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List of Tables Table 1.1: Alternative diagnoses in children with whee2e............... ........................g lable 3.1: Properties of nitric oxide .................71 Table 3.2: Reactions with nitric oxide ..............72 Table 3.3: The characteristics of the nitric oxide synthase isoen2ymes................................... g1 Table 4.1: The companies providing chemiluminescence analysers adaptable for nitric oxide measurement in 1995. ...................101 Table 5.1: The delay and response time of the NO, COz, mouth pressure and flow meter analysers used.......... ...llg fu9l" 6.1: The published results of exhaled nitric oxide in adults.... ...................127 full" 6.2: Compete results for an individual subjecr .......143 Table 6.3 NO and COz results from single exhalitions in twelve adult subjects............. ......143 Table 7.1: NO, COz and duration of each exhalation at different expiratory flows...............157 Table 7.2: Comparison of the first and repeated last set of exhalation, uf the same expiratory flow""""" ...................16r Table 7.3: NO, COz and duration of each exhalation at different expiratory mouth pressures .....,....,,,.,.., |62 Table 7.4: Comparison of the first and repeated last set of exhalations performed at the same SPt]afory mouth pressure ............162 Table 7.5: Exhaled NO results with high and low background NO concentrations...............l6g Table 7.6: Exhaled COz results with high and low background NO concentrations .............16g Table 8.1: Coefficients of variation of peak NO, peak COz and mouth pressure measurements made by both the direct and rpiece systems, and of flow made by the rpiece system......... lg5 Table 9.1: The recommended standard for single breath online Nb meaiur.-"nt ...............206 Table 9.2: The recommended standards for single breath and tidal breathing off-line NO measurement.............. ..,,,...,,,,.....,.21g Table 9.3: The recommended standard for nasal No measurement...... ...............220 XV Page
List of Figures Figure l.l: Top l0 causes of avoidable admissions, 0-24 years, 1999.......... .......... 3 Figure 2.1: Diagram of blood vessels in cross section showing the endothelial layer. ...........59 Figure 3.1: The molecular structure of NO....... ................. 70 Figure 3.2: The reaction to generate nitric oxide ...............71 Figure 3.3: The nitric oxide synthase reaction showing the generation of the constituent atoms of nitric oxide........ ....... 80 Figure 3.4: The chemical structures of the nitric oxide synthase inhibitors ..........90 Figure 4.1: Chemical reaction between nitric oxide and ozone. .......... 98 Figure 4.2:Diagram of the chemiluminscence analyser.... .................. 99 Figure 4.3: Relationship between chemiluminscence in millivolts to nitric oxide concentration in picomo1es.............. ................... 100 Figure 4.4: Reaction equations used to release nitric oxide from other nitrogen compounds 103 Figure 5.1: Schematic diagram of how the analysers were placed .... Llz Figure 5.2: An example of tracing from the testing....... .. 113 Figure 5.3: Photographs of one of the children performing the exhalation........................... I 16 Figure 6.1: Recording of the calibrations for NO, CO2 and pressure ana1ysers.................... 133 Figure 6.2: Recording of the calibration of the flow rotameter and pneumotachograph....... 135 Figure 6.3: Schematic diagrams of the two different types of connections: direct and t-piece measurements............. .................. 137 Figure 6.4: Example of the chart recording rolls for the direct versus t-piece measurements. 140 Figure 6.5: Example of recording on one subject - Page direct and t-piece measurements .......... 141 Figure 6.6: Mean exhaled NO levels measured by direct and t-piece systems......................I42 Figure 6.7: Example of a recording for the two systems............... .... L42 Figure 6.8: Mean exhaled COz levels measured by direct and t-piece systems..... ................ I44 Figure 6.9: Comparisons of the peak NO with area under the curve... ................ 145 Figure 6.10a: Time to peak NO and peak CO2 measured by the direct system..................... 146 Figure 6.10b: Time to peak NO and peak CO2 measured by the t-piece system...................147 Figure 6.1Ia: COz levels at peak NO and at peak CO2 measured by the direct system ........147 Figure 6.1Ib: CO2 levels at peak NO and at peak CO2 measured by the t-piece system ...... 148 Figure 7.1: Exhaled NO results with increasing expiratory flows .....I57 Figure 7.2:Example of the tracing in one subject at two different expiratory flows ............ 158 Figure 7.3: The effect of pressure on the calibration gas measurement ......... ..... 160 Figure 7.4: Exhaled NO results at increasing expiratory mouth pressure ........... 161 Figure 7.5: Measurement of exhaled NO incorporating the reservoir system ..... 165 Figure 7.6: Photographs of the changing ambient NO concentration recordings.................. 166 Figure 7.7: Recording from one subject showing NO results with exhalations from low and high background NO.... ................ 167 Figure 7.8: The effect of high and low pressure on the calibration gas measurement........... 167 Figure 7 .9: The effect of consuming water on the subsequent exhaled NO levels measured 170 Figure 7.10: Hyperbolic relationship between exhaled NO and sampling flow rate.............172 Figure 7.11: Exhaled NO determined at single breath plateau concentrations at increasing expiratory flows and at increasing expiratory mouth pressures... ......173 Figure 8.1: Peak exhaled NO results in healthy children.... ............... 183 Figure 8.2a: Comparison of peak exhaled NO in boys and girls measured by the direct system. 184 Figure 8.2b: Comparison of peak exhaled NO in boys and girls measured by the t-piece system...... ................... 184 XVI
Page 1 and 2: http://researchspace.auckland.ac.nz
Page 3 and 4: UNIVERSITV OF AUCKI'AND Abstract -
Page 5 and 6: There was no significant difference
Page 7 and 8: This is Dedicated: Dedication To th
Page 9 and 10: New Zealand The Paediatric Departme
Page 11 and 12: Contents Abstract ........tr Dedica
Page 13 and 14: 6.5.4 The subjects............... .
Page 15: XIV
Page 19 and 20: List of Abbreviations ABPA allergic
Page 21 and 22: LADA N*N* dimethyl L-arginine LFA1
Page 23 and 24: t}ryem(eNoS)Typeltrendothelialnifti
Page 25 and 26: area, some of it has been expanded
Page 27 and 28: In addition, both of these groups a
Page 29 and 30: studies conducted throughout the Un
Page 31 and 32: Video clips of infants with a varie
Page 33 and 34: the Paediatric Society of New 7*ala
Page 35 and 36: inhaled anti-cholinergic agents and
Page 37 and 38: ecommended to monitor asthma at hom
Page 39 and 40: improvement to 70Vo PEF would have
Page 41 and 42: Furthermore, investigators have als
Page 43 and 44: poorer predictor of a diagnosis of
Page 45 and 46: Bronsky et al. 1998), and a long-te
Page 47 and 48: SIGN guideline (SIGN 2005) stated "
Page 49 and 50: In brief, the human airway can be d
Page 51 and 52: The ability to biopsy has led to st
Page 53 and 54: small proportion of cells recovered
Page 55 and 56: methodology of sputum induction and
Page 57 and 58: et al. 1999; Giannini, Di Franco et
Page 59 and 60: over a six month treatment prograrn
Page 61 and 62: There are other studies suggesting
Page 63 and 64: So is induced sputum in adults and
Page 65 and 66: asymptomatic patients independent o
Page 67 and 68:
onchial hyper-responsiveness (Reich
Page 69 and 70:
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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subjects with respiratory disease,
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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
Page 313 and 314:
de Blic, J., V. Marchac, et al. (20
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Donaldson, S. H., W. D. Bennett, et
Page 317 and 318:
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
Page 335 and 336:
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
Page 341 and 342:
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
Page 355 and 356:
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. (
Page 369 and 370:
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
Page 375 and 376:
Williams, O., R. Y. Bhat, et al. (2
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Yates, D. H., S. A. Kharitonov, et
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