A Greenhouse Gas Is Used in the Treatment of Respiratory Failure

by Daniel E. Supkis, Jr., M.D and Mark Graber

Medical science has long made the improbable probable, saving lives and improving quality of life. Upon the introduction of medical devices that can deliver safe quantities of the poisonous gas nitric oxide to help patients with respiratory and other illnesses, the FDA requested ASTM Committee F29 on Anesthetic and Respiratory Equipment to provide standards for these devices. Dr. Daniel Supkis and Mark Graber explain the delicate process of delivering NO to patients and how ASTM standards now in development will increase the safety of this procedure.

Research Discovery

Three American researchers recently won the Nobel Prize for their work in the 1970s and 80s in characterizing nitric oxide’s role in the relaxation of blood vessels. As is often the case with medical research, their published results opened the doors for other researchers to examine the reported effect and its potential applications in modern medicine. Figure 1 shows that in 1990 the number of published scientific articles containing reference to nitric oxide (NO) numbered about 300, while in 1999 the number was over 5,000. Many of these studies have centered around the effectiveness of inhaled nitric oxide in the treatment of different life threatening lung conditions found in both neonates and adults.

Nitric Oxide Approved for Use

In December 1999 the U.S. Food and Drug Administration approved the use of inhaled NO as a pulmonary vasodilator for the treatment of hypoxic respiratory failure (HRF) in full- and near-term infants (greater than 34 weeks gestation). HRF is a condition that affects an estimated 30,000 full- and near-term infants per year. The heart and lung systems of patients diagnosed with HRF are not capable of transporting adequate oxygen to the tissues, creating a condition sometimes referred to as “blue baby syndrome.” Conventional treatment for hypoxic respiratory failure in infants traditionally consists of high frequency mechanical ventilation (the use of smaller volumes of oxygen at more rapid rates (usually over 50 breaths per minute)), and can progress to the need to initiate extracorporal membrane oxygenation (wherein deoxygenated blood is removed, warmed and passed through an oxygenator, then returned to the patient). These treatments carry significant morbidity and mortality and have limited success rates. Neonatologists and cardiac surgeons expect nitric oxide (which allows more oxygen to be transported through the lungs to the blood), when used with ventilatory support and other drugs, to reduce the need for the highly invasive procedure currently used in treating infants with HRF.

Research, Hazards, and Approved Uses

Although inhaled nitric oxide is currently only approved for use in the treatment of HRF, researchers continue to study the possible effects of NO on a wide variety of illnesses such as intestinal eschemia, clotting disorders, and sickle cell anemia where the relaxation of blood vessels is believed to hold some benefit.

Due to nitric oxide’s toxicity (see sidebar), the current approved use of the gas requires its delivery in very small quantities (i.e., less than 100 parts per million (ppm)) into a gas stream provided by a ventilator, which in turn delivers the gaseous mixture to the patient’s lungs. Intensivists and other specialists find that the process of adding NO to a gas stream is a more difficult task than the description implies. The hazards of using NO include its inadvertent combination with oxygen, forming deadly nitrogen dioxide. The Occupational Safety and Health Administration has set the eight-hour time-weighted average exposure limits of nitrogen dioxide at five ppm (in contrast with the recommendation of 25 ppm for NO (see sidebar on right)).

Another hazard involves the hydration of nitrogen dioxide with moisture in the respiratory tract, forming lung-destroying nitric acid. In this reaction, the water that is present in respiratory gases and on the inner surface of the respiratory tract combines with nitrogen dioxide to produce this corrosive acid.

A third hazard involves confusion of state-of-the-art electronic ventilators and monitors through introduction of the additional gases of NO and the carrier gas nitrogen. Nitric oxide also carries the risk of drug withdrawal. Clinical studies have shown that abrupt withdrawal of nitric oxide therapy can be harmful to patients and can lead to the decreased ability of the lungs to deliver oxygen to the blood. As a result, patients must be weaned gradually from nitric oxide therapy.

A Standard Needed—and Requested by the FDA

In the middle of 1998 ASTM Committee F29 on Anesthetic and Respiratory Equipment approved a new work item to begin the development of a standard so that a minimum degree of safety would be applied to nitric oxide delivery systems. The need for the standard originated from a proliferation of in-house designed systems and a request from 5the U.S. Food and Drug Administration to have a commercially available standard.

F29’s working group realized that the nitric oxide delivery device is actually three different devices used in combination, necessitating three standards. The three standards under development are:

• Specification for the Safety of Nitric Oxide Monitors for Use with Nitric Oxide Delivery Systems;

• Specification for the Safety of Nitrogen Dioxide Monitors for Use with Nitric Oxide Delivery Systems; and

• Specification for the Safety of Nitric Oxide Delivery Systems.

The FDA has participated actively in the development of the three standards, bringing in technical experts from a variety of fields to the standards development process. NIST (the National Institute of Standards and Technology), at the invitation of the FDA, has actively participated in standard drafting for gas accuracy, calibration, and testing procedures. This series of standards will differ significantly from other F29 standards in that all the requirements found in the FDA Guidance document for anesthetic and respiratory care equipment used for device evaluation are included within the standard. It is hoped that the FDA will be able to adopt the nitric oxide standards in their entirety, without major exceptions. //

Copyright 2000, ASTM