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One aim of investigating the parameters that altered the levels of exhaled NO in these methodological studies was to enable standardisations for future studies. In the next chapter, I will describe the exhaled No research that I did with healthy and asthmatic children. The results presented here in chapters 6 and 7 did make up some of the literature reviewed for the first American Thoracic society and European Respiratory society recommendations to standardise the methods of measuring exhaled NO' The work in this chapter formed the basis of the publication: . Byrnes CA, Dinarevjc g Bnsst CA, Bush A, Shinebournes EA. Is nitric oxide produced at airway or alveolar level? European Respiratory Journal 1997 I0 (5) 1021-1025 In addition Mr Ron Logan-Sinclair went on to d.evelop the LR2000 series of NO analysers using some of the ideas generatedfrom this research (I'agan Research Ltd, Unit 82, Spectrum Business Centre, Anthony's Way, Rochester, Kent, United Kingdom), while Carolyn Busst went on to run a ski lodge in Switzerland! 177
8.1 Chapter 8: Exhaled nitric oxide in healthy and asthmatic children Introduction The protocol was now established and I felt we would be able to measure NO in a reproducible manner in children by standardising all of the parameters discovered to alter NO readings. Initially I wanted to measure exhaled NO in healthy children: that is children with no respiratory diagnosis or any acute or chronic respiratory symptoms. This was to confirm that the technique was possible in children and to confirm some of the findings from the adult studies presented in the previous chapters. Included was a comparison of the results from the direct versus t-piece sampling systems that incorporated a change in flow. I then wanted to compare the exhaled NO levels from these healthy 'control' children to those from asthmatic children in two categories; children on bronchodilator therapy only versus those on regular IHCS. Finally I wanted to measure the exhaled NO pre and post IHCS cornmencement in any child who was on bronchodilator therapy only but who clinically required the introduction of a preventer for asthma control. At the time of corlmencement of this research there had been very little published on exhaled or nasal NO in children. There had been a series of studies looking at the levels of NO from nasal and sinus passages. High concentrations of NO were found when aspirating air from the sinuses of five patients undergoing surgery at 9.1 parts per million (note that most of the exhaled NO reported is measured in parts per billign) (Lundberg, Farkas-Szallasi et al. 1995). An age-dependent increase in mean nasal NO plateau concentrations was also demonstrated in 49 subjects with an age range of 0-62 years, thought to be consistent with the development and pneumatisation of the paranasal sinuses (diagram included in the next chapter as Figure 9.2) (Lundberg, Farkas-Szallasi et al. 1995). The NO levels sampled directly from one nostril and in exhaled air were also significantly less in four children with Kartageners syndrome at 4ppb when compared to 20 healthy children at22lppb (Lundberg, Weitzberg et al. 1994). The following experiments ran from 1995-1997. At the time that we published these findings in 1996 and through 1997, a number of research groups also published results of their investigations into exhaled and nasal NO in children. In the main these were comparisons between control subjects and those with respiratory diseases. In the next section, I will present the subjects, protocols and results from the studies we conducted in healthy children and discuss the findings comparing with these other results from the literature. In the second part of the chapter I will present the literature available from studies in groups of adult asthmatics as again these were published ahead of any results in children. The procedures followed were 178
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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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Page 151 and 152: Authors and Pap€r Sublect numbers
Page 153 and 154: only those measured by mouth or low
Page 155 and 156: 6. Check that the pens work. Fill w
Page 157 and 158: keys but it is currently in the mid
Page 159 and 160: Calibration pressures: the test por
Page 161 and 162: T-piece: tO The first figure shows
Page 163 and 164: the rotameter. Tracings of each par
Page 165 and 166: Figure 6.6: Mean exhaled NO levels
Page 167 and 168: NO and COz results from single exha
Page 169 and 170: 6.6.4 (iii) Comparison of exhaled n
Page 171 and 172: Figure 6.11b: COz levels at peak NO
Page 173 and 174: I also considered whether the diffe
Page 175 and 176: the direct to the indirect method l
Page 177 and 178: need for methodological experiments
Page 179 and 180: The exhalations were carried out in
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
Page 187 and 188: The second set of exhalations invol
Page 189 and 190: Figure 7.6: Photographs of the chan
Page 191 and 192: Table 7.5: Exhaled NO results with
Page 193 and 194: the NO concentrations taken pre and
Page 195 and 196: Figure 7.10: Hyperbolic relationshi
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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 217 and 218: direct method in asthmatic children
Page 219 and 220: Figure 8.4a: The eftect of commenci
Page 221 and 222: had last used her p2 agonist inhale
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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
Page 233 and 234: compartment correlated with the ser
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
Page 241 and 242: (Hyde, Geigel et al. 1997; Tsoukias
Page 243 and 244: 9.6 Nasal nitric oxide measurement
Page 245 and 246: measured over two 24 hour periods,
Page 247 and 248: women who coincidently experienced
Page 249 and 250: 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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