Severe Persistent Pulmonary Hypertension Research Articles

Inhaled Nitric Oxide Treatment for Stabilization and Emergency Medical Transport of Critically Ill Newborns and Infants

Stabilization and transport of critically ill newborns and infants is a vital component of regionalized care. With the advent and proliferation of new therapies for the management of severe hypoxemic respiratory failure, emergency medical transport to tertiary care centers increasingly requires novel transport innovations. Inhaled nitric oxide (NO) therapy has been used in the management of severe persistent pulmonary hypertension of newborns (PPHN) and of hypoxemic respiratory failure in older pediatric patients.1-5 We report the use of inhaled NO therapy during transport in six patients with critical hypoxemia. This report describes a practical approach to stabilization and transport of critically ill newborns and infants using inhaled NO.

Endotracheal tolazoline for severe persistent pulmonary hypertension of the newborn.

The condition of a neonate with severe persistent pulmonary hypertension who became severely hypoxic and acidotic despite intensive conventional treatment improved dramatically after endotracheal administration of tolazoline. This logical mode of administration of vasodilator therapy for this condition has not been reported before. It seemed to be life saving in this case and it warrants further clinical trial.

The Effect of On-Site Extracorporeal Membrane Oxygenation on the Therapy Choice and Outcomes of Neonates With Persistent Pulmonary Hypertension

The effect of on-site extracorporeal membrane oxygenation (OS-ECMO) and selection criteria on the utilization rate of this technology is unknown. We retrospectively studied 55 neonates who were admitted to Arkansas Children's Hospital from 1985 to 1993. We compared the ECMO utilization, mortality, and morbidity rates for outborn neonates with moderate and severe persistent pulmonary hypertension (PPHN) before and after the establishment of an ECMO program with guidelines for its use at our institution. The rate of ECMO use was three times higher and the mortality rate was 13 times lower in the period after OS-ECMO compared with the period when ECMO was available only at other institutions. No differences were observed in the morbidity rates between the two periods. Physician decisions to initiate ECMO involved more than guidelines, since 37% of the increased ECMO use was not associated with use of the guidelines. Possible reasons for noncompliance with the guidelines are discussed. Neonates who had received medical therapy only and who had an oxygenation index > or = 30 and < 40 had no mortality. Our findings suggest that the need for ECMO in this group of neonates is low.

Shunts in Patients With Respiratory Distress Syndrome

In Reply.— We agree with Dr Evans that bidirectional ductal shunting is more common than net right-to-left ductal shunting in premature neonates with severe RDS and persistent pulmonary hypertension. Our conclusion that large right-to-left shunts via the ductus are common findings in these cases was not intended to exclude the presence of concomitant left-to-right shunting. In our study population the incidence of right-to-left ductal shunting at 12 and 24 hours of age was 86% and 94% in premature neonates with fatal RDS, 39% and 34% in the severe RDS group, 4% and 0% in the no/mild RDS group, and 6% and 0% in the full-term neonates without RDS.

Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide

We studied the efficacy of low-dose nitric oxide inhalation in nine consecutive patients with severe persistent pulmonary hypertension of the newborn (PPHN) who were candidates for extracorporeal membrane oxygenation (ECMO). All patients had marked hypoxemia despite aggressive ventilator management and echocardiographic evidence of pulmonary hypertension. Associated diagnoses included meconium aspiration syndrome (3 patients), sepsis (3 patients), and congenital diaphragmatic hernia (2 patients). Infants were initially treated with inhaled nitric oxide at 20 ppm for 4 hours and then at 6 ppm for 20 hours. In all infants, oxygenation promptly improved (arterial/alveolar oxygen ratio, 0.077 +/- 0.016 at baseline vs 0.193 +/- 0.030 at 4 hours; p < 0.001) without a decrease in systemic blood pressure. Sustained improvement in oxygenation was achieved in eight patients treated with inhaled nitric oxide for 24 hours at 6 ppm (arterial/alveolar oxygen ratio, 0.270 +/- 0.053 at 24 hours; p < 0.001 vs baseline). One patient with overwhelming sepsis had an initial improvement of oxygenation with nitric oxide but required ECMO for multiorgan and cardiac dysfunction. We conclude that low doses of nitric oxide cause sustained clinical improvement in severe PPHN and may reduce the need for ECMO. However, immediate availability of ECMO is important in selected cases of PPHN complicated by severe systemic hemodynamic collapse.

Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn

We studied the effects of inhaled nitric oxide (NO) in 9 newborn infants with severe persistent pulmonary hypertension (PPHN) who were candidates for extracorporeal membrane oxygenation treatment. With low doses of NO (10-20 ppm) all showed rapid improvement in oxygenation without reduction of systemic blood pressure. In 6 infants treated with inhaled NO for 24 h, clinical improvement was sustained at 6 ppm.

Hearing and Neurodevelopmental Outcome in Survivors of Persistent Pulmonary Hypertension of the Newborn

Thirty-four infants who had a diagnosis of severe persistent pulmonary hypertension of the newborn at birth (alveolar-arterial oxygen difference greater than 600) were treated without paralysis or hyperventilation to induce alkalosis. All survived. Twenty-seven of these 34 eligible infants (79%) underwent neurologic, intelligence, and audiologic testing between 10 months and 6 years of age. Children who were younger than 1 year of age at the initial hearing test were retested after they reached 2 years of age. The average IQ was within the normal range (mean = 96.23). None had sensorineural hearing loss. Severe neurologic abnormalities were seen in 4 children, 3 of whom had been severely asphyxiated at birth (determined by biochemical criteria). Mild neurologic abnormalities were observed in 5 children. Two infants had bronchopulmonary dysplasia because they required supplemental oxygen for 29 and 66 days, respectively, and had abnormal chest roentgenograms; 1 patient takes intermittent doses of albuterol (Ventolin) and neither currently requires supplemental oxygen. This study of 27 infants with severe persistent pulmonary hypertension of the newborn suggests that conservative management without induced alkalosis or respiratory paralysis is accompanied by no sensorineural hearing loss and a good neurologic outcome.

Treatment of severe persistent pulmonary hypertension of the newborn with magnesium sulphate.

Eight of nine newborn infants with severe persistent pulmonary hypertension of the newborn (PPHN), and a predicted mortality of 100%, and one infant with a predicted mortality greater than 94% based on alveolar-arterial oxygen tension difference [A-a)DO2) were treated with magnesium sulphate (MgSO4) as a life saving therapy after they failed to improve with conventional treatment. Magnesium at high serum concentrations decreases pulmonary pressures and is a muscle relaxant and sedative. Diluted MgSO4.7H2O solution (200 mg/kg) was given intravenously over 20-30 minutes. No changes in the treatment were made after MgSO4. Mean serum magnesium concentration was maintained between 2.88 and 5.67 mmol/l by continuous intravenous infusion (six infants). Baseline arterial oxygen tension (PaO2) and haemoglobin oxygen saturation had mean (SD) values of 4.66 (1.8) kPa and 60.4 (29.7)% respectively, which started to increase one hour after MgSO4 infusion, and increased significantly at six hours to 12.04 (7.07) kPa and 91.8 (10.88)% respectively. Arterial carbon dioxide tension (PaCO2) decreased and pH increased significantly after one hour compared with the baseline value. PaO2 increases are probably secondary to a decrease in pulmonary vascular resistance and pressure, decrease in a right to left shunt, better ventilation:perfusion ratio, and PaCO2 decrease and pH rise. Seven infants survived (77.8%). These results demonstrate the beneficial effect of magnesium in the management of PPHN when other accepted treatment fails, is contraindicated, or not available.

Extracorporeal Membrane Oxygenation and Conventional Medical Therapy in Neonates With Persistent Pulmonary Hypertension of the Newborn: A Prospective Randomized Study

Thirty-nine newborn infants with severe persistent pulmonary hypertension and respiratory failure who met criteria for 85% likelihood of dying were enrolled in a randomized trial in which extracorporeal membrane oxygenation (ECMO) therapy was compared with conventional medical therapy (CMT). In phase I, 4 of 10 babies in the CMT group died and 9 of 9 babies in the ECMO group survived. Randomization was halted after the fourth CMT death, as planned before initiating the study, and the next 20 babies were treated with ECMO (phase II). Of the 20, 19 survived. All three treatment groups (CMT and ECMO in phase I and ECMO, phase II) were comparable in severity of illness and mechanical ventilator support. The overall survival of ECMO-treated infants was 97% (28 of 29) compared with 60% (6 of 10) in the CMT group (P less than .05).

Morbidity for Survivors of Extracorporeal Membrane Oxygenation: Neurodevelopmental Outcome at 1 Year of Age

Extracorporeal membrane oxygenation is an important technology in the treatment of high-risk infants whose long-term outcome is being followed prospectively at our institution. The extracorporeal membrane oxygenation procedure allows temporary cardiopulmonary support for critically ill full-term neonates who are refractory to maximum ventilatory and medical management as a consequence of severe persistent pulmonary hypertension. The technique necessitates both the permanent ligation of the right common carotid artery and jugular vein and systemic heparinization. The survivors constitute a unique group of high-risk infants, from the standpoint of the hypoxic-ischemic insults preceding extracorporeal membrane oxygenation and the risks associated with the procedure. Our results indicate that most of our survivors are developing normally at 1 year. Major morbidity, in terms of either significant developmental delay (Bayley mental and motor indices less than 70) or significant neuromotor abnormality, occurred in only 10% of these infants. Poor outcome was associated with major intracranial hemorrhage and chronic lung disease. Ligation of the right carotid artery and jugular vein was not associated with a consistent lateralizing lesion. Long-term follow-up through school age is essential.

Persistent pulmonary hypertension of the newborn treated with hyperventilation: clinical features and outcome.

Twenty-seven infants with severe persistent pulmonary hypertension of the newborn were seen in 33 months. Asphyxia with or without meconium aspiration was the cause in the majority of cases. Other causes were group B streptococcal sepsis and acute fetal blood loss. The mortality rate was 11%. Twenty-three of the 24 survivors were followed. Their age at follow-up ranged 12-37 months. The mean score for mental development was within the normal range while that for psychomotor development was 1 standard deviation below normal. Seven infants were judged to be at risk of attention deficit disorder. Predictor variables related to these outcomes were cardiotocography, meconium aspiration, first pH, highest PaCO2 after resuscitation and mother's education. All infants except one were perceived as normal by their parents.

Coexisting left diaphragmatic hernia and esophageal atresia

Coexisting left diaphragmatic hernia (DH) and esophageal atresia, a rare phenomenon, is described in two newborns, one with tracheoesophageal fistula (TEF) and the other without. The coexistence of DH and TEF in the one resulted in uncontrolled gastrointestinal distention with severe respiratory distress. Transabdominal division of the TEF was feasible and was performed concurrently with the diaphragmatic repair. Severe hypoplastic lungs and persistent pulmonary hypertension resulted in early postoperative death in both cases.

Efficacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy

Twenty-three newborn infants with severe bilateral pulmonary disease and persistent pulmonary hypertension received mechanical ventilation to pH greater than 7.55 and PaCO2 less than 25 torr. Response, as defined by attainment of a PaO2 greater than 100 torr, occurred in 87% of patients. Analysis of sequential arterial pH determinations revealed a linear increase in the number of infants responding as arterial pH increased. However, individual patients varied greatly in the optimal pH necessary to correct hypoxemia (range pH 7.50 to 7.75). Sixteen patients who had received mechanical hyperventilation were observed for 11.1 +/- 2.3 months. Virtually all had normal growth and development on follow-up physical and neurologic examinations, often despite profound or prolonged alkalosis and hypocarbia. In 11 infants at a corrected gestational age of 1 year, Bayley Scales of Infant Development revealed normal mental developmental indices (mean 106.2 +/- 15.4) and normal, but significantly lower, psychomotor developmental indices (93.2 +/- 11.7) (P less than 0.005). Although response and short-term outcome of neonatal hyperventilation appear favorable, this technique should be reserved for critically ill infants, because its long-term effects on the central nervous system are unknown.

Vasodilator response and prediction of survival in congenital diaphragmatic hernia

In an effort to find an accurate prediction of survival in congenital diaphragmatic hernia (CDH) patients with severe respiratory distress and persistent pulmonary hypertension, we reviewed the response to vasodilators and te clinical course of 13 patients with this condition. All patients had been operated upon within the first 24 hr of life and had postoperative descending aortic PaO2 values less than or equal to 50 torr on maximum ventilatory support. The only significant change in standard blood gas values after an intravenous test dose of 2 mg/kg of tolazoline was in the PaO2 (p less than 0.05). Patients with good response (PaO2 increase greater than 100 torr) survived. Patients with fair response (PaO2 increase between 20 and 100 torr) had equivocal survival. Patients with poor response (PaO2 increase less than 20 torr) died. There was a postoperative period up to several weeks of marked fluctuations in arterial oxygen tension in survivors before stability occurred. Vasodilator responsiveness appears to be an accurate, therapeutic indicator of the chances for survival in CDH patients with persistent pulmonary hypertension and right to left shunting.