This writing is intended to briefly introduce ARDS patients, their families, and significant others, with the properties of nitric oxide and the clinical implications associated with the use of this gas. Nitric oxide (NO) should not be confused with nitrous oxide (N20), the mild anesthetic often used by dental professionals that is more commonly known as "laughing gas." As a matter of fact, nitric oxide was known as a common environmental pollutant and contaminant during the manufacturing process of nitrous oxide. NO is normally manufactured from the reaction of sulfur dioxide with nitric acids. Nitric oxide is a component of smog that can be measured in urban area air at 10 to 100 parts per billion (ppb), is naturally produced in the body in the upper and lower airway at 100 to 1000 ppb, and is present in cigarette smoke at 400 to 1000 parts per million (ppm). Clinical research found that the concentration of exhaled NO is increased during exercise and in patient's with asthma.

Inhaled NO is a relatively new United States Food and Drug Administration (FDA) investigational drug and numerous facilities are involved in clinical trials utilizing this gas. Until approved by the FDA, its use is limited to those facilities that have gone through the application process for drug evaluation and research and have been granted permission (known asan Investigational New Drug [IND] number) to conduct such studies utilizing NO. In addition, an informed consent procedure must be obtained from each patient or legal representative prior to the administration of NO.

Physiology of ARDS

Those of you familiar with this newsletter may have as much information on ARDS as many physicians and researchers. Nevertheless, a limited review of the pulmonary disease ARDS is necessary to gain an understanding of the way in which NO affects this pulmonary ailment.

Patients with ARDS, whether precipitated by inhalation of vomited stomach contents (aspiration), injury, pneumonia, inhalation of toxic substances, or a severe infection somewhere in the body (sepsis), usually all have high blood pressure in the vessels leading to and around the lungs (pulmonary hypertension.) Also, under normal conditions, if the tiny air sacs in the lung (alveoli) do not receive enough air or are collapsed (atelectasis), the blood vessels supplying these alveoli will constrict (become smaller or narrower). In ARDS however, these collapsed or underventilated alveoli continue to receive full blood supply from the surrounding blood vessels (capillaries). Since these collapsed or underventilated alveoli are not receiving oxygen, they are not capable of providing oxygen to the blood stream. The net effect may be a severe reduction in oxygen levels in the blood stream.

Basic Science

Certain substances that occur naturally in the body exert control over blood flow in and around the lungs. These substances can cause blood vessels near the lungs to dilate (become wider or larger, vasodilation). They produce this vasodilation by causing cells lining the blood vessels to produce the gaseous product NO. NO accounts for the physiological effects of vasodilating drugs such as nitroglycerin; a drug commonly used to treat high blood pressure. Recent studies have found that excess NO production in the body plays a role in the massive vasodilation and low blood pressure associated with septic shock syndrome.

Since NO exists in a gaseous form, it can be applied to the pulmonary vessels by administering it as an inhaled gas. What this means, is that when NO is inhaled, it selectively dilates blood vessels in only those lung segments that are actively participating in gas exchange (oxygen & carbon dioxide) at the alveolar-capillary level. In other words, this increases the blood flow to areas of the lung where oxygen is being provided and thus improves oxygen levels in the body. This is known as ventilation-perfusion (V/Q) matching.

NO was not the first drug discovered that causes pulmonary vasodilation. There are several other drugs that are known vasodilators that have been on the market for years. These include the aforementioned nitroglycerin and nitroprusside. The shortcoming of these types of drugs is that they increase the pulmonary blood flow to all lung segments, including those that are not well ventilated. This further inhibits oxygen delivery to the blood stream because capillaries are dilated that are in contact with alveoli that are not providing or do not contain oxygen. (See fig. 1).

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fig. 1

Fig. 1. A. Schematic of vasoconstriction of pulmonary bed with normal and atelectatic alveoli. B. Nitroprusside (NTP) causes non-selective vasodilation of all pulmonary arteries, which may worsen ventilation-perfusion (V/Q) matching. C. Inhaled nitric oxide (NO) dilates only ventilated alveoli, an outcome that improves V/Q matching. (From Lunn R: Subspecialty clinics: Anesthesiology; Inhaled nitric oxide therapy. (Mayo Clin Proc 1995; 70:247-255; with permission.)

After the NO is inhaled and passes through the lungs and into the patient's blood stream, its effects are quickly deactivated. This is because NO quickly reacts with the iron-containing pigment of the red blood cell that functions to carry oxygen from the lungs to the tissues (hemoglobin). Hemoglobin inactivates NO and thus when it is carried to the rest of the body, it does not cause vasodilation to blood vessels beyond the lung area. This is in stark contrast with some of the other pulmonary vasodilator drugs that not only cause vasodilation of blood vessels in and around the lungs, but also cause vasodilation throughout the body. This can potentially lead to a serious decrease in a patient's blood pressure.

Gas Delivery Systems

As mentioned earlier, the way in which this drug is administered is simply by providing the gas for the patient to inhale. There are a variety of delivery systems that are presently in use. These either encompass a homemade or "rigged" system or a commercially available delivery system. They can provide gas delivery via a ventilator circuit, a facemask, or a nasal cannula.

The basic design and goal of each system is to provide a system for safe gas delivery and precision gas analysis or monitoring. If delivering the gas through a ventilator, either a continuos or intermittent flow of NO is fed into the inspiratory limb of the ventilator tubing. The rate of NO gas flow is controlled to maintain the desired levels of NO. Prior to the patient connection of the ventilator tubing, a sensor or sample line is connected to an analyzer that displays NO, NO2 (discussed in further detail later) and possibly oxygen levels. Usually the displayed NO and NO2 readings are measured in parts per million.

Safety Concerns

As with any drug, there are legitimate safety and toxicity concerns regarding the use of inhaled NO. Inhaling very high levels of NO (5,000 to 20,000 ppm) can be lethal causing a severe and acute accumulation of fluid in the lungs (pulmonary edema) and methomoglobinemia (described below). However, there is little evidence of such toxicity when the concentration is kept in the normal concentration range (1 to 80 ppm). Animals have breathed the gas in concentrations of 10 to 40 ppm, for six days to six months, without evidence of toxicity.

Virtually all patients receiving NO will also be receiving oxygen (O2). ARDS patients usually require high levels of O2. The by-product of NO and O2 yields nitrogen dioxide (NO2). NO2 is a highly toxic chemical. Although OSHA has set the safety limit for NO2 at 5 ppm, some investigators have found that prolonged exposure to even 2 ppm of NO2 can be injurious to the lungs. The amount of NO2 produced is dependent upon the levels of NO and O2 and the amount of time they are combined together prior to inhalation. Therefore, the lowest dose of NO and lowest concentration of O2 that achieve the desired effect are used. NO is usually fed into the ventilator tubing as close to the patient as possible, limiting the mixing time between O2 and NO.

All delivery systems monitor NO2 levels continuously. Newer delivery systems have been designed to limit NO2 production or inhibit its delivery to the patient, but situations may occur where the NO dose, the O2 concentration, or both, may have to be reduced.

One of the potential adverse side effects for patients receiving inhaled NO is the formation of methemoglobin. Methemoglobin is hemoglobin that cannot release the oxygen its carrying, nor can it combine with more oxygen. Therefore, it impairs the blood's ability to deliver oxygen to the tissues. This is a rare complication because the body contains certain chemicals and enzymes that convert methemoglobin back to hemoglobin. Nevertheless, blood levels should be closely monitored.

Patient Outcomes

Virtually since the discovery of NO for medical use in the mid-to-late '80s, it has been trialed on patients with acute respiratory distress syndrome (ARDS). Numerous formal studies have been completed that examined the effect NO had on ARDS patients. Virtually every study found that inhaled NO: 1) induced a redistribution of blood flow in the lungs to areas that were well ventilated, 2) reduced the blood pressure in the arteries surrounding the lungs, and 3) improved oxygen levels in the blood. How NO is capable of producing this effect was described earlier.

This research has also found that not every patient responds to inhaled NO in the same manner. Some patients have an almost immediate positive and recognizable response. While others have a limited response. Some studies have found that only about one-third of patients with ARDS due to sepsis had a positive response to inhaled NO. Among other factors, patients who had high blood pressure in the arteries near the lungs and who demonstrated a positive response to PEEP (positive end-expiratory pressure from the ventilator), appeared to be most likely to have a positive response to inhaled NO. For some patients, the positive response to inhaled NO appears to last for only hours to days while others respond positively for weeks. The reason for this phenomenon is still being investigated.

As mentioned earlier, ARDS patients are usually receiving high concentrations of oxygen. High-level oxygen administration for an extended period of time (usually > 72 hours) is well known for its pulmonary toxicity. Since NO has been proven to improve oxygen levels in the body, numerous clinical studies have found that adding NO to a patient's inhaled gas allowed a reduction in the oxygen concentration being delivered to the patient, and thus a concomitant reduction in possible toxicity to the lungs.

So how has NO affected mortality and length of intensive care unit or hospital stays? Since NO is a relatively new medical adjunct, there have been only a limited number of studies that have tracked and reported patient outcomes. Most research has focused on the physiological effects and patient response to inhaled NO.

In the largest study to date, 177 patients diagnosed with ARDS, from various test sites throughout the country, were randomized to receive NO or a control gas (placebo). Results of this study were: 1) an initial increase in oxygenation allowed a reduction in O2 concentration, 2) there were no differences among the groups receiving NO and the placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting a criteria for removal of mechanical ventilation, 3) however, the percentage of patient's alive and off mechanical ventilation by day 28 that were receiving 5 ppm of inhaled NO, was higher (62% vs. 44%) than the placebo group. Even though most other studies were conducted using much smaller patient populations, almost all had the similar findings of improved gas exchange, but no effect on mortality.

The difficulty in analyzing the success or failure of patient outcomes (mortality and length of stay) for patients with ARDS is that the reversal of lung failure may be obscured by the development of other organ system malfunctions that often may occur with ARDS.

Studies continue to address the use of NO to improve the overall prognosis for ARDS patients. Actual studies that are underway include methods of predicting which patients will respond positively to inhaled NO, the optimal dose concentrations, patient positioning during NO delivery, and examination of potential long term toxicity. Research has been proposed that would make comparisons of NO delivery devices on patient outcomes, and standardization of ventilator management during NO administration.

By Dean Miller, BSRC, RRT
Education Coordinator
Respiratory Care Services
St. Luke's Medical Center
Milwaukee, WI

The author would like to acknowledge the kind support of Dr. David Rein and Dr. Stuart Levy, St. Luke's Medical Center, and Dr. Robert Lunn, Sioux Valley Hospital, Sioux Falls, SD.