Nitric oxide enabled an infant with severe, ventilator-dependent bronchopulmonary dysplasia to tolerate substantial reductions in supplemental oxygen and ventilatory support.
Advances in neonatal intensive care over the past 2 decades have markedly improved survival for infants of extremely low birth weight (less than 1 kg). A remaining problem, however, is the occurrence of bronchopulmonary dysplasia (BPD) in this patient population. BPD, characterized by a persistent supplemental oxygen requirement beyond a postmenstrual age of 36 weeks, continues to be a major source of morbidity and mortality. This chronic lung disease is thought to be the result of mechanical, inflammatory, and oxidative stress, as well as of pulmonary hypertension.
Inhaled nitric oxide has been demonstrated to improve oxygenation in various disease states characterized by pulmonary hypertension and ventilation-
perfusion mismatch. It acts as a selective pulmonary vasodilator in diseases such as persistent pulmonary hypertension of the newborn without having any apparent effect on systemic blood pressure.1,2 It is currently under investigation in a variety of clinical settings.
In this case, inhaled nitric oxide was used to improve oxygenation in one infant with severe, ventilator-dependent BPD.
Inhaled nitric oxide therapy is currently under investigation for the treatment of severe BPD in the Newborn Infant Center of The Children’s Hospital of Philadelphia and the Neonatal Intensive Care Unit (NICU) of the Hospital of the University of Pennsylvania, Philadelphia. The unit at The Children’s Hospital of Philadelphia is a referral-only service with 42 patient beds and receives patients from all areas of the United States. It is also affiliated with an active lung transplantation program in the hospital. The Hospital of the University of Pennsylvania unit is a 31-bed tertiary NICU serving the institution. Both units are staffed around the clock with a group of dedicated RCPs trained in all aspects of neonatal and pediatric respiratory care.
At the present time, nitric oxide therapy is classified as investigational and to be used only within specific boundaries in approved medical studies. Both hospitals’ institutional review boards approved the protocol and standardized consent forms prior to this study. The protocol was also reviewed and approved by the US Food and Drug Administration. The study is being performed under standard guidelines for the investigation of new drugs. Parental consent is required for participation in this open-labeled, non-controlled trial.
Infants are eligible for enrollment if they are more than 4 weeks old, with ventilator-dependent BPD, and require a mean airway pressure (MAP) of>10 cm H2O and a fraction of inspired oxygen (Fio2) of >0.45. Infants with congenital heart disease are excluded from the study.3
Infants enrolled in the study are treated using inhaled nitric oxide at 20 parts per million (ppm) for 72 hours. During this period, Fio2 levels and ventilator settings are adjusted to maintain an oxygen saturation of more than 92 percent and Paco2 levels of 50 to 55 mm Hg.
Following 72 hours of nitric oxide at 20 ppm, ventilator settings and oxygen requirement are assessed. Infants are considered to be responders if they show a reduction of more than 15 percent in Fio2. Those who do not respond are rapidly weaned from inhaled nitric oxide. Responders receive a prolonged, tapering course of nitric oxide therapy. Every 3 days, an effort is made to decrease the nitric oxide dose by 20 percent. If the patient’s oxygen saturation falls more than 5 percent and persists at that level for more than 10 minutes during the weaning attempt, the nitric oxide dose is returned to the previously tolerated level. Weaning is attempted again after an additional 3 days at the current nitric oxide level. During the prolonged course of therapy, blood gas and methemoglobin levels are evaluated every 3 to 7 days.
The study infant was an 880-g product of a 26-week gestation, born to an 18-year-old mother with an obstetrical history of incompetent cervix. His neonatal course was complicated by respiratory distress syndrome (treated using surfactant), systemic hypotension requiring dopamine, a patent ductus arteriosus that was closed with indomethacin, and a pulmonary hemorrhage.
On his sixth day of life, he developed evidence of severe sepsis and pneumonia with increased ventilatory requirements, systemic hypotension requiring dopamine and epinephrine infusions, anasarca, and thrombocytopenia. He was treated with broad-spectrum antibiotics and acyclovir, but his condition continued to deteriorate.
By his 15th day, the infant was requiring a ventilator peak inspiratory pressure (PIP) of 30 cm H2O, a positive end-expiratory pressure (PEEP) of 9 cm H2O, and 70 percent to 100 percent oxygen. His chest radiograph showed complete whiteout in both lung fields. He was treated with high-frequency oscillatory ventilation for a period of 5 days without improvement. He did not respond to a course of dexamethasone treatment.
On his 29th day of life, after 2 weeks of requiring 100 percent oxygen and showing no significant clinical improvement, he was given a trial of inhaled nitric oxide in a final effort to improve his respiratory status.
METHODS AND MATERIALS
A constant-flow, time-cycled, pressure-preset infant ventilator was adapted to accommodate a nitric oxide delivery/analysis system. The injector module for delivering nitric oxide was placed proximal to the humidifier, and the gas-sampling line for nitric oxide analysis was placed on the inspiratory limb of the ventilator circuit 6 inches from the patient wye.
The system allows continuous monitoring of Fio2, nitric oxide, and nitrogen dioxide in the ventilator circuit. Nitrogen dioxide is a potentially dangerous by-product of the prolonged exposure of nitric oxide to oxygen that can cause acute lung injury at very low doses.4,5 For safety purposes, the level of nitrogen dioxide must be measured throughout the treatment’s course. Alarms are set appropriately for all three monitored gases.
At the initiation of nitric oxide therapy, the patient’s ventilator settings were: PIP of 35 cm H2O; PEEP of 8 cm H20; synchronized intermittent mandatory ventilation (SIMV) rate of 40 breaths per minute; 100 percent oxygen with an MAP of 18 cm H20. His Pao2/Fio2 ratio was 48, and his oxygenation index (OI) (MAP x Fio2divided by Pao2 x100)was 37.
Nitric oxide was delivered via ventilator circuit at an initial level of 20 ppm, as specified by the study protocol. Following an hour of inhaled nitric oxide, the patient’s Pao2 increased from 48 mm Hg to 80 mm Hg. After 24 hours of inhaled nitric oxide, he was gradually weaned to 70 percent oxygen. He continued to improve during his 1-month course of treatment, with an oxygen requirement, after 33 days, of 40 percent.
During the first week of nitric oxide therapy, the patient tolerated substantial reductions in his ventilatory support, with a decrease in mean airway pressure from 18 cm H2O to 11 cm H2O. This progressive decrease in ventilatory support was sustained throughout the treatment period.
We closely monitored vital signs, respiratory status, and serum methemoglobin levels throughout the course of therapy. The reaction of nitric oxide with hemoglobin ultimately forms methemoglobin, an abnormal type of hemoglobin that is incapable of oxygen transport and may contribute to arterial and tissue hypoxia. Methemoglobin levels in this patient were obtained at regular intervals and never exceeded 0.2 percent (acceptable range of 0 percent to 2.8 percent).
At the end of 33 days, the patient’s ventilator settings were: PIP of 22 cm H2O; PEEP of 7 cm H2O; SIMV rate of 32 breaths per minute; 40 percent supplemental oxygen; and MAP of 11 cm H2O. His Pao2/Fio2 ratio was 161 and his OI was 6.
No increase in ventilatory support was necessary on discontinuation of nitric oxide therapy. Table 1 summarizes the patient’s oxygenation status throughout his course of nitric oxide therapy.
Inhaled nitric oxide therapy seemed to be valuable for this patient with severe,ventilator-dependent BPD. He was able to tolerate lower Fio2 levels and decreased ventilatory support. This improvement was sustained after the course of nitric oxide therapy had ended.
The rationale for using inhaled nitric oxide therapy in patients with BPD includes its ability to decrease pulmonary vascular resistance and, potentially, to improve
ventilation-perfusion mismatch. Direct measurement of pulmonary artery pressures in this patient population is not feasible, and there are no validated noninvasive measurements available at present. Therefore, tracking supplemental oxygen and ventilation requirements may indicate response to this therapy as accurately as is now possible.
Potential mechanisms through which inhaled nitric oxide therapy may improve oxygenation and lead to improved
ventilation-perfusion mismatch include direct pulmonary vasodilation, reduced vascular remodeling due to decreased expression of vascular growth factors, bronchodilation, and decreased airway inflammation.
While the findings in this case suggest that inhaled nitric oxide may be beneficial for patients with severe, ventilator-
dependent BPD, this conclusion is limited by the fact that it was used in an open-label, nonrandomized fashion. However, the fact that this patient had no clinical improvement for a significant time prior to study enrollment despite maximum conventional management makes it unlikely that his improvements were independent of the inhaled nitric oxide therapy.
This study is ongoing at The Children’s Hospital of Philadelphia and at the University of Pennsylvania, with 31 patients enrolled to date. RCPs are also examining the effects of inhaled nitric oxide therapy on patients with less severe BPD in a double-blinded, randomized crossover trial. Continued study of inhaled nitric oxide therapy is essential to the assessment of its potential clinical use in this patient population.
Sandra R. Wadlinger, RRT, CPFT, perinatal/pediatrics specialist, is the neonatal clinical specialist in the Department of Respiratory Care Services, Children’s Hospital of Philadelphia.
1. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597-604.
2. Roberts JD, Fineman JR, Morin FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med. 1997;336:605-610.
3. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics. 1999;103:610-618.
4. Williams RA, Rhoades RA, Adams WS. The response of lung tissue and surfactant to nitrogen dioxide exposure. Arch Intern Med. 1971;128:101-108.
5. Stephens RJ, Freeman G, Evans MJ. Early response of lungs to low levels of nitrogen dioxide: light and electron microscopy. Arch Environ Health. 1972;24:160-179.