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Non-invasive method of measuring airway inflammation: exhaled nitric oxide Dr Catherine Ann BYRI\IES FRACB MBChB (New Zeatand) Graduate certificate in crinicat Education (New south wales) The University of Auckland Department of Paediatrics Faculty of Medical & Health Sciences Private Bag92ol9 Auckland 1142 New Zealand Ph: &93737 599extn 89770 Fax: @93737 486 Email: c.byrnes@auckland.ac.nz Senior Lecturer & Honorary Consultant Paediatric Respiratory Medicine
UNIVERSITV OF AUCKI'AND Abstract - - oEC 2008 Backeround UBRARY Nitric oxide (NO) was well known to be a component of air pollution, often in the form of nitrogen dioxide (NOt. However its importance in biological systems altered dramatically with the discovery in 1987 that it was the 'endothelial-derived relaxing factor'. Since then there has been an explosion of research on NO demonstrating that this gaseous molecule was a widespread physiological mediator and was simultaneously recognised as a vital component of immune function contributing to macrophage-mediated cytotoxicity. NO was therefore a key molecule in modulating inflammation, including airway inflammation. The aim of this thesis was: l. To adapt a NO chemiluminscence analyser from measuring ainvay pollution to measuring exhaled air in human subjects. 2. To measure NO levels in exhaled air in adult subjects. 3. To evaluate whether altering measurement parameters altered the levels of NO obtained. 4. To adapt this technique from adults to measure exhaled NO in children. 5. To compare levels of NO from healthy children to groups of asthmatic children on either bronchodilator therapy only, or on regular inhaled corticosteroids. 6. To compare the levels of NO in a pilot group of asthmatic children before and after commencement of inhaled corticosteroids. Methods A Dasibi Environmental Corporation Model 2t07 chemiluminescence analyser was adapted specifically requiring a reduction in response time, which was achieved by modification of the circuitry and re-routing of the analogue signal directly to a chart recorder, achieving a reduction of the response time by 807o. Addition of a number of analysers allowed the measurement of exhaled NO, carbon dioxide (COz), mouth pressure and flow for each exhalation from total lung capacity. Twenty adult subjects (in total) were then studied looking at direct (NO, CO2, mouth pressure) versus t-piece (with the addition of flow) measurements making five exhalations from total lung capacity, at 3-minute intervals (direct/t-piece/direct or t-piece/direct/t-piece in series). The area of NO under the curve versus the peak of the NO trace was compared and the exhalation pattern of NO versus COz was compared. Measurement conditions were altered to evaluate the effect of individual parameters on the exhaled NO result. This included separately assessing different expiratory flows, different expiratory mouth pressures, the effect of a high versus a low background NO level and the tl
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Page 5 and 6: There was no significant difference
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Page 11 and 12: Contents Abstract ........tr Dedica
Page 13 and 14: 6.5.4 The subjects............... .
Page 15 and 16: XIV
Page 17 and 18: List of Figures Figure l.l: Top l0
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
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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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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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