At Home with Nitric Oxide

At Home with Nitric Oxide

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At Home with Nitric Oxide

nitric boy in bath faded

NO Shows Promise as a Long-term Therapy for Chronic Disease

By Francie Scott

Stephen Kenny expected to die three years ago. Crippled by pulmonary fibrosis and pulmonary hypertension, he could barely walk, even with 6 liters per minute of supplemental oxygen. Today, the San Diego resident often takes two-hour walks, pushing a 40-pound cart containing two cylinders: one oxygen and the other nitric oxide.

Kenny exercises in his backyard swimming pool tethered to the therapeutic gases with 20 feet of tubing. Although he is 65 years old, he is near the top of the lung transplant list and expects to undergo surgery soon. Kenny attributes his dramatically improved health to Richard Channick, MD, and the small breaths of nitric oxide Dr. Channick prescribes for him.

“I am their poster boy,” Kenny says, explaining that he “gasps like a fish,” if he loses the nitric oxide for five minutes.

Kenny isn’t Dr. Channick’s only poster boy. In another suburb of San Diego, 4-year-old Luke Nothaft plays energetic games. He swings a baseball bat like a pro and fights like a Jedi knight with a light phaser. Luke also wears a nasal cannula with two ports; one is for oxygen, and one is for nitric oxide.

Born with diaphragmatic hernia, Luke’s corrective surgery left him with dangerously high pulmonary artery pressures that could eventually damage his heart. His parents learned of Dr. Channick’s work, and Luke started nitric oxide therapy in April. They’re delighted with the results.

“Before the nitric oxide, his oxygen flow was set at 2.5 liters,” explains Ruja Nothaft, Luke’s mother. “Now he is down to 1 liter. His energy level and activity level have dramatically increased.”

Clinicians know that nitric oxide is a powerful vasodilator but encountered difficulty finding a therapeutic home for NO therapy. In critical care, some ARDS patients seemed to improve with nitric oxide, but others did not. Although clinicians continue to test the efficacy of the gas in acute lung injury, they have not yet identified a subgroup of patients who respond to supplemental NO.

The role of NO in neonatology is clearer, with many clinicians showing they could get term babies through a crisis with nitric oxide therapy and avoid a stint on the invasive ECMO pump.

Dr. Channick, an associate professor of medicine at the University of California San Diego Medical Center, introduced a new twist when he sent his first patient home with a cylinder of NO four years ago, offering the gas as long-term therapy for chronic diseases like primary pulmonary hypertension.

“I think it has a big future,” the doctor says enthusiastically. He explains that NO not only lowers pulmonary artery pressure, but it also vasodilates functional areas of the lung. By shifting the blood flow towards the functional regions, NO improves overall gas exchange.

Dr. Channick currently has four patients on NO at home, but he has treated 12 patients during the past five years.

While he has concentrated on patients with primary pulmonary hypertension, Dr. Channick believes NO may have its greatest application to pulmonary fibrosis or COPD. He is currently preparing protocols for a multi-center study to evaluate efficacy.

Promising data from animal studies first convinced Dr. Channick that continuous NO therapy might be beneficial for patients with pulmonary artery hypertension. He then focused on devising a system to deliver the gas and found a commercial device to deliver pulsed NO through a nasal catheter. He could deliver oxygen through one tube and NO through the other.

“We found that the gas worked well with very small amounts delivered at the beginning of each breath,” he explained.

Dr. Channick selected a woman with advanced primary pulmonary hypertension as the first patient to take NO home.

“There were no other treatment options for her,” he explains.

This first patient, Lynn Larson, who now lives in Phoenix, responded beautifully, and Dr. Channick reports five years later the NO “erased most of her symptoms, and her pulmonary artery pressure is basically normal now.” Larson still uses NO continuously. “I have complete faith in nitric oxide,” she says. “It made more sense to me than anything else.”

Larson says doctors finally diagnosed her pulmonary hypertension four years ago, when she was 44 years old. Prior to that, she was told she was “a hysterical female,” and offered tranquilizers. Although she welcomed the diagnosis, she worried about the shadow it cast over her future. Doctors said they expected her life expectancy to be about one year.

After two bouts with cervical cancer, the first when she was 21, Larson was no stranger to bad news at the doctor’s office. Pulmonary hypertension was just one more battle. She lived in San Diego at the time and ended up in Dr. Channick’s office.

She wears a small cannula, which she describes as “a great source of conversation,” and carries the NO cylinder under her arm easily.

“I’m really used to it,” she says.

In the past, Dr. Channick notes, the disease was debilitating and eventually terminal. Motivated by these good results, Dr. Channick enrolled other patients in his trial, including Kenny and Luke.

Luke’s cardiologist, Abraham Rothman, MD, chief of pediatric cardiology at UCSD Medical Center, blazed a trail by supporting continuous NO therapy for Luke. Although he has not yet tested for clinical benefits, he says, “He is better in terms of symptoms.” Dr. Rothman has scheduled a catheterization for Luke in the near future. Based on this initial positive experience, Dr. Rothman is about to start a 1-year-old child on NO. Although this child’s diagnosis is unclear, primary pulmonary hypertension is suspected, and he believes the NO therapy may be beneficial.

David Wessel, MD, who directs the cardiac ICU at Children’s Hospital of Boston, also wondered about the efficacy of home NO therapy for some of his young patients. But he had safety concerns and did extensive testing at the hospital before sending anyone home with an NO cylinder. Dr. Wessel has not completed his trial and did not wish to discuss details, but he acknowledged that he has sent a few patients home with NO.

“We’ve limited long-term exposure to six months,” he said.

The prospect of spiraling pulmonary artery pressures if the gas supply was accidentally interrupted haunted Dr. Wessel. He explains that NO remains in the blood stream for about two minutes after the supply is disconnected. If patients suffered a withdrawal response, they could end up with higher pulmonary artery pressures than their original pressures that indicated NO therapy in the first place. To prevent this scenario, Dr. Wessel and his team tested patients by abruptly withdrawing the NO.

“The patients have to prove to us that they do not have a withdrawal response before they take nitric oxide home,” he said.

To reduce this reaction, which is more risky in children, Dr. Wessel and his colleagues are exploring the efficacy of classes of drugs that may counteract the withdrawal response, thus increasing the safety of NO therapy.

“If you wanted to prolong the effects of the drug when it is withdrawn and make it safer, combine it with phosphodiesterase inhibitors,” he suggests.

He explains that NO has the ability to inhibit smooth muscle proliferation and helps grow new blood vessels. By targeting a substance inside the smooth muscle called cyclic GMP, Dr. Wessel believes clinicians could prolong the therapeutic effect of NO after the gas is withdrawn. He is evaluating drugs in the Viagra family to achieve this result.

Chuckling about this unusual use for the agent that appears to cure impotency, Dr. Wessel notes, “It’s a great drug to relax blood vessels.”

Therapeutic use of NO has always raised concerns about toxicity, and clinicians are careful to deliver NO supplements in small doses. Dr. Channick believes the doses he prescribes for patients are well within those limits.

“I don’t think there is toxicity at the dose and the way we deliver it,” he says.

Although Dr. Wessel said he worries about toxicity, he also believes that the dose and delivery methods he uses are safe for his patients.

The doctors do use different devices to deliver the NO gas. Dr. Wessel, who only sees pediatric patients, mixes the NO and O2 at a “Y” shaped tube just before the gas enters the cannula, while Dr. Channick uses a pulsing device and delivers NO and O2 through a split cannula.

Although Dr. Wessel is “cautiously optimistic” about continuous NO for a selected number of patients with chronic lung disease, he believes the field is still “highly investigational.”

Dr. Rothman is “cautiously optimistic” about NO therapy, but he shares some of Dr. Wessel’s concerns. He notes that natural production of NO within the body may diminish when patients get the gas from a tank, which may leave a patient “with none on board,” if the supplemental supply ceases. He also raises questions about the long-term effects of NO therapy.

“We don’t know if (patients) will have a sustained benefit,” he says.

Dr. Channick advocates additional studies too, and he is delighted about the potential for a multi-centered funded study in patients with chronic lung disease.

In the meantime, patients like Kenny demonstrate the benefits of NO therapy. Back in 1997, he had traveled from his home in New York City to Florida for a vacation and ended up in a hospital bed at the University of Florida in Gainesville.

His heart caused this crisis, and he was soon hustled to the operating room for triple bypass surgery. Recovering from the anesthesia, Kenny learned that nitric oxide therapy eased his pulmonary hypertension.

Kenny intended to enroll in a lung transplant program in Gainesville, but his daughter-in-law persuaded him to move to San Diego to be close to the University of San Diego Medical Center where she was a medical resident. He and his son drove across country in a car loaded with oxygen cylinders, and Kenny was accepted into the lung transplant program there. Even without the transplant, both patient and physician believe nitric oxide changed Kenny’s quality of life.

“He was essentially bedridden, now he walks several miles a day,” Dr. Channick says.

Francie Scott is senior editor of ADVANCE.

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