exhaled nitric oxide: application measurement interpretation marshall b dunning iii phd, ms, rpft,...
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Exhaled Nitric Oxide:
ApplicationMeasurement
Interpretation
Marshall B Dunning III PhD, MS, RPFT, RCP
53rd AARC Congress
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Nitric oxide (NO):
•1987 discovered that NO was the previously described endothelial- derived relaxing factor (EDRF)
•Colorless, odorless gas, slightly soluble in water
•Half-life is a few seconds
•NO promotes both vascular and bronchial dilation in the respiratory system
•Facilitates coordinated ciliary beating
•Serves as a neurotransmitter for NANC neurons in the bronchial wall
Drs. Robert F. Furchgott,Louis Ignarro & Ferid Murad1998 Nobel Prize inPhysiology or Medicine
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Biology of NO:
Formed by action of nitric oxide synthase (NOS) on L-arginine
3 isoforms-
•type I or neuronal NOS, NOS-1, nNOS•type II or inducible NOS, NOS-2, iNOS•type III or constitutive NOS, NOS-3, cNOS, eNOS
nNOS and eNOS produce low amounts of NO
iNOS can generate large amounts of NO
Stronger affinity for hemoglobin than CO•up to 1,000 times more
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Biosynthesis of NO:Under basal conditions:
NO continually being produced by eNOS (calcium dependent)Activity of iNOS is very low (calcium independent)
Stimulation of eNOS:Shear forces (increase in blood flow) flow-dependent NO formationEndothelial receptor ligands (vasoactive substances)
receptor-stimulated NO formation
Stimulation of iNOS:Inflammation by bacterial endotoxins, and cytokines and interleukinsAmount of NO produced may be 1,000-fold greater than that produced by eNOS
Source: Klabunde RE: Cardiovascular Physiology Concepts, Philadelphia, LWW 2005
Mechanism of action:Mediated via cGMP
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Produced by: •Vascular endothelial cells•Airway neurons •Airway inflammatory cells•Airway epithelial cells
Vascular Effects of NO:
•Direct vasodilation•Anti-thrombotic activity•Anti-inflammatory
Nitric oxide, nitrogen monoxide
N=O
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Clinical use of FENO:
• Adjuvant diagnostic tool
• Non-invasive inflammatory biomarker
• Observe response to anti-inflammatory therapy
• Monitor treatment compliance
• Detect “occult” airway inflammation
• Predict potential asthma exacerbations
• Guide step-down treatment of asthma
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Online measurement:
“…exhalations where the expirate is continuously sampled by the NO analyzer, and the resultant NO profile versus time or exhaled volume…is captured and displayed in real time…” (ATS)
FENO
= fractional concentration of exhaled NO
Expressed as ppb (equivalent to nl/L)
NIOX® Flex, Aerocrine, New Providence, NJ
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Offline measurement:
“…fractional NO concentration in exhalate from a vital capacity collection…” (ATS)
FENO
= fractional concentration of NO
Expressed as ppb (equivalent to nl/L)
ATS/ERS Recommendations for standardized procedures for the online and offlinemeasurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med 171:912-930, 2005.
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•Ambient NO at the time of test should be <5 ppb
•Inhale to TLC, over 2-3 seconds, through mouth avoiding nasal inspiration
•Exclude nasal NO by exhaling against a resistance: 5 cmH2O
•Recommended expiratory flow rate: 50 mL/sec or 0.05 L/sec (+10%)
•The duration of exhalation must be sufficient (>6 sec) to obtain plateau
•3 second NO plateau: <10% or 1 ppb change
•Single-breath NO profile: exhaled NO vs time plot
•Suboptimal exhalations: identified and discarded
•3 repeated with 2 reproducible (+10%) plateau values
•30 sec relaxed tidal breathing between exhalations
•Mean of 2 NO concentration expressed in ppb
ATS recommendations for online measurement of FENO
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NO concentration (ppb) and airway opening pressure versus time for three separate exhalations by the same subject, showing reproducible profiles and plateaus
ATS/ERS Recommendations for standardized procedures for the online and offlinemeasurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med 171:912-930, 2005.
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Left-hand tracing performed with oral inspiration of gas containing <5 ppb NORight-hand tracing performed after subject asked to inhale nasallyNO plateau essentially unchanged once peak washed out
ATS/ERS Recommendations for standardized procedures for the online and offlinemeasurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med 171:912-930, 2005.
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•Ambient NO at the time of test should be <20 ppb
•Nose clips are not required
•Inhale orally to TLC and than immediately perform a slow VC
•Exclude nasal NO by exhaling against a resistance: 5 cmH2O
•Recommended expiratory flow rate: 350 mL/sec or 0.35 L/sec (+10%)
•Reservoir for collection must be nonreactive and relatively impermeable
•Reservoir bag should be stable for at least 48 hours
•NO concentration expressed FENO,0.35
ATS recommendations for offline measurement of FENO
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Technical factors that affect FENO values:
Method of collection•online vs. offline•nasal nitric oxide•expiratory flow rate
Time of day•circadian rhythm
Age/sex •no consistent relationship
Food and beverages•nitrate-containing food•Avoid for 1 hour
Medications•Oral corticosteroids
Respiratory tract infections•Wait until recovery
Exercise•Avoid for 1 hour
Deykin A, Massaro AF, Drazen JM, Israel E: Exhaled nitric oxide as a diagnostic test for asthma; Online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 165:1597-1601, 2002
ATS/ERS Recommendations for standardized procedures for the online and offlinemeasurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med 171:912-930, 2005.
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FENO contamination
Sinus: 1,000-30,000 ppbMouth: 5-15 ppb
Nasal: 15-40 ppb
Trachea: <3 ppb
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Am J Respir Crit Care Med 176:238-242, 2007
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Chemoluminescence analyzerSIR N-6008, Madrid, Spain
Fortuna AM, Feixas T, Gonzalez M, Casan P: Diagnostic utility in asthma: Exhaled nitric oxide and induced sputum eosinophil count. Resp Med 101:2416-2421, 2007
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Respiratory Research 7:94;2006
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What about me
Mr. I. Novent
Therapeutic•Pulmonary hypertension in newborn•Hypoxic respiratory failure in near-term
•Reduce PVR and enhance RV stroke volume post cardiac transplant•Ischemic-reperfusion injury•Acute respiratory distress syndrome
Diagnostic•Pulmonary vasoreactivity in cardiac cath lab
Datex-Ohmeda INOvent, INO Therapeutics, Inc., Clinton, NJ
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Conclusions
• Marker of airway inflammation
• Multiple factors contribute to variation in FENO values
• Should be used in conjunction with other pulmonary function tests
• Monitor treatment compliance
• Research tool useful tool clinical practice
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References:
1) ATS/ERS Recommendations for standardized procedures for the online and offlinemeasurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med 171:912-930, 2005.2) Deykin A, Massaro AF, Drazen JM, Israel E: Exhaled nitric oxide as a diagnostic test for asthma; Online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 165:1597-1601, 20023) Ichinose F, Roberts JD, Zapol WM: Inhaled nitric oxide: a selective pulmonaryvasodilator, current uses and therapeutic potential. Circulation 109:3106-3111, 20044) Smith AD, Cowan JO, Brassett K, Herbison GP, Taylor DR. Use of exhaled nitricoxide measurements to guide treatment in chronic asthma. N Engl J Med 352:163-73,2005.5) Travers J, Marsh S, Aldington S, et al: Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 176:238-242, 20076) Yates DH. Role of exhaled nitric oxide in asthma. Immunol Cell Bio 79:178-90, 2001