At Thomas Jefferson University Hospital, RCPs have excelled in monitoring weaning techniques and investigating nitric oxide’s effect on patients with bronchopulmonary dysplasia.

Once nitric oxide therapy has been initiated and has been seen to be clinically therapeutic, the real work begins. Nitric oxide weaning has been discussed and researched extensively in the United States and abroad, and it is the subject of debate and discussion. Neonatal and pediatric conferences, journal articles, and lectures still focus on this important topic; what has been learned so far?

The indications for nitric oxide have become less diverse since nitric oxide was approved by the US Food and Drug Administration as a drug. This drug is indicated for pulmonary hypertension in newborns. Inhaled, it acts as a pulmonary vasodilator.

Nitric oxide increases Pao2 by dilating pulmonary vessels in ventilated areas of the lungs. Since nitric oxide affects pulmonary vascular tone, infants with persistent pulmonary hypertension of the newborn (PPHN) respond well.

In the intensive care nursery at Thomas Jefferson University Hospital, Philadelphia, nitric oxide therapy is indicated for infants who require conventional or high-frequency ventilation, who are in hypoxic respiratory failure, and who show clinical or echocardiographic evidence of pulmonary hypertension.

Optimizing Ventilator Settings
An important step that physicians and RCPs must take upon the initiation of therapy is the optimization of the patient’s ventilator settings. Otherwise, nitric oxide will be ineffective due to decreased lung recruitment. Most patients seen at Thomas Jefferson University Hospital are supported using high-frequency oscillatory ventilation. Recently, research has been completed on the use of a high-frequency jet ventilator for centers in general that use jet ventilators.

At Thomas Jefferson University Hospital, the patient’s mean airway pressure is set to maintain lung volumes extending to the eighth or ninth rib to allow for adequate lung expansion. Frequency is set at 10 Hz (600 breaths per minute) and amplitude is set to produce acceptable chest vibration.

The initial nitric oxide dose is 20 ppm and the fraction of inspired oxygen (Fio2) is set at 97% to maintain a Pao2 of 80 to 100 mm Hg and a pulse-oximetry result (Spo2) of more than 94%. An arterial blood-gas (ABG) sample is drawn every 1 to 2 hours initially. Later, ABG samples can be drawn every 2 to 4 hours.

Methemoglobin levels should be assessed at least every 12 hours, since caution in using nitric oxide must be exercised to prevent methemoglobinemia. This can occur as a result of an overdose, which would produce higher levels of nitrogen dioxide. To treat an overdose, reduce or stop the delivery of nitric oxide and use an Fio2 of 100 and use intravenous methylene blue at 1-2 mg per kg per dose over a 5 minute period every 4 hours prn as needed.

Once the ventilator settings have been optimized, the RCP should calculate an oxygen index. This index indicates how well oxygenated the patient is in relation to the level of ventilatory support being provided. It is calculated by multiplying the mean airway pressure by the Fio2, dividing the product by the Pao2, and multiplying the result by 100. If the patient’s oxygen index is between 15 and 25, nitric oxide is initiated. Patients with oxygen indices of more than 25 are not disqualified from using nitric oxide, but staff members at Thomas Jefferson University Hospital try to initiate nitric oxide therapy when the oxygen index is between 15 and 25 because the higher the number, the worse the infant’s oxygenation will be. We choose to go on early so we are not starting nitric oxide when the patient is in extremely critical condition.

Weaning Strategies
Weaning from nitric oxide is central to the subsequent need for extracorporeal membrane oxygenation (ECMO). If you fail nitric oxide, the next step is ECMO, which is used as a last resort since it is an invasive procedure (requiring surgery). This is important because ECMO is expensive, requires a specially trained team, and is not available in some areas. The typical duration of nitric oxide therapy is less than 5 days, which correlates with the resolution of PPHN.1 The protocol used for neonates at Thomas Jefferson University Hospital is shown in the figure on page 32.

The neonatal intensive care unit’s guideline for nitric oxide therapy is the presence of respiratory distress syndrome in a newborn of more than 34 weeks’ gestation who has PPHN and an oxygen index of 15 or more. It was hypothesized that weaning neonates with PPHN from supplemental oxygen first and then weaning them from nitric oxide in increments of 5 ppm would be appropriate.

Thomas Jefferson University Hospital—ICN Inhaled Nitric Oxide In PPHN Treatment Protocol (This May Not Apply to CDII Patients)

Beginning in 2000, 24 patients with respiratory distress syndrom were studied at Thomas Jefferson University Hospital using a high-frequency oscillator ventilator to optimize ventilation and oxygenation. These patients with respiratory distress syndrome were selected who had 34 or greater weeks gestation and an oxygen index greater than 15. Nitric oxide was supplied at 20 ppm, and the Fio2 was reduced by 2% to 4% every 30 to 60 minutes as long as the Spo2 was greater than 94% and the Pao2 was 80 mm Hg or more. ABG analysis was conducted every 2 to 4 hours.

Once the Fio2 had been reduced to 60%, nitric oxide was decreased to 15 ppm and then to 10 ppm if the Spo2 was greater than 94% and/or Pao2 was 80% or more criterion continued to be met. The Fio2 was then reduced again by 2% to 4% every hour as long as the Pao2 was 80 mm Hg or more and the Spo2 was more than 94%. Once the Fio2 had reached 40%, nitric oxide was reduced to 5 ppm and then 2 ppm, if the same criteria were met. At 2 ppm, with a Pao2 of 80 mm Hg or more and an Spo2 of more than 94%, nitric oxide was reduced to 1 ppm and then discontinued.

Results differed by diagnosis. The 14 meconium aspiration patients with meconium aspiration syndrome used nitric oxide for a mean of 38.6 hours, with 7% of the patients requiring ECMO. The six patients with respiratory distress syndrome had a mean nitric oxide time of 68 hours and 23% of the patients required ECMO. The four patients with congenital diaphragmatic hernia spent a mean of 36 hours using nitric oxide, and 75% of them required ECMO.

Since the mean duration of nitric oxide therapy was 52 hours for all three diagnoses combined, and since only 25% of the 24 patients studied required ECMO, the investigators concluded that decreasing the Fio2 first and then decreasing nitric oxide in small increments yields positive results. Some centers reduce nitric oxide from 20 ppm to 6 ppm or even 1 ppm after 4 hours and see no acute changes in oxygenation.¹

Successful Weaning
At Thomas Jefferson University Hospital, however, successful weaning has been attributed to the fact that nitric oxide levels are left unchanged until the Fio2 has reached 60%. This ensures that pulmonary hypertension is resolved or resolving before the nitric oxide dose is decreased.

The discontinuation of nitric oxide treatment needs to be taken very seriously. Special consideration is required because of the negative response that neonates can have when nitric oxide therapy is withdrawn too abruptly. There can be a rebound effect due to the downregulation of endogenous nitric oxide production that is produced by the provision of exogenous nitric oxide. This decrease in the patient’s own nitric oxide production can contribute to vasospasm when nitric oxide treatment is withdrawn abruptly.¹ At Thomas Jefferson University Hospital, nitric oxide delivery is decreased to 1 ppm for 30 minutes and then discontinued while supplemental oxygen is still being delivered at an Fio2 of 40%. This allows oxygen supplementation to be increased if the patient needs it.

In 2000, weaning was more aggressive and nitric oxide was discontinued at 5 ppm. Subjectively, it seems that more patients experienced decreases in Pao2 and that more were returned to nitric oxide delivery at 5 ppm. Since nitric oxide is now discontinued at 1 ppm, rebound effects and reinstatement of nitric oxide therapy are rarely seen. The fact that the Fio2 is lower also means that PPHN is more likely to be resolved or resolving at the time of weaning.

Bronchopulmonary Dysplasia
Since mid 2001, a few patients with bronchopulmonary dysplasia have required an Fio2 of 70% or more to maintain a Pao2 of 60 to 80 mm Hg. These patients also have many desaturation periods due to hypoxemia. This presents problems, since there is no way to decrease the Fio2 and allow time to let the lungs heal. Infants with bronchopulmonary dysplasia who have been intubated for 2 weeks or more begin therapy at an Fio2 of 70% or more and a nitric oxide concentration of 10 ppm. The Fio2 is decreased by 2% to 4% if the Pao2 is greater than 60 mm Hg with an Spo2 of 92% or more. Once the patient’s Fio2 has been decreased to 50% to 60%, nitric oxide is decreased by 2 ppm while these criteria are maintained. Since these patients have more compromised lung function secondary to being intubated for more than 2 weeks, they usually continue nitric oxide therapy for approximately 2 weeks, but they can be maintained within a lower range of Fio2. Further studies are being conducted to document the efficacy of using nitric oxide in patients with bronchopulmonary dysplasia.

Nitric oxide is very important in treating neonates of 34 or more weeks’ gestation who have PPHN. Qualifying patients and initiating therapy seem simple, compared with the work necessary in weaning neonates from the drug.

Great progress has been made in optimizing ventilatory support to stabilize oxygenation and in weaning patients from nitric oxide. At Thomas Jefferson University Hospital, RCPs will continue to monitor weaning techniques and to investigate nitric oxide’s effects on patients with bronchopulmonary dysplasia.

Raymond Malloy, RRT, is director of pulmonary care, Thomas Jefferson University Hospital, Philadelphia.

Reference
1. Kinsella J, Abman S. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. 2000;136:717-726.