design:  Infants diagnosed with PPHN at Hat Yai Hospital from January 2012 to December 2016 were retrospectively reviewed., Results:  Of the 109 included PPHN infants, 28.4% (31/109) died, and AKI was found in 28.4% following neonatal KDIGO classification. Of the 31, 19 who died (61.3%) reached stage 1, 3 (9.7%) reached stage 2, and 9 (29.0%) reached stage 3. AKI (all stages combined) was significantly associated with increased mortality with an odds ratio (OR) of 8.71 (95% confidence interval [CI], 3.37-22.49). Multivariate logistic regression analysis indicated that male gender (adjusted OR = 8.56; 95% CI = 0.84-85.09) and urine output of < 1 mL/kg/h in 12 hours of admission (adjusted OR = 15.57; 95% CI = 2.58-93.98) were the main factors associated with an increased risk for AKI, while birth by cesarean delivery was associated with reduced risk of AKI (adjusted OR = 0.10; 95% CI = 0.16-0.68)., Conclusion:  The incidence of AKI in PPHN was high in this study, and this complication was also significantly associated with higher mortality. In PPHN neonates, AKI should be especially closely monitored in males and infants who have a urine output of < 1 mL/kg/h in the first 12 hours of admission., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The prevalence of PPHN has been estimated at 1.9 per 1000 live births. After the discovery of iNO's, its efficacy and benefit in PPHN is well established. Even in the best of centers equipped with iNo and ECMO the mortality is around 20%. Also, iNO is expensive and difficult to administer and monitor which makes it difficult choice in our part of the world. Furthermore About 40% of patients do not respond or have rebound pulmonary hypertension after discontinuation. Owing to these reasons, other treatment modalities like phosphodiesterase inhibitors such as Sildenafil need to be evaluated., Methods: We report a retrospective case series of eighteen patients with PPHN admitted in NICU and treated with oral sildenafil., Results: Three (17%) babies had mild, 5 (28%) moderate and 10 (55%) severe PPHN based on echocardiography. Sildenafil was started on all patients on a mean of 1.67 days and stopped on mean 12.6 days. Initial fio2 was 100%, which after starting sildenafil decreased gradually to 40% on mean 10 days. Average length of stay in NICU was 13 days. Twelve (67%) patients survived whereas 6 (33%) expired (Figure 2). No improvement in oxygen Index after 36 hours (p<0.05) was the independent predicting risk factor for PPHN related mortality in the expired patients., Conclusions: Oral sildenafil can be a used in conjunction with other treatment modalities for PPHN especially in resource limited settings. However further studies regarding its comparative efficacy need to be done.

Background and Objectives: There are limited epidemiologic data on persistent pulmonary hypertension of the newborn (PPHN). We sought to describe the incidence and 1-year mortality of PPHN by its underlying cause, and to identify risk factors for PPHN in a contemporary population-based dataset., Methods: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharges, readmissions, and birth and death certificates from 1 year before to 1 year after birth. We searched the database (2007-2011) for cases of PPHN (identified by International Classification of Diseases, Ninth Revision codes), including infants ≥34 weeks' gestational age without congenital heart disease. Multivariate Poisson regression was used to identify risk factors associated with PPHN; results are presented as risk ratios, 95% confidence intervals., Results: Incidence of PPHN was 0.18% (3277 cases/1 781 156 live births). Infection was the most common cause (30.0%). One-year mortality was 7.6%; infants with congenital anomalies of the respiratory tract had the highest mortality (32.0%). Risk factors independently associated with PPHN included gestational age <37 weeks, black race, large and small for gestational age, maternal preexisting and gestational diabetes, obesity, and advanced age. Female sex, Hispanic ethnicity, and multiple gestation were protective against PPHN., Conclusions: This risk factor profile will aid clinicians identifying infants at increased risk for PPHN, as they are at greater risk for rapid clinical deterioration., (Copyright © 2017 by the American Academy of Pediatrics.)

In infants with congenital diaphragmatic hernia (CDH), a posterolateral diaphragmatic defect results in herniation of abdominal contents into the chest and compression of the intrathoracic structures. In the most severe cases, hypoplasia of the ipsilateral and contralateral lungs, severe pulmonary hypertension (PH) and left ventricular (LV) hypoplasia/dysfunction all contribute to increased mortality. The management of PH in CDH is complicated by structural and functional changes in the heart, pulmonary vasculature, airways and lung parenchyma; consequently, determining optimal management strategies is challenging. Treatment of PH in patients with CDH changes as the underlying pathophysiology evolves in the days and weeks after birth. During the early transition, the use of pulmonary vasodilators is limited by LV structural and functional abnormalities, and pulmonary vasodilators such as inhaled nitric oxide (iNO) may have a limited role (for example, stabilization for extracorporeal membrane oxygenation (ECMO), treatment of marked preductal desaturation and treatment of PH as LV performance improves). In contrast, subacute treatment of PH in CDH with iNO has an important role in recurrent or persistent PH and potentially improves survival. Chronic PH and vascular abnormalities may persist into childhood in patients with CDH, contributing to late mortality. It is unclear how pulmonary vasodilator therapies, such as iNO, sildenafil and bosentan, will modulate late outcomes in CDH with late/chronic PH.

Objective: There is a paucity of data on clinical correlates and outcomes of pulmonary hypertension (PH) in patients with D-transposition of the great arteries (D-TGA) in the era of inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO). Our objective was to compare clinical characteristics and outcomes of infants with D-TGA with and without PH, defined as hypoxemia that required iNO and/or ECMO., Methods: We undertook a single-center retrospective chart review involving infants with gestational age ≥32 weeks with D-TGA who, underwent arterial switch operation over a 12-year period. Demographic and clinical data, details of the repair and postoperative complications were abstracted., Results: Our cohort (n = 93), 61 (66%) of whom were males, had a mean (SD) gestational age and birth weight of 38.7 (1.8) weeks and 3.2 (0.6) kg, respectively. PH requiring iNO and/or ECMO was noted in 20 (21.5%) infants. Infants with PH had significantly lower birth weight [2.8 (0.56) vs. 3.33 (0.61)] and gestational age [37.7 (2.1) vs. 38.9 (1.7)] than those without PH. Rates of postoperative complications (duration of pressors, sedative medicaiton and duration of hospital stay, and mechanical ventilation were higher in the group with PH. Of the five (5.4%) infants who died, four received iNO and ECMO. Death or postoperative complications tended to be associated with lower gestational age [OR 0.689; 95% CI: 0.469-1.012, P = 0.058] but not with D-TGA category or bypass duration., Conclusions: Despite aggressive treatment with iNO and ECMO, the coexistence of PH in this population is associated with higher rates of mortality and postoperative complications. Our results also suggest that an early term birth may be associated with PH in infants with D-TGA., (© 2015 Wiley Periodicals, Inc.)

Aim: Use of inhaled nitric oxide (iNO) in preterm infants is not supported by current evidence. In 2013, in Australia and New Zealand, 14% infants' ≤25 weeks of gestations were administered iNO. Within the cohort administered iNO, we aimed to identify subgroups where it may be more efficacious and compared characteristics before and after the set-up of the functional echocardiography (fEcho) programme., Methods: A retrospective audit for the period 2000-2013 involving preterm infants administered iNO in the first four weeks of life was performed. Comparisons were made between the two time epochs: up to 2007 and post-2007., Results: Eighty-five infants fulfilled the inclusion criteria; 62 (73%) were ≤28 weeks of gestation; 51 (60%) survived. Amongst survivors, gestation and birthweight were higher and oxygenation index (OI) was lower. Fourteen (16.5%) infants weighed small for gestation age; survival was lower in this subgroup (6/14, 43%, p = 0.0005). The fEcho programme increased prenitric assessments for a definitive diagnosis and monitoring; iNO was started earlier, at a lower OI with a trend towards reduced usage (hours)., Conclusion: Characteristics of subgroups (within the cohort of infants ≤34 weeks of gestation) more likely to benefit from iNO therapy were identified. Use of fEcho could rationalise usage., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: To describe the clinical characteristics, diagnostic methods, treatment modalities, and complications, and identify the mortality risk factors, of infants with short-term persistent pulmonary hypertension of the newborn (PPHN)., Methods: The clinical data of infants diagnosed with PPHN at Hat Yai Hospital from January 2010 to February 2014 were retrospectively reviewed. Cox proportional hazard regression analysis was performed to assess factors associated with mortality., Results: The records of 119 infants were analyzed. Of these, 47 died giving an in-hospital mortality rate of 39.5%. The prevalence of PPHN (based on inborn births) was 2.8 per 1000 live births. The mean gestational age and birth weight were 39.1 ± 1.6 weeks and 3044 ± 563 g, respectively. Multivariate Cox regression analysis indicated that pneumothorax [adjusted hazard ratio (HR) = 2.07 (95% CI 1.09-3.93)] and acute kidney injury [adjusted HR = 2.99 (95% CI 1.59-5.61)] were factors associated independently with an increased risk for death, while infants who received total parenteral nutrition [adjusted HR = 0.22 (95% CI 0.10-0.50)] had lower mortality., Conclusion: A high mortality rate of PPHN was observed in this study. Significantly higher mortality was noted in infants complicated with pneumothorax and acute kidney injury.

Aims: Infants with persistent pulmonary hypertension of the newborn (PPHN) have elevated pulmonary vascular resistance that can lead to right ventricular (RV) failure and death. Clinicians must decide which infants will fail conventional therapy and require transfer to extra corporeal membrane oxygenation (ECMO) centres, but accurate echocardiographic predictors have not been identified. We assessed echocardiographic measurements of RV pressure and function in predicting progression to death or ECMO in infants with PPHN., Methods and Results: Echocardiograms for infants ≥35-week gestation with a clinical diagnosis of PPHN were retrospectively reviewed. Traditional and strain echocardiographic measures were compared for those with or without the primary outcome of ECMO/cardiovascular death. Receiver operator curves identified cut points for measures that were significantly different. Of the 86 subjects analysed, 25 (29%) of the patients had the primary outcome of ECMO/death. The ECMO/death group had diminished tricuspid annular plane systolic excursion (TAPSE; P = 0.002) and RV global longitudinal peak strain (GLPS; P = 0.03), a predominant right-to-left shunt across the patent ductus arteriosus (PDA; P = 0.05), and an elevated oxygenation index (OI; P < 0.001). Sensitivity/specificity for TAPSE <4 mm was 56 and 85%, and for GLPS greater than or equal to -9% was 52 and 77%., Conclusion: TAPSE, GLPS, and right-to-left PDA shunting were associated with progression to death/ECMO. RV free wall strain was not associated with the outcome, suggesting that diminished global strain better reflects clinical outcomes in this group. These thresholds may assist in the decision-making to transfer high-risk infants to ECMO centres., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: We report a single centre experience of neonatal respiratory ECMO using the Avalon® double-lumen venous cannula and compare it with reports in the literature., Results: Between 2008 and 2012, the Avalon® cannula was used in 72 neonates: median age at cannulation was 1.8 days (IQR 1.2-2.8 days) and bodyweight 3.4 Kg (3.0-3.7 Kg). Meconium aspiration syndrome (61.1%), persistent hypertension of the newborn (25%) and congenital diaphragmatic hernia (5.6%) were the most common diagnoses. Complications occurred in 19 patients (26.4%): cannula site bleeding in 6 (8.3%), the cannula perforating the right atrial wall and requiring emergency midline sternotomy in 5 (6.9%) and the cannula needing repositioning in 3 (4.2%). Overall survival at discharge or transfer to the referring hospital was 88.8%. Successful wean off ECMO occurred in 68 patients (94.4%) after a median of 90.5 hours (63.4-136.11). ECMO support was withdrawn in 4 patients (5.6%)., Conclusions: The Avalon® dual-lumen veno-venous cannula can be used for respiratory ECMO in the neonatal population. However, as the incidence of right atrial perforation is not negligible, we suspended its used in this group of patients., (© The Author(s) 2014.)

Purpose: Preferential streaming of the ductus venosus (DV) toward the right atrium has been observed in fetuses with left diaphragmatic hernia (LDH). The purpose of this retrospective study was to compare survival rates to discharge between a group with preferential streaming of the DV toward the right heart and a group in which this abnormal flow pattern was not present., Materials and Methods: We retrospectively searched our patient records for fetuses with LDH in whom liver position, DV streaming and postnatal outcome information was available. 55 cases were found and divided into two groups: Group I fetuses exhibited abnormal DV streaming toward the right side of the heart; group II fetuses did not. Various prognostic and outcome parameters were compared., Results: 62 % of group I fetuses and 88 % of group II fetuses survived to discharge (p = 0.032). Fetoscopic tracheal balloon occlusion (FETO) was performed in 66 % of group I fetuses and 23 % of group II fetuses (p = 0.003). Postnatal ECMO therapy was performed in 55 % of group I fetuses and 23 % of group II infants (p = 0.025). Moderate to severe chronic lung disease in survivors was observed in 56 % of the survivors of group I and 9 % of the survivors of group II (p = 0.002)., Conclusion: Preferential streaming of the DV toward the right heart in human fetuses with left-sided diaphragmatic hernia was associated with a poorer postnatal outcome despite a higher rate of invasive pre- and postnatal procedures compared to fetuses without this flow abnormality. Specifically, abnormal DV streaming was found to be an independent predictor for FETO., (© Georg Thieme Verlag KG Stuttgart · New York.)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis., (© 2013 Wiley Periodicals, Inc.)

Purpose: Despite improvements in the management of persistent pulmonary hypertension of the newborn (PPHN), a number of infants with inadequate gas exchange are treated with extracorporeal membrane oxygenation (ECMO). The objectives of this study were to use the Extracorporeal Life Support Organization Registry to review the outcomes of neonates with PPHN receiving ECMO, and to identify pre-ECMO variables that may be associated with increased mortality., Materials and Methods: The study is a retrospective analysis of all patients with PPHN supported with ECMO and reported to the Extracorporeal Life Support Organization registry from 2000 to 2010. Prematurity was defined as <37 wk gestation. Univariate analysis was performed using Student's t-test or Fisher's exact test. Variables found to be statistically significant underwent multivariate analysis by logistic regression. Kaplan-Meier survival curves were generated to analyze the relationship between duration of ECMO support and patient survival., Results: A total of 1569 neonates with PPHN received ECMO support during the study period, at an average age of 3.1 d of life and for a duration of 6.9 d. Survival among neonates with PPHN receiving ECMO support was 81%, and those receiving support for 7, 10, 14, and 21 d survived at rates of 88%, 78%, 55%, and 25%, respectively. By logistic regression, prematurity (P < 0.01), pre-ECMO pH ≤7.2 (P = 0.02), pre-ECMO SaO(2) ≤65% (P = 0.01), and duration of ECMO ≥7 d (P < 0.001) were independent predictors of death in this group. An average of 2.2 complications occurred per patient, with cardiovascular, mechanical, and renal complications being the most common., Conclusions: Neonates with PPHN have high survival rates with ECMO support. Prematurity, acidosis, and profound hypoxemia are independently associated with increased mortality. Furthermore, prolonged ECMO support (>7 d) is associated with a higher risk of mortality in this cohort than in patients supported for <1 wk., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: We investigated persistent pulmonary hypertension of the newborn (PPHN) among monochorionic-diamniotic (MD) twins., Methods: A retrospective cohort study examined MD twins from 195 deliveries and 373 live-born neonates at our center., Results: PPHN occurred in three cases (3/373: 0.8%), all of which were recipients of twin-twin transfusion syndrome (TTTS), after fetoscopic laser surgery (FLS) (3/117: 2.6%). Although the clinical course of the three cases differed, all cardiothoracic area ratios exceeded 40%, and other cardiac parameters also worsened after FLS., Conclusions: The occurrence of PPHN in TTTS recipients should be noted, particularly when fetal cardiac function declines following FLS.

We delineate the natural history of a right-to-left or bidirectional (RL/BD) patent ductus arteriosus (PDA) in preterm infants and compare outcomes of an RL/BD and a left-to-right (LR) ductal shunt. We performed a retrospective chart review of preterm infants (< 32 weeks), who, between 2 and 30 days of age, had an RL/BD PDA > 1.5 mm (study group; N = 74) or an LR PDA (N = 87) on echocardiogram (ECHO). In the study group, 27% of infants who were of significantly lower gestational age and birth weight had a "prolonged" RL/BD PDA on two or more ECHOs. Infants with RL/BD PDA required significantly greater surfactant (98.6% versus 94.2%) and less PDA therapy (27% versus 92%) and had higher mortality (48.6% versus 21.8%) compared with those with LR PDA. On regression analysis, lower gestation (odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.15 to 1.83) and RL/BD PDA (OR 4.74; 95% CI: 2.18 to 10.3) were significantly associated with mortality. The independent association between an RL/BD PDA shunt and mortality warrants further investigation. Insights into the etiology of pulmonary hypertension may optimize outcomes in this population., (© Thieme Medical Publishers.)

Aim: To evaluate the ability of the Score for Neonatal Acute Physiology-Version II (SNAP-II) to predict mortality in infants with persistent pulmonary hypertension of the newborn (PPHN)., Methods: A prospective cohort study of 41 infants with PPHN admitted to our neonatal intensive care unit between June 2008 and March 2010, who underwent a SNAP-II test within 12 h of admission., Results: Of the 41 infants, 14 died (34.1%) and 27 survived (65.9%). The SNAP-II scores were significantly higher in infants who died (50.1 ± 18.5 vs. 35.7 ± 16.8, P=0.02). Each point increase in the SNAP score increased the odds of mortality by 1.04 [95% confidence interval (CI) 1.01-1.07, P<0.01]. Infants who had a SNAP-II score of ≥ 43 had the greatest mortality risk with an odds ratio (OR) of 10.00 (95% CI 1.03-97.50). The SNAP-II model showed moderate discrimination in predicting mortality with a result of 0.72 (95% CI 0.56-0.88) under the receiver operating characteristic curve. The lowest blood pressure, lowest PaO(2)/FIO(2) ratio, and urine output within the first 12 h of admission were also independently found to be good predictors of an increased risk for death., Conclusion: The SNAP-II scoring system significantly predicted mortality. PPHN infants with a SNAP-II score of ≥ 43 had the greatest mortality risk.

Newer bedside pulmonary mechanics using conventional ventilators allow for CONTINUOUS serial determinations of tidal volume (V(T)). We sought to determine whether the degree of pulmonary hypoplasia could be measured using bedside pulmonary graphics and whether survival could be predicted in potential extracorporeal membrane oxygenation (ECMO) candidates. Data on all neonates considered for or treated with ECMO at our center between April 2000 and March 2005 were collected. The "maximal bedside V(T)" was measured daily at the peak pressure where "beaking" began with a peak end expiratory pressure of 4 cm H(2)O. Twenty-two patients were reviewed: eight ECMO plus fourteen similar patients in whom the threshold for ECMO intervention was not achieved. Independent of need for ECMO, any patient with V(T) of < 3 mL/kg or < 0.2 mL/cm length died ( N = 4). All other measures of lung capacity or blood gas assessments were less valuable than V(T) in predicting survival. We conclude that bedside V(T) can be easily measured and that values < 3 mL/kg or < 0.2 mL/cm length demarcate severe lung hypoplasia, which in our patient population was incompatible with survival. We speculate that bedside V(T) may assist in evaluating the utility of ECMO., (© Thieme Medical Publishers.)

Despite the recent advances, the clinical approach to persistent pulmonary hypertension of the newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of nitric oxide and high-frequency ventilation. However, not all the neonates with PPHH are responsive to this clinical approach. Recent studies have proposed the use of sildenafil, a phosphodiesterase 5 inhibitor, in refractory forms of PPHN. The aim of this study is to review the cases and the clinical approach of PPHN in the Neonatal Intensive Care Unit of Meyer Children Hospital in the year 2009 and to discuss the possible role of sildenafil in the management of PPHN.

Persistent pulmonary hypertension of the newborn is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extra-pulmonary shunting of blood. In the treatment of persistent pulmonary hypertension of the newborn, the goal is to increase oxygen flow to the baby's organs to prevent serious health problems. Treatment may include medication, mechanical ventilation and respiratory therapy. We performed a retrospective, descriptive and transversal study to investigate the prevalence and treatment of neonatal patients with persistent pulmonary hypertension who were admitted at the Hospital del Niño DIF from 2004 to 2008. Data, collected from hospital charts, included demographic, clinical course and use of medication. A total of 38 patients were included (prevalence of 5.7%). The average age of patients was 8.4 +/- 1.4 days. The mortality rate was 42.1%. Data were collected and 45 different drugs were given to the pediatric patients. The median number of drugs/inpatient was 8.3 (1-18). The therapeutic class most prescribed was anti-infective (29.9% of all the prescriptions), followed by cardiovascular and renal drugs (26.4% of all the prescriptions) and gastrointestinal agents (14.6% of all the prescriptions). Ranitidine was the drug most commonly used, followed by ampicillin and midazolam. We found a high mortality rate and as in many studies, the therapeutic class most used were anti-infectives.

Inhaled nitric oxide (iNO) has been used to treat both term and preterm infants with respiratory failure. Term infants with persistent pulmonary hypertension, either as a primary cause or secondary to other disease processes, respond to iNO with improvement in oxygenation indices and a decreased need for extracorporeal membrane oxygenation. Infants with congenital diaphragmatic hernia are the exception to this finding, with little clinical benefit observed with iNO treatment. Although respiratory disease in preterm infants has a component of increased pulmonary vascular resistance, little benefit of iNO administration has been observed in premature infants either early in their course or later as a treatment to prevent the evolution of chronic lung disease.

Compared with whole body cooling (WBC), selective head cooling (SHC) of asphyxiated newborns presumably allows effective brain cooling with less systemic hypothermia and potentially fewer systemic adverse effects. It is not known if pulmonary dysfunction, one of the potential adverse systemic effects of therapeutic hypothermic neuroprotection, differs with the method of cooling. We sought to investigate if pulmonary mechanics and gas exchange during therapeutic hypothermia differ between WBC and SHC. The severity of pulmonary dysfunction was determined in 59 asphyxiated newborns receiving therapeutic hypothermic neuroprotection by either SHC ( N = 31) or WBC ( N = 28). Ventilatory parameters and simultaneous alveolar-arterial oxygen gradient (A-a DO (2)) and partial pressure of carbon dioxide, arterial (PaCO (2)) were measured before the start of cooling (baseline), and at 4, 8, 12, 24, 48, and 72 hours of cooling. The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was established by echocardiography. Clinical monitoring and treatment during cooling, whether SHC or WBC, were similar. All (96%) but two infants (from the SHC group) required mechanical ventilation of varying duration during cooling, and nine infants (15%) developed PPHN. The baseline ventilator pressures requirement, and A-a DO (2) were similar among the 48 ventilated infants without PPHN (WBC 23, SHC 25) at the start of cooling. Ventilatory requirements remained modest and did not differ with the method of cooling. Similar numbers of infants without PPHN were able to be extubated after improvement in respiratory status while being cooled (WBC 42.8% versus SHC 37.9%, P = 0.79, odds ratio [OR] 1.2, 95% confidence interval [CI] 0.4 to 3.5). Nine infants (WBC 5, SHC 4) developed PPHN. Six of the nine (WBC 4, SHC 2) required inhaled nitric oxide therapy, and one infant from the WBC group subsequently required extracorporeal membrane oxygenation. The incidence of PPHN was similar in both the WBC and SHC groups (17.8% versus 12.9%, P = 0.72, OR 1.5, 95% CI 0.3 to 6.1). Pulmonary dysfunction is common but not severe in asphyxiated infants during therapeutic hypothermia. Pulmonary mechanics and gas exchange do not differ with the method of achieving hypothermia.

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes morbidity and mortality in neonates. High-frequency ventilation (HFV), inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO) are used when conventional treatment fails. This study aimed to identify echocardiographic predictors of progression to these therapies before clinical deterioration., Methods: Echocardiographic parameters were compared for survival and need for ECMO, HFV, iNO, and prolonged mechanical ventilation (MV, >or=10 days)., Results: Of 63 neonates, 95% survived, with 14% requiring ECMO, 52% requiring HFV, 67% requiring iNO, and 35% requiring MV. The following echocardiographic indices reflecting left ventricular output were decreased in sicker infants: (1) A decreased ascending aortic velocity time integral indicated an increased likelihood of ECMO (p=0.02), iNO (p=0.01), or MV (p=0.05), (2) Shorter transverse aortic arch antegrade ejection time indicated HFV (p<0.01), iNO (p<0.01), and MV (p=0.03), (3) Absent or retrograde transverse aortic diastolic flow correlated with HFV (p=0.01, iNO (p=0.01), and MV (p<0.01). These sicker patients were more likely to have smaller left ventricular end-diastolic areas (p<0.03 for all) and right-to-left atrial shunting (ECMO, HFV, and MV). There were no differences in survival., Conclusions: Decreased left ventricular size and output correlates with the need for advanced therapies in infants with PPHN. Early identification may allow more effective management and placement of neonates at risk.

The objective of the study was to compare the effectiveness of surfactant treatment either by bolus or surfactant lung lavage followed by inhaled nitric oxide (iNO) therapy in infants with meconium aspiration syndrome (MAS) complicated by persistent pulmonary hypertension (PPHN). In this study, thirteen infants with diagnosis of MAS and PPHN were first treated with conventional respiratory support. Then between 2 and 22h of life they were randomized either to bolus surfactant treatment (n=6) or surfactant lung lavage (SLL, n=7) treatment. Then all infants were treated with iNO therapy. The groups were compared with regard to their clinical course: changes in PaO(2), FiO(2), MAP, OI, A-a oxygen gradient, duration of iNO therapy, length of ventilation and hospitalization. Complications and mortality were also compared. The results showed that infants treated with SLL had significant improvements in oxygenation, decreases in MAP and A-a gradients. But there were no significant differences in duration of ventilation, iNO treatment, length of hospitalization or complications. In conclusion these data show no advantage of SLL therapy over bolus surfactant treatment in infants with MAS complicated by PPHN.

Our aim was to determine whether starting inhaled nitric oxide (iNO) on critically ill neonates with severe hypoxemic respiratory failure and/or persistent pulmonary hypertension (PPH), at a referring hospital at the start of transport, decreases the need for extracorporeal membrane oxygenation (ECMO), lessens the number of hospital days and improves survival in comparison with those patients who were started on iNO only at the receiving facility. The study was a retrospective review of 94 charts of neonates that had iNO initiated by the transport team at a referring hospital or only at the tertiary neonatal intensive care unit (NICU) of the receiving hospital. Data collected included demographics, mode of transport, total number of hospital days, days on inhaled nitric oxide and ECMO use. Of the 94 patients, 88 were included. Of these, 60 were started on iNO at the referring facility (Field-iNO) and 28 were started at the receiving NICU (CHLA-iNO). All patients survived transport to the receiving NICU. Death rates and ECMO use were similar in both groups. Overall, patients who died were younger and had lower birth weights and Apgar scores. For all surviving patients who did not require ECMO, the length of total hospital stay (median days 22 versus 38, P = 0.018), and the length of the hospital stay at the receiving hospital (median days 18 versus 29, P = 0.006), were significantly shorter for the Field-iNO patients than for the CHLA-iNO patients, respectively. Earlier initiation of iNO may decrease length of hospital stay in surviving neonates with PPH not requiring ECMO.

Background: Persistent pulmonary hypertension (PPHN) occurs in as many as 6.8 of 1000 live births. Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are not available. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance., Objective: Our goal was to evaluate the feasibility of using oral sildenafil and its effect on oxygenation in PPHN., Design: This study was a proof-of-concept, randomized, masked study in infants >35.5 weeks' gestation and <3 days old with severe PPHN and oxygenation index (OI) >25 admitted to the NICU (Hospital Niño Jesús, Barranquilla, Colombia). The sildenafil solution was prepared from a 50-mg tablet. The first dose (1 mg/kg) or placebo was given by orogastric tube <30 minutes after randomization and every 6 hours. Preductal saturation and blood pressure were monitored continuously. OI was calculated every 6 hours. The main outcome variable was the effect of oral sildenafil on oxygenation. Sildenafil or placebo was discontinued when OI was <20 or if there was no significant change in OI after 36 hours., Results: Six infants with an OI of >25 received placebo, and 7 received oral sildenafil at a median age of 25 hours. All infants were severely ill, on fraction of inspired oxygen 1.0, and with similar ventilatory parameters. Intragastric sildenafil and placebo were well tolerated. In the treatment group, OI improved in all infants within 6 to 30 hours, all showed a steady improvement in pulse oxygen saturation over time, and none had noticeable effect on blood pressure; 6 of 7 survived. In the placebo group, 1 of 6 infants survived., Conclusions: Oral sildenafil was administered easily and tolerated as well as placebo and improved OI in infants with severe PPHN, which suggests that oral sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial.

As in the adult with acute lung injury and acute respiratory distress syndrome, the use of lung-protective ventilation has improved outcomes for neonatal lung diseases. Animal models of neonatal respiratory distress syndrome and congenital diaphragmatic hernia have provided evidence that 'gentle ventilation' with low tidal volumes and 'open-lung' strategies of using positive end-expiratory pressure or high-frequency oscillatory ventilation result in less lung injury than do the traditional modes of mechanical ventilation with high inflating pressures and volumes. Although findings of retrospective studies in infants with respiratory distress syndrome, congenital diaphragmatic hernia, and persistent pulmonary hypertension of the newborn have been similar to those of the animal studies, prospective, randomized, controlled trials have yielded conflicting results. Successful clinical trial design in these infants and in children with acute lung injury/acute respiratory distress syndrome will require an appreciation of the data supporting the modern ventilator management strategies for infants with lung disease.

Patients: We studied retrospectively the echocardiographic features of newborns with persistent pulmonary hypertension who had been randomised to receive inhaled nitric oxide or conventional therapy. We sought to identify the predictors of extracorporeal membrane oxygenation therapy, death, and response to inhaled nitric oxide., Results: Among 85 neonates studied, an extrapulmonary right-to-left shunt through either an oval foramen and/or an arterial duct was present in 80 (94%) cases. In the 64 patients (75%) with adequate images for measurements, left ventricular ejection fraction was normal or mildly depressed in 87%, but there was a decreased index of left ventricular output, inferior to 2 l/min/m2, in 61% of the cases. Using multivariate analysis, an exclusive right-to-left ductal shunt was found to be an independent predictor of death, with odds ratio of 7.8, and 95% confidence intervals from 1.2 to 52.8, with a p value of 0.04. There was also a non-significant trend toward greater use of extracorporeal membrane oxygenation in patients with a predominant left-to-right ductal shunt, the odds ratio being 0.13, with 95% confidence intervals from 0.01 to 1.22, and a p value of 0.07. In the 40 patients randomised to receive inhaled nitric oxide, 28 had a positive response as defined by a 20% reduction in the index of oxygenation as measured from the post-ductal arterial blood gas sample. A left-to-right atrial shunt increased the risk of failing to respond to inhaled nitric oxide, with an odds ratio of 7.46, 95% confidence intervals from 1.23 to 45.1, and a p value of 0.028., Conclusion: Detailed Doppler echocardiographic screening of patients with suspected persistent pulmonary hypertension of the newborn may refine the selection of groups for specific treatment, and identify risk factors.

We identified seventeen infants with Down syndrome without structural congenital heart disease who presented with persistent pulmonary hypertension in the newborn period. Respiratory distress with or without hypoxia was the presenting feature in these infants. Pulmonary hypertension resolved in the majority of the survivors. Two infants with refractory pulmonary hypertension benefited from patent ductus arteriosus ligation. Autopsies in two infants demonstrated structural lung immaturity. We suggest that infants with Down syndrome are at risk of developing persistent pulmonary hypertension even in the absence of structural heart disease and these infants should be followed up until resolution of the pulmonary hypertension.

Objective: To evaluate the effect of inhaled nitric oxide (INO) in pulmonary hypertension of the newborn (PH) in a single center over 5 years using gentle ventilation (GV), without hyperventilation or induced alkalosis., Methods: Data from 229 consecutive infants with PH of varied etiology treated with INO and GV, and from 67 infants with meconium aspiration syndrome (MAS) and primary PH (PPHN) treated with GV alone were reviewed over a 5-year period (86% outborn). INO was initiated at 25 ppm when PH and severe hypoxemia persisted despite maximal optimal ventilation. Hyperventilation or systemic alkalosis were not attempted., Results: Mean duration of ventilation was 9.9 +/- 14 days (median 6.5 days). Average mean airway pressure (MAP) dropped from 17.7 +/- 4.3 cm H(2)O at the referral hospital to 13.2 +/- 2.5 cm H(2)O (p < 0.001) following admission to our unit using conventional settings and GV, before starting INO. Mean oxygenation index (OI) dropped from 46.8 +/- 24.5 to 22.7 +/- 21.4 within 24 hours of INO therapy (p < 0.001). Infants with higher baseline pH and lower baseline OI responded better to INO (p < 0.02). Overall survival was 72%. Patients with MAS and PPHN had the best response, 92% survived and there was a 46% reduction in need for extracorporeal membrane oxygenation (ECMO) compared to historical pre-INO period controls (23.9% vs. 12.8%, p < 0.01). In the infants treated with GV alone, the MAP dropped from 17.2 +/- 4.3 cm H2O at the referral hospital to 12.6+/-2.4 after GV was started in our unit., Conclusions: We conclude that INO is an effective and well-tolerated therapy for PH in infants receiving GV.

Twenty seven newborn infants with persistent hypoxemia in the first 3 days after birth were enrolled for hemodynamic assessment using echocardiography. Measurements included pulmonary arterial pressure (peak velocity of tricuspid regurgitation (TR), patent ductus arteriosus (PDA) flow pattern, interatrial shunting flow pattern and pulmonary flow velocity ratio (the time to peak velocity/right ventricle ejection time ratio (TPV/RVET)) and left ventricular ejection fraction. The estimated systolic pulmonary arterial pressure and the systemic arterial pressure determined via an indwelling arterial line were recorded at the time of echocardiographic examination, and pulmonary arterial pressure/systemic arterial pressure was calculated. Nineteen infants (70.4%) had a TR sufficient to estimate systolic pulmonary arterial pressure. The median value of pulmonary arterial pressure/systemic arterial pressure was 1.02 (range, 0.68 to 1.78). Twenty two infants (81.5%) had a PDA and flow patterns indicating pulmonary arterial pressure above or approaching systemic arterial pressure. All infants had a foramen ovale and flow patterns were bi-directional or pure right-to-left. TPV/RVET had a wide range of values (0.23 to 0.55), and only 44.5% of infants had high pulmonary arterial pressure as reflected by low TPV/RVET ratio. Eleven infants (40.7%) had an ejection fraction below the normal range. Results of 17 survivors were compared with 8 deceased infants (2 infants of birth weight less than 1000 gm were excluded who died of massive pulmonary hemorrhage). There were no significant differences for any parameter of pulmonary arterial pressure, but ejection fraction was significantly lower in deceased infants. This study has demonstrated that it is possible to evaluate pulmonary arterial pressure noninvasively by using echocardiography in most newborn infants with clinical evidence of persistent pulmonary hypertension of the newborn (PPHN). Ejection fraction is an echocardiographic parameter which can significantly predict mortality.

Introduction: Because of the high mortality, potential limitations, and inherent adverse effects associated with conventional therapies, as well as extracorporeal membrane oxygenation, for persistent pulmonary hypertension of the newborn (PPHN), alternative modes of ventilatory support have been researched. There is anecdotal evidence that high-frequency flow interruption ventilation (HFFI) benefits neonates with severe air leak and lung diseases unresponsive to conventional ventilation, so we conducted a study to compare the hospital course, survival rate, and incidence of chronic lung disease of neonates with PPHN treated with hyperventilation (HV) and HFFI., Methods: Enrolled in the study were 36 neonates who (1) were treated with HV and a fraction of inspired oxygen of 1.0 for PPHN, (2) had arterial partial pressure of oxygen (P(aO2)) values or= 120 mm Hg; (3) shorter mean time to P(aO2) >or= 120 mm Hg (13.5 vs 50.2 h, p = 0.001); (4) shorter mean time to reduced fraction of inspired oxygen (16 vs 84 h, p < 0.001); (5) shorter mean time to fraction of inspired oxygen 0.70 (53 vs 187 h, p < 0.001); (6) shorter mean time to extubation (8.1 vs 18.7 d, p = 0.033); (7) shorter length of hospitalization (22.7 vs 50.6 d, p = 0.025); and (8) fewer neonates with chronic lung disease (1 vs 5, p = 0.018)., Conclusions: HFFI with the ventilation strategy we describe accomplishes sustained hyperoxygenation without hypocarbia and alkalosis, and response to HFFI can predict outcomes. HFFI does not significantly reduce mortality, but it does reduce the length of mechanical ventilation, the length of hospitalization, and the incidence of chronic lung disease in neonates with PPHN. The nonrandomized design of our study precludes firm conclusions about the potential benefits of HFFI. The results may be biased by practice variations. Additional randomized controlled trials are warranted to determine the efficacy of HFFI in neonates with PPHN.

Purpose: Congenital diaphragmatic hernia (CDH) is associated with thickened pulmonary arteries (PA) contributing to pulmonary hypertension. In the current study, the effects of antenatal glucocorticoids and reversible tracheal occlusion (TO) on PA structure were assessed in a hypoplastic lung model., Methods: A left-sided CDH was created in fetal lambs at 80 days gestation, TO at 108 days, and release of the occlusion (TR) at 129 days. All were given 1 dose of maternal glucocorticoids at 135 days. At 136 days (term, 145 days), the fetus was delivered by cesarian section. CDH (n = 7), CDH + TO (n = 6), CDH + TO + TR (n = 6), and unoperated twin controls (n = 16) were compared. Outcome measurements were (1) lung growth, represented by lung weight to body weight ratio (LW/BW), (2) lung structural maturation, which is inversely proportional to mean terminal bronchiole density (MTBD), (3) PA medial and adventitial areas (square micrometers), (4) lung capillary load, which is the ratio of vessel surface area (SA) to tissue SA ratio., Results: CDH lungs were hypoplastic with a low LW/BW and high MTBD. The small PAs (<75 microm) of CDH had an increased medial area, indicating increased muscle mass and an increased adventitial area. CDH + TO +/- TR increased LW/BW and achieved normal structural lung maturity with a low MTBD. Only CDH + TO thinned the PA medial area closer to control values. The adventitial area remained thick in CDH +/- TO +/- TR when compared with controls. All 4 groups had similar capillary load., Conclusions: TO may be especially important for PA remodeling in the latter part of gestation, because TR 1 week before delivery prevents thinning of the small PAs in CDH. The shaping achieved by TO in terms of lung growth, structural maturity, and pulmonary artery medial area thinning may prove beneficial in lessening the severity of the associated pulmonary hypertension in CDH., (Copyright 2001 by W.B. Saunders Company.)

Persistent pulmonary hypertension of the newborn (PPHN) due to meconium aspiration syndrome (MAS), has a high morbidity and mortality especially in centres with limited access to extra-corporeal membrane oxygenation or nitric oxide therapy. In such a setting, we conducted a pilot study to evaluate the effect of dexamethasone on severe respiratory failure with PPHN due to MAS with a view to exploring possible justification for randomised controlled trials in similar patients. We prospectively managed a consecutive case series of 14 infants over a 3-year period with the above mentioned diagnosis, who were ventilated and with an oxygenation index >25. Dexamethasone was commenced in a dose of 0.5 mg/kg per day and given for up to a maximum of 9 days in a reducing schedule. Differences between time points were analysed using analysis of variance for repeated measures. The mean age of commencing dexamethasone was 79.9 h. There was a rapid, significant improvement (P < 0.05) in the respiratory status in 13 of these infants after commencing dexamethasone, allowing weaning from the ventilator and eventual extubation at a mean age of 8.7 days. One infant died. Two infants had infective episodes. Conclusion. Dexamethasone, if started early in infants with respiratory failure and persistent pulmonary hypertension of the newborn due to meconium aspiration syndrome may be effective in improving gas exchange, and possibly avoiding extra-corporeal membrane oxygenation. A randomised controlled trial of using dexamethasone early in similar patients and setting is warranted.

Objective: We previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV)., Design: Single-center, prospective, randomized, controlled trial., Setting: Newborn intensive care unit of a tertiary care teaching hospital., Patients: We studied infants with a gestational age of > or =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2 < or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded., Interventions: The treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted., Measurements and Main Results: Primary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively; p = .007). Mortality did not differ with treatment assignment., Conclusions: Among infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease.

Background: Inhaled nitric oxide improves gas exchange in neonates, but the efficacy of low-dose inhaled nitric oxide in reducing the need for extracorporeal membrane oxygenation has not been established., Methods: We conducted a clinical trial to determine whether low-dose inhaled nitric oxide would reduce the use of extracorporeal membrane oxygenation in neonates with pulmonary hypertension who were born after 34 weeks' gestation, were 4 days old or younger, required assisted ventilation, and had hypoxemic respiratory failure as defined by an oxygenation index of 25 or higher. The neonates who received nitric oxide were treated with 20 ppm for a maximum of 24 hours, followed by 5 ppm for no more than 96 hours. The primary end point of the study was the use of extracorporeal membrane oxygenation., Results: Of 248 neonates enrolled, 126 were randomly assigned to the nitric oxide group and 122 to the control group. Extracorporeal membrane oxygenation was used in 78 neonates in the control group (64 percent) and in 48 neonates in the nitric oxide group (38 percent) (P=0.001). The 30-day mortality rate in the two groups was similar (8 percent in the control group and 7 percent in the nitric oxide group). Chronic lung disease developed less often in neonates treated with nitric oxide than in those in the control group (7 percent vs. 20 percent, P=0.02). The efficacy of nitric oxide was independent of the base-line oxygenation index and the primary pulmonary diagnosis., Conclusions: Inhaled nitric oxide reduces the extent to which extracorporeal membrane oxygenation is needed in neonates with hypoxemic respiratory failure and pulmonary hypertension.

Background/purpose: Infants with congenital diaphragmatic hernia have pulmonary hypoplasia resulting in persistent pulmonary hypertension of neonates (PPHN), which is the main contributor to both high mortality and morbidity. The pulmonary artery bed in patients with congenital diaphragmatic hernia (CDH) is underdeveloped and is very sensitive to slight stimuli. It is, therefore, vital to avoid any factors that might increase pulmonary vascular resistance during the perinatal treatment of these patients. Recently, fetal anesthesia for perinatal stabilization in patients with CDH has been reported. However, the efficacy of this method remains controversial. The aim of this study is to analyze the benefits of fetal stabilization using fetal anesthesia in patients with CDH., Methods: The authors have seen 9 cases of antenatally diagnosed CDH and attempted fetal stabilization. The indication for fetal stabilization was a lung thoracic ratio of less than 0.2, without any severe associated anomalies. The protocol for fetal stabilization was (1) monitoring the fetal respiratory movement and heart beat by ultrasonography, (2) the administration of morphine (20 to 30 mg) and diazepam (5 mg) to the mother, (3) the confirmation of any interruptions in fetal movement followed by a cesarean section, (4) pancuronimum (0.5 mg) was given through the umbilical vessels, (5) intubation before clamping of the umbilical cord, and (6) high-frequency oscillatory ventilation (HFO) without bagging., Results: The lung-thratic ratio (LTR) was between 0.06 to 0.17 (average, 0.10+/-0.04). Operation was performed in 7 of 9 patients at between 2.5 and 27 hours after birth. The overall survival rate was 66.7% (6 of 9). All of the patients who underwent operation within 5 hours after birth survived., Conclusions: Perinatal stabilization using fetal anesthesia was found to be effective in preventing PPHN and shortening the period of preoperative stabilization. It also improved the survival rate of patients with severe CDH.

Objective: To describe the results of treatment with extracorporeal membrane oxygenation (ECMO) in newborns with severe cardiorespiratory insufficiency., Design: Prospective, descriptive., Methods: For all 100 newborns treated with ECMO in 1989-1997 in the Academic Hospital Nijmegen, department of Neonatology, the Netherlands, indications for treatment, complications during treatment and mortality within 6 weeks after cessation of ECMO were registered., Results: The 100 children comprised 66 boys and 34 girls, with a mean age of 2 days (range: 1-15). Indications for ECMO treatment were: meconium aspiration syndrome: 39 with 37 survivors (95%), congenital diaphragmatic hernia: 31 with 23 survivors (74%), sepsis or pneumonia: 20 with 14 survivors (70%) and 'others' among which persistent pulmonary hypertension of the newborn: 10 with 8 survivors (80%). Eighteen children died (18%). Causes of death were rebound pulmonary hypertension (9 times), intracranial haemorrhage (4), multi-organ failure (3) and pulmonary problems (2). The most important complications during treatment were bleeding problems (29), clotting problems (20) and infections (11).

A randomized nonblinded comparison of two treatment groups was performed to determine whether treatment of infants with persistent pulmonary hypertension of the newborn using a continuous 6-ppm dose of inhaled nitric oxide (iNO) changes the likelihood of death or utilization of extracorporeal membrane oxygenation (ECMO) when compared to infants treated with 20 ppm iNO for 4 h followed by 6 ppm. Twenty-nine infants with a gestational age >/=34 weeks and a diagnosis of persistent pulmonary hypertension of the newborn were enrolled during the 3- year study period. The relative risk (20/6 vs. 6 ppm) for treatment with ECMO was 3.11 (p = 0.02), for death it was 2.80 (p = 0.32), and for either death or ECMO it was 3.42 (p = 0. 006). There was no apparent advantage of treatment with a higher dosage of iNO at the initiation of therapy in the reduction of death or utilization of ECMO. These data suggest that a continuous lower dose of iNO results in a comparable improvement in oxygenation as a short exposure of higher dose iNO at the initiation of therapy.

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10-80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51+/-21 vs 23+/-17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45+/-20 vs 20+/-17, P < .0001), 'idiopathic' PPHN (39+/-14 vs 14+/-9, P < .0001), and sepsis (55+/-25 vs 26+/-20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI=41+/-16 vs 28+/-18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI=58+/-25 vs 46+/-32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age > or =34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants.

We studied 13 consecutive infants admitted to our Neonatal Intensive Care Unit over 37 months from 1 June 1994 to 30 June 1997, who were diagnosed with severe persistent pulmonary hypertension (PPHN) meeting extracorporeal membrane oxygenation (ECMO) criteria as defined by Bartlett and/or Short. They were managed with conservative ventilation strategy, with emphasis on the use of moderate ventilatory pressures whilst avoiding paralysis. Peak inspiratory pressure (PIP) on intermittent mandatory ventilation was adjusted according to adequate chest excursion. High PIP was avoided. Two main ventilatory techniques were used: 1) low ventilatory rate < or = 40/min, PIP 20 to 30 cmH2O, inspiratory time (IT) 0.5 seconds, positive end-expiratory pressure (PEEP) 5 cmH2O, and 2) high ventilatory rate 100/min, PEEP 0 cmH2O, IT 0.3 seconds. The aim was to keep preductal PaO2 > or = 50 mmHg. We did not sought to achieve alkalotic pH or low PaCO2. When PIP requirements exceeded 30 to 35 cmH2O, the use of an alternative rescue therapy such as pulmonary vasodilator, high frequency ventilation and/or surfactant were considered. Only 1 infant died of PPHN. Low mortality due to PPHN can be achieved using this strategy. There is a need for a randomised controlled trial to compare this strategy with other alternative treatment strategies.

Objectives: To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety., Methods: Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [FIO2] of 1.0, a mean airway pressure >/=10 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned)., Results: The baseline oxygenation index (OI) was 24 +/- 9 at 25 +/- 17 hours old (mean +/- SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the PaO2 for only the NO groups increased significantly from 64 +/- 39 to 109 +/- 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 +/- 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (>7%) and nitrogen dioxide (NO2) (>3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD., Conclusion: For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.

Objective: To determine the effect of inhaled nitric oxide (NO) on clinical outcome in newborns with persistent pulmonary hypertension (PPHN)., Design: A prospective, randomized trial of patients referred to a level 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted., Methods: We randomized 49 mechanically ventilated newborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO2] <100; fractional inspired oxygen = 1) to treatment with or without NO. Patients with gestational age <34 weeks or with congenital heart disease or diaphragmatic hernia were excluded. High-frequency oscillatory ventilation was used but not allowed concomitantly with NO. Primary outcome variables were oxygenation, mortality, and use of extracorporeal membrane oxygenation (ECMO)., Results: Meconium aspiration syndrome and isolated PPHN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study was similar between groups, 25 hours for control patients and 18 hours for NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI = 29) and 26 NO (OI = 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and duration of supplemental oxygen (13 days) were not different between treatment groups. PaO2, oxygen saturation, and OI improved in the NO group compared with baseline and to control patients at 15 minutes. The median percent change in OI (-31%) in the NO group was significantly different from baseline and from the control group. The difference in oxygenation between treatment groups was still apparent 12 hours after baseline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed on ECMO, the median time from baseline to ECMO cannulation was 2.4 hours (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendency to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar capillary dysplasia confirmed by postmortem examination could not be weaned from 80 parts per million of NO and transiently developed methemoglobinemia (peak methemoglobin level = 17%). No other side effects were observed., Conclusions: Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiation of ECMO may have important clinical benefits. We speculate that modification of treatment to include specific lung expansion strategies with NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls.

Objective: To determine the impact of new treatment modalities, including high-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (INO), on extracorporeal membrane oxygenation (ECMO) use and outcome of neonatal patients with persistent pulmonary hypertension of the newborn., Study Design: We reviewed the medical records of neonatal patients meeting established ECMO criteria from 1988 to 1995. Clinical data were gathered from this retrospective chart review. Comparison of ECMO experiences were made between the 1988-90 period (pre-HFOV and INO, or period 1) and the 1993-95 period (HFOV and INO fully established as treatment modalities, or period 2)., Results: One hundred three patients were treated with ECMO during the 8-year study period. After HFOV and INO were introduced in 1991 and 1992 respectively, the number of patients meeting established ECMO criteria who subsequently required ECMO therapy progressively declined, from 22.3 +/- 2.3 (mean +/- SD) patients per year during period 1 to 12 patients in 1991 when HFOV was introduced, 8 patients in 1992 when INO was introduced, and 5.3 +/- 2.9 patients per year in period 2. The number of patients referred for ECMO over time did not change. Survival after ECMO dropped from 84% during period 1 to 56% in period 2. Introduction of new pre-ECMO therapies has not delayed institution of ECMO, significantly increased the length of ECMO runs, or lengthened the hospital course of ECMO survivors. A comparison of the eight infants treated with ECMO in 1992 with the 10 infants treated with INO in 1993 showed a longer hospital stay and a larger average patient bill for the patients treated with ECMO., Conclusion: New treatment approaches for severe persistent pulmonary hypertension have reduced ECMO use, shortened the duration of hospitalization, and reduced costs for those infants responding to HFOV and INO. However, survival of patients requiring ECMO therapy has decreased.

A complex vascular abnormality in the lungs, termed alveolar capillary dysplasia (ACD) and misalignment of the lung vessels, has been recently recognized in some infants with persistent pulmonary hypertension. These infants die despite maximal medical support including extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide has been reported to improve oxygenation in neonates with persistent pulmonary hypertension of the newborn, and may allow some infants to avoid the need for ECMO. We identified five infants who had received inhaled nitric oxide to treat refractory hypoxemia caused by persistent pulmonary hypertension of the newborn, and who subsequently died and had autopsy confirmation of ACD. Each infant received care at a different medical center. In each patient, inhaled NO increased the arterial partial pressure of oxygen dramatically. Despite initial clinical improvement, the response to NO was not sustained in any patient. As responsiveness was lost, each infant with ACD required inhaled NO concentrations of 80 ppm or higher to sustain oxygenation. Each infant died, four after extensive periods of ECMO support. This experience demonstrates that a short-term improvement after inhalation of nitric oxide does not lead to long-term survival in ACD. Further, in three infants the diagnosis of ACD was established by lung biopsy before death. Increasing awareness of this clinical entity may allow for the avoidance of costly, invasive procedures such as ECMO until more specific therapies become available.