NO-body's Perfect

THE search for a selective pulmonary vasodilator that might improve, rather than worsen, arterial oxygenation has produced dozens of possible therapies and thousands of research reports. Over the past 10 yr, this search finally has been fruitful, and has brought several new therapies into clinical use. One such therapy is inhaled nitric oxide (iNO). In this issue, Stuart Lowson reviews some important alternatives to iNO therapy. 1Nitric oxide is a lipophilic, endogenous, free radical molecule with biologic activity identical to endothelium-derived relaxing factor (EDRF). It acts as an important messenger throughout the body by increasing local concentrations of guanosine 3′, 5′-cyclic monophosphate (cGMP), by nitrosylation of proteins, and by interacting with many blood elements and cell types. 2When inhaled, NO is delivered to areas of the lungs that are best ventilated, and, because it is rapidly bound to hemoglobin and inactivated in the circulation, can selectively vasodilate ventilated lung regions with increased vascular tone. It therefore can provide selective pulmonary vasodilation, improve arterial oxygenation, and through the NO-cGMP pathway and direct effects, modulate function within blood elements as well as at distant sites. 3–5 

Currently, substantiated indications for iNO include the treatment of hypoxic respiratory failure of the newborn (PPHN), 6–9and the assessment of pulmonary vascular reactivity in patients with pulmonary hypertension. 10To date, the U.S. Food and Drug Administration has approved nitric oxide only for the treatment of term and near-term (more than 34 weeks of gestational age) neonates with hypoxic respiratory failure associated with pulmonary hypertension. Inhaled NO clearly is effective for this indication and reduces the severity of subsequent lung disease and the necessity for extracorporeal membrane oxygenation in these infants. Off-label clinical use is widespread, and includes using inhaled NO to treat acute respiratory distress syndrome (ARDS); complications of lung and cardiac transplantation; pulmonary hypertension associated with congenital and acquired heart disease, as well as chronic pulmonary diseases; and to produce desirable direct effects on blood elements, specifically during the treatment of acute chest syndrome in sickle cell disease. 11 

Lowson describes several alternatives to inhaled NO, and focuses his review on inhaled prostacyclin (PGI²). Why do we need additional drugs if we have nitric oxide? Expense is only one criterion for drug selection. Efficacy, safety, availability, and ease-of-use are other important considerations.

Efficacy of inhaled NO for its off-label uses has been difficult to demonstrate. Placebo-controlled trials of iNO to treat ARDS have been disappointing, demonstrating only transient improvements in oxygenation and no effect on outcome. 12,13While in many patients inhaled NO provides selective pulmonary vasodilation, large multicenter trials examining the effect of inhaled NO therapy on clinical course and outcome of patients with diverse causes of pulmonary hypertension have not been performed.

Physiologically, it seems reasonable that a selective pulmonary vasodilator might be effective in treating ARDS. Reduced pulmonary capillary pressure should decrease the extent of pulmonary edema; should improve lung compliance; and might speed resolution of lung injury. Improved oxygenation should permit a reduction of the inspired oxygen concentration and airway pressure. But these effects may be insufficient to alter outcome. Usually, pulmonary artery pressure is only modestly elevated in ARDS. Even in severe cases, the mean pulmonary artery pressure is usually about 30 mmHg. 14This degree of pulmonary hypertension is well tolerated, and few patients with ARDS die of their pulmonary hypertension. Rather, the survival of patients with ARDS appears to depend more on the occurrence of sepsis and multiple organ failure than on blood gas tensions or pulmonary artery pressure. 15–17 

The effect of iNO varies among patients. Approximately one-third of patients fail to demonstrate improved oxygenation or decreased pulmonary artery pressure. 12,18The cause of hyporesponsiveness remains under investigation. We cannot predict which patients may benefit and why pulmonary vasodilation does not occur in others.

Consequently, the search for ways of improving the efficacy of iNO and designing effective alternative therapies continues. Combinations of therapies have been developed that aim to improve the matching of ventilation-to-perfusion or increase the biologic activity of inhaled NO. Alternative therapies have been suggested that may provide equivalent pulmonary vasodilation. While such therapies are attractive, whether they will affect clinical outcome is unknown.

Ventilatory techniques that increase alveolar recruitment, such as the use of high-frequency oscillation in neonates, 7or prone positioning of ARDS patients, 19may improve the response to inhaled NO. Recruiting lung volume, by adding PEEP 20or by the use of partial liquid ventilation with perfluorocarbons, 21has been used to augment the response to iNO. The coadministration of vasoconstrictors, such as almitrine and norepinephrine, may enhance pulmonary vasoconstriction and accentuate the improvement in Pao²observed during inhaled NO therapy, presumably by improving the matching of ventilation to perfusion. 22,23Inhibition of the phosphodiesterase (PDE) enzymes that hydrolyze cGMP can also increase the efficacy and duration of action of iNO. 24,25 

Even if efficacy were improved, however, iNO therapy still has several drawbacks. It is expensive, cumbersome devices are necessary to administer the drug safely, and continuous administration is required. Especially for chronic treatment of pulmonary hypertension, therapies that are inexpensive, available in convenient forms (such as a tablet or simple multidose inhaler), and allow for intermittent dosing would be advantageous.

Does inhaled prostacyclin fulfill these goals? First, and probably most importantly, the efficacy of inhaled PGI²has been tested inadequately. Randomized, double-blind, multicenter trials that assess the effect of inhaled PGI²on clinical outcomes (i.e. , survival, severity, or duration of disease) have not been performed. It would be unwise to substitute an untested therapy for one that has been proved effective, such as the use of iNO for the treatment of PPHN. While it is an effective vasodilator, the biochemical effects of PGI²are quite different from those of NO. They affect different pathways and mechanisms. Whether PGI²can be used to treat the underlying disease state and modify the extent of cellular injury in diseases such as ARDS is unclear. Second, little is known of the toxicity of inhaled PGI². Long-term toxicity testing has yet to be performed in humans. Third, administration of inhaled PGI²is also cumbersome, requiring continuous administration via  a gas-powered nebulizer.

So, our work is not yet done, and our search for the ideal molecule, or combination of molecules, continues. Areas of research include the use of inhaled Type V phosphodiesterase inhibitors, such as sildenafil, 25–27administration of NO-donor compounds that can release predictable amounts of NO at specific rates, 28,29and directly manipulating the genes controlling the NO-cGMP pathway. 30These might be administered by intermittent inhalation, intravenous infusion, or even oral routes. We also may find other prostacyclin analogs that can be administered orally 31or subcutaneously 32to be effective.

When examining alternatives to iNO therapy, it is crucial to not lose sight of what is supported by evidence and what is suggested by anecdote. The pharmacologic and toxicologic profiles of these compounds remain incomplete. Clearly, selective pulmonary vasodilation can be life-saving, and this work must be continued. But while expensive and time-consuming, there can be no substitute for testing these new compounds in randomized placebo-controlled trials and in carefully defined disease states.