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EDITORIALS: Niall D Ferguson Inhaled nitric oxide for acute respiratory distress syndrome BMJ 2007; 334: 757-758 [Full text]

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How NO therapy was introduced into clinical practice

Colin D R Borland   (16 April 2007)

How NO therapy was introduced into clinical practice 16 April 2007
Colin D R Borland, Consultant Physician Hinchingbrooke Hospital, Huntingdon, Cambs PE29 6 NT Send response to journal: Re: How NO therapy was introduced into clinical practice	I could not suppress a wry smile at Niall Ferguson’s plea that trials of nitric oxide in ARDS should be “ grounded in solid observations from physiological animal and early phase human studies.” I suspect few among your readership are aware of the boldness, serendipity and lateral thinking surrounding the introduction of this therapy. In the late 1970’s there was concern about the harmful respiratory effects of “oxides of nitrogen” in the atmosphere and in cigarette smoke. Nitrogen dioxide exposure was known to cause emphysema in laboratory animals though histologically the lesion is very different to that caused by tobacco smoke (1). A reanalysis of data from the Whitehall study apparently failed to relate smokers’ tar exposure to airflow obstruction suggesting gases could be responsible (2). Prof Tim Higenbottam therefore initiated a study of cigarette nitric oxide inhalation which formed my MD thesis. We used an analyser built by British American Tobacco’s research division based on Brian Thrush’s description of NO chemiluminescence (3). We modelled smokers’ inhalation using 40 parts per million (40 ppm) nitric oxide. This was my (erroneous) estimate of the alveolar nitric oxide concentration when a puff of smoke from a Benson and Hedges cigarette is inhaled. This concentration is also stable to oxidation in air with a half life of about an hour (4).When in 1987 NO and endothelium derived relaxing factor were found to be pharmacologically identical Higenbottam et al (5) administered 40 ppm to eight patients with pulmonary hypertension reasoning that this dose was safe since I, other volunteers (and countless smokers!) had come to no immediate harm. A decline in pulmonary vascular resistance was observed and others extended the therapy to the adult respiratory distress syndrome (6) using 5-20 ppm for 3-53 days. Wide usage and the randomised controlled trials described in Adhikari et als systematic review soon followed. 1.Roe FJC Certain aspects of the responses of laboratory rats to exposure to (a) nitrogen dioxide and (b) tobacco smoke Tokai J Exp Clin Med 1985;10:363-369 2. Higenbottam T, Clark TJH, Shipley MJ et al Lung function and symptoms of cigarette smokers related to tar yield and numbers of cigarettes smoked Lancet 1980 I 409-11 3.Clyne MAA, Thrush BA and Wayne RP Kinetics of the chemiluminescent reaction between nitric oxide and ozone Trans Faraday Soc 1964;60:359-367 4.Borland CDR and Higenbottam TW A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide Eur Respir J 1989:2 :56-63 5.Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D and Wallwork J Inhaled NO as a cause of selective pulmonary vasodilatation in pulmonary hypertension Lancet 1991;338:1173-4 6.Rossaint R, Falke KJ, Lopez F, Slam K, Pison K, Zapol WM Inhaled nitric oxide for the adult respiratory distress syndrome New England Journal of Medicine 1993;328:399-405 Competing interests: None declared