Effective ventilation of the lungs is essential in mediating pulmonary vasodilation at birth to allow effective gas exchange and an increase in systemic oxygenation. Unsuccessful transition prevents the increase in pulmonary blood flow after birth resulting in hypoxemia and persistent pulmonary hypertension of the newborn (PPHN). Management of neonates with PPHN includes ventilation of the lungs with supplemental oxygen to correct hypoxemia. Optimal oxygenation should meet oxygen demand to the tissues and avoid hypoxic pulmonary vasoconstriction (HPV) while preventing oxidative stress. The optimal target for oxygenation in PPHN is not known. Animal models have demonstrated that PaO₂<45 mmHg exacerbates HPV. However, there are no practical methods of assessing oxygen levels associated with oxidant stress. Oxidant stress can be due to free radical generation from underlying lung disease or from free radicals generated by supplemental oxygen. Free radicals act on the nitric oxide pathway reducing cGMP and promoting pulmonary vasoconstriction. Antioxidant therapy improves systemic oxygenation in an animal model of PPHN but there are no clinical trials to support such therapy. Targeting preductal SpO₂ between 90 and 97% and PaO₂ at 50-80 mmHg appears prudent in PPHN but clinical trials to support this practice are lacking. Preterm infants with PPHN present unique challenges due to lack of antioxidant defenses and functional and structural immaturity of the lungs. This review highlights the need for additional studies to mitigate the impact of oxidative stress in the lung and pulmonary vasculature in PPHN.

Background

Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.

Aim

To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms.

Results

PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB.

Conclusion

Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

The regionalization of pediatric services has resulted in differential access to care, sometimes creating barriers to those living in underserved, rural communities. These disparities in access contribute to inferior healthcare outcomes among infants and children. We review the medical literature on telemedicine and its use to improve access and the quality of care provided to pediatric patients with otherwise limited access to pediatric subspecialty care. We review the use of telemedicine for the provision of pediatric subspecialty consultations in the settings of ambulatory care, acute and inpatient care, and perinatal and newborn care. Studies demonstrate the feasibility and efficiencies gained with models of care that use telemedicine. By providing pediatric subspecialty care in more convenient settings such as local primary care offices and community hospitals, pediatric patients are more likely to receive care that adheres to evidence-based guidelines. In many cases, telemedicine can significantly improve provider, patient, and family satisfaction, increase measures of quality of care and patient safety, and reduce overall costs of care. Models of care that use telemedicine have the potential to address pediatric specialists' geographic misdistribution and address disparities in the quality of care delivered to children in underserved communities.

Objectives

Therapeutic hypothermia is standard of care in management of moderate/severe hypoxic-ischemic encephalopathy. Persistent pulmonary hypertension of the newborn is associated with hypoxic-ischemic encephalopathy and is exacerbated by hypoxemia and hypercarbia. Gas exchange is assessed by arterial blood gas analysis (with/without correction for body temperature), pulse oximetry, and end-tidal CO2.

Design

A retrospective chart review.

Settings

Regional perinatal center in Western New York.

Patients

Fifty-eight ventilated neonates with indwelling arterial catheter on therapeutic hypothermia.

Intervention

None.

Measurement and main results

We compared pulse oximetry, PaO2, end-tidal CO2, and PaCO2 during hypothermia and normothermia in neonates with hypoxic-ischemic encephalopathy using 1,240 arterial blood gases with simultaneously documented pulse oximetry. During hypothermia, pulse oximetry 92-98% was associated with significantly lower temperature-corrected PaO2 (51 mmHg; interquartile range, 43-51) compared with normothermia (71 mmHg; interquartile range, 61-85). Throughout the range of pulse oximetry values, geometric mean PaO2 was about 23% (95% CI, 19-27%) lower during hypothermia compared with normothermia. In contrast, end-tidal CO2 accurately assessed temperature-corrected PaCO2 during normothermia and hypothermia.

Conclusions

Hypothermia shifts oxygen-hemoglobin dissociation curve to the left resulting in lower PaO2 for pulse oximetry. Monitoring oxygenation with arterial blood gas uncorrected for body temperature and pulse oximetry may underestimate hypoxemia in hypoxic-ischemic encephalopathy infants during whole-body hypothermia, while end-tidal CO2 reliably correlates with temperature-corrected PaCO2.

Phosphodiesterase-5 (PDE5) is the primary phosphodiesterase in the pulmonary vasculature. It degrades cyclic guanosine monophosphate (cGMP) and inhibits cGMP-mediated vasorelaxation. We previously reported that hydrocortisone treatment decreased hyperoxia-induced PDE5 activity and markers of oxidative stress in lambs with persistent pulmonary hypertension of the newborn (PPHN) ventilated with 100% O2. The objective of our study was to determine the molecular mechanism by which hydrocortisone downregulates PDE5 and oxidative stress in fetal pulmonary artery smooth muscle cells (FPASMCs) from PPHN lambs. PPHN FPASMC were incubated for 24 hours in either 21% or 95% O2. Some cells were treated with 100 nM hydrocortisone and/or ±1 μM helenalin, an inhibitor of nuclear factor κ B (NFκB), a redox-sensitive transcription factor. Exposure to hyperoxia led to increased PDE5 activity, oxidative stress, and NFκB activity. Pretreatment of PPHN FPASMC with hydrocortisone normalized PDE5 activity, decreased cytosolic oxidative stress, increased expression of extracellular superoxide dismutase and NFκB inhibitory protein, and decreased NFκB activity. Similarly, treatment with NFκB inhibitor, helenalin, decreased PDE5 activity. These data suggest that hyperoxia activates NFκB, which in turn induces PDE5 activity in PPHN FPASMC, whereas treatment with hydrocortisone attenuates these changes by blocking reactive oxygen species-induced NFκB activity.

In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway. In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions. Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62.9 ± 5.9% vs. 33.3 ± 5.7% maximal oxidation), as measured by the intracellular redox sensor roGFP. Cyclic stretch also increased sGCβ protein expression (2.5 ± 0.9-fold), sGC activity (1.5 ± 0.2-fold) and cGMP levels (1.8 ± 0.2-fold), as well as iNOS mRNA and protein expression (3.0 ± 0.9 and 2.6 ± 0.7-fold, respectively) relative to control cells. An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity. Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls. In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs. The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress. A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension.

BACKGROUND: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW). METHODS: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). RESULTS: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). CONCLUSION: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

Background

Persistent pulmonary hypertension in the newborn remains a syndrome with high mortality. Knowledge of changes in myocardial architecture in the setting of heart failure in persistent pulmonary hypertension is lacking, and could aid in the explanation of the prevailing high mortality.

Methods

Persistent pulmonary hypertension was induced by antenatal ligation of the arterial duct in six ovine fetuses. The hearts were compared ex vivo with five matched control hearts, using diffusion tensor imaging to provide the overall anatomical arrangement, and assessment of the angulations and course of the cardiomyocytes. Fibrosis was assessed with histology.

Results

We found an overall increase in heart size in pulmonary hypertension, with myocardial thickening confined to the interventricular septum. An increase of 3.5° in angulation of myocyte aggregations was found in hypertensive hearts. In addition, we observed a 2.2% increase in collagen content in the right ventricular free wall. Finally, we found a previously undescribed subepicardial layer of strictly longitudinally oriented cardiomyocytes confined to the right ventricle in all hearts.

Conclusion

Myocardial fibrosis and possibly changes in angulations of myocytes seem to play a part in the etiology of persistent pulmonary hypertension. Moreover, a new anatomical arrangement of right ventricular mural architecture is described.

Background

Postnatal growth restriction (PNGR) in premature infants increases risk of pulmonary hypertension (PH). In a rodent model, PNGR causes PH, while combining PNGR and hyperoxia increases PH severity. We hypothesized that PNGR causes intestinal dysbiosis and that treatment with a probiotic attenuates PNGR-associated PH.

Method

Pups were randomized at birth to room air or 75% oxygen (hyperoxia), to normal milk intake (10 pups/dam) or PNGR (17 pups/dam), and to probiotic Lactobacillus reuteri DSM 17938 or phosphate-buffered saline. After 14 days, PH was assessed by echocardiography and right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricle + septal weight). The small bowel and cecum were analyzed by high-throughput 16S ribosomal RNA gene sequencing.

Results

PNGR with or without hyperoxia (but not hyperoxia alone) altered the microbiota of the distal small bowel and cecum. Treatment with DSM 17938 attenuated PH and RVH in pups with PNGR, but not hyperoxia alone. DSM 17938 treatment decreased α-diversity. The intestinal microbiota differed based on oxygen exposure, litter size, and probiotic treatment.

Conclusion

PNGR causes intestinal dysbiosis and PH. Treatment with DSM 17938 prevents PNGR-associated RVH and PH. Changes in the developing intestine and intestinal microbiota impact the developing lung vasculature and RV.

Optimal oxygen saturation as measured by pulse oximetry (Sp_O2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the Sp_O2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO₂) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (Fi_O2) = 1.0 irrespective of Sp_O2, and three groups had Fi_O2 titrated to keep preductal Sp_O2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% Sp_O2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO₂ but were exposed to higher Fi_O2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO₂ through the first 6 hours are higher with target Sp_O2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower Fi_O2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% Sp_O2 target range in term infants with PPHN are warranted.