Nitric oxide gas improves treatment of deadly infant lung disease

BOSTON — February 26, 1997 — Treatment with nitric oxide, a common gas, significantly improves the condition of many infants with persistent pulmonary hypertension of the newborn (PPHN), a rare but life-threatening condition affecting full-term babies. In a study published in the Feb. 27 New England Journal of Medicine, members of a multicenter research collaboration, led by Jesse D. Roberts, MD, of the Massa-chusetts General Hospital, report that breathing tiny quantities of nitric oxide doubled blood oxygen levels in half the treated infants. Treatment with a control gas mixture lacking nitric oxide produced similar improvement in only a few treated infants.

In addition to the MGH, the other institutions conducting the study are the University of California at San Francisco, State University of New York at Buffalo, University of Texas Southwestern Medical Center at Dallas, Yale University, University of Chicago and the Children’s Hospital of Philadelphia.

"One of the exciting things about this treatment is that its effects can be seen in minutes," says Roberts, who is a member of both the MGH Departments of Pediatrics and of Anesthesia and Critical Care. "It is obvious right away whether the baby is going to respond to nitric oxide, and if it doesn’t, you can stop administration with no harmful effects. It’s so safe and so simple that it probably should be available in most hospitals where babies are born."

PPHN affects between 1,000 and 2,000 newborns in the US every year. When an infant is born and takes its first breath, the blood vessels within the lungs nor-mally expand, exposing large amounts of blood to life-sustaining oxygen. In PPHN, the lung’s vessels do not expand, preventing sufficient blood from entering the lungs. The baby seems to breath normally but cannot get enough oxygen into the blood.

For most infants with PPHN, therapy with inhaled oxygen and mechanical ventilation is ineffective, and many of them may die. Other therapies that can be used have significant hazards and limitations. Intravenous drugs to relax lung blood vessels affect the entire body, often producing dangerous drops in blood pressure. Use of ECMO, an artificial lung machine, involves surgical intervention and blood-thinning medication with attendant risks. In addition, because ECMO is so expensive, the treatment is only available at major medical centers.

Over the past decade, studies have shown that nitric oxide gas — not to be confused with the anesthetic nitrous oxide — plays many roles in the body, including relaxation of blood vessels. At the MGH, anesthesiology researchers pioneered the study of nitric oxide by inhalation and were the first to show that the gas could relax blood vessels in the lung alone, without affecting the rest of the circulatory system. In 1992, Roberts and a group of MGH colleagues conducted a pilot study of brief nitric oxide administration in six critically ill infants with PPHN. Five of the six recovered, and none showed any ill effects from the gas.

In the current study, 58 infants treated at the participating institutions for severe hypoxemia (low blood oxygen) and PPHN received oxygen mixed with low levels of a study gas — either nitric oxide or nitrogen — through a ventilator for 20 minutes. (Nitro-gen is the most common gas in normal air.) If their condition improved, measured by increased blood oxygen levels, they continued to receive the study gas at progres-sively lower concentrations. If an infant’s condition did not improve after 20 minutes, the study gas was discontinued and other therapies, including ECMO, attempted.

Of the 30 infants who received the nitric oxide study gas, 16 (53 percent) showed significantly increased blood oxygen levels during the initial 20-minute period. In contrast, only 2 (7 percent) of the 28 infants receiving the control gas showed similar improvement. Of the 16 infants who responded to initial nitric oxide therapy, 12 (75 percent) continued to maintain adequate blood oxygen levels with continued nitric oxide administration. The need for ECMO was significantly reduced in the group receiving nitric oxide, 40 percent versus 71 percent for the control group. In both groups of infants, all of whom were critically ill, two babies eventually died; but none of the deaths nor any significant ill effects could be attributed to nitric oxide treatment.

"In those babies who respond to nitric oxide, we’ve seen a spectacular improvement in the oxygen levels needed to protect vulnerable brain cells," says Warren M. Zapol, MD, Chief of Anesthesia and Critical Care at the MGH and senior author of the paper. "The therapy is fast, safe, effective and so simple it can be delivered anywhere, from major medical centers to third-world hospitals. We expect that it will be made available across the country as early as this summer."

Roberts adds that widespread use of inexpensive nitric oxide therapy, rather than costly high-technology interventions like ECMO, could save more than $1 million in medical costs annually in the US while improving patient outcomes.

The MGH holds a patent on the use of nitric oxide by inhalation to treat pulmonary disease and has licensed the therapy in the United States to Ohmeda, the health care business of the BOC Group.

Contact Sue McGreevey in the MGH Public Affairs Office.

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