VIENNA—Pulmonary hypertension occurs in up to 40% of patients with severe chronic obstructive pulmonary disease (COPD) and is associated with increases in mortality, exacerbation rates, and length of hospital stay. Although long-term oxygen therapy (LTOT) can improve survival, it has little effect on pulmonary hemodynamics in COPD patients by itself. In a recent trial, adding long-term pulsed nitric oxide (NO) effectively reduced pulmonary vascular resistance and pulmonary arterial pressure in COPD patients receiving LTOT.[1]

“The impact that the addition of NO to oxygen gives is mainly … a better match of ventilation and perfusion,” said study author Rolf Ziesche, MD. For COPD patients already using LTOT, pulsed delivery “might be a good way, just for practical reasons, to add NO to improve [pulmonary] circulation,” said Dr. Ziesche, Associate Professor of Internal Medicine at the Vienna Medical School. But combining NO with oxygen can be tricky: These gases can react to produce potentially damaging nitrogen dioxide. However, the new study shows “that you can combine a highly volatile gas … with oxygen in a certain way that can be given effectively over months” without adverse effects.

The equipment is compact enough for ambulatory use, noted Dr. Ziesche. “A titanium storage tank allows for a relatively small volume of liquid NO; then you have valves that are connected with a small computerized system, which is activated by the inspiratory drop in pressure.” To avoid nitrogen dioxide production, exposure of NO to oxygen must be minimized. After oxygen release begins, the device emits NO in a very short pulse. “This is a very, very small volume: microliters of NO,” Dr. Ziesche emphasized. Yet, this quantity is adequate for generating hemodynamic effects.

PULSED NO REDUCES PRESSURE

Forty patients with COPD who had pulmonary artery pressures of at least 25 mm Hg were recruited for the study. All patients had received LTOT for 15 or more hours per day for the previous six months. At baseline, patients’ acute responses to NO were tested to determine the most effective NO concentration. Half of the patients were then randomized to receive pulsed NO at optimal concentration in addition to LTOT, and half to receive LTOT alone.

During acute testing, the combination of inhaled NO and oxygen significantly decreased pulmonary vascular resistance and pulmonary artery pressure in all patients. The mean optimal dose of NO was 20 ppm. After three months of treatment, combined treatment significantly reduced mean pulmonary vascular resistance from 276.9 to 173 dyne/s/cm5. Mean cardiac output increased from 5.6 to 6.1 L/min, and mean pulmonary artery pressure fell from 27.6 to 20.6 mm Hg. These measurements were unchanged in patients who received LTOT alone.

Although no significant differences between the groups were seen in ventilatory parameters or arterial oxygen tension, arterial carbon dioxide tension in the NO recipients decreased from 7.4 to 6.7 kPa, possibly indicating enhanced perfusion in well ventilated areas of the lung. Additionally, 38.5% of the patients receiving NO reported improvements in physical performance, whereas only 12.5% of patients receiving LTOT alone did so.

Sensitization to Inhaled NO May Block Clinical Benefit for ARDS

BERLIN—Inhaled nitric oxide (iNO) improves systemic oxygenation in patients with acute respiratory distress syndrome (ARDS) by reducing pulmonary hypertension and intrapulmonary shunt. Unfortunately, sustained treatment with NO concentrations above 5 ppm fails to improve outcome. A recent dose-response study demonstrated increased iNO sensitivity with continued treatment, possibly explaining the deteriorating oxygenation observed in these patients.1 Lowering the iNO concentration may be one strategy for avoiding this decline. Clinical trials testing high iNO concentrations in ARDS patients showed initial improvement in the ratio of arterial oxygen tension to fraction of inspired oxygen (Pao2/Fio2), yet long-term treatment yielded no clinical benefit. “All these trials were performed with 5 to 10 ppm, with some up to 20 ppm,” noted primary author Herwig Gerlach, MD, PhD. “You have an effect in the first 24 hours; you see that it is possible to reduce Fio2,” observed Dr. Gerlach, Professor and Chairman of Anesthesiology and Intensive Care Medicine at the Vivantes-Klinikum Neukölln in Berlin, “but then afterwards … you don’t see any difference.” He cautioned, however, “we have to be very careful not to interpret this as a failure of NO—we have to consider that this might be an unintended overdosing.” Although previous work by Dr. Gerlach’s group had suggested that lower iNO concentrations were effective, these were never evaluated in large-scale studies. The researchers therefore investigated the possibility that patients’ responses to continued iNO might change over time. HIGH iNO YIELDS SENSITIZATION Forty ARDS patients were randomized to receive conventional therapy or treatment with the addition of 10 ppm iNO; both regimens were continued until patients could be weaned from mechanical ventilation. During the course of treatment, daily dose-response measurements were made to determine the sensitivity of Pao2/Fio2 to various iNO levels. Whereas 10-ppm iNO test doses yielded maximal responses on day 0, four days of continued iNO treatment shifted the dose-response curve: Responses were maximal at only 1 ppm. Furthermore, 10 and 100 ppm doses produced deterioration in oxygenation following four days of iNO. In contrast, iNO sensitivities of control patients remained steady throughout the experiment. Outcomes did not differ between treatment groups. Dr. Gerlach observed, “Individual sensitivity is more or less constant if the patients do not get any NO, but you have a phenomenon of sensitization during NO inhalation.” He explained, “Continuous inhalation of NO reduces the endogenous NO production,” prompting reactive vasoconstriction. Additionally, animal work demonstrates “increased activity of vasoconstrictors in a lung which is treated with inhaled NO,” Dr. Gerlach pointed out. This suggests that reactive production of endogenous vasoconstrictors may be induced in patients receiving continuous iNO. In the future, effective iNO therapy might start with 1 to 5 ppm; after one or two days, iNO could be reduced to 0.1 ppm, suggested Dr. Gerlach. “An alternative would be to use [a] physiological dose, which is about 0.1, 0.2 ppm” from the start. “This concentration is produced in the inspiratory air when you inhale through the nose,” Dr. Gerlach noted. —Mimi Zucker, PhD

Reference 1. Gerlach H, Keh D, Semmerow A, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167:1008-1015.

—Mimi Zucker, PhD

Reference
1. Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58:289-293.

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