Severe Persistent Pulmonary Hypertension Of The Newborn Research Articles

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn.

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20 ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaDO2) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30 min, three had an intermediate response within 8 h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30 min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.

Pathophysiologic principles relevant for therapeutic procedures in persistent pulmonary hypertension of the newborn.

Though the various pathophysiologic mechanisms underlying persistent pulmonary hypertension of the newborn (PPHN) necessitate rather specific therapeutic concepts, in the majority of infants with PPHN management is mainly focused on the treatment of the symptoms respiratory failure and cardiovascular abnormalities. For the few neonates with severe PPHN who fail to respond to optimized conventional ventilatory support, high-frequency oscillatory ventilation and extracorporeal membrane oxygenation are available. Treatment of cardiovascular abnormalities should be based on knowledge of the pathophysiologic events in the heart and in the pulmonary and systemic circulation of the newborn with PPHN at least as far as these events are known or suspected based on animals studies. The primary goals of therapy in PPHN must be reduction of right ventricular afterload and support of myocardial function. In this context inhalational nitric oxide therapy may be effective as a new therapeutic strategy to decrease pulmonary vascular resistance.

Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension

To study the potential role of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, in the pathophysiology of persistent pulmonary hypertension of the newborn (PPHN), we measured arterial concentrations of immunoreactive endothelin-1 (irET-1) in 24 neonates with PPHN. Secondary diagnoses included meconium aspiration syndrome (13 patients), sepsis (2), congenital diaphragmatic hernia (1), asphyxia (1), pulmonary hemorrhage (1), aspiration of blood (1), and respiratory distress syndrome (1). Compared with irET-1 levels in umbilical cord blood in normal infants (15.1 +/- 4.1 pg/ml; mean +/- SEM) and in newborn infants with hyaline membrane disease who were supported by mechanical ventilation (11.8 +/- 1.2 pg/ml), infants with PPHN had markedly elevated circulating irET-1 levels (27.6 +/- 3.6 pg/ml; p < 0.01 vs cord blood, hyaline membrane disease). Infants with severe PPHN requiring extracorporeal membrane oxygenation (ECMO) therapy had higher irET-1 levels than infants with milder disease (31.0 +/- 4.7 for ECMO-treated infants vs 21.2 +/- 2.0 for non-ECMO-treated infants; p < 0.05). In patients treated without ECMO, irET-1 progressively decreased during the following 3 to 5 days, paralleling clinical improvement. In contrast, irET-1 concentrations remained elevated in infants with severe PPHN during ECMO therapy. We conclude that circulating irET-1 levels are elevated in newborn infants with PPHN, are positively correlated with disease severity, and decline with resolution of disease in patients who do not require ECMO therapy. Whether endothelin-1 contributes directly to the pathophysiology of PPHN or is simply a marker of disease activity remains speculative.

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.

Investigating Therapies of Potentially Great Benefit: ECMO

Conventional randomized clinical trials provide a powerful and scientifically rigorous method for comparing medical therapies, but designs using 50-50 randomization (or any other constant assignment probabilities) can raise ethical difficulties when there is strong evidence, either a priori or from study data, that one of the therapies may offer great benefit to individual patients. This article describes such a situation, the evaluation of extracorporeal membrane oxygenation (ECMO) for treatment of persistent pulmonary hypertension of the newborn (PPHN). For many years, the mortality rate among infants with severe PPHN treated with conventional medical therapy (CMT) was 80${\tt\%}$ or higher. ECMO treatment of PPHN was introduced in 1977 and, by 1985, several centers had reported survival rates of 80${\tt\%}$ or better in infants treated with ECMO. Only one randomized trial was reported by the end of 1985. This trial used a randomized play-the-winner design. Eleven patients received ECMO therapy and all survived. Only one patient received CMT and this patient died. In part because of the success of ECMO therapy, this trial provided very little comparative data on the two therapies. The author and medical colleagues reviewed these data in 1985 and concluded that they did not justify routine use of ECMO without further study. A review of historical experience at two Harvard hospitals showed, however, that 13 infants had developed severe PPHN in 1982 and 1983 and 11 (85${\tt\%}$) had died. All received CMT. Thus, there was a strong possibility that a randomized trial would show large differences in survival rates in the ECMO and CMT groups. To balance ethical and scientific concerns, we designed a clinical trial with a treatment assignment procedure that would begin as conventional randomization but switch to a single therapy study when a prespecified number of deaths was observed in either group. This article describes the study design and results. Nineteen (19) patients were enrolled during the randomized phase; 6 of 10 survived in the CMT group and 9 of 9 in the ECMO group. In the second nonrandomized phase, 20 patients were assigned to ECMO therapy and 19 survived. The survival rates in the two treatment groups were significantly different $(P < .05$ with curtailed sampling) and the profile likelihood for the difference in survival rates between the ECMO and CMT groups gave a one-sided 95${\tt\%}$ confidence interval with a lower limit of .131. We conclude that ECMO therapy increases survival relative to CMT therapy in patients with severe PPHN.

Extracorporeal membrane oxygenation as treatment of severe meconium aspiration syndrome.

Meconium aspiration syndrome (MAS) is a common cause of morbidity and mortality in neonates. Chemical pneumonitis can lead to persistent pulmonary hypertension of the newborn (PPHN) with irreversible hypoxia and death. Extracorporeal membrane oxygenation (ECMO) for the treatment of severe PPHN became available at the Ochsner Foundation Hospital in September 1983. We reviewed the first 28 cases in which ECMO was used for the treatment of PPHN due to severe MAS; 26 of the 28 infants survived. During the three years preceding our development of ECMO capability, ten neonates had PPHN due to severe MAS and met the criteria for ECMO; only three survived. The difference in survival demonstrates the efficacy of ECMO for the treatment of severe MAS. We believe that when established criteria are met, ECMO should be instituted without delay.

Acute and Chronic Fetal Pulmonary Hypertension Alter Pulmonary Vasoreactivity

Persistent pulmonary hypertension of the newborn (PPHN) is the failure of the pulmonary circulation to adapt successfully to postnatal conditions. Associated with a wide variety of neonatal cardiopulmonary disorders, PPHN represents the inability to achieve or sustain a drop in pulmonary vascular resistance during the immediate newborn period. Previous clinical and experimental studies suggested that intrauterine events may play important roles in its pathogenesis. Supportive evidence includes: (1) the timing of onset of disease within hours of birth; (2) the severity of histologic findings at autopsy of infants with severe PPHN dying within the first few days, including marked smooth muscle and perivascular adventitial thickening;1 and (3) animal studies suggesting that fetal stresses, such as hypoxia or hypertension, can cause smooth muscle thickening of small pulmonary arteries.

An Economic Analysis of Extracorporeal Membrane Oxygenation

Financial considerations, in concert with clinical effec tiveness, are of increasing importance in the assessment of technological innovations. One such innovation, ex tracorporeal membrane oxygenation (ECMO), is now in use at over twenty centers nationwide to treat new borns with severe, acute lung disease. Use of ECMO therapy for one year at Children's Hospital National Medical Center, Washington, DC, in a population of pa tients with persistent pulmonary hypertension of the newborn (PPHN) is reported, comparing outcome and financial considerations with a similar group of infants treated conventionally prior to ECMO. A historical con trol group of infants with severe PPHN showed that before ECMO was available the survival rate in this criti cally ill population was only 21%. With ECMO, infants with the same clinical characteristics have an 80% chance of survival. Analysis of hospital and physician charges for these two groups (pre-ECMO and ECMO) reveals that ECMO therapy is about 2% less expensive than conventional treatment. When only survivors in each group are compared, ECMO is 43% less costly. These differences are attributable to reductions in aver age length of hospital stay with ECMO therapy, and they are conservative in that they do not take into considera tion the marked economic advantage to society of avert ing unnecessary deaths.