Management of pulmonary hypertension in infants with congenital diaphragmatic hernia.

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.

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.

Is age at initiation of extracorporeal life support associated with mortality and intraventricular hemorrhage in neonates with respiratory failure?

OBJECTIVE: To describe differences in characteristics among neonates treated with extracorporeal life support (ECLS) in the first week of life for respiratory failure compared with later in the neonatal period and to assess risk factors for central nervous system (CNS) hemorrhage and mortality among the two groups. STUDY DESIGN: Review of the Extracorporeal Life Support Organization registry from 2001 to 2010 of neonates ⩽30 days comparing two age groups: those ⩽7 days (Group 1) to those >7 days (Group 2) at ECLS initiation. RESULT: Among 4888 neonates, Group 1 (n=4453) had significantly lower mortality (17 vs 39%, P<0.001) but greater CNS hemorrhage (11 vs 7%, P=0.02) than Group 2 (n=453). Mortality and CNS hemorrhage improved significantly with increasing gestational age only for Group 1 patients. CNS hemorrhage occurred more frequently in Group 1 patients receiving venoarterial (VA) than with venovenous ECLS (15 vs 7%, P<0.001). In Group 1, lower birth weight and pre-ECLS pH and VA mode were independently associated with mortality. In Group 2, higher mean airway pressure was independently associated with mortality. Complications of ECLS therapy, including CNS hemorrhage and renal replacement therapy were independently associated with mortality for both groups. CONCLUSION: Neonates cannulated for ECLS after the first week of life had greater mortality despite lower CNS hemorrhage than neonates receiving ECLS earlier. Premature infants cannulated after 1 week had fewer CNS hemorrhages than premature infants treated with extracorporeal membrane oxygenation starting within the first week of life.

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation.

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.

Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation.

Prolonged infusions of 17beta-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (FI(O(2))). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low FI(O(2)) [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05] without reducing the vasodilator response to ventilation with high FI(O(2)) [change in PVR, -73 +/- 3% (CTRL) vs. -77 +/- 4%, (ICI); P = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation.

Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus.

To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO(2) (<10%), high FIO(2) (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO(2) decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO(2) may activate NOS II release at birth.

Lung volume recruitment in lambs during high-frequency oscillatory ventilation using respiratory inductive plethysmography.

Monitoring lung volume is important in the treatment of acute hypoxemic respiratory failure. However, there are no tools available for lung volume measurement to guide ventilator management during high-frequency oscillatory ventilation (HFOV) and during dynamic changes in conventional ventilation (CV). We studied the performance of a new respiratory inductive plethysmograph (RIP) with modified software. We measured Delta changes in lung volume above end-expiratory volume (V(RIP)) during HFOV and studied whether changes in V(RIP) parallel changes in mean airway pressure. Calibration of the plethysmograph was made by serial injections of a known gas volume in six term (140 d gestation) and eight preterm (125 d gestation) lambs. Linear regression analysis of the relationship between injected gas volume and V(RIP) showed strong correlation (r(2) = 0.93-1.00 term animals, r(2) = 0.86-1.00 preterm animals). The pressure volume curves from the calibration with the injected gas volumes also correlated well with the pressure volume curves extrapolated from changes in V(RIP). Lung hysteresis was clearly demonstrated with RIP after changes in mean airway pressure during HFOV and after changes in positive end-expiratory pressure during CV. We conclude that measurements of lung volume in term and preterm lambs by use of modified RIP correlate well with changes in mean airway pressure during HFOV, with static pressure volume curves and with changes in positive end-expiratory pressure during CV. We speculate that this technique may provide clinically useful information about changes in lung volume during HFOV and CV. However, evaluation of the precision and chronic stability of RIP measurements over prolonged periods will require further studies.

High-frequency oscillatory ventilation and partial liquid ventilation after acute lung injury in premature lambs with respiratory distress syndrome.

OBJECTIVE: Conventional mechanical ventilatory support (CV) contributes to lung injury in premature lambs with respiratory distress syndrome, a disease that is characterized by progressive deterioration of gas exchange and increased lung inflammation. Lung recruitment strategies, such as high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV), improve gas exchange and attenuate lung inflammation when instituted immediately after birth. However, whether these recruitment strategies are effective as rescue treatment after established lung injury is unknown. To determine the separate and combined effects of HFOV and PLV when initiated after the establishment of acute lung injury in severe respiratory distress syndrome, we studied the effects of these strategies on gas exchange and histologic signs of acute lung injury in premature lambs. DESIGN: Animals were intubated, treated with surfactant and ventilated with 1.00 FIO2 for 4 hrs. After 2 hrs, animals were either continued on CV (controls) or treated with one of three strategies: HFOV; CV + PLV; or HFOV + PLV. The response to low-dose inhaled nitric oxide (5 ppm) was measured in each group at the end of the study. SETTING: An animal laboratory affiliated with University of Colorado School of Medicine. SUBJECTS: A total of 20 premature lambs at 115-118 days of gestation (term = 147 days). MEASUREMENTS AND MAIN RESULTS: In comparison with control animals, each of the rescue therapies improved PaO2 after 1 hr of treatment. The HFOV and HFOV + PLV groups had higher PaO2 than CV + PLV or CV alone (p < .05). Mean airway pressure (Paw) was lower in the PLV groups during CV or HFOV compared with their controls (p < .05). Inhaled NO improved PaO2 in all groups; however, the increase in PaO2 was greatest in the HFOV + PLV group (p < .05). Histologic examination and myeloperoxidase assay were not different between groups. CONCLUSION: We conclude that each lung recruitment strategy improved oxygenation in premature lambs with established lung injury.

Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb.

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Developmental changes in endothelin expression and activity in the ovine fetal lung.

Mechanisms that regulate endothelin (ET) in the perinatal lung are complex and poorly understood, especially with regard to the role of ET before and after birth. We hypothesized that the ET system is developmentally regulated and that the balance of ET(A) and ET(B) receptor activity favors vasoconstriction. To test this hypothesis, we performed a series of molecular and physiological studies in the fetal lamb, newborn lamb, and adult sheep. Lung preproET-1 mRNA levels, tissue ET peptide levels, and cellular localization of ET-1 expression were determined by Northern blot analysis, peptide assay, and immunohistochemistry in distal lung tissue from fetal lambs between 70 and 140 days (term = 145 days), newborn lambs, and ewes. Lung mRNA expression for the ET(A) and ET(B) receptors was also measured at these ages. We found that preproET-1 mRNA expression increased from 113 to 130 days gestation. Whole lung ET protein content was highest at 130 days gestation but decreased before birth in the fetal lamb lung. Immunolocalization of ET-1 protein showed expression of ET-1 in the vasculature and bronchial epithelium at all gestational ages. ET(A) receptor mRNA expression and ET(B) receptor mRNA increased from 90 to 125 and 135 days gestation. To determine changes in activity of the ET(A) and ET(B) receptors, we studied the effect of selective antagonists to the ET(A) or ET(B) receptors at 120, 130, and 140 days of fetal gestation. ET(A) receptor-mediated vasoconstriction increased from 120 to 140 days, whereas blockade of the ET(B) receptor did not change basal fetal pulmonary vascular tone at any age examined. We conclude that the ET system is developmentally regulated and that the increase in ET(A) receptor gene expression correlates with the onset of the vasodilator response to ET(A) receptor blockade. Although ET(B) receptor gene expression increases during late gestation, the balance of ET receptor activity favors vasoconstriction under basal conditions. We speculate that changes in ET receptor activity play important roles in regulation of pulmonary vascular tone in the ovine fetus.

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group.

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.

Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension.

Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.

Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung.

Endothelial nitric oxide (NO) synthase (eNOS) produces NO, which contributes to vascular reactivity in the fetal lung. Pulmonary vasoreactivity develops during late gestation in the ovine fetal lung, during the period of rapid capillary and alveolar growth. Although eNOS expression peaks near birth in the fetal rat, lung capillary and distal air space development occur much later than in the fetal lamb. To determine whether lung eNOS expression in the lamb differs from the timing and pattern reported in the rat, we measured eNOS mRNA and protein by Northern and Western blot analyses and NOS activity by the arginine-to-citrulline conversion assay in lung tissue from fetal, newborn, and maternal sheep. Cellular localization of eNOS expression was determined by immunohistochemistry. eNOS mRNA, protein, and activity were detected in samples from all ages, and eNOS was expressed predominantly in the vascular endothelium. Lung eNOS mRNA expression increases from low levels at 70 days gestation to peak at 113 days and remains high for the rest of fetal life. Newborn eNOS mRNA expression does not change from fetal levels but is lower in the adult ewe. Lung eNOS protein expression in the fetus rises and peaks at 118 days gestation but decreases before birth. eNOS protein expression rises in the newborn period but is lower in the adult. Lung NOS activity also peaks at 118 days gestation in the fetus before falling in late gestation and remaining low in the newborn and adult. We conclude that the pattern of lung eNOS expression in the sheep differs from that in the rat and may reflect species-related differences in lung development. We speculate that the rise in fetal lung eNOS may contribute to the marked lung growth and angiogenesis that occurs during the same period of time.

Prolonged infusions of estradiol dilate the ovine fetal pulmonary circulation.

Factors mediating both the rapid and sustained fall in pulmonary vascular resistance (PVR) at birth are incompletely understood. Acute or prolonged estrogen treatment causes vasodilation of several vascular beds in adults. Although fetal estrogen levels rise in late gestation, their effects in the fetal pulmonary circulation have not been studied. To determine whether estrogens can cause pulmonary vasodilation in the fetus, we infused 17beta-estradiol (E2) into the left pulmonary artery (LPA) of chronically catheterized fetal lambs, measured pulmonary artery pressure and LPA blood flow, and calculated PVR. Brief E2 administration (1-, 10-, and 100-microg doses) did not change baseline pulmonary hemodynamics and failed to enhance endothelium-dependent vasodilation as assessed by the dilator response to acetylcholine. However, prolonged E2 infusion (2- 8 d) caused a 2.6-fold increase in pulmonary blood flow (73+/-6 versus 188+/-44 mL/min, baseline versus E2 treatment, p<0.05), and the response was sustained for at least several hours. Treatment with the nitric oxide synthase inhibitor nitro-L-arginine (L-NA) reversed the E2-induced fall in PVR (0.15+/-0.05 versus 0.51+/-0.15 mm Hg/mL/min; before versus after L-NA, p<0.05). Endothelial nitric oxide synthase expression and endothelin-1 content were not different in E2-responders and controls, suggesting that altered expression of these mediators did not account for the increased flow. We conclude that prolonged E2 infusion causes an unusual pattern of vasodilation in the ovine fetal lung. On the basis of these observations of exogenous E2 treatment, we speculate that endogenous E2 enhances pulmonary vasodilation at birth.

Inhaled nitric oxide: current and future uses in neonates.

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, is available for treatment of persistent pulmonary hypertension of the newborn in term and near-term neonates. iNO decreases pulmonary vascular resistance leading to diminished extrapulmonary shunt and also has a microselective effect which improves ventilation/perfusion matching. Clinical trials indicate the need for extracorporeal membrane oxygenation (ECMO) is diminished by iNO. Information suggests a 20 ppm starting dose; doses greater than 40 ppm offer no advantage. The typical duration of therapy in responders is less than one week. Several approaches to weaning have been successful. Abrupt discontinuation should be avoided. Ventilatory management remains important when parenchymal lung disease accompanies pulmonary hypertension of the newborn; HFOV used to optimize lung inflation facilitates the action of iNO. Non-ECMO centers should be able to provide iNO during transport to an ECMO center. Data suggest a possible role for iNO in preterms with hypoxemic respiratory failure and studies in this group should proceed.

Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial.

BACKGROUND: Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease. METHODS: We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age. FINDINGS: The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%). INTERPRETATION: Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury.

Congenital pulmonary venous stenosis presenting as persistent pulmonary hypertension of the newborn.

Congenital pulmonary venous stenosis (CPVS) has been previously described in older infants and children, typically manifesting as failure to thrive with congestive heart failure and subsequent respiratory deterioration. We report on 2 cases of CPVS which presented during the immediate newborn period as severe persistent pulmonary hypertension of the newborn.