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Turktas, oguzulgen et a:.2003; Mappa, cardinale et al. 2005; Spergel, Fogg et al' 2005; Thomas, Gibson et al. 2005; Zietkowski, Bodzenta-Lukaszyk et al. 2006). Again some of these studies described correlations with certain parameters only such as FEF25-75 (Mahut' Delacourt et al. 2004; Battaglia, den Hertog et al. 2005; Irhtimaki, Kankaanranta et al' 2005)' FEVr/FVC ratio (Strunk, Szefler et al. 2003), residual volume (Mappa' Cardinale et al' 2005)' or peak flow lability (al-Ali, Eames et al. 1998; Lim, Jatakanon et al' 2000)' In other studies the correlations were only significant in certain groups such as atopic, rather than non-atopic' asthmatics (Franklin, Stick et al. 2004)' Positive correlations have been demonstrated between NO levels and airway reactivity as measured by methacholine challenges (Jatakanon, Lim et al' 1998; Henriksen' Lingaas- Holmen et al. 2000; wilson, Dempsey et al. 2001; Prieto, Gutierrez et al' 2002; Prieto' Gutierrez et al. 2002; Buchvald, Eiberg et al. 2003; Langley, Goldthorpe et al' 2oo3; Malmberg, Pelkonen et al. 2003; Nogami, Shoji et al. 2003; Berkman' Avital et al' 2005; Ehrs, Sundblad et al. 2006), histamine challenges (al-Ali, Eames et al' 1998; de Gouw' Hendriks et al. 1998; Dupont, Rochette et al. 1998; Dupont, Demedts et al' 2003; Zietkowski' Bodzenta-Lukaszyk et al. 2006), or adenosine S-monophospate challenges (de Gouw' Hendriks et al. 1998; Aziz,wilson et al. 2000; Prieto, Gutierrez et al' 2002; Prieto' uixera et aI.2002;Prieto, Bruno et al. 2003; Berkman, Avital et al' 2005)' Again some studies found correlations only in certain groups of subjects such as atopic asthmatics (Franklin' Stick et al' 2004) or those on IHCS (Reid, Johns et al. 2003) rather than all asthmatic and control subjects. g.8.3 Can nitric oxide be usedfor diagnosis of asthma? Studies have assessed whether measurement of exhaled NO can be used to diagnose asthma' either to screen a general population or to screen new clinic referrals' One group evaluated 47 consecutive adult patients referred with symptoms suggestive of asthma' The individual sensitivities for each of the conventional tests (p.* flow, spirometry, serum eosinophils, bronchodilator responsiveness and airway challenge) were up to 47Vo; much lower than for exhaled No at ggvo andsputum eosinophili a at 86Vo. The results for conventional tests were not improved when using a trial of oral steroid as a diagnostic test. The researchers concluded that exhaled No and induced sputum analysis, particularly when combined, were superior to the other conventional approaches in diagnosing asthma (smith, cowan et al' 2004)' The same group looked at the predictive accuracy of exhaled NO to identify steroid responsiveness to IHCS for four weeks in 52 adults presenting with undiagnosed respiratory 227
symptoms. Steroid response was significantly greater in those with the higher exhaled NO levels (> a7ppb) independent of the original diagnostic label (asthma, COPD or chronic bronchitis) (Smith, Cowan et al. 2005). A similar study evaluated 95 patients presenting with respiratory symptoms in which 40 were subsequently diagnosed as asthmatic. A baseline value of NO at >7ppb best differentiated between asthmatics and non-asthmatics with a sensitivity of 82.5Vo and a specificity of 88.9Vo. The generated receiver-operated curves (ROC) gave a value for exhaled NO of 0.89, similar to both methacholine and adenosine-S monophosphate challenges, better than lung function or exercise testing (Berkman, Avital et al. 2005). In 50 consecutive subjects being screened for exercise induced bronchospasm, exhaled NO at
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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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toxic products such as isoprostanes
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Figure 3.3: The nitric oxide syntha
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providing NO as a neurotransmitter
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The enzyme of this second pathway -
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inappropriate production from comme
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Nicotinamide adenosine dinucleotide
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enzyme and are competitively revers
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4.1 Introduction Chapter 4: Methods
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4.4 Nitrite and nitrate The measure
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insensitive (Braker and Mossman 197
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A group of instruments have been de
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The original group demonstrated tha
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equired it. For example, there was
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helium for 30 minutes to remove Oz.
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(Postlethwait and Bidani 1990; Post
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is set at 5ppm (AIHA 1966) based on
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5.1 Chapter 5: Methodological asses
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wanted to compare the patterns of e
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in different colours that became th
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an advisor for this work and main s
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Delay time: the time between turnin
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led to an increased water content t
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Chapter 6: Methodological studies o
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pulmonary circulation appeared to c
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al found levels of 10.3ppb compared
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Authors and Pap€r Sublect numbers
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only those measured by mouth or low
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6. Check that the pens work. Fill w
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keys but it is currently in the mid
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Calibration pressures: the test por
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T-piece: tO The first figure shows
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the rotameter. Tracings of each par
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Figure 6.6: Mean exhaled NO levels
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NO and COz results from single exha
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6.6.4 (iii) Comparison of exhaled n
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Figure 6.11b: COz levels at peak NO
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I also considered whether the diffe
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the direct to the indirect method l
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need for methodological experiments
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The exhalations were carried out in
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Figure 7.2: Example of the tracing
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7.4.4 Results There was an increase
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Table 7.3: NO, COz and duration of
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The second set of exhalations invol
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Figure 7.6: Photographs of the chan
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Table 7.5: Exhaled NO results with
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the NO concentrations taken pre and
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Figure 7.10: Hyperbolic relationshi
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pressure over the likely range enco
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Page 201 and 202: 8.1 Chapter 8: Exhaled nitric oxide
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Page 207 and 208: Figure 8.2a: Comparison of peak exh
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Page 211 and 212: There are limitations with regard t
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Page 219 and 220: Figure 8.4a: The eftect of commenci
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Page 225 and 226: 9.1 Introduction Chapter 9: Exhaled
Page 227 and 228: For the oral measurements options i
Page 229 and 230: Table 9.1: The recommended standard
Page 231 and 232: taken from the available literature
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Page 235 and 236: measurement with variable expirator
Page 237 and 238: to settle. We may have been measuri
Page 239 and 240: 9.5 Off-line measurement NO determi
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Page 243 and 244: 9.6 Nasal nitric oxide measurement
Page 245 and 246: measured over two 24 hour periods,
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Page 249: While these cross-sectional and the
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Page 261 and 262: FEV9.5, symptom score and airways r
Page 263 and 264: Indomethacin - This medication alte
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Page 267 and 268: This low NO occurs despite higher t
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Page 273 and 274: 9.L6 Nitric oxide levels in exercis
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Page 277 and 278: Almost all studies used sedation, w
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Page 285 and 286: Chapter 10: Reflections The outcome
Page 287 and 288: and I enrolled 52 asthmatic childre
Page 289 and 290: Edwards EA, Douglas C, Broome S, Je
Page 291 and 292: o Cass Byrnes & Nicky Holt. "Drugs
Page 293 and 294: o Byrnes CA. Paediatric fibreoptic
Page 295 and 296: Appendix 2: Questionnaire for enrol
Page 297 and 298: Al-Ali, M. K. and P. H. Howarth (20
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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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