DURHAM, NC--Most full-term newborns make the transition from womb to world with ease, but several thousand each year develop respiratory problems and pulmonary hypertension. In severe cases, the resulting respiratory failure requires the use of extracorporeal membrane oxygenation (ECMO) to support adequate oxygenation.

Babies treated with ECMO are not only subjected to an invasive procedure and the need for large amounts of blood products, but they are also at increased risk for intracerebral bleeding and chronic lung disorders. However, findings from a recent study suggest that a few days of low-dose, inhaled nitric oxide (NO) can improve gas exchange, reverse respiratory failure, and reduce the need for ECMO in many newborns with hypoxemic respiratory failure.[1]

EARLY ALTERNATIVES

Reese H. Clark, MD, and members of the Clinical Inhaled Nitric Oxide Research Group conducted a clinical trial to determine whether low-dose inhaled NO would reduce the use of ECMO in neonates with pulmonary hypertension. They randomized 248 such newborns to receive either usual care or inhaled NO. Inclusion criteria were: birth after at least 34 weeks' gestation, age 4 days or younger at entry, need for assisted ventilation, and hypoxemic respiratory failure (defined by an oxygenation index of 25 or higher). The primary study end point was the need for ECMO. The investigators' goal was to stabilize these neonates before they progressed to the point where ECMO was the only treatment option.

The researchers found that inhaled NO was very effective for this purpose (Table 1). ECMO was needed significantly less often in the babies given inhaled NO than in those who received usual care (38% vs 64%, respectively). In addition, infants treated with inhaled NO were less likely to develop chronic lung disease. There was no difference in 30-day mortality between the two groups, however.

Treatment with inhaled NO was given at 20 ppm for a maximum of 24 hours, followed by 5 ppm for no more than 96 hours. Treatment was discontinued if the neonate:

• Could be weaned from the study gas.
• Met the criteria for treatment failure (inability to tolerate the decreased dose at 24 hours).
• Met the criteria for requiring ECMO (oxygenation index of more than 40 on three of five measurements at least 30 minutes apart, arterial oxygen tension below 40 mm Hg for two hours, or progressive hemodynamic deterioration).

CLINICAL SIGNS

Respiratory problems commonly associated with pulmonary hypertension include meconium aspiration syndrome, pneumonia, idiopathic pulmonary hypertension, respiratory distress syndrome, congenital diaphragmatic hernia, and pulmonary hypoplasia. Neonates eligible for this study "all had clinical signs of persistent pulmonary hypertension. These patients often quickly become critically ill," Dr. Clark said.

Persistent pulmonary hypertension in such infants usually results from a failed transition from fetal to neonatal pulmonary circulation. The first lung inflation should cause a rush of blood to the lungs, Dr. Clark explained, and this transition from fetal to neonatal circulation is in part mediated by endogenous NO. The inhaled therapy is based on the idea that increasing the alveolar NO concentration might improve pulmonary blood flow in neonates who have persistent fetal circulation and pulmonary hypertension.

However, the researchers found that inhaled NO was not helpful in cases of pulmonary hypertension due to congenital diaphragmatic hernia. "We would have thought that babies with congenital diaphragmatic hernia would benefit, so this result was counterintuitive," Dr. Clark told PULMONARY REVIEWS. "This may have been related to heart abnormalities affecting left ventricular function."

The results of this study confirmed findings from the Neonatal Inhaled Nitric Oxide Study, which showed that nitric oxide is effective across a broad range of diagnoses. However, in contrast with the previous study, Clark et al used much lower doses of inhaled NO for a shorter duration of treatment. The researchers did this in order to avoid delaying ECMO beyond the point at which its efficacy might be reduced.

AVOIDING ECMO

The researchers are working to find ways to avoid using ECMO because, according to Dr. Clark, "It requires sticking large tubes into the carotid artery and jugular vein [and] affects blood flow to the brain on that side. Blood is removed and pumped across an external membrane with gas flowing over it. The blood then must be rewarmed before it is returned to the baby. The procedure requires keeping the baby heparinized. ECMO is associated with damage to major vessels in the neck and loss of platelets, which stick to the membrane."

--Janis Kelly

Reference
1. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000;342:469-474.

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