Report 2 of the Council on Scientific Affairs (I-01)
Full Text

Marketing and Clinical Use of Inhaled Nitric Oxide

Resolution 417, introduced by the Oregon Delegation and referred to the Board of Trustees at the 2000 American Medical Association (AMA) Interim Meeting, asked:

Testimony provided at the Reference Committee also noted that the efficacy of nitric oxide therapy, including potential off-label uses, should be evaluated in this report.

Methods

Literature searches were conducted in the MEDLINE database for English-language articles published between 1990 and September 2001 using the search term nitric oxide in combination with administration and dosage, adverse effects, diagnostic use, therapeutic use, and human, but not air pollution or animal. The Cochrane Library of Systematic reviews and randomized controlled trials was searched using the term nitric oxide, which identified 3 existing systematic reviews on the use of nitric oxide for respiratory failure in preterm infants, infants born at or near term, and in children and adults suffering from acute hypoxemic respiratory failure. Additional references were culled from the bibliographies of these references. In addition, the manufacturer (INO Therapeutics) of inhaled nitric oxide (INOmax®) was contacted for relevant information on the marketing of this substance.

Background

Previously seen as a noxious pollutant and poison, nitric oxide (NO) plays a vital role in many physiologic processes, including vasodilation, neurotransmission, and inflammation. In vivo, NO accounts for the activity of endothelium-derived releasing factor.¹ It is derived from L-arginine in a one-step process synthesized by NO synthase in endothelium, neurons, and leukocytes. Leukocyte-derived NO synthase is inducible during infection and inflammation.²

L-arginine + O₂ + NADPH ® NO + L-citrulline + NADP

Nitric oxide dilates vascular smooth muscle, suppresses platelet adhesion/aggregation and leukocyte migration/adhesion, attenuates vascular smooth muscle proliferation, and under certain conditions exhibits anti-inflammatory and anti-oxidant properties.^3-5 Nitric oxide inhaled in high concentrations causes methemoglobinemia and is converted to NO₂, which exerts oxidant and cytotoxic effects.⁶

Physiologically, NO binds to the heme moiety of soluble guanyl cyclase, increasing the concentration of cyclic GMP, which relaxes vascular smooth muscle. Diminished NO synthesis, increased destruction, or reduced cellular sensitivity to its effects are associated with advanced age and have been noted in patients with hyperlipidemia, atherosclerosis, hypertension, chronic renal failure, and diabetes mellitus.⁶ Endogenous NO appears to play an important role in the transition to pulmonary circulation at birth and in the regulation of pulmonary vascular resistance.^7,8

Disposition and Toxicity of Inhaled Nitric Oxide. Between 75% to 90% of inhaled nitric oxide (iNO) in taken up by pulmonary capillary beds where it combines (predominately) with oxyhemoglobin to produce methemoglobin (MetHb). The latter is metabolized by methemoglobin reductase to hemoglobin and nitrate.⁹ Most of the absorbed NO is eventually eliminated as nitrate via glomerular filtration.

Nitric oxide is an evanescent compound with a half-life of £ 40 seconds. The reaction of NO with oxyhemoglobin limits the systemic effects of iNO, which tends to dilate only those vessels directly adjacent to alveoli that are being ventilated. At low oxygen saturation, NO can combine with deoxyhemoglobin, forming a nitrosylhemoglobin intermediate that, in the presence of O₂ converts to MetHb and nitrogen oxide. Nitric oxide also can combine with oxygen and water to form nitrogen dioxide and nitrite, respectively, which also can interact with oxyhemoglobin to produce MetHb and nitrate. Methemoglobin levels remain below 1% and NO₂ concentrations are generally <0.5 ppm when NO is administered at concentrations of 5 to 20 ppm. In patients receiving larger doses of iNO (80 ppm), MetHb levels may exceed 7%, and mean NO₂ values may exceed 2.5 ppm.⁹ Monitoring for PaO₂, methemoglobin, and NO₂ should accompany NO administration.

Nitric oxide can also form other cytotoxic intermediates such as peroxynitrite and nitrotyrosime in the presence of superoxide anion. Both NO and NO₂ are potentially directly toxic, capable of causing pulmonary edema and hypoxemia. Because NO inhibits platelet aggregation, it also increases bleeding time in neonates and adults.^10-12

FDA Approval of Inhaled Nitric Oxide

The Drug. Inhaled nitric oxide (INOmax®) was approved as an orphan drug in December 1999 for use in near-term and term infants (>34 weeks) with hypoxemic respiratory failure associated with clinical or electrocardiographic evidence of pulmonary hypertension. The orphan product designation carries with it a 7-year patent exclusivity for the use of iNO. Inhaled nitric oxide improves oxygenation in these infants and reduces the need for extracorporeal membrane oxygenation (ECMO), an effective but invasive procedure with significant potential morbidity and mortality. INOmax® is a gaseous blend of NO (0.1% or 0.8%) and nitrogen (99.9% or 99.2%) that is supplied in aluminum cylinders as a compressed gas.¹³

FDA approval was based on studies in neonates up to 14 days of age. The recommended dose is 20 ppm.¹³ Treatment should be maintained for up to 14 days or until the underlying oxygen desaturation has resolved and the neonate can be weaned from iNO therapy. In clinical trials, the NO delivery systems provided operator-determined concentrations of NO in the breathing gas, and the concentration was constant throughout the respiratory cycle. The FDA specified that INOmax® must be delivered through a system with these characteristics and which does not cause generation of excessive inhaled nitrogen dioxide.¹⁴ Inspired NO and NO₂ must be monitored using a properly calibrated analysis device with alarms. The concentration of NO₂ is dependent on the concentration of NO delivered, the concentration of oxygen with which it mixes, and the residence time in the delivery circuit. This system should be calibrated using a precisely defined calibration mixture of NO and NO₂.

The Device. At the time the FDA approved INOmax®, no devices were approved for the delivery and monitoring of this potentially noxious substance. On January 6, 2000, the FDA issued an order classifying the Datex-Ohmeda’s device (INOvent® Delivery System) as a Class III device. Such devices are not substantially equivalent to devices that were introduced or delivered for introduction into interstate commerce for commercial distribution before 1976, or to a device that was subsequently reclassified into Class I or Class II.¹⁴ On January 7, 2000, Datex-Ohmeda submitted a petition requesting classification of the components of the INOvent® delivery system.¹⁴

On January 11, 2000, the FDA issued an order to Datex-Ohmeda classifying the INOvent® Delivery System as a Class II device with special controls.¹⁴ The delivery system consists of 3 devices, to which the FDA assigned the generic names "nitric oxide administration apparatus," "nitric oxide analyzer," and "nitrogen dioxide analyzer." The special control developed by the agency is a guidance document, the purpose of which is to facilitate the preparation and the review of premarket notifications for the NO delivery apparatus, NO analyzers, and NO₂ analyzers, 3 devices that may be separately manufactured.¹⁵

Marketing of INOmax®

The marketing of INOmax® is based on method-of-use patents licensed by INO Therapeutics from Massachusetts General Hospital (personal communication, Ashleigh Palmer, INO Therapeutics, August 2001). The patents cover both use of the gas and the device for delivering and monitoring NO for immediate inhalation into the ventilatory circuit. In North America, the INOvent® delivery system is currently available under exclusive license through INO Therapeutics. To ensure safe and effective delivery of the therapy, INO Therapeutics offers INOmax® as part of a commercial package, called INOtherapy™, which includes the following components: INOmax® (nitric oxide) for inhalation, INOvent® delivery system, INOcal® calibration mixtures, and the INO Therapeutics service. The INOvent® system was selected for ease and simplicity of use, its safety record, and its compatibility with various ventilators in common use (personal communication, Ashleigh Palmer, INO Therapeutics, August, 2001).

During the 1990s and prior to approval of INOmax®, INO Therapeutics provided the iNO free of charge to sites and investigators operating under an Investigational New Drug Application. After FDA approval, the gas and delivery device and services were made available to "inhaled nitric oxide ready" facilities. During the initial marketing phase of this product, services included stocking of NO cylinders, and at least 2 devices. When therapy needed to be initiated, the company was notified, and supplied at least one additional device for back-up and additional cylinders at a cost of $3,000/day/patient regardless of the duration of use. One hundred eight delivery centers are maintained nationwide, capable of reaching any center within 2 hours. This practice and price created a backlash among practitioners and hospitals who had been getting the drug free and fostered the impression that the company was taking advantage of a monopoly situation by bundling the product, device, and maintenance agreements. The cost has been justified on economic grounds, given the high costs of ECMO, which iNO reduces the need for, in properly selected patients.^16-19 In one limited, short-term cost-effectiveness analysis of the use of iNO versus oxygen administered to near-term infants with severe respiratory illness who were referred for consideration of ECMO, the cost-effectiveness ratio for iNO was approximately $23,000 per life saved.²⁰ Additional pharmacoeconomic studies are needed within the framework of clinical practice to place the current cost of NO therapy in proper perspective. Subsequently, INO Therapeutics has modified the unitary charge approach. Administration devices are now equipped with a timing device that records the actual duration of administration. Instead of a flat $3,000/day fee per patient, hospitals are charged a usage fee at a rate of $125/hour, regardless of the number of patients who might receive therapy in a given day from a given cylinder.

Clinical Uses of Inhaled Nitric Oxide

Nitric Oxide for Respiratory Failure in Infants Born at or Near Term: Persistent pulmonary hypertension of the newborn (PPHN) is an important cause of cardiorespiratory failure, either as a primary condition or secondary to hyaline membrane disease, meconium aspiration, infection, congenital diaphragmatic hernia, and other diverse cardiac and pulmonary disorders.^21,22 The syndrome is characterized by high pulmonary vascular resistance that causes extrapulmonary right-to-left shunting of blood across the ductus arteriosus, the foramen ovale, or both. It is the most common factor in infants who require treatment with ECMO. Recent evidence indicates that infants with persistent pulmonary hypertension have low plasma concentrations of arginine (the precursor for NO) and NO metabolites, a pattern that is based on the genetically determined capacity of the urea cycle, which normally supplies arginine as an intermediate.²³

Prior to the use of iNO, conventional therapies included high concentrations of inspired oxygen, hyperventilation, high-frequency ventilation, induction of alkalosis, use of positive inotropic agents, systemic vasodilators, paralysis and sedation.²⁴ Results have been mixed at best. None of the above therapies has been proven by prospective randomized trials to reduce mortality or the need for ECMO. Much of the morbidity and mortality in neonatal lung diseases results from therapies targeted at enhancing gas exchange (eg, bronchopulmonary dysplasia as a result of mechanical ventilation, oxygen toxicity, and the risks inherent in ECMO).

The physiologic effects of iNO were first reported in infants with PPHN in 1992.^25,26 The early indication was that some neonates could avoid ECMO as a result of iNO.²⁷ Subsequently, 11 randomized trials have been conducted that analyzed outcomes in term or near-term infants (>34 weeks gestation) with hypoxemia due to either lung disease or pulmonary hypertension with right-to-left shunting who were treated with iNO.^28-38

In the 7 trials that reported on subsequent requirements for ECMO, meta-analysis showed a significant effect of iNO in reducing this intervention and a reduction in the combined outcome of death or requirement for ECMO.³⁹ When analyzed separately, none of the 8 trials that reported mortality data found a significant effect, nor did the meta-analysis. Most studies found large increases in Pa0₂ within 30 to 60 minutes after treatment and significant improvements in the oxygenation index. The use of high frequency oscillatory ventilation plus iNO may be more successful than either treatment alone.³²

Large increases in oxygenation in response to iNO probably represent reversal of extrapulmonary right-to-left shunting of blood secondary to pulmonary vasodilation; lesser improvements in oxygenation represent improvement in ventilation-perfusion matching secondary to redistribution of pulmonary blood flow to well-ventilated lung regions.⁴⁰ Infants with diaphragmatic hernia do not appear to share these benefits of iNO.^29,33 Limited controlled data indicate that survivors treated with iNO have comparable neurodevelopmental outcomes, consistent with previous uncontrolled reports.^41-44 Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary diseases, or neurological sequelae.

Information available at this time suggests that iNO therapy in hypoxemic term or near-term neonates decreases their need for ECMO. Inhaled nitric oxide also can improve oxygenation in some newborns with hypoxemia who have V/Q disturbances or intrapulmonary right-to-left shunting, although effects may be suboptimal when lung volume is decreased in association with pulmonary parenchymal disease.⁴⁵ It is not known whether earlier intervention may improve mortality.

Unlabeled Uses: The American Academy of Pediatrics recommends that administration of iNO for indications other than those approved by the FDA or in other neonatal populations, including compassionate use, remain experimental. As such, iNO should be administered according to a formal protocol that has been approved by the FDA and the institutional review board and with informed consent. Generally, use should be offered only at centers that are qualified to provide multisystem support, including on-site ECMO capability. If ECMO is not available on site, mechanisms for timely transfer of infants to a collaborating ECMO center should be established; transfer must be accomplished without interruption of iNO therapy, given the potential for progressive worsening of oxygenation upon abrupt withdrawal of iNO.⁴⁶

Inhaled Nitric Oxide for Respiratory Failure in Preterm Infants

Since the introduction of surfactant, mortality from respiratory failure in preterm infants has fallen significantly.⁴⁴ However, some infants do not have adequate improvement in oxygenation following surfactant treatment. Three randomized trials have examined the use of inhaled nitric oxide in preterm infants who had either a high risk of developing bronchopulmonary dysplasia,⁴⁵ a 50% predicted mortality,⁴⁶ or oxygenation indices between 12.5 and 30.⁴⁷ Although short-term improvement in oxygenation may occur (and one study showed a reduction in days receiving assisted ventilation), iNO had no significant effect on mortality, the incidence of intraventricular hemorrhage, or the occurrence of bronchopulmonary dysplasia. Current evidence does not support the use of iNO in preterm infants with hypoxemic respiratory failure.⁴⁸ However, three multicenter trials are currently investigating the potential use of iNO in preterm infants.

Inhaled Nitric Oxide for Acute Hypoxemic Respiratory Failure in Children and Adults

Acute hypoxemic respiratory failure (AHRF) occurs in patients with acute respiratory distress syndrome (ARDS), acute lung injury, or other causes of hypoxemic respiratory failure. Hypoxemia is a consequence of ventilation/perfusion mismatch. Because mortality in AHRF is often due to the primary disease process rather than hypoxemia per se, treatments aimed at improving lung oxygenation may not affect ultimate outcome. ARDS is defined as acute onset of non-cardiac pulmonary disease in patients >1 month of age, associated with diffuse, bilateral pulmonary infiltrates on chest radiograph, a pulmonary wedge pressure of 18 mm Hg or absent left atrial enlargement, and hypoxemia defined by a hypoxia score (PaO₂/FiO₂) less than 200 mg Hg, irrespective of positive end-expiratory pressure. Acute lung injury incorporates a hypoxia score between 200 and 300 mg Hg in addition to the other ARDS criteria. When the ARDS criteria are not fulfilled, patients experiencing respiratory failure have "hypoxemic respiratory failure."⁴⁹

Five peer-reviewed, published randomized trials have been conducted in children or adults with AHRF that: (1) compared iNO with "inhaled placebo" or no treatment and maximal conventional ventilator therapy; (2) obtained data during and after therapy; and (3) did not employ multiple cross-over arms.⁵⁰ Outcome measures included improvement in oxygenation as measured by the oxygenation index and hypoxia scores (PaO2/FiO2), ventilator-free days over a 30-day period, duration of stay in the hospital or intensive care unit, and mortality.^51-55 Temporary improvements in arterial oxygenation in the first 24 hours of treatment were reported, but no significant differences in mortality or other clinical indicators of effectiveness have been realized.^51,55

Other Unlabeled Uses. Case reports and case series have noted potential utility of iNO in a number of other conditions including the treatment of pulmonary hypertension following cardiopulmonary bypass or the use of a ventricular assist device, for mitral valve replacement, coronary bypass graft, heart or lung transplantation, and for pulmonary embolism.^56-60 Also, iNO has been used for the treatment of respiratory failure in children with serious burns, and in patients undergoing lung transplantation, or suffering from progressive congestive heart failure, status asthmaticus, sickle cell acute chest syndrome, or high-altitude pulmonary edema. ^61-67

Use in infants with congenital heart disease is controversial. In one small randomized trial, iNO did not substantially improve pulmonary hemodynamics and gas exchange immediately after operation for congenital heart disease and did not significantly decrease the incidence of pulmonary hypertensive crises.⁶⁸ Another small randomized controlled trial found that low doses of iNO decreased the incidence of pulmonary hypertensive crises in infants treated after congenital heart surgery.⁶⁹

Although product labeling warns against use of iNO in pregnancy, case reports have noted beneficial effects for the treatment of pregnancy-associated pulmonary hypertension or Eisenmenger syndrome.^70,71 Inhaled nitric oxide does not improve function in patients with exacerbation of chronic obstructive pulmonary disease.⁷²

Summary and Conclusion

Inhaled nitric oxide is effective in decreasing the requirement for ECMO in term and near-term neonates with persistent pulmonary hypertension. Beneficial effects on mortality have not been shown, but studies are underway to evaluate the earlier use of iNO in these infants. Inhaled nitric oxide has been used in the treatment of acute hypoxemic respiratory failure in preterm infants, as well as older children and adults. Use in these patients and for several other conditions remains promising but experimental.

The marketing of INOmax® is based on method-of-use patents. Preliminary pharmacoeconomic analyses support the concept that iNO is a cost-effective intervention, but additional data obtained within the framework of clinical practice are needed. Recent changes in the charge-back arrangements to allow for hourly use of INOmax® in multiple patients may relieve some of the budgetary pressure on hospital pharmacies and respiratory therapy departments.

RECOMMENDATION

As recommended by the Council on Scientific Affairs, the AMA House of Delegates did not accept Resolution 417 (I-00).

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