Drug Criteria & Outcomes-Nitric oxide (INOmax) for newborns
By Melvin J. Clark, PharmD
Drug Information Pharmacy Practice Resident
Medical University of South Carolina
Charleston, SC
Introduction:
Persistent pulmonary hypertension of the newborn (PPHN) affects one in every 500 to 1,000 live births, or approximately 10,000 newborns per year.1,2 PPHN is a syndrome of acute respiratory failure that causes arterial hypoxemia.1,3 The hypoxemia is caused by insufficient perfusion of the alveoli due to increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood.1-2 PPHN may be idiopathic, or it may be caused by an underlying secondary condition such as meconium aspiration, respiratory distress syndrome, sepsis, lung hypoplasia, or congenital diaphragmatic hernia.1,2
Mortality of PPHN ranges between 20% and 50%.2 Treatment strategies include inspired oxygen, assisted ventilation, vasodilators, and extracorporeal membrane oxygenation (ECMO).1-2 These strategies are not without complications or significant adverse sequelae. Vasodilators may act upon the systemic vasculature and produce severe hypotension.3 Hyperventilation with oxygen may lead to lung injury, pneumothorax, and permanent neurologic disability. ECMO improves survival; however, it is expensive, causes important morbidity, and is associated with increased intracranial hemorrhage and ischemia.2,3 Nitric oxide (NO) is a gas that selectively vasodilates the pulmonary vasculature. There is evidence to suggest that neonates with PPHN have decreased NO production.2 Additionally, NO improves oxygenation in neonates with pulmonary hypertension.3
Indications:
Nitric oxide (INOmax), by INO Therapeutics Inc., in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (> 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.4
Pharmacology:
Once known as endothelium-derived relaxing factor, NO produces pulmonary vasodilation upon inhalation. Intracellular free calcium is responsible for the contraction of smooth muscle. NO promotes a decrease in the intracellular concentration of free calcium. Upon inhalation, NO diffuses the membrane of smooth muscle cells and activates cytosolic guanylate cyclase, which then increases levels of cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinase. Activated protein kinase accelerates the reuptake of calcium by the sarcoplasmic reticulum. This subsequent decrease in intracellular calcium promotes relaxation of smooth muscle.5
Pharmacokinetics:
The pharmacokinetics of NO have been studied in adults. After inhalation, NO is systemically absorbed.4 In healthy volunteers who inhaled NO for one hour, 90% of the NO delivered to the alveolar space was absorbed.6 In patients with acute lung injury, 35% of the total amount of NO delivered was absorbed. In contrast, 70% of the NO that reached the alveolar space was absorbed. The difference in total uptake between healthy patients and patients with lung injury is probably due to differences in alveolar dead space.8 NO is predominantly metabolized to nitrate,4,8 and greater than 70% of the total inhaled dose is excreted as nitrate in the urine. The plasma clearance of nitrate is approximately the rate of glomerular filtration.4
Selected clinical trials:
The Neonatal Inhaled Nitric Oxide Study Group (NINOS) conducted a prospective, multicenter, randomized, double-blind, controlled trial to determine whether inhaled NO would reduce mortality or reduce the need for ECMO in term or near-term infants who developed hypoxic respiratory failure that was unresponsive to conventional therapy. Two hundred and thirty-five patients were enrolled to receive either NO 20 parts per million (PPM) inhaled (n = 114) or oxygen 100% inhaled (n = 121). The NO gas could be increased to 80 PPM if response to 20 PPM was inadequate. Treatment response was defined as a change in baseline PaO2 30 minutes after initial exposure to NO. A complete response was defined as an increase in PaO2 of > 20 mm Hg. A partial response was defined as an increase of 10 to 20 mm Hg. No response was defined as an increase in PaO2 of < 10 mm Hg. The primary endpoints of this study were death by day 120 and need for ECMO by day 120. Death and need for ECMO also were combined and analyzed as a third primary endpoint. Secondary endpoints included length of hospitalization, duration of assisted ventilation, air leak after randomization, and development of bronchopulmonary dysplasia.
Infants were eligible for enrollment if they were born at ³ 34 weeks of gestation, required assisted ventilation for hypoxic respiratory failure, and had an oxygenation index of at least 25 on two measurements determined at least 15 minutes apart. Exclusion criteria included age greater than 14 days, congenital diaphragmatic hernia, congenital heart disease, or the decision not to provide full treatment. The two study groups did not differ significantly with respect to patient characteristics, treatment status, or status at the time of randomization.
A statistically significant difference in mortality between patients treated with NO and those treated with oxygen was not detected. Fourteen percent (n = 16) of patients treated with NO died by day 120, compared with 16.5% (n = 20) of patients treated with oxygen (p = 0.60). However, 54.5% (n = 66) of patients treated with oxygen required ECMO, compared with 38.6% (n = 44) of patients treated with NO (p = 0.014). In addition, 63.6% (n = 77) of patients treated with oxygen reached the combined endpoint of death or ECMO by day 120, compared with 45.6% (n = 52) of patients treated with NO.
None of the secondary endpoints reached statistical significance. None of the infants discontinued the study due to adverse events from NO. The concentration of NO was reduced in 11 infants (9%) because of elevated methemoglobin levels. There were no significant differences between the treatment groups with respect to the following adverse events: periventricular leukomalacia, brain infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, and gastrointestinal hemorrhage.2 The data support that inhaled NO decreases the need for ECMO in neonates with pulmonary hypertension.7
Clark and colleagues conducted a study in neonates that evaluated the efficacy of low-dose inhaled NO for the treatment of pulmonary hypertension. The primary endpoint of this double-blind, multicenter, controlled trial was to determine if inhaled NO would reduce the need for ECMO. Secondary endpoints included: improvement ratio of arterial to alveolar oxygen; incidence of short-term complications (hypotension, methemoglobinemia, deterioration of gas exchange); incidence of long-term complications; and incidence of death.
Two hundred and forty-eight neonates were randomized to receive either nitric oxide 20 PPM inhaled (n = 126) or oxygen 100% inhaled (n = 122). Patients were included in the study if they met the following criteria: ³ 34 weeks gestation, £ 4 days old, required assisted ventilation, had an oxygen index of 25 or higher, and had clinical or echocardiographic evidence of pulmonary hypertension without structural heart disease. A 5% difference between preductal and post-ductal oxygen saturation or a twofold decrease in oxygen saturation (< 85%) in a 12-hour period defined pulmonary hypertension. Additionally, neonates who required extreme alkalosis (pH > 7.55) to maintain a PaO2 of ³ 60 mm Hg were considered eligible for the study. Patients were excluded if ECMO was urgently needed for refractory hypotension (SBP < 35 mm Hg); if they had profound hypoxemia (PaO2 < 30 mm Hg); if they had a lethal congenital anomaly; or if they had a substantial bleeding diathesis, active seizures, or a history of asphyxia.
Before randomization, each neonate was assigned to one of five diagnostic categories to ensure an even distribution of pulmonary diagnoses between the patient groups. The diagnostic categories were meconium aspiration syndrome, pneumonia, respiratory distress syndrome, lung hypoplasia syndromes (congenital diaphragmatic hernia, prolonged oligohydraminos, hydrops fetalis), and idiopathic persistent pulmonary hypertension.
NO was administered at 20 PPM and continued for four hours. After four hours, both arterial blood gasses and methemoglobin were measured. The dose was then decreased to 5 PPM if the neonate's condition was stable, if PaO2 ³ 60 mm Hg, and pH £ 7.55. If any of the three criteria were not met, the administration of study gas was maintained at 20 PPM, and the neonate was evaluated every four hours until the criteria were met or until the time frame of NO administration reached 24 hours. After 24 hours, the treatment dose was decreased to 5 PPM. Treatment was continuous at 5 PPM until one of the following events occurred: the fraction of inspired oxygen was < 0.7, the neonate had been treated for 96 hours, or the neonate was 7 days old.
There was a significant difference in the use of ECMO between the two groups. Only 38% (n = 48) of patients receiving NO required ECMO, compared with 64% (n = 78) of patients receiving oxygen (p = 0.0001). The difference was significant across all five diagnostic groups with the exception of congenital diaphragmatic hernia. Evaluation of the secondary endpoints also revealed a statistically significant difference in two of the four outcomes. The neonates treated with NO had a higher increase in the ratio of arterial to alveolar oxygen than those treated with oxygen (by 0.10 vs. 0.05; p = 0.02). There also was a decreased incidence of long-term complications in the subjects treated with NO. Seven percent (n = 16) of patients treated with NO developed chronic lung disease, compared with 20% (n = 45) of the neonates treated with oxygen (p = 0.02). No difference was detected between the two groups with respect to incidence of short-term complications or death. The investigators mentioned that the use of NO was not associated with an increase in the occurrence of intracranial hemorrhages or chronic lung disease. These data support that NO reduces the need for ECMO in neonates with pulmonary hypertension.8
Adverse events:
In the NINOS trial, no patient discontinued nitric oxide therapy due to adverse events. There was no statistically significant difference detected between NO and oxygen treatment with respect to intracranial hemorrhage, periventricular leukomalacia, brain infection, seizures requiring anticonvulsant therapy, pulmonary edema, or gastro- intestinal hemorrhage.7 Table 1, p. 8, lists adverse events reported in the product package insert that occurred in more than 5% of patients.4
Pregnancy:
The FDA classifies NO as a pregnancy category C agent. This means either that studies in animals have revealed adverse effects on the fetus and there are no controlled studies in women, or that studies in women and animals are not available. Reproduction studies with NO have not been conducted in animals. The potential for NO to cause fetal harm or affect reproductive capacity is not known. NO is not intended for use in adults.4
Drug-drug interactions:
To date, studies evaluating drug-drug interactions with NO have not been performed. NO donor compounds, such as sodium nitroprusside and nitroglycerin, may increase the risk of developing methemoglobinemia. In clinical trials, NO has been delivered with the following agents: tolazoline, dopamine, dobutamine, steroids, and surfactant.4
Contraindications:
Nitric oxide should not be used in the treatment of neonates known to be dependent on right-to-left shunting of blood.4
Precautions:
Abrupt discontinuation of NO may result in a rebound effect in which an increase in pulmonary artery pressure may occur. This rebound may lead to worsening of blood oxygenation. NO should be weaned cautiously.4
Dosing and administration:
The recommended dose of NO is 20 PPM. Treatment should be maintained up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from NO therapy. NO must be delivered through a system that provides operator-determined concentrations of NO in the breathing gas. Monitoring of PaO2, methemoglobin, and NO2 should be performed during the delivery of NO. A backup battery power supply and reserve NO delivery system should be available in the event of a system failure or power outage. NO should be weaned cautiously.4
Conclusions:
PPHN affects approximately 10,000 newborns each year and is associated with high morbidity and mortality. Although ECMO improves the survival of neonates with PPHN, caveats to its use include high cost and an increased incidence of intracranial hemorrhage and ischemia. NO selectively vasodilates pulmonary vasculature and increases oxygenation in neonates with pulmonary hypertension. NO improves oxygenation by causing pulmonary vasodilation upon inhalation. It is dosed at 20 PPM for up to 14 days or until the underlying oxygen desaturation has resolved, and it should then be weaned slowly.
Clinical trials have demonstrated a clinically relevant difference in the need for ECMO between neonates treated with NO vs. those treated with oxygen. Adverse events occurring greater than 5% of the time with NO administration include the following: hypotension, withdrawal, hematuria, hyperglycemia, sepsis, infection, stridor, and cellulitis. NO should not be used in infants dependent on right-to-left shunting of blood.
NO is a new option for the treatment of PPHN. Institutions need to address issues surrounding the use of NO such as storage of the containers, who will be responsible for delivery of the gas, and which department will be responsible for the acquisition cost. The high cost of therapy with NO is justified because the agent eliminates the need for ECMO in significant numbers of patients.
References
1. Davidson D, Barefield ES, Kattwinekel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the newborn: A randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998; 101:325-333.
2. Mariani G, Barefield ES, Carlo WA. The role of nitric oxide in the treatment of neonatal pulmonary hypertension. Curr Opin Pediatr 1996; 8:118-125.
3. Roberts JD, Fineman JR, Morin FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. NEJM 1997; 336:605-610.
4. INOmax package insert. Clinton, NJ: INO Therapeutics Inc; Label No. 300 200.00.
5. McHugh J, Cheek DJ. Nitric oxide and regulation of vascular tone: Pharmacological and physiological considerations. Am J Critical Care 1998; 7:131-140.
6. Nathorst WU, Benthin G, Lundin S, et al. Conversion of inhaled nitric oxide to nitrate in man. Br J Pharmacol 1995; 114:1,621-1,624.
7. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. NEJM 1997; 336:597-604.
8. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. NEJM 2000; 342:469-474.
9. Westfely UN, Lundin S, Stevqvist O. Uptake of inhaled nitric oxide in acute lung injury. Acta Anaesthol Scand 1997; 41:818-823.
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