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.

Patent ductus arteriosus in preterm infants: is early transcatheter closure a paradigm shift?

The optimal management approach of the patent ductus arteriosus (PDA) in premature infants remains uncertain owing the lack of evidence for long-term benefits and the limited analyses of the complications of medical and surgical interventions to date. In recent years, devices suitable to plug the PDA of premature infants (including extremely low birthweight, <1000 g) have become available and several trials have demonstrated successful and safe transcatheter PDA closure (TCPC) in this population. Whether TCPC represents a paradigm shift in PDA management that will result in improved short- and long-term outcomes, less bronchopulmonary dysplasia, improved neurodevelopment, or better long term renal function remains to be seen. Careful rigorous study of the potential benefits of TCPC in this highly vulnerable population in the context of well-designed adequately powered trials is needed prior to widespread adoption of this approach.

Apnea, bradycardia and desaturation spells in premature infants: impact of a protocol for the duration of 'spell-free' observation on interprovider variability and readmission rates.

OBJECTIVE: To study the impact of implementing a protocol to standardize the duration of observation in preterm infants with apnea/bradycardia/desaturation spells before hospital discharge on length of stay (LOS) and readmission rates. STUDY DESIGN: A protocol to standardize the duration of in-hospital observation for preterm infants with apnea, bradycardia and desaturation spells who were otherwise ready for discharge was implemented in December 2013. We evaluated the impact of this protocol on the LOS and readmission rates of very low birth weight infants (VLBW). Data on readmission for apnea and an apparent life-threatening event (ALTE) within 30 days of discharge were collected. The pre-implementation epoch (2011 to 2013) was compared to the post-implementation period (2014 to 2016). RESULTS: There were 426 and 368 VLBW discharges before and after initiation of the protocol during 2011 to 2013 and 2014 to 2016, respectively. The LOS did not change with protocol implementation (66±42 vs 64±42 days before and after implementation of the protocol, respectively). Interprovider variability on the duration of observation for apneic spells (F-8.8, P=0.04) and bradycardia spells (F-17.4, P<0.001) decreased after implementation of the protocol. The readmission rate for apnea/ALTE after the protocol decreased from 12.1 to 3.4% (P=0.01). CONCLUSION: Implementing an institutional protocol for VLBW infants to determine the duration of apnea/bradycardia/ desaturation spell-free observation period as recommended by the American Academy of Pediatrics clinical report did not prolong the LOS but effectively reduced interprovider variability and readmission rates.

Unexpected source of latex sensitization in a neonatal intensive care unit.

We report a term infant with gastroschisis who presented with a systemic allergic reaction at a specific time of each day coinciding with infusion from a new preparation of total parenteral nutrition and intravenous lipid emulsion. The source of latex was traced to the rubber stopper of the lipid emulsion. We present this case to highlight the possibility of allergy from this unexpected source in a neonate.

Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis.

OBJECTIVE: To evaluate the prevalence of hereditary prothrombotic mutations, and their effect on the incidence and severity of umbilical arterial or venous catheter (UAC or UVC)-associated thrombosis. STUDY DESIGN: All neonates with a UAC or UVC were studied prospectively for the presence, severity and timing of thrombosis with duplex Doppler ultrasound scan. Genetic testing for factor V Leiden (FVL), prothrombin mutation (PTm) and methylene-tetrahydrofolate reductase (MTHFR) mutations was performed using PCR and restriction fragment length polymorphism assays. RESULT: Umbilical catheter (UC)-associated thrombosis developed in 16/53 (31%) neonates; 23% of UACs and 22% of UVCs were associated with thrombosis. The prevalence of a significant prothrombotic mutation was present in 10/51 (20%) of infants: FVL (8%), MTHFR667 homozygosity (10%), MTHFR1298 homozygosity (2%) and PTm (0%). There was no increase in the risk of UC-associated thrombus in patients carrying these prothrombotic mutations; our study had the power to detect a 2.5-fold increased risk of thrombosis for any of these significant mutations. In addition, MTHFR667 heterozygosity was found in 41% of infants and MTHFR1298 heterozygosity in 52% and also were not associated with increased risk of UC-associated thrombus. The risk of MTHFR double heterozygosity (db het) was 14%, the risk of a significant or db het was 17/51 (33%) and the risk of any mutation was 90%. CONCLUSION: Prothrombotic genetic mutations are common in our Neonatal Intensive Care Unit population but do not appear to increase the risk of UC-associated thrombosis.

Characteristics of pulmonary hypertension in preterm neonates.

OBJECTIVE: Characteristics of preterm infants who develop pulmonary hypertension (PHT) and their response to inhaled nitric oxide (iNO) are not well described. Our objective was to identify risk factors for PHT in infants <37 weeks gestational age (GA) and to evaluate their response to iNO. STUDY DESIGN: A retrospective chart review was conducted in infants <37 weeks GA born from July/2000 to October/2005 who had an echocardiographic diagnosis of PHT in the first 4 weeks of life. A comparison non-PHT group was generated matched for GA and birth date. Data on prenatal and postnatal characteristics, response to iNO and mortality were collected. RESULTS: Low Apgar scores, preterm premature rupture of membranes, oligohydramnios, pulmonary hypoplasia and sepsis were independently predictive of PHT. Mortality was significantly higher in the PHT group (26.2% versus 4.1%; P<0.0001) compared to the control group. Low birth weight, severe intraventricular hemorrhage and male sex were significantly associated with death in infants with PHT. Thirty-seven percent (23/61) of infants with PHT were treated with inhaled NO. Infants < 29-week GA had poor response to iNO and the response to iNO increased with GA (P<0.02). CONCLUSIONS: Low Apgar scores, oligohydramnios and pulmonary hypoplasia are associated with the development of PHT in premature infants. The percentage of infants responding to iNO increases with advancing GA.

Placental transfusion: a review.

Recently there have been a number of studies and presentations on the importance of providing a placental transfusion to the newborn. Early cord clamping is an avoidable, unphysiologic intervention that prevents the natural process of placental transfusion. However, placental transfusion, although simple in concept, is affected by multiple factors, is not always straightforward to implement, and can be performed using different methods, making this basic procedure important to discuss. Here, we review three placental transfusion techniques: delayed cord clamping, intact umbilical cord milking and cut-umbilical cord milking, and the evidence in term and preterm newborns supporting this practice. We will also review several factors that influence placental transfusion, and discuss perceived risks versus benefits of this procedure. Finally, we will provide key straightforward concepts and implementation strategies to ensure that placental-to-newborn transfusion can become routine practice at any institution.

Permission form synopses to improve parents' understanding of research: a randomized trial.

OBJECTIVE: We hypothesized that, among parents of potential neonatal research subjects, an accompanying cover sheet added to the permission form (intervention) would increase understanding of the research, when compared to a standard form (control). STUDY DESIGN: This pilot study enrolled parents approached for one of two index studies: one randomized trial and one observational study. A one-page cover sheet described critical study information. Families were randomized 1:1 to receive the cover sheet or not. Objective and subjective understanding and satisfaction were measured. RESULTS: Thirty-two parents completed all measures (17 control, 15 intervention). There were no differences in comprehension score (16.8±5.7 vs 16.3±3.5), subjective understanding (median 6 vs 6.5), or overall satisfaction with consent (median 7 vs 6.5) between control and intervention groups (all P>0.50). CONCLUSION: A simplified permission form cover sheet had no effect on parents' understanding of studies for which their newborns were being recruited.

Evaluation of critical congenital heart defects screening using pulse oximetry in the neonatal intensive care unit.

OBJECTIVE: To evaluate the implementation of early screening for critical congenital heart defects (CCHDs) in the neonatal intensive care unit (NICU) and potential exclusion of sub-populations from universal screening. STUDY DESIGN: Prospective evaluation of CCHD screening at multiple time intervals was conducted in 21 NICUs across five states (n=4556 infants). RESULTS: Of the 4120 infants with complete screens, 92% did not have prenatal CHD diagnosis or echocardiography before screening, 72% were not receiving oxygen at 24 to 48 h and 56% were born ⩾2500 g. Thirty-seven infants failed screening (0.9%); none with an unsuspected CCHD. False positive rates were low for infants not receiving oxygen (0.5%) and those screened after weaning (0.6%), yet higher among infants born at <28 weeks (3.8%). Unnecessary echocardiograms were minimal (0.2%). CONCLUSION: Given the majority of NICU infants were ⩾2500 g, not on oxygen and not preidentified for CCHD, systematic screening at 24 to 48 h may be of benefit for early detection of CCHD with minimal burden.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

White blood cell left shift in a neonate: a case of mistaken identity.

We present a full-term male infant who presented with tachypnea and an increased band count on his complete blood count (CBC) with an immature to total neutrophil (I:T) ratio of 0.6 raising suspicion of early onset sepsis. A blood culture was drawn and he was started on appropriate antibiotics. The patient's clinical condition rapidly improved; however, the white cell count 'left shift' persisted. When a detailed family history was obtained, it was discovered that the father, paternal uncle and the grandfather had been diagnosed with Pelger-Huet anomaly (PHA). As the urine, blood and CSF cultures were all negative in this now well-appearing infant, the left shift on the CBC was believed to be due to inheritance of the PHA. We present this case to emphasize that even in this age of sophisticated laboratory evaluation, a good clinical history, including family history, and clinical evaluation, are essential for accurate diagnosis.

The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy.

Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes.

Considerations in the management of hypoxemic respiratory failure and persistent pulmonary hypertension in term and late preterm neonates.

Recent advances in our understanding of neonatal pulmonary circulation and the underlying pathophysiology of hypoxemic respiratory failure (HRF)/persistent pulmonary hypertension of the newborn (PPHN) have resulted in more effective management strategies. Results from animal studies demonstrate that low alveolar oxygen tension (PAO2) causes hypoxic pulmonary vasoconstriction, whereas an increase in oxygen tension to normoxic levels (preductal arterial partial pressure of oxygen (PaO2) between 60 and 80 mm Hg and/or preductal peripheral capillary oxygen saturation between 90% and 97%) results in effective pulmonary vasodilation. Hyperoxia (preductal PaO2 >80 mm Hg) does not cause further pulmonary vasodilation, and oxygen toxicity may occur when high concentrations of inspired oxygen are used. It is therefore important to avoid both hypoxemia and hyperoxemia in the management of PPHN. In addition to oxygen supplementation, therapeutic strategies used to manage HRF/PPHN in term and late preterm neonates may include lung recruitment with optimal mean airway pressure and surfactant, inhaled and intravenous vasodilators and 'inodilators'. Clinical evidence suggests that administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of HRF and duration of hospital stay. Milrinone may be beneficial as an inodilator and may have specific benefits following prolonged exposure to iNO plus oxygen owing to inhibition of phosphodiesterase (PDE)-3A. Additionally, sildenafil, and, in selected cases, hydrocortisone may be appropriate options after hyperoxia and oxidative stress owing to their effects on PDE-5 activity and expression. Continued investigation into these and other interventions is needed to optimize treatment and improve outcomes.

Does measurement of four-limb blood pressures at birth improve detection of aortic arch anomalies?

OBJECTIVE: To determine normal four-extremity blood pressure (BP) in the neonatal intensive care unit (NICU) at birth and the utility of upper (UE) and lower extremity (LE) BP difference to screen for coarctation of the aorta (Co-A) and interrupted the aortic arch (IAA). STUDY DESIGN: Retrospective study of BP at birth (n=866), and case-control study of Co-A/IAA infants and matched controls (1:2). RESULT: Although BP increased with gestational age (R(2)=0.3, P<0.0001), the pressure gradient between UE and LE did not change with gestation (P=0.68). Forty-six cases of Co-A/IAA were identified, with 92 controls. Pressure gradient was significantly higher in patients with Co-A/IAA (7.6±14.8 versus 0.4±10 mm Hg, P=0.004). However, there was overlap between cases and controls resulting in low sensitivity (41.3% with ⩾10 mm Hg gradient cutoff). CONCLUSION: Evaluation of UE-LE BP gradient at birth is a poor screening test for Co-A/IAA with low sensitivity. Repeating four-limb BP after ductal closure at 24 to 48 h along with SpO2 screening for critical congenital heart disease may increase sensitivity.

Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.

Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.

Critical congenital heart disease screening by pulse oximetry in a neonatal intensive care unit.

OBJECTIVE: Critical congenital heart disease (CCHD) screening is effective in asymptomatic late preterm and term newborn infants with a low false-positive rate (0.035%). (1) To compare 2817 neonatal intensive care unit (NICU) discharges before and after implementation of CCHD screening; and (2) to evaluate CCHD screening at <35 weeks gestation. STUDY DESIGN: Collection of results of CCHD screening including pre- and postductal pulse oximetry oxygen saturation (SpO2) values. RESULT: During the pre-CCHD screen period, 1247 infants were discharged from the NICU and one case of CCHD was missed. After 1 March 2012, 1508 CCHD screens were performed among 1570 discharges and no CCHDs were missed. The pre- and postductal SpO2 values were 98.8 ± 1.4% and 99 ± 1.3%, respectively, in preterm and 98.9 ± 1.3% and 98.9 ± 1.4%, respectively, in term infants. Ten infants had false-positive screens (10/1508 = 0.66%). CONCLUSION: Performing universal screening in the NICU is feasible but is associated with a higher false-positive rate compared with asymptomatic newborn infants.

Oxygen targeting in preterm infants: a physiological interpretation.

Randomized controlled trials evaluating low-target oxygen saturation (SpO2:85% to 89%) vs high-target SpO2 (91% to 95%) have shown variable results regarding mortality and morbidity in extremely preterm infants. Because of the variation inherent to the accuracy of pulse oximeters, the unspecified location of probe placement, the intrinsic relationship between SpO2 and arterial oxygen saturation (SaO2) and between SaO2 and partial pressure of oxygen (PaO2) (differences in oxygen dissociation curves for fetal and adult hemoglobin), the two comparison groups could have been more similar than dissimilar. The SpO2 values were in the target range for a shorter period of time than intended due to practical and methodological constraints. So the studies did not truly compare 'target SpO2 ranges'. In spite of this overlap, some of the studies did find significant differences in mortality prior to discharge, necrotizing enterocolitis and severe retinopathy of prematurity. These differences could potentially be secondary to time spent beyond the target range (SpO2 <85 or >95%) and could be avoided with an intermediate but wider target SpO2 range (87% to 93%). In conclusion, significant uncertainty persists about the desired target range of SpO2 in extremely preterm infants. Further studies should focus on studying newer methods of assessing oxygenation and strategies to limit hypoxemia (<85% SpO2) and hyperoxemia (>95% SpO2).

Pulmonary vascular biology during neonatal transition.

Although the normal pulmonary vascular transition at birth takes place quickly in the delivery room, it has its basis in the complex structural and biochemical development of the lung. It is not surprising that this process can be easily disrupted by factors such as prematurity, intrauterine hypoxia, and parenchymal lung disease. The stimuli that initiate and maintain the transition are only beginning to be understood. Understanding the normal structure and function of the neonatal lung provides the foundation that will enable clinicians to enhance resuscitation to accomplish a normal transition in the delivery room.