Method-analysis of nitric-oxide weaning is important as method-dependent variations in weaning outcomes become clear

a02a.jpg (7781 bytes)In the past, nitric oxide was considered a pollutant found in secondary cigarette smoke. During the past 5 or 6 years, however, there has been extensive evidence that nitric oxide is an important endogenous mediator for smooth-muscle relaxation. Nitric oxide is approved by the US Food and Drug Administration for inhalation by newborns with pulmonary hypertension as a vasodilator. The approved proprietary agent is a gaseous blend of 99.2% nitrogen and 0.8% nitric oxide, compressed at 2,000 psig.

Nitric oxide increases Pao2 by dilating pulmonary vessels in well-ventilated areas of the lung. Newborns with Persistent Pulmonary Hypertension of the Newborn (PPHN) respond to nitric oxide due to its effects on pulmonary vascular tone. Endogenous production of nitric oxide causes pulmonary vasodilatation by activating the enzyme guanylate cyclase. In turn, this enzyme produces cyclic guanylase monophosphate, causing smooth-muscle relaxation. Inhaled nitric oxide enhances this vasodilating effect. In contrast to most pulmonary vasodilators, inhaled nitric oxide has no systemic dilation effects because it is inactivated in the blood by hemoglobin.

Common causes of PPHN are meconium aspiration, pneumonia, sepsis, respiratory distress syndrome, and congenital diaphragmatic hernia. Clinical trials1 of nitric oxide involved term and near-term infants who were in respiratory failure. Results showed acute increases in Pao2, decreases in mean pulmonary arterial pressure, and decreases in oxygen indices, or fraction of inspired oxygen (Fio2) times mean airway pressure divided by the Pao2 times 100.

Of the patients receiving nitric oxide, 60% had an increase of 20% or more in Pao2. Studies2 suggest that strategies to improve lung volume, such as high-frequency oscillatory ventilation (HFOV), may accentuate the vasodilatory effect of nitric oxide.

Nitric oxide decreases the need for extracorporeal membrane oxygenation (ECMO) in newborns.2 This is important, since ECMO is expensive, requires a specially trained team, and is unavailable in many areas. In a multicenter trial,2 71% of full-term or nearly full-term infants with PPHN needed ECMO. Of patients treated with nitric oxide, 40% required ECMO.

In the intensive care nursery of Thomas Jefferson University, Philadelphia, the indications for inhaled nitric oxide are

• a need for mechanical ventilation or HFOV,
• hypoxic respiratory failure, and
• clinical or echocardiographic evidence of pulmonary hypertension.

It is contraindicated in any neonate who is dependent on right-to-left shunting of blood. These patients present with cyanotic heart defects. The primary cause for caution in using inhaled nitric oxide is its rebound effect. Rapid discontinuation of treatment can cause declining oxygenation. Another area of caution is methemoglobinemia due to overdosage, which produces higher levels of nitric dioxide. The treatment, of course, is to reduce or stop nitric-oxide therapy, IV methylene blue, and IV vitamin C.

The usual nitric-oxide therapy consists of 20 ppm for 8 hours, 10 ppm for 8 hours, and 5 ppm for 8 hours. To help reduce the rebound effect, it is necessary to decrease the nitric oxide to 1 ppm an hour prior to the discontinuation of therapy. If a patient shows a significant increase in the oxygen index, the patient can go back to using 5 ppm of nitric oxide for up to 5 days.

Initiating Inhaled Nitric Oxide
The initiation of inhaled nitric-oxide treatment begins with a telephone call to the vendor. The patient’s therapy is started by the RCP using an on-site machine and a D cylinder, which will last 4 to 6 hours. The vendor has 2 to 4 hours to bring a backup unit and an 88 cylinder for the continuation of therapy. When inhaled nitric-oxide treatment is discontinued, the company is called to halt charges (at $3,000 for 24 hours) and retrieve its unit.

Certain units are capable of being used during patient transport. It is very important that inhaled nitric-oxide treatment started at a referring hospital remain uninterrupted. The transport unit has a battery that lasts up to 3 hours, and the unit comes with a small cylinder of nitric oxide that will last 4 to 6 hours.

Using this system does not call for nitric-oxide scavenging because the delivered concentration of the gas is so low. It is important to scavenge nitric oxide only if it is being used at a concentration of 80 ppm or more.

Important data2 have proven to ECMO centers that nitric oxide is important in treating PPHN patients of more than 34 weeks’ gestation. At Thomas Jefferson University Hospital, we treat about 50 such patients per year; our results are similar to those seen nationally2 in avoiding ECMO. For this reason, nitric oxide is offered for the treatment of patients with PPHN.

Method Analysis
Recently, we began method analysis of nitric-oxide weaning. The neonatal intensive care unit’s protocol for nitric-oxide therapy calls for its use in newborns with respiratory distress syndrome who are of more than 34 weeks’ gestational age, who have PPHN, and who have an oxygen index of more than 15. Infants who meet these criteria are treated with nitric-oxide therapy. The method with which infants are weaned from nitric oxide is central to their subsequent need for ECMO.

We hypothesized that weaning patients on nitric oxide by reducing the nitric-oxide concentration every 8 hours (from 20 to 10 to 5 ppm) was appropriate. If, after 24 hours, the oxygen index was more than 15, nitric-oxide therapy was restarted at 5 ppm; a trial period without nitric oxide was attempted every 24 hours. After this period, a measured oxygen index of 15 was used to determine the success of weaning.

Nine consecutive patients were studied. HFOV was used to optimize ventilation and oxygenation. Nitric-oxide therapy was started at 20 pm and reduced 50% every 8 hours. Our results indicated that the average time spent using nitric oxide was 31.3 hours, with seven patients (78%) requiring ECMO, one (11%) not requiring ECMO, and one (11%) deceased (Table 1).

1        Meconium aspiration                      12                                 YES
2        Respiratory distress syndrome        24                                   NO
3        Meconium aspiration                     120                                 YES
4        Meconium aspiration                         4                                 YES
5        Meconium aspiration                         3                                 YES
6        Left congenital diaphragmatic hernia 63                                 YES
7        Right congenital diaphragmatic hernia 45                               YES
8 (deceased)Respiratory distress syndrome  2                                   —
9        Respiratory distress syndrome         9.5                                  YES
Table 1. Results of a weaning protocol in which nitric-oxide concentrations were reduced 50% every 8 hours; ECMO=extracorporeal membrane oxygenation.

We concluded that weaning by reducing nitric oxide every 8 hours by 50% was too aggressive. Further studies were undertaken in which 5-ppm reductions were used after the Fio2 was less than 60%.

After these results were analyzed, we hypothesized that weaning patients from nitric oxide by reducing its concentration when the Fio2 reached specific percentages would be appropriate. We reduce Fio2 every 2-3 hours by 2% using blood gas analysis to ensure that the Pao2 remains at 80-100 mm Hg and saturation determined using pulse oximetry is more than 94%. When the Fio2 was 60%, the nitric-oxide concentration was reduced to 15 ppm and then to 10 ppm; when the Fio2 was 40%, the nitric-oxide concentration was reduced to 5 ppm and then to 2 ppm. The concentration was then decreased to 1 ppm, and an arterial blood-gas analysis was performed using a sample drawn an hour after this change. If blood gases were stable, nitric oxide was discontinued.

Eleven patients were studied using HFOV to optimize ventilation and oxygenation. Nitric-oxide therapy was started at 20 ppm and reduced according to the preceding protocol to maintain a Pao2 of 80 to 100 mm Hg. The average time on nitric oxide was 59 hours, with 10 (91%) of the patients not requiring ECMO, one (9%) requiring ECMO, and none deceased. We conclude that weaning from nitric oxide in smaller increments (5 ppm) after the Fio2 reaches 60% and 40% is advantageous (and is not too aggressive) (Table 2).

Meconium aspiration
Primary pulmonary hypertension  
Meconium aspiration   
Primary pulmonary hypertension
Meconium aspiration
Meconium aspiration
Meconium aspiration 
Meconium aspiration 
Meconium aspiration

Meconium aspiration
Respiratory distress syndrome              

Table 2. Results of a weaning protocol in which nitric-oxide concentrations were reduced based on fraction of inspired oxygen being delivered; ECMO=extracorporeal membrane oxygenation.

Further studies are investigating protocols that keep the Fio2 at 100% and decrease the nitric oxide from 20 ppm to 5 ppm in small increments (2 to 5 ppm), as long as the Pao2 is 80 to 100 mm Hg and the pulse oximetry reading (Spo2) is more than 94%. When the 5-ppm level has been reached, the Fio2 will be decreased 2% to 4%, as tolerated and with the Spo2 remaining above 94%. Once the Fio2 is down to 40% to 50%, the nitric-oxide level will be decreased to 2 ppm and then 1 ppm before discontinuation of therapy. It may be wise to increase the Fio2 10% just prior to the discontinuation of nitric oxide in order to help reduce any rebound effects.

As method-dependent variations in weaning outcomes make clear, method analysis of nitric-oxide weaning is important. Work will continue at Thomas Jefferson University Hospital to find the best results and to prevent ECMO. There are also concerns associated with the cost of nitric-oxide treatment, so a formal weaning guideline will be helpful to clinicians in managing patients who are receiving nitric-oxide therapy.

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

The author would like to thank Brian Glynn, RRT, staff therapist, pulmonary care, Thomas Jefferson University Hospital, Philadelphia, for assistance in research for this paper.

1. Giaclia G. Nitric oxide: a selective pulmonary vasodilator. South Med J. 1995;88:33-41.
2. Roberts JD. Inhaled nitric oxide for hypoxemic respiratory failure of the newborn. Respiratory Care. 1999;44:169-172.