Correspondence
Inhaled Nitric Oxide for the Adult Respiratory Distress Syndrome
N Engl J Med 1993; 329:206-207July 15, 1993
- Article
To the Editor:
Rossaint et al. (Feb. 11 issue)1 discussed the potential benefits of inhaled nitric oxide in the adult respiratory distress syndrome (ARDS). Their hypothesis is that inhalation of nitric oxide causes selective vasodilation of the pulmonary vascular bed in the ventilated lung regions, improving oxygenation and cardiac performance and reducing the accumulation of extravascular lung water. The study patients had a mild elevation of pulmonary-artery pressure that was of no apparent hemodynamic consequence, since their cardiac output was normal. Inhalation of nitric oxide reduced pulmonary-artery pressure slightly and did not change cardiac output. This confirms that its hemodynamic effects were inconsequential. The presence of nitrogen in the inspired air and of methemoglobin in the blood could have adversely affected arterial and tissue oxygenation. The authors could have resolved this issue by presenting data on measures of oxygen transport and tissue oxygenation.
The observed increase in the partial pressure of oxygen in mixed venous blood during the inhalation of nitric oxide is surprising. When other factors were unchanged, cardiac output increased only during the infusion of prostacyclin. Prostacyclin, rather than nitric oxide, should have led to a higher partial pressure of oxygen in mixed venous blood, unless the latter reduced oxygen consumption or caused local arteriovenous shunting.
The hemodynamic and oxygen-transport consequences of ARDS result from pathophysiologic processes in the “involved” regions of the lung. How could an agent that “selectively” affects only the “uninvolved” regions be expected to have any substantial influence on the outcome of ARDS? The claim that inhalation of nitric oxide can decrease microvascular filtration pressure and reduce the accumulation of extravascular lung water is unfounded. According to the hypothesis, the gas would not reach the diseased regions in any substantial degree. Further vasodilation of the “normally ventilated” zones of the lung may improve intrapulmonary shunting by 3 percent, according to Rossaint et al. This change will not alter the course of a complex disease such as ARDS.
1 ReferencesHamid Sahebjami, M.D.
Veterans Affairs Medical Center, Cincinnati, OH 452201
Rossaint R ,Falke KJ ,Lopez F ,Slama K ,Pison U ,Zapol WM . Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405
Full Text | Web of Science | Medline
To the Editor:
The potential toxicity of inhaled nitric oxide is of concern, especially through the formation of nitrogen dioxide1. Indeed, the risk of oxidation of nitric oxide to nitrogen dioxide is proportional to the initial concentration of nitric oxide, the fraction of inspired oxygen, and the contact times of nitric oxide with oxygen2. It is necessary to reduce the toxicity of inhaled nitric oxide without losing the beneficial effects -- for example, by testing lower concentrations of the gas.
There are theoretical grounds to hypothesize that the amounts of nitric oxide administered by Rossaint et al -- i.e., 18 and 36 ppm -- are actually higher than what is needed. First, the amount of endogenous nitric oxide generated in the lungs, as measured in the exhaled air, averages only 8 ppb in healthy humans,3 which is approximately 2000 to 4000 times less than the amount of nitric oxide inhaled by the patients tested by Rossaint et al. Second, the amount of inhaled nitric oxide that is actually delivered to the lungs, as assessed by the difference between the concentrations of inspired gas and expired gas, averages only 5 ppm in healthy young adults (Renaudin MH: personal communication). It is therefore conceivable that concentrations of inhaled nitric oxide higher than 5 ppm would be unnecessary.
Inhaled nitric oxide may improve gas exchange and reduce pulmonary hypertension at concentrations as low as 5 and 3 ppm. Such lower concentrations may represent a smaller risk of toxicity for patients.
3 ReferencesMehran Monchi, M.D.
Fabrice Brunet, M.D.
A. Tuan Dinh-Xuan, M.D., Ph.D.
Cochin University Hospital, 75014 Paris, France1
Clutton-Brock J . Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth 1967;39:388-392
CrossRef | Web of Science | Medline2
Foubert L ,Fleming B ,Latimer R , et al. Safety guidelines for use of nitric oxide. Lancet 1992;339:1615-1616
CrossRef | Web of Science | Medline3
Gustafsson LE ,Leone AM ,Persson MG ,Wiklund NP ,Moncada S . Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991;181:852-857
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Author/Editor Response
The authors reply:
To the Editor: In response to Dr. Sahebjami, we agree that inhalation of nitric oxide did not increase cardiac output in the patients we described. We have, however, treated patients with ARDS who have higher degrees of pulmonary hypertension; inhaled nitric oxide has markedly reduced the pulmonary-artery pressure and increased cardiac output. Nitric oxide causes vasodilation of ventilated lung regions and augments arterial oxygenation. Inhalation of nitric oxide could increase survival in ARDS if hypoxemia, pulmonary edema, and respiratory failure are severe. If arterial oxygen saturation increases while a patient breathes nitric oxide despite an unchanged cardiac output, oxygen delivery to systemic tissues will increase.
In response to Dr. Monchi et al., another study has reported that low levels of nitric oxide improve the oxygenation of infants with persistent pulmonary hypertension of the newborn.1 We have noted marked improvement in oxygenation in patients with ARDS at inhaled levels of nitric oxide as low as 250 ppb. In each patient with ARDS, the lowest level of inhaled nitric oxide should be sought that produces the desired improvement in oxygenation, the reduction of pulmonary hypertension, or both.
The methemoglobin levels in our patients remained below 1.3 percent, an insubstantial amount. Inhaling high concentrations of nitric oxide can cause severe acute pulmonary edema and methemoglobinemia. However, we consider it vital for safety that during the inhalation of nitric oxide several conditions be observed: (1) circulating methemoglobin levels should be measured daily, and more frequently in children; (2) levels of nitric oxide and nitrogen dioxide should be measured continuously by chemiluminescence; (3) calibrated stock tanks of nitric oxide containing no more than 200 to 1000 ppm nitric oxide in nitrogen should be bought from a manufacturer and not mixed personally; and (4) systems used to blend nitric oxide in ventilators should be carefully examined to avoid administering high inhaled levels of nitric oxide or nitrogen dioxide.
1 ReferencesWarren M. Zapol, M.D.
Massachusetts General Hospital, Boston, MA 02114Konrad J. Falke, M.D.
Rolf Rossaint, M.D.
Universitatsklinikum Rudolf Virchow, Freie Universitat Berlin, 1000 Berlin 65, Germany1
Kinsella JP ,Neish SR ,Shaffer E ,Abman SH . Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-820
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- Citing Articles (5)
Citing Articles
1
Jose Eduardo Tanus-Santos, Heitor Moreno, Aldete Zappellini, Gilberto de Nucci. (1999) Small-Dose Inhaled Nitric Oxide Attenuates Hemodynamic Changes After Pulmonary Air Embolism in Dogs. Anesthesia & Analgesia 88:5, 1025-1029
CrossRef2
J. D. Chiche, J. L. Canivet, P. Damas, J. Joris, M. Lamy. (1995) Inhaled nitric oxide for hemodynamic support after postpneumonectomy ARDS. Intensive Care Medicine 21:8, 675-678
CrossRef3
J. P. Mira, M. Monchi, F. Brunet, L. Fierobe, J. F. Dhainaut, A. T. Dinh-Xuan. (1994) Lack of efficacy of inhaled nitric oxide in ARDS. Intensive Care Medicine 20:7, 532-532
CrossRef4
ChristopherC Miller. (1994) Chemiluminescence analysis and nitrogen dioxide measurement. The Lancet 343:8892, 300-301
CrossRef5
A. T. Dinh-xuan. (1994) Rôles du NO en physiopathologie cardiovasculaire et respiratoire. Archives Of Physiology And Biochemistry 102:4, A3-A9
CrossRef
