While infants are benefitting from the newly FDA-approved delivery of nitric oxide, hospitals are up in arms over the cost involved.

Since inhaled nitric oxide received the approval of the Food and Drug Administration (FDA) in December 1999, RCPs have been worrying about whether the drug will continue to be made available to several types of critically ill patients for whom it is still being tested. Some RCPs are also surprised at the amount that the manufacturer has decided to charge for supplying nitric oxide to the specific population for which the drug has now been approved: full-term and nearly full-term infants with hypoxic respiratory failure.

Clinicians agree that the company deserves to recoup its investment, but some seem shocked at the price involved. According to Mark Heulitt, MD, professor of pediatrics and critical care at Arkansas Children’s Hospital, Little Rock, the manufacturer plans to station delivery equipment in each hospital, with enough nitric oxide to last for several hours.

When an infant is born or admitted needing the therapy, RCPs can start treatment right away. They must also notify a subcontractor. Within 2 hours, the subcontractor will deliver a backup machine and enough gas for an extended treatment. A brief trial of therapy lasting 20 minutes or less will not generate a charge, but once backup equipment is on the way, the facilities will be charged $3,000 for the first day. After the first 24 hours, continued therapy will cost $125 per hour, up to a maximum of $12,000 (or 4 days of treatment). Clinicians, however, must apply for this cap. There will also be a charge for equipment stationed in the hospital that is not used.

It is an unusual arrangement, but inhaled nitric oxide is an unusual drug. According to Jeffery Griebel, clinical research therapist at The Children’s Hospital, Denver, the inhaled gas passes easily through cell membranes; once it enters the vascular endothelium, it causes an enzymatic change that results in the relaxation of vascular smooth muscle. Nitric oxide then attaches rapidly to hemoglobin, forms methemoglobin, and is inactivated.

Griebel explains that because nitric oxide acts locally in the lungs and is inactivated so quickly, it does not have a systemic effect. It is a selective pulmonary vasodilator. As such, it is uniquely appropriate for patients with pulmonary hypertension, since drugs that dilate blood vessels systemically can cause shock. One of the first uses of nitric oxide was in full-term infants born with rare, idiopathic pulmonary hypertension. In these infants, the lungs are healthy, but the pulmonary vessels are so constricted that blood cannot be oxygenated. Nitric oxide relieves the vasoconstriction and improves oxygenation. According to Griebel, two randomized trials1,2 have now shown that in these infants, and in infants with meconium aspiration and congenital diaphragmatic hernia, a significantly greater percentage of those who receive nitric oxide can be treated without resorting to extracorporeal membrane oxygenation (ECMO). It is this population for which nitric oxide has now been approved by the FDA.

According to Heulitt, however, nitric oxide has also been widely used as an investigational drug in many other types of patients in whom pulmonary hypertension occurs. These include premature infants, as well as children and adults with the adult respiratory distress syndrome (ARDS). It is also used after surgery for congenital cardiac defects; after heart, liver, or lung transplantation; and in the cardiac catheterization laboratory. According to Heulitt, physicians who want to test an unapproved drug must submit a protocol to the FDA. If the application is approved, the investigator receives a number under which he or she is allowed to prescribe the drug for evaluation in patients with a particular indication. For the past 6 years, the manufacturer has provided nitric oxide at no charge for testing under dozens of such investigator numbers.

According to Heulitt, while many investigators have been meticulous in collecting data under their investigator numbers, others have been lax. Nitric oxide has also been freely given under compassionate use clauses to many patients who do not fit the criteria for a particular investigator number. Because the patients who receive nitric oxide are critically ill, and many appear to benefit, it has become the standard of care in several clinical situations.

According to Bill Howard, MBA, RRT, director of respiratory care at New England Medical Center and the Floating Hospital for Children, Boston, RCPs are often called to bring nitric oxide to the operating room or the catheterization laboratory on short notice. “About 70% of our use of nitric oxide is for such off-label indications,” Howard says. He has been told that such use is still permissible, but now that the drug is FDA approved, the hospital may have to pay for it. “I’m worried about not having a budget to support that, but if a physician orders it, I feel obligated to provide it. If they call me from the operating room, I’m not in a position to say no,” Howard says.

One indication for which he would like to see nitric oxide approved is ARDS. Howard has witnessed successful rescues several times in ARDS patients who received nitric oxide, “but all our evidence is anecdotal,” he says. To convince the FDA, he knows that investigators will need to find an outcomes measure in which nitric oxide can be seen to make a significant, long-lasting difference in the results of treatment. According to Howard, in earlier studies with ARDS, patients who received nitric oxide showed improvement in oxygenation and a reduction in ventilator days, but, ultimately, there was no significant difference in survival.

According to Sandra Wadlinger, RRT, neonatal specialist for respiratory care at the Children’s Hospital of Philadelphia, studies of nitric oxide in premature infants have also been equivocal. “We’ve used it for rescue many times, but we are not sure whether it has helped,” Wadlinger says. Her group will coordinate a randomized, multicenter trial in premature infants that will investigate whether treatment with nitric oxide helps to reduce the incidence or severity of chronic lung disease. According to Wadlinger, the mechanisms of pulmonary hypertension are poorly understood in premature infants. “Nitric oxide might help them tolerate lower ventilator settings, which could reduce the incidence of chronic lung disease or give them better neurodevelopmental outcomes later,” she speculates.

The study will involve 726 infants. “That’s how many we need to study to achieve 80% power to detect a statistically significant difference,” she says. The study will also afford an opportunity to discover any deleterious side effects. “That is always a possibility,” Wadlinger warns. Nitric oxide appears to be so safe, and the doses are so low, that there is a great temptation just to go ahead and use it. This is working to its detriment. “The more we can place patients in approved, well-designed studies and stop random compassionate use (and stop breaking out of studies to give treatment), the sooner we can look at a larger patient base and have nitric oxide approved for other disease processes,” she says.

According to Heulitt, FDA approval of nitric oxide will be a disaster if it puts an end to research into the many questions that remain unanswered. “Some patients respond dramatically to nitric oxide, but they are few and far between. An occasional patient does very well with it, but when we look at the data in all the studies that are out there, including our own, we see that lung recruitment strategies have been employed at the same time nitric oxide was given. We don’t know if it is the lung recruitment, other interventions, or the nitric oxide that causes improvement,” Heulitt says.

Even in the approved population, he is disappointed in the data. In the face of those data, Heulitt believes that the high price of nitric oxide could discourage some institutions from using it. “In a lot of institutions, the data are just not strong enough to justify these kinds of charges. I know that many of our patients do not have money; they are on Medicaid, and so we have to think about whether we can absorb that kind of expense,” Heulitt says. “I know that the company has to recoup its investment, but it has built the whole company on this one product. It represents the manufacturer’s survival, and that worries me,” Heulitt says.

According to Griebel, the manufacturer has invested approximately $250 million in clinical testing since purchasing patents from Massachusetts General Hospital, Boston, in 1994. “I think that the respiratory community has become addicted to free gas. All you had to do was pick up the phone and order it, and you could use it any time you wanted to, but there has to be some payback for all of this,” Griebel says.

Griebel notes that the gas can be delivered to the patient in several ways. For example, one of the solenoids on the ventilator used to mix air and oxygen can be connected to a cylinder of nitric oxide. “On other ventilators, such as infant ventilators, we can actually just bleed it into the circuit through a basic flow meter,” Griebel says. In approving nitric oxide, however, the FDA required that it be delivered through an approved device. Only one is currently approved. Many institutions already own one or more of these machines, and they are generally well accepted, Griebel says. While hospitals that already own machines may not need the maintenance or calibration services included in the manufacturer’s proposed program, neonatal intensive care units that will now be starting to use nitric oxide for the first time may not have prior experience with the equipment.

The potential for toxicity to the patient is low, Griebel says. During administration, methemoglobin concentrations increase, but rarely is the increase greater than 1% to 2%. RCPs need to be vigilant, however, with certain infants who may be deficient in an enzyme needed to break down methemoglobin. “Premature infants and infants of Inuit descent can actually form methemoglobin pretty readily,” Griebel says.

Controlled studies are difficult in critically ill patients, and, in Griebel’s mind, this goes a long way toward explaining why nitric oxide has been used so widely in the absence of the usual randomized trials. Pulmonary hypertension can occur in many acute situations (for example, after heart transplantation). “That can be really tough on a new heart,” Griebel says, “but in that setting, it is hard to study nitric oxide. When you can’t get a child off the pump, you make so many changes, and you try so many things. You may throw some nitric oxide in there, but it is not a controlled situation.”

Griebel believes that once an indication is approved by the FDA, gaining reimbursement may be less of a struggle. “I think that is one of the concerns of the manufacturer. Its intention is to funnel users into studies so that additional indications can be approved. That is why it is discouraging nitric oxide use outside of formal studies,” he says.

The manufacturing company has set up a reimbursement hotline, with experts to assist hospitals in finding appropriate billing codes and obtaining reimbursement from insurance companies. The company’s program includes equipment as well as gas, and the subcontractor will be responsible for maintaining the equipment in readiness. The manufacturer has also agreed to buy back the machines, costing about $22,000 each, that many institutions have purchased in order to conduct research on nitric oxide.

The manufacturer has received permission from its investors to sponsor six randomized trials, and it hopes to coordinate many other collaborative projects. There will be studies in prematurity, sickle-cell disease, ARDS, and many other potential indications. The company encourages researchers to contact its medical affairs department to discuss protocols and be put in touch with potential collaborators. Although how the FDA plans to treat existing investigator numbers is unknown, the company stands ready to provide free nitric oxide to investigators who propose scientifically sound protocols.

Martin Keszler, MD, professor of pediatrics at Georgetown University Medical Center, Washington, DC, says, “If they are going to support research, it would go a long way toward alleviating my concerns.” Keszler has been vocal in criticizing the company’s plans for marketing nitric oxide and has publicized his concerns via Internet. He wishes that the company had communicated more clearly with the clinical community regarding its intention to coordinate and support research on additional off-label indications for nitric oxide use.

Although the manufacturer has not ruled out the possibility that it would supply gas to individual investigators with scientifically valid protocols, Keszler sees advantages to shifting much of the research currently being conducted under individual investigator numbers into larger, collaborative studies. “Multicenter studies are really the only way to study premature newborns or postoperative cardiac patients—the other groups of patients who fall outside the approved use,” Keszler says.

“I’m a clinician and my concern is my patients. Research is also my concern, however. I do not think we should just go ahead and use nitric oxide on everyone. In fact, I’ve been pressuring my colleagues to limit its use responsibly,” Keszler says. Thus, he is relieved to know that the manufacturer’s ability to market the drug will not put an end to research that needs to be done.

He is still concerned, however, about the price that the company is proposing to charge for approved use. “I have heard that the price is justified because the treatment enables the patient to avoid ECMO, but in the two key studies that led to FDA approval, almost half the control patients did not require ECMO,” he notes. “There will also be patients who will receive nitric oxide for 2 or 3 days and then go on to ECMO,” he says. Even if, ultimately, some insurance companies agree to pay for the new program, this will take time. In the interim, some hospitals are currently so short of cash that Keszler believes that they may not be able to purchase nitric oxide at the proposed price.

This, Keszler feels, explains why the respiratory care community is upset. “What do I do if I get an infant who needs nitric oxide today or tomorrow? Do I tell the parents that we have a therapy that might help, but because it has been approved by the FDA, I can’t afford to give it to their infant?”

India Smith is a contributing writer for RT Magazine.

1. Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med. 1997;336:605-610.
2. 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.