Meconium aspiration syndrome: a comprehensive review.

Meconium aspiration syndrome (MAS) is a complex respiratory disease that continues to be associated with significant morbidities and mortality. The pathophysiological mechanisms of MAS include airway obstruction, local and systemic inflammation, surfactant inactivation and persistent pulmonary hypertension of the newborn (PPHN). Supplemental oxygen and non-invasive respiratory support are the main therapies for many patients. The management of the patients requiring invasive mechanical ventilation could be challenging because of the combination of atelectasis and air trapping. While studies have explored various ventilatory modalities, evidence to date does not clearly support any singular modality as superior. Patient's pathophysiology, symptom severity, and clinician/unit expertise should guide the respiratory management. Early identification and concomitant management of PPHN is critically important as it contributes significantly to mortality and morbidities.

Costs associated with acute kidney injury in critically Ill neonates with patent Ductus arteriosus: pediatric health information system (PHIS) analysis.

OBJECTIVE: Compare costs of hospitalization between critically-ill neonates with patent ductus arteriosus (PDA) who did and did not develop acute kidney injury (AKI). STUDY DESIGN: Using the Children's Hospital Association's Pediatric Health Information System (PHIS) database, we ascertained the marginal estimated total cost of hospitalization between those who did and did not develop AKI. RESULTS: Query of 49 PHIS centers yielded 14,217 neonates with PDA, 1697 with AKI and 12,520 without AKI. Predictors of cost included AKI, birth weight, ethnicity, race, length of stay (LOS), and Feudtner Complex Chronic Conditions Classification System. LOS was the strongest predictor (AKI: median 71 days [IQR 28-130]; No AKI: 28 days [10-76]; p < 0.01). Neonates with AKI had $48,416 greater costs (95% CI: $43,804-53,227) after adjusting for these predictors (AKI: $190,063, 95% CI $183,735-196,610; No AKI: $141,647, 95% CI $139,931-143,383 l; p < 0.01). CONCLUSION: AKI is independently associated with increased hospital costs in critically-ill neonates with PDA.

Pulmonary vasodilator strategies in neonates with acute hypoxemic respiratory failure and pulmonary hypertension.

The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and mortality, especially when accompanied with persistent pulmonary hypertension of the newborn (PPHN). PPHN is a syndrome characterized by marked hypoxemia secondary to extrapulmonary right-to-left shunting across the ductus arteriosus and/or foramen ovale with high pulmonary artery pressure and increased pulmonary vascular resistance (PVR). After optimizing respiratory support, cardiac performance and systemic hemodynamics, targeting persistent elevations in PVR with inhaled nitric oxide (iNO) therapy has improved outcomes of neonates with PPHN physiology. Despite aggressive cardiopulmonary management, a significant proportion of patients have an inadequate response to iNO therapy, prompting consideration for additional pulmonary vasodilator therapy. This article reviews the pathophysiology and management of PPHN in term newborns with AHRF while highlighting both animal and human data to inform a physiologic approach to the use of PH-targeted therapies.

Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. METHODS: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. RESULTS: Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. CONCLUSIONS: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.

Two cases of different genetic variants of alveolar capillary dysplasia associated with left-sided obstructive CHDs.

Alveolar capillary dysplasia with misalignment of the pulmonary veins is an uncommon disorder that affects the lung vasculature development in the neonatal period and leads to pulmonary hypertension. We describe two patients with alveolar capillary dysplasia associated with left-sided obstructive heart defects with two different genetic variants. Our cases highlight the importance of early recognition of this disease in the setting of persistent and supra-systemic pulmonary hypertension despite surgical correction of the associated lesions. Identification of these cases will facilitate the development of a multidisciplinary approach and provide guidance to the affected families.

Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies.

OBJECTIVE: To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia. METHODS: We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, "usual care" arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18-22 months adjusted for severity of HIE, center, and RCT. RESULTS: Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR: 1.65, 0.86-3.14) and death was 26% vs. 12% (adjusted OR: 2.04, 0.92-4.53), respectively. CONCLUSIONS: PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.

Widefield Fluorescein Angiography in the Fellow Eyes of Patients with Presumed Unilateral Persistent Fetal Vasculature.

PURPOSE: To examine the retinal vascular findings on widefield fluorescein angiography (FA) in the fellow eyes of patients with unilateral persistent fetal vasculature (PFV). DESIGN: Retrospective case series. PARTICIPANTS: Consecutive patients with unilateral PFV evaluated by a single physician at an academic medical center from February 1, 2011, to November 30, 2018. METHODS: Clinical and demographic information, including age, gender, race, ethnicity, affected eye, subtype, stalk origin, complications on presentation, length of follow-up, and examination findings, was reviewed using the electronic medical record. Fluorescein angiograms of the affected and fellow eyes were reviewed by 2 authors for characteristic retinal vascular abnormalities. Agreement between the authors' scores was analyzed using Cohen's Kappa. MAIN OUTCOME MEASURES: Fluorescein angiography abnormalities, including peripheral vessel avascularity, aberrant circumferential vessels, terminal supernumerary branching, regional capillary dropout, terminal bulbing, abnormal choroidal flush, abnormal vessel straightening, and peripheral vessel leakage or dilation. RESULTS: Inclusion criteria were met by 41 patients. The average age at initial visit was 10.0 months. The average length of follow-up was 36.4 months. Abnormalities on FA were seen in 31 (75.6%) fellow eyes: peripheral vessel avascularity in 27.5 (67.1%), aberrant circumferential vessels in 20 (48.8%), terminal supernumerary branching in 17 (41.5%), regional capillary dropout in 9 (22.0%), terminal bulbing in 6 (14.6%), abnormal choroidal flush in 3.5 (8.5%), and abnormal vessel straightening and peripheral vessel leakage in 2.5 (6.1%). Statistical analysis disclosed an overall observed agreement of 93.4% among the raters (κ = 0.84, P < 0.0001). CONCLUSIONS: Retinal vascular abnormalities seen in patients with unilateral PFV were present in the majority of fellow eyes. This suggests that unilateral PFV may in fact be a bilateral, asymmetric process, but the clinical significance of these subtle findings is not known.

Correlation between changes in brain natriuretic peptide and echocardiographic features in persistent pulmonary hypertension of newborn.

Objective: To investigate the correlation between changes in brain natriuretic peptide (BNP) and echocardiographic features in persistent pulmonary hypertension of newborn (PPHN).Patients and methods: A total of 76 patients with PPHN treated in our hospital from March 2017 to February 2018 were divided into mild group (n = 33), moderate group (n = 22) and severe group (n = 21) according to the pulmonary arterial systolic pressure, and they were compared with 30 normal newborns (control group) during the same period. All newborns underwent echocardiography, the BNP level was detected, and the correlation between echocardiographic features and BNP changes was analyzed.Results: The BNP level in control group was significantly lower than those in PPHN groups, and it was constantly increased from mild group to severe group (p<.05). There were no significant differences in left atrial diameter (LA) and left ventricular diameter (LV) among groups (p>.05), while there were significant differences in the right atrial diameter (RA), right ventricular diameter (RV) and peak velocity of tricuspid regurgitation (VTR) (p<.05). BNP had no correlations with LA and LV (p>.05), but had positive correlations with RA, RV and VTR (r = 0.527, 0.503 and 0.524, p<.05).Conclusion: The BNP level of patients with PPHN increases with the increasing severity of disease. BNP has close correlations with echocardiographic features of neonatal patients. Predicting the BNP changes via echocardiography is of certain value in guiding the clinical treatment.

Methemoglobin and the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn.

BACKGROUND: We aimed to investigate whether the change in methemoglobin levels (ΔMHb) predicts oxygenation response to inhaled nitric oxide (iNO) in persistent pulmonary hypertension of the newborn (PPHN) with lung disease, with or without pulmonary hypoplasia. METHODS: In this prospective observational study, infants were categorized based on ΔMHb and oxygenation response (ΔPaO2/FiO2) following iNO: ΔMHb ≤0 or ΔMHb>0, and ΔPaO2/FiO2 < 20 mmHg (Non-responder) or≥20 mmHg (Responder). ΔMHb levels were compared among infants with or without pulmonary hypoplasia. RESULTS: Among infants with pulmonary hypoplasia (n = 28), ΔMHb was not associated with an oxygenation response to iNO or survival without ECMO. Among infants without hypoplasia (n = 29), subjects with ΔMHb>0 following iNO (n = 21) had a greater ΔPaO2/FiO2 (median, 64 mmHg; IQR, 127; p < 0.01) and 100% survival without extracorporeal membrane oxygenation (ECMO) when compared to infants with ΔMHb ≤0 (n = 8; median 10 mmHg; IQR, 33). CONCLUSIONS: PPHN secondary to lung disease without hypoplasia with increased ΔMHb following iNO was associated with better oxygenation response and survival without ECMO compared to subjects without an increase in MHb.

Severe Pulmonary Arteriopathy in a Neonate with Congenital Rubella Syndrome and Patent Ductus Arteriosus.

Neonates with congenital rubella syndrome (CRS) are known to have associated congenital cardiac malformations. Patent ductus arteriosus (PDA) is one the most common cardiac anomalies associated with CRS. PDA refractory to medical management and associated with ventilatory dependence is considered for surgical ligation. However, the management of PDA can be challenging in the presence of underlying lung disease or pulmonary vascular disease. Outcomes after closure in neonates are dependent upon age, weight, nutritional status, pre-operative pulmonary arterial hypertension and presence of chronic lung disease. We present a neonate with CRS who required surgical PDA closure. The neonate developed severe pulmonary arterial hypertension which led to fatal outcome. The clinical course is corroborated with histo-pathological changes observed on the autopsy of this neonate.

Nitric Oxide in Pulmonary Hypoplasia: Results from the European iNO Registry.

OBJECTIVES: The aim of this work was to describe treatment response and outcome data for preterm infants with pulmonary hypoplasia treated with inhaled nitric oxide (iNO). We hypothesised that an acute oxygenation response to iNO would be associated with survival. DESIGN: A retrospective observational study design was used to identify cases of pulmonary hypoplasia in preterm infants <34 weeks' gestation reported to the European iNO Registry. Demographic and clinical data were collected including oxygenation and echocardiographic parameters. The primary outcome was acute oxygenation response defined as a reduction in fractional inspired oxygen of >0.15. Outcome data included chronic lung disease (CLD) and death. RESULTS: Seventy-two infants with pulmonary hypoplasia were treated with iNO during a 10-year period (2007-2016). In total, 30/69 (43%) of the infants showed a significant improvement in oxygenation and were categorised as "responders." Thirty-one treated infants died, and 19 survivors developed CLD. Although there were no differences in demographics and baseline cardiorespiratory parameters between responders and non-responders, an acute response was significantly associated with survival. Neither pulmonary hypertension nor PPHN (persistent pulmonary hypertension of the newborn) physiology predicted the acute response to iNO or survival. CONCLUSION: Although the acute oxygenation response to iNO therapy in pulmonary hypoplasia is comparable to other respiratory disorders in preterm infants, mortality in this group remains very high. An acute response is associated with survival and suggests that a short therapeutic trial of iNO therapy is warranted in this population. This study underscores the value of registries in evaluating therapies for rare neonatal disorders, although their limitations must be recognised.

Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life.

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.

The Use of Cardiotonic Drugs in Neonates.

There is a distinct lack of age-appropriate cardiotonic drugs, and adult derived formulations continue to be administered, without evidence-based knowledge on their dosing, safety, efficacy, and long-term effects. Dopamine remains the most commonly studied and prescribed cardiotonic drug in the neonatal intensive care unit (NICU), but evidence of its effect on endorgan perfusion still remains. Unlike adult and pediatric critical care, there are significant gaps in our knowledge on the use of various cardiotonic drugs in various forms of circulatory failure in the NICU.

Are Cardiac Anomalies and Persistent Fetal Circulation a Risk Factor for Cardiovascular Events During Minimally Invasive Surgery in Neonates?

Introduction: Minimally invasive surgery (MIS) in neonates is progressively performed. The aim of this study was to evaluate the risk for cardiovascular events during endoscopic surgery in neonates and to analyze the influence of persistent fetal circulation and/or cardiac anomalies. Materials and Methods: This is a retrospective single institution study including all neonates undergoing MIS. The charts were reviewed for intraoperative cardiovascular events and operative procedure was performed. Special attention was paid to cardiac anomalies and persistent fetal circulation. In addition, a review of the literature was performed. Results: Between January 2004 and December 2012, 108 neonates underwent MIS at our institution. Laparoscopic surgery was performed in 91 (84.3%) and thoracoscopy in 17 (15.7%) babies. None of these 108 patients developed a cardiovascular event during endoscopic surgery (0.0%). Persistent fetal circulation and/or cardiac anomalies were evaluated in 50 of 108 (46.3%) neonates. In the additionally performed review of the literature, four single case reports were identified. All 4 authors published a major cardiovascular event during laparoscopic surgery in neonates. In all 4 patients, gas embolism through a patent umbilical vein was assumed to be responsible for the cardiovascular event. Conclusions: In our opinion, the main risk factor for the development of a major cardiovascular event during MIS in neonates is vascular injury of a persistent umbilical vein. Persistent fetal circulation and/or cardiac anomalies seem to be less important. In case of injury of a persistent umbilical vein, the risk of gas embolism has to be respected and conversion to the open approach has to be considered.

The effect of hemodynamically significant patent ductus arteriosus on acute kidney injury and systemic hypertension in extremely low gestational age newborns.

Background: Acute kidney injury (AKI) in preterm neonates is becoming an increasingly recognized morbidity in the neonatal intensive care unit neonatal intensive care unit (NICU), yet its epidemiology, delineation and relation to numerous toxic exposures and common morbidities such as systemic hypertension is just evolving. With a frequency of the patent ductus arteriosus (PDA) as high as 70% in preterm infants born before 28-week gestation, the role of the hemodynamically significant PDA (hs-PDA) remains unclear. Objective: To determine if AKI and systemic hypertension is more common in extremely low gestational age newborns (ELGAN) with hs PDA compared to ELGAN with no or non-hs PDA using modified AKIN and Neonatal Risk, Injury, Failure, Loss of Kidney Function, and End-stage (N-RIFLE) scoring systems. Methods: This was a retrospective cohort study of infants ≤28 weeks gestational age born between 2010 and 2016 who had echocardiographic PDA evaluation completed for hemodynamical significance as well as serial serum creatinine and urine output measurement documented, needed for the two AKI scoring systems: modified AKIN (based on serial serum creatinine) and N-RIFLE (using urine output data). Blood pressure measurements and therapy were evaluated during the hospitalization and on the day of NICU discharge. Baseline characteristics and outcome variables were compared between the hs-PDA and no or non-hs PDA using unpaired t-tests for continuous variables and chi square tests for categorical data. Results: One hundred fifty-one infants were eligible of which 110 had hs-PDA. Infants with hs-PDA were smaller (777 versus 867 g, p = .026), less mature (25.8 versus 26.4 weeks, p = .023) and had greater exposure to nephrotoxic drugs (14 versus 9.4 days, p = .001). Other clinical and demographic variables were similar between the two groups. The overall incidence of AKI was not different between the hs-PDA and no PDA or non-hs PDA groups when evaluated by the acute kidney injury network (AKIN) or N-RIFLE staging; however, preterm newborns with hs-PDA demonstrated a trend towards increased risk of AKI injury (12.7 versus 0.02%, p = .06). The N-RIFLE and AKIN scoring systems demonstrated very poor degree of agreement (kappa = 0.00853) in our study. There was no difference in the rates of hypertension during the hospitalization as well as on the day of NICU discharge. Conclusion: Preterm neonates with hs-PDA had similar rates of AKI and hypertension as neonates with no or non-hs PDA.

Hypertrophic pyloric stenosis following persistent pulmonary hypertension of the newborn: a case report and literature review.

BACKGROUND: Although persistent pulmonary hypertension of the newborn (PPHN) and infantile hypertrophic pyloric stenosis (HPS) are both well-known diseases that occur in early infancy, PPHN complicated by HPS is rare. As nitric oxide (NO) is an important mediator of biological functions, on both the vascular endothelium and smooth muscle cells, the decreased production of NO might play a role in the pathogenesis of both PPHN and HPS. We present the case of a neonate who developed HPS following PPHN, including a detailed review on research published to date, and we discuss the pathogenesis of PPHN and HPS. CASE PRESENTATION: A female neonate born at 38 weeks of gestation, weighing 3140 g, developed PPHN due to meconium aspiration syndrome. Intensive treatment with high frequency oscillations and inhaled NO were initiated, and sildenafil and bosentan were added. She gradually recovered. At 15 days of age, the patient developed recurrent vomiting after feeding and the diagnosis of HPS was made. Intravenous atropine therapy was started at 20 days of age, but the efficacy was clinically unsatisfactory. The coadministration with transdermal nitroglycerin improved the symptoms, and oral feeding was successfully re-introduced. CONCLUSIONS: Our patient recovered from both PPHN and HPS using NO-related medications. A decrease in NO synthesis is likely to be a common pathway for PPHN and HPS.

Peripheral Persistent Fetal Vasculature: A Report of Three Cases.

The authors report three cases of persistent fetal vasculature (PFV) presenting with an atypical peripheral fibrovascular stalk. A 5-month-old with congenital exotropia with a vitreous hemorrhage in the right eye underwent vitrectomy, and a mid-peripheral vitreal vascular stalk was visualized within the area of hemorrhage. The second case is of an 8-year-old with two fetal vascular remnants in the right eye: (1) a stalk superotemporally extending from the pars plana to the mid-peripheral retina that was associated with a retinal break and (2) a focal lens opacity. The third case is a 12-year-old with a history of familial exudative vitreoretinopathy and peripapillary choroidal neovascular membrane found to have a peripheral vitreal stalk in the right eye. These cases demonstrate a rare form of PFV with primarily peripheral remnants. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e83-e88.].

Lethal persistent pulmonary hypertension of the newborn in Bohring-Opitz syndrome.

Bohring-Opitz syndrome (BOS) is a rare disease with a number of characteristic features, including hypertelorism, prominent metopic suture, exophthalmos, cleft palate, abnormal posture, and developmental retardation. Here, we report a BOS patient presenting with lethal persistent pulmonary hypertension of the newborn (PPHN) and inspiratory respiratory failure. The female infant was treated with nitric oxide and vasodilator, which did not improve her condition. The inspiratory respiratory failure required management with deep sedation. She died on postnatal day 60 due to progressed heart failure. Whole exome sequencing revealed de novo mutation in the ASXL1 gene, c.1934dupG, p.Gly646TrpfsTer12.