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Authors and PaPer Sublect numbers Method of meagurement Persson et al, 1994 (Persson, Zetterstrom et al. 1994) Kharitonov et al, 1994 (Kharitonov, Yates et al. 1994) Kharitonov et al, 1995 (Kharitonov, Yates et al. 1995) Massaro et al, 1996 (Massaro, Mehta et al. 1996) Massaro et al 1995 (Massaro, Gaston et al. 1995) Kharitonov et al, 1995 (Kharitonov, Robbins et al. 1995) schilling et al, 1994 (Schilling, Holzer et al. 1994) Kharitonov et al, 1996 (Kharitonov, Yates et al. 1996) Kharitonov et al, 1995 (Kharitonov, Yates et al. 1995) Kharitonov et al, 1995 (Kharitonov, Wells et al. 1995) 20 controls 23 asthmatics 6 smokers 67 controls 61 asthmatics 52 asthmatics on tHcs 25 asthmatics: single responders baseline single responders 27 hours dual responders baseline dual responders 27 hours 5 controls 5 asthmatics 90 controls 43 asthmatics 73 controls 41 smokers 21 female controls 12 female smokers 24 male controls 24 male smokers 10 with hypertension 11 asthmatics baseline following IHCS 18 (URTI) during recovery 79 (controls) 20 bronchiectasis 19 bronchiectasis on IHCS mixed exhaled air ,t at aa single exhalation single exhalation pre and post allergen challenge mixed expired air at carina with bronchoscoPe mixed expired air at carina with bronchoscoPe mixed air single exhalation reservoir collection single exhalation single exhalation single exhalation Resulte In contlols Rasults In dlsease 8.4ppb 80.2ppb 4.7ppb 7.0ppb 6.2ppb 88ppb 21 ppb 1 9ppb 89ppb 10.3ppb 3.9ppb 283ppb 101ppb 214ppb 233ppb 258ppb 264ppb 13.2ppb 40.Sppb 13.9ppb 42ppb 16ppb 1 5ppb 13.7ppb 203ppb 120ppb 31 Sppb 88.3ppb 285ppb 88ppb This table lists the published results of exhaled NO in adults by the beginning of 1997 showing the wide range of techniques and even with app-arentty similar. techniquei the wide range of results reported. The mean refufts of the exhaleo No ior eac'h subiect group are presented here. I have listed 129
only those measured by mouth or lower respiratory tract rather than nasal or sinus measurement which will be discussed in a later chapter. (exp = expiratory, IHCS = inhaled corticosteroids, insp = inspiratory, rg = nanogram, ppb = parts per billion, s = seconds, single responders = edrly asthmatic response only, late responders = both early and late asthmatic response, URTI = upper respiratory tract infection). 6.4 The aims of the exhaled nitric oxide methodological experiments The following methodological experiments were therefore designed and conducted in adult subjects to try and answer two main questions: 1. Were NO and CO2 produced from the same region within the lung? 2. Which technical factors during measurement led to changes in the NO results and therefore would require standardisation in future research in this area? The aims of the methodological investigations were: L. To determine whether exhaled NO could be measured by the chemiluminscence analyser now modified from its original purpose of measuring NO in air pollution. 2. To compare the exhalation pattern of NO versus COz from a series of single exhalations. 3. To compare the results of NO using the peak level versus the area under the curve of the recording trace. 4. To compare the results of NO and COz between two methods of measurement; either direct exhalation to the NO analyser (which also allowed measurement of CO2, and mouth pressure) or exhalation via a t-piece system (which measured these parameters with the additional measurement of expiratory flow). 5. To assess the reproducibility of the NO and COz measurements. 6. To investigate whether altering the expiratory flow changed the exhaled NO levels measured. 7. To assess whether pressure had any effect on the exhaled NO levels by two methods: (a) Delivering the calibration gas at different pressures to the NO analyser. (b) Altering the expiratory mouth pressure voluntarily by adult subjects. 8. To investigate whether ambient NO levels affected exhaled NO levels. 9. To investigate whether water consumption immediately before exhalation changed the NO results obtained (this was added in response to a chance finding). The experiments and results from aims one to five listed above will be detailed in this chapter. The experiments and results conducted to answer aims six to nine where a specific single condition was varied to assess the effect on the exhaled NO levels obtained are detailed in Chapter 7. 130
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UNIVERSITV OF AUCKI'AND Abstract -
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There was no significant difference
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This is Dedicated: Dedication To th
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New Zealand The Paediatric Departme
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Contents Abstract ........tr Dedica
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6.5.4 The subjects............... .
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XIV
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List of Figures Figure l.l: Top l0
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List of Abbreviations ABPA allergic
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LADA N*N* dimethyl L-arginine LFA1
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t}ryem(eNoS)Typeltrendothelialnifti
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area, some of it has been expanded
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In addition, both of these groups a
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studies conducted throughout the Un
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Video clips of infants with a varie
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the Paediatric Society of New 7*ala
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inhaled anti-cholinergic agents and
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ecommended to monitor asthma at hom
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improvement to 70Vo PEF would have
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Furthermore, investigators have als
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poorer predictor of a diagnosis of
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Bronsky et al. 1998), and a long-te
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SIGN guideline (SIGN 2005) stated "
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In brief, the human airway can be d
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The ability to biopsy has led to st
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small proportion of cells recovered
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methodology of sputum induction and
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et al. 1999; Giannini, Di Franco et
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over a six month treatment prograrn
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There are other studies suggesting
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So is induced sputum in adults and
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asymptomatic patients independent o
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onchial hyper-responsiveness (Reich
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led to research which looked for le
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analyser machines. This thesis pres
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The pollution of the 'great smog of
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adults greater than 65 years (Ostro
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levels compared to those children l
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More recently 'Air Quality Indexes'
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acetylcholine. These were known to
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cyclase does not produce significan
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Garthwaite l99l), and the non adren
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significant complication, this trea
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locus for the enzyme is a susceptib
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NO synthesis and in so doing blocke
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3.1 Chapter 3: The synthesis, react
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BHa = tetrahyrobiopterin, FAD = fla
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(Knowles, McWeeny et al. 1974) and
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more potent at low oxygen tensions
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Page 115 and 116: 4.1 Introduction Chapter 4: Methods
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Page 121 and 122: A group of instruments have been de
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Page 133 and 134: 5.1 Chapter 5: Methodological asses
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Page 149 and 150: al found levels of 10.3ppb compared
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Page 181 and 182: Figure 7.2: Example of the tracing
Page 183 and 184: 7.4.4 Results There was an increase
Page 185 and 186: Table 7.3: NO, COz and duration of
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Page 201 and 202: 8.1 Chapter 8: Exhaled nitric oxide
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standard error of the mean (SEM), s
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T-piece sampling system to analyser
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Figure 8.2a: Comparison of peak exh
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if yes who? if yes who? if yes who?
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There are limitations with regard t
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significantly between research grou
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controls. Kharitinov et al reported
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direct method in asthmatic children
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Figure 8.4a: The eftect of commenci
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had last used her p2 agonist inhale
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higher level of exhaled NO at 4.9pp
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9.1 Introduction Chapter 9: Exhaled
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For the oral measurements options i
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Table 9.1: The recommended standard
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taken from the available literature
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compartment correlated with the ser
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measurement with variable expirator
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to settle. We may have been measuri
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9.5 Off-line measurement NO determi
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(Hyde, Geigel et al. 1997; Tsoukias
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9.6 Nasal nitric oxide measurement
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measured over two 24 hour periods,
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women who coincidently experienced
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While these cross-sectional and the
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symptoms. Steroid response was sign
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'difficult asthma' also had higher
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season and then reduced down to bas
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of cross sectional studies with a t
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Ciabattoni et al. 2004; Petersen, A
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FEV9.5, symptom score and airways r
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Indomethacin - This medication alte
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89Vo for PCD, and above that exclud
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This low NO occurs despite higher t
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patients were followed through one
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differences noted based on filter,
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9.L6 Nitric oxide levels in exercis
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another study of 111 school childre
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Almost all studies used sedation, w
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peak exhaled NO production in the f
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flow and to minimize nasal contamin
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ecruit blood vessels in the lung. S
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Chapter 10: Reflections The outcome
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and I enrolled 52 asthmatic childre
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Edwards EA, Douglas C, Broome S, Je
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o Cass Byrnes & Nicky Holt. "Drugs
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o Byrnes CA. Paediatric fibreoptic
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Appendix 2: Questionnaire for enrol
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Al-Ali, M. K. and P. H. Howarth (20
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Archer, S. L., P. J. Shultz, et al.
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Baraldi, E., N. M. Azzolin, et al.
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Belda, J., P. Hussack, et al. (2001
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Bongers, T. and B. R. ODriscoll (20
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Brown, G. C. and C. E. Cooper (1994
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Castro-Rodriguez, J. A., C. J. Holb
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Cockcroft, D. W., D. N. Killian, et
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de Blic, J., V. Marchac, et al. (20
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Donaldson, S. H., W. D. Bennett, et
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Emi-Miwa, M., A. Okitani, et al. (1
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Frey, U., J. Stocks, et al. (2000).
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Gershman, N. H., H. Liu, et al. (19
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Grasemann, H., E. Michler, et al. (
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Hashimoto, T., K. Minoguchi, et al.
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Holgate, S. T., D. E. Davies, et al
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Iriso, R., P. M. Mudido, et al. (20
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Jones, A. W., M. Fransson, et al. (
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Kercsmar, C. M. (2006). Wheezing in
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Kleinert, H., T. Wallerath, et al.
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Lamblin, C., P. Gosset, et al. (199
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Li, X. and J. W. Wilson (1997). "In
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Lymar, S. V. and J. K. Hurst (1996)
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Massaro, A. F., S. Mehta, et al. (1
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Miyabara, Y., R. Yanagisawa, et al.
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contribute to impaired endothelium-
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ODell, T. J., R. D. Hawkins, et al.
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Panza, J. A., C. E. Garcia, et al.
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Peters, S. P. (2006). "Safety of in
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Prieto, L., L. Bruno, et al. (2003)
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Ribbons, K. A., X. J. Zhang, et al.
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Sacco, O., R. Sale, et al. (2003).
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Sessa, W. C., K. Pritchard, et al.
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Silvestri, M., F. Sabatini, et al.
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Stamler, J. S. (1994). "Redox signa
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Stuehr, D. J., N. S. Kwon, et al. (
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Tierney, W. M., J. F. Roesner, et a
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Upchurch, G. R., G. N. Welch, et al
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Wadsworth, R., E. Stankevicius, et
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Williams, O., R. Y. Bhat, et al. (2
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Yates, D. H., S. A. Kharitonov, et
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