Abstract
Objective
The study was performed to determine the changes in blood methaemoglobin level during the inhalation of nitric oxide.
Design
The study was an unblinded dose-response study.
Participants
5 healthy adult volunteers aged 30–36 (4 male and 1 female) were studied on 4 occasions separated by at least one week.
Intervention
Nitric oxide was inhaled at inspired concentrations of 32, 64, 128, and 512 volumes per million (vpm) in air. Venous blood samples were taken every 10 min for methaemoglobin determination. Inhalation continued for 3 h (32, 64 and 128 vpm) or until the methaemoglobin exceeded 5% of the total haemoglobin (512 vpm). The methaemoglobin levels were also recorded for 3 h after 512 vpm nitric oxide had been stopped.
Measurements and results
Both the increase in methaemoglobin fraction during nitric oxide inhalation and the decay after ceasing inhalation fitted well with a first order model describing methaemoglobin elimination. The calculated time constants were between 39–91 min. The predicted mean maximum methaemoglobin levels that would be achieved during inhalation of 32, 64, 128, and 512 vpm nitric oxide were 1.04% (0.92–1.16), 1.75% (1.80–1.90), 3.75% (3.58–4.05), 6.93% (5.70–8.16) respectively (95% confidence interval of estimate in brackets).
Conclusions
In normal individuals inhalation of up to 128 vpm of nitric oxide, greater than any dose used clinically to date, does not result in clinically significant methaemoglobinaemia. Maximum methaemoglobin levels are likely to be reached in 3–5 h after inhalation begins. However, these figures may not apply to critically ill adults and infants. Nitric oxide may have other toxic effects not examined in this study.
References
Fratacci MD, Frostell CG, Chen TY, Wain JC, Jones R, Zapol WM (1991) Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Anesthesiology 75:990–999
Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM (1991) Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038–2047
Frostell C, Blomqvist H, Hedenstierna G, Lundberg J, Zapol W (1993) Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilatation. Anesthesiology 78:427–435
Girad C, Lehot JJ, Pannetier J-C, Filley S, Ffrench P, Estove S (1992) Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary hypertension. Anesthesiology 77:880–883
Kinsella JP, Neish SR, Shaffer E, Abman SH (1992) Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:819–820
Roberts JD, Polaner DM, Lang P, Zapol WM (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:818–819
Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399–405
Greenbaum R, Bay J, Hargreaves MD, Kain ML, Kelman GR, Nunn JF, Prys-Roberts C, Siebold K (1967) Effects of higher oxides of nitrogen on the anaesthetized dog. Br J Anaesth 39:393–404
Gibson QH, Roughton FJW (1957). The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol 136:507–526
Jaffe ER, Neumann G (1964) A comparison of the effect of menadione, methylene blue and ascorbic acid on the reduction of methaemoglobin in vivo. Nature (London) 202:607–608
Severinghaus JW, Xu FD, Spellman MJ Jr (1991) Benzocaine and methaemoglobin: recommended actions. Anesthesiology 74: 385–387
Frayling IM, Addison GM, Chattergee K, Meakin G (1990) Methaemoglobinaemia in children treated with prilocaine-lignocaine cream. Br Med J 301:153–154
Bojar RM, Rastegar H, Payne DD, Harkness SH, England MR, Stetz JJ, Weiner B, Cleveland RJ (1987) Methemoglobinemia from intravenous nitroglycerine, a word of caution. Ann Thorac Surg 43:332–334
Ellis M, Hiss Y, Shenkman L (1992) Fatal methaemoglobinemia caused by inadvertent contamination of a laxative solution with sodium nitrite. Isr J Med Sci 28:289–291
Kearns GL, Fiser DH (1988) Metoclopramide-induced methaemoglobinaemia. Pediatrics 82:364–366
Magna LA, Beiguelman B (1984) NADH-methemoglobin reductase and methemoglobin among leprosy patients. Int J Lepr Other Mycobact Dis 52:475–481
Fleetham JA, Tunnicliffe BW, Munt PW (1978) Methaemoglobinaemia and the oxides of nitrogen. N Engl J Med 298:1150
Scott EM (1968) Congenital methemoglobinemia due to NADH-diaphorase deficiency. In: Beutler E (ed) Hereditary disorders of erythrocyte metabolism. Grune and Stratton, New York, pp 102–108
Scott EM, Duncan IW, Ekstrand V (1965) The reduced pyridine nucleotide dehydrogenases of human erythrocytes. J Biol Chem 1965 240:481–485
Borgese N, Pietrini G, Gaetani S (1987) Concentration of NADH-cytochrome b5 reductase in erythrocytes of normal and methemoglobinemic individuals measured with a quantitative radioimmunoblotting assay. J Clin Invest 80:1296–1302
Jaffe ER (1981) Methaemoglobinaemia. Clin Haematol 10:99–122
Caudill L, Walbridge J, Kuhn G (1990). Methemoglobinemia as a cause of coma. Ann Emerg Med 19:677–679
Guenard H, Varene N, Vaida P (1987) Determination of lung capillary volume and membrane diffusing capacity in man by the measurements of NO and CO transfer. Respir Physiol 70:113–120
Marrs TC, Bright JE (1986) Kinetics of methaemoglobin production (1). Kinetics of methaemoglobinaemia induced by cyanide antidotes,p-aminopropiophenone,p-hydroxyaminopropiophenone orp-dimethylaminophenol after intravenous administration. Hum Toxicol 5:295–301
Schneider F, Lutun Ph, Hasselmann M, Stoclet JC, Tempe JD (1992) Methylene blue increases systemic vascular resistance in human septic shock. Intensive Care Med 18:309–311
Mansouri A (1985) Methemoglobinemia. Am J Med Sci 289: 200–209
Chun-Lap Lo S, Agar NS (1986) NADH-methaemoglobin reductase activity in the erythrocytes of newborn and adult mammals. Experientia 42:1264–1265
Choury D, Reghis A, Pichard A-L, Kaplan J-C (1983) Endogenous proteolysis of membrane-bound red cell cytochrome-b5 reductase in adults and newborns: its possible relevance to the generation of the soluble “methemoglobin reductase”. Blood 61:894–898
Pavri RS, Gupta AD, Baxi A, Advani SH (1983) Further evidence for oxidative damage to hemoglobin and red cell membrane in leukemia. Leuk Res 7:729–733
Oda H, Nogami H, Kusumoto S, Nakajima T, Kurata A (1980) Lifetime exposure to 2.4ppm nitric oxide in mice. Environ Res 22:254–263
Oda H, Nogami H, Kusumoto S, Nakajima T, Kurata A, Imai K (1976) Long-term exposure to nitric oxide in mice. J Jpn Soc Air Pollut 11:150–160
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Young, J.D., Dyar, O., Xiong, L. et al. Methaemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intensive Care Med 20, 581–584 (1994). https://doi.org/10.1007/BF01705726
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DOI: https://doi.org/10.1007/BF01705726