Residual pulmonary hypertension in children after treatment with inhaled nitric oxide: a follow-up study regarding cardiopulmonary and neurological symptoms

Inhaled nitric oxide is a potent vasodilator in acute severe pulmonary hypertension and is increasingly used as rescue treatment in intensive care algorithms aiming at reducing severe hypoxaemia in neonates and children. Although the immediate effects may seem impressive, longterm outcome regarding residual pulmonary hypertension and other sequelae has been studied in only a very few patients. The aim of the present study was to evaluate residual pulmonary hypertension, cardiopulmonary or neurological symptoms in children after treatment with inhaled nitric oxide in severely hypoxaemic and/or pulmonary hypertensive mechanically ventilated children. The study was performed in four paediatric intensive care units in university hospitals in Sweden, Norway and Australia. Patients who had received inhaled nitric oxide as part of their intensive care treatment for severe hypoxaemia and/or pulmonary hypertension, and in whom 6 mo had elapsed since treatment, were included for evaluation. Thus 36 paediatric or neonatal patients were examined for circulatory, respiratory or neurological disorders with clinical examination, echocardiography, chest X-ray and a capillary blood sample. Four patients with congenital heart disease had residual pulmonary hypertension. Nine patients were receiving bronchodilators. Sixteen patients had minor (n = 15) or moderate (n = 1) changes on a chest X-ray. One patient had a possible delay in psychomotor development. Conclusions: In spite of the severity of their primary illness, we found that the overwhelming majority of the surviving children were asymptomatic and doing well. The few residual circulatory and respiratory symptoms could be related to the initial condition.     

Intravenous magnesium sulphate vs. inhaled nitric oxide for moderate, persistent pulmonary hypertension of the newborn. A Multicentre, retrospective study

We have compared intravenous magnesium sulphate vs. inhaled nitric oxide in the therapy of moderate persistent pulmonary hypertension of the neonate. A retrospective collection of clinical data from 58 neonates was carried out in six neonatal intensive care units of Southern Italy sharing the same operational protocols. In our setting, both drugs were effective in treating moderate persistent pulmonary hypertension of the neonate but nitric oxide (NO) treatment resulted in much faster amelioration of oxygenation index, taken as a marker of the underlying condition. No significant difference was recorded in immediate or long-term complications. We conclude that, wherever NO facilities are not readily available, magnesium sulphate is a safe and cheaper alternative for first-line treatment of moderate persistent pulmonary hypertension of the neonate.     

Inhaled Iloprost as a Rescue Therapy for Transposition of the Great Arteries With Persistent Pulmonary Hypertension of the Newborn

Transposition of the great arteries (TGA) in the newborn combined with persistent pulmonary hypertension was reported previously to occur in 3–12 % of full-term neonates with TGA. Right-to-left shunting at the ductal level causes severe hypoxemia despite prostaglandin infusion and balloon atrial septostomy. Although the introduction of inhaled nitric oxide (iNO) has improved the prognosis, this condition still is associated with high preoperative mortality. This report describes the case of a newborn with TGA and persistent pulmonary hypertension, which was managed successfully with oral sildenafil, iNO, and inhaled iloprost during life-threatening acute pulmonary hypertension, thus preventing the use of extracorporeal membrane oxygenation.     

Inhalation of nitric oxide - dependence: case report

OBJECTIVE: Describe the hemodynamic response with rebound of pulmonary hypertension after withdrawal of inhaled nitric oxide (NO) in a pediatric patient with acute respiratory distress syndrome (ARDS). METHODS: Case report of a child with ARDS and pulmonary hypertension evaluated through ecocardiografic with dopller, receiving inhaled NO for a period of 21 days. RESULTS: There was a decrease of the pulmonary artery pressure (PAP) from 52 mmHg to 44 mmHg after the initial titulation of NO inhalation dose. After the withdrawal of inhaled NO an elevation of PAP was observed (55 mmHg). It was necessary to reinstall the inhaled NO to obtain a more appropriate value (34 mmHg). A new attempt of interruption of the inhaled NO after prolonged inhalation (20 days) resulted in a new clinic worsening and increase of PAP, with the indication to reinstall the inhaled NO. In the 24th day of permanence in the intensive care unit the patient died due to multiple organ dysfunction. CONCLUSIONS: The possibility of pulmonary hypertension rebound after withdrawal of inhaled NO is a complication that may have important clinical implications for patients who need a prolonged treatment with NO. This case report emphasizes these implications.     

Life-threatening effects of discontinuing inhaled nitric oxide in children

We treated 40 children, aged between 15 d and 17 y, diagnosed with acute respiratory distress syndrome and/ or pulmonary hypertension, with inhaled nitric oxide. The most frequent underlying diagnosis associated with ARDS were bronchopneumonia (eight), cardiac surgery (five), and sepsis (three). Pulmonary hypertension was secondary to cardiomyopathy in 2 patients and occurred in the postoperative period of cardiac surgery in 17 patients–the most frequent were ventricular septal defect (5), transposition of great arteries (4), and atrioventricular septal defect (3). In 11 patients, sudden discontinuation of nitric oxide induced a decrease in oxygenation associated in some of the patients with an increase in pulmonary artery pressure. In two patients discontinuation of nitric oxide induced severe pulmonary hypertension, extreme bradycardia and hypoxaemia, which required cardiopulmonary resuscitation. When exogenous nitric oxide is abruptly interrupted, hypoxaemia and pulmonary hypertension are found in some patients, due to a decrease in the nitric oxide concentration in the pulmonary circulation. This may be caused by the exogenous nitric oxide administration that may have inhibited endogenous production. We recommend making a progressive withdrawal of inhaled nitric oxide to avoid the side effects observed in the sudden discontinuation.     

Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide

We report the use of inhaled prostacyclin (PGI(2)) in 4 neonates with persistent pulmonary hypertension and hypoxemia refractory to inhaled nitric oxide. Oxygenation rapidly improved after inhalation of PGI(2) in all infants. The condition of one infant subsequently deteriorated, and alveolar capillary dysplasia was found at autopsy. The surviving infants were discharged with normal oxygen saturations in room air.     

Recent developments in inhaled nitric oxide therapy of the newborn

Inhaled nitric oxide therapy improves oxygenation and reduces the need for extracorporeal life support in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension of the newborn. Previous studies demonstrated that the efficacy of inhaled nitric oxide therapy is related to the underlying disease associated with persistent pulmonary hypertension and that lung recruitment strategies augment the response to this inhalational vasodilator. This review of recent studies evaluates new insight into important questions regarding the optimal dose of inhaled nitric oxide, potential adverse effects associated with inhaled nitric oxide therapy, and the potential role of inhaled nitric oxide in the premature newborn with hypoxemic respiratory failure.     

Inhaled nitric oxide in neonatal and paediatric transport

Since the first reports of the use of inhaled nitric oxide in the early 1990s its applications have been refined to a number of specific conditions. Pre-term and term neonates benefit significantly in the improvement of oxygenation in conditions such as hypoxic respiratory failure and persistent pulmonary hypertension of the neonate and the reduction in referral rates to extra corporeal membrane oxygenation. Many neonatal units still do not have the ability to administer inhaled nitric oxide though an increasing number of neonatal units have acquired the capability to deliver inhaled nitric oxide in recent years with commercially available delivering devices. In either case if the neonate needs transfer for further management or extra corporeal membrane oxygenation the journey can be improved if inhaled nitric oxide is introduced during transport or could deteriorate if inhaled nitric oxide was discontinued during transport.Delivery of inhaled nitric oxide during transport can be technically challenging and the consequences of increased or interrupted delivery can be dangerous. The different modes of transport either by road or air can influence the method of delivery.We describe our method of delivering inhaled nitric oxide during the retrievals we undertake and how this changes depending upon the type of journey performed. We also suggest guidelines for its use during transport and outline the precautions we take to ensure safety of patient and carers during transport.     

Adjunct pharmacotherapy in acute lung disease in children

Mechanical ventilation, while accepted as standard therapy for critically ill infants and children with respiratory failure, has significant morbidity and mortality. While recent emphasis on low tidal volume ventilation and low airway pressures may result in decreased lung stretch and limit lung disease, adjunctive therapies have been tried to reduce the stressors of mechanical ventilation. Therapies included inhaled nitric oxide, heliox and surfactant. There are compelling physiological reasons why these drugs may be of benefit in these patients. However, our understanding of their role is hindered by studies with small numbers of patients and its use in diseases with varied pulmonary pathology. Studies have shown potential for benefit of inhaled nitric oxide in newborns with hypoxemic respiratory failure and pulmonary hypertension, surfactant in respiratory distress syndrome in preterm neonates and heliox in severe upper airway obstruction. However, the use in other respiratory conditions has led to mixed results and hence paucity of firm recommendations.     

Inhaled nitric oxide therapy in premature newborns

PURPOSE OF REVIEW: Inhaled nitric oxide therapy reduces the need for extracorporeal membrane oxygenation in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension, and is now a standard of care for this population. There is also considerable interest, however, in the potential role of inhaled nitric oxide in premature newborns with hypoxemic respiratory failure. The purpose of this review is to summarize the results of clinical trials of inhaled nitric oxide in premature newborns, with particular emphasis on studies published in the last 12 months. RECENT FINDINGS: Several trials of inhaled nitric oxide in premature newborns with respiratory failure have been published in the last year. Interpretation of the findings is complicated by differences in the severity of illness of the study populations, the trial designs, and relevant outcome measures recorded. SUMMARY: Trials of inhaled nitric oxide in premature newborns have yielded conflicting results to date, and the role of inhaled nitric oxide therapy in this population remains controversial. The largest trials of inhaled nitric oxide therapy in premature newborns have completed enrollment but have yet to be published. The results of these ongoing trials will help clarify the potential risks and benefits of inhaled nitric oxide therapy in the premature newborn.     

Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure

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

Neonatal acute respiratory failure

Acute respiratory failure is the most common problem seen in the preterm and term infants admitted to neonatal intensive care units. In preterm infants, the most common cause of acute respiratory failure is respiratory distress syndrome caused by surfactant deficiency. Acute respiratory failure in term and near term infants is usually a result of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn. The response to various methods of treatment may vary, depending on the severity of respiratory failure and the cause of the acute respiratory failure. We reviewed the evidence for efficacy and current utilization of newer treatment modalities, including exogenous surfactant administration, high frequency ventilation, inhaled nitric oxide therapy, antenatal steroids for the prevention of respiratory distress syndrome, and use of postnatal steroids for the prevention of chronic lung disease.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10–20 ppm), short-duration (1–2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10-20 ppm), short-duration (1-2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Congenital chylothorax and pulmonary hypertension complicated with heart failure and hepatopathy

Respiratory difficulty resulting from congenital chylothorax is usually relieved by postnatal thoracentesis, closed chest drainage, and oxygen therapy. However, early occurrence of congenital chylothorax or accumulation of a large amount of chylous fluid sometimes leads to pulmonary hypoplasia or persistent pulmonary hypertension of the newborn, which requires further customized mechanical ventilatory support. In these cases, conventional mechanical ventilation is primarily used during initial treatment and is later replaced by high‐frequency ventilation, but the advantages of inhaled nitric oxide treatment have rarely been described. This case suggests the benefits of inhaled nitric oxide in patients with congenital chylothorax, even when mechanical ventilation cannot improve respiratory distress because of severe pulmonary hypertension of the newborn leading to right cardiac dysfunction and possibly cholestasis.     

Persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide and prostacyclin, responsive to neuromuscular blockade

Neonatal pulmonary hypertension refractory to high frequency ventilation (HFOV) and inhaled nitric oxide (iNO) is an occasional occurrence. We report a full-term neonate with severe pulmonary hypertension unresponsive to the treatment with HFOV and iNO, later associated with prostacyclin, who rapidly improved after the addition of vecuronium, a neuromuscular blocker.     

Endothelin-A receptor blockade and inhaled nitric oxide in a porcine model of meconium aspiration syndrome

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.     

Abnormal vascular tone in infants and children with lung hypoplasia: Findings from cardiac catheterization and the response to chronic therapy.

OBJECTIVE: We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients). DESIGN: Case series. SETTING: Tertiary academic center. PATIENTS: Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3). INTERVENTIONS: Catheterization and pulmonary vasodilator therapy. MEASUREMENTS AND MAIN RESULTS: Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide. CONCLUSIONS: Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.     

Reversal of Pulmonary Hypertension Associated with Plexiform Lesions in Congenital Heart Disease: A Case Report

We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.     

Monitoring cardiovascular function in infants with chronic lung disease of prematurity

In addition to persistent airways disease, survivors of premature birth with chronic lung disease are at risk of cardiovascular sequelae, including pulmonary hypertension, systemic hypertension, left ventricular hypertrophy, and exercise intolerance. The major treatment of pulmonary hypertension is supplemental oxygen, but drugs such as calcium channel blockers may also be required. The use of inhaled nitric oxide for its long term management is being investigated