Difference between dosimeter and tidal breathing methacholine challenge - Contributions of dose and deep inspiration bronchoprotection

Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Chest (Impact Factor: 7.48). 01/2006; 128(6):4018-23. DOI: 10.1378/chest.128.6.4018
Source: PubMed


Two bronchoprovocation methods are widely used. Compared to the tidal breathing method, the dosimeter method delivers approximately half the dose and involves five deep inhalations. Both the lower dose and the bronchoprotective deep inhalations contribute to the lesser airway response of the dosimeter.
To determine the relative role of dose and deep inspiration in the difference between the two methods.
Subjects with asthma (n = 24) underwent three methacholine challenges: a dosimeter challenge, a 2-min tidal breathing challenge (twice the dose), and a modified 2-min tidal breathing challenge (twice the dose plus five deep inhalations).
The dosimeter method produced a nonsignificantly lower response than the modified tidal breathing method (p = 0.14). Both deep inhalation methods produced significantly less response than did the standard tidal breathing method (p = 0.011). In the 12 subjects with the most mild airway hyperresponsiveness (AHR), the differences between the deep inhalation method and the tidal breathing method were greater (p = 0.007). By contrast, deep inhalations produced no effect in the 12 subjects with greater AHR; the two tidal breathing methods produced identical results, while the dosimeter produced less response than either (p = 0.033). Six current asthmatics with mild airway responsiveness (tidal breathing method) had negative dosimeter methacholine challenge results.
In subjects with moderate airway responsiveness, the difference between the methods is due to the difference in dose, whereas in subjects with mild AHR, deep inhalations had a large effect overwhelming the dose effect and producing false-negative methacholine challenge results in 25% of the subjects.

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    • "It is possible that there could be important differences in the physiology of milder versus more severe asthma. Finally, the deep inhalations performed during the dosimeter protocol for methacholine challenge have been reported to result in bronchoprotection and falsely negative challenge results among mild asthmatics, compared to the tidal breathing protocol[17,18]. It would be of interest to have data on the relationship of Rmin to airway responsiveness assessed by both protocols. "
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    ABSTRACT: Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R(min)) is abnormally elevated in subjects with airway hyperresponsiveness. The R(min) was measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R(min) and spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R(min) values. Asthmatics had a higher baseline R(min) % predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R(min) was able to identify subjects with airway hyperresponsiveness (PC20 < 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R(min) % predicted, FEV1 % predicted, and FEF25-75 % predicted, respectively). Also, 80% of the subjects with baseline R(min) < 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R(min) > 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic. These findings suggest that baseline R(min), a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R(min) to asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R(min) could provide a clinically useful tool for assessing asthma and monitoring response to treatment.
    Full-text · Article · Jul 2011 · Respiratory research
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    • "Recent studies performed in large numbers of individuals showed that approximately equivalent results for the two methods are seen in subjects with mild to moderate or greater airway hyperresponsivenss.8 However, the five-breath dosimeter method might protect from bronchoconstriction to methacholine in asthmatics with very mild airway hyperresponsiveness.9,10 These findings may result in the negative response regarding NSAH to methacholine seen in our patient. "
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    ABSTRACT: Hydroxyapatite is commonly used as a filler to replace amputated bone or as a coating to promote bone ingrowth into prosthetic implants. Many modern implants, such as hip replacements and dental implants, are coated with hydroxyapatite. We report a patient with occupational asthma due to hydroxyapatite, proven by a specific inhalation challenge, who experienced an early asthmatic reaction after exposure to hydroxyapatite, without increased airway responsiveness to methacholine despite an increased eosinophil count in the peripheral blood. A 38-year-old male dental implant worker visited our allergy department for the evaluation of occupational asthma. He had treated dental implant titanium surfaces with hydroxyapatite for 1.5 years. One year after starting his employment, he noticed symptoms of rhinorrhea, paroxysmal cough, and chest tightness. His symptoms were aggravated during and shortly after work and subsided several hours after work. When he stopped working for 2 months because of his chest symptoms, he became asymptomatic. After restarting his work, his symptoms reappeared and were aggravated. A methacholine bronchial challenge test had a negative response. The following day, a specific bronchial provocation test with wheat powder was negative. On the third day, a specific bronchial provocation test with hydroxyapatite powder produced an early asthmatic response. On the fourth day, a methacholine bronchial challenge test was negative. Further studies are needed to evaluate the exact pathogenetic mechanism of hydroxyapatite-induced occupational asthma.
    Full-text · Article · Apr 2011 · Allergy, asthma & immunology research
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    • "To determine whether that third component of the mechanical response was a uniquely cholinergic phenomenon, we repeated this experiment using 10 7 M 5-HT and obtained the same relationship between test pressure pulse amplitude and magnitude of R stretch (Fig. 2C). To characterize the mechanisms underlying R stretch , all subsequent experiments used a standard test pulse of 30 cm H 2 O because the contractile response (R stretch,30 ) was maximal at this point (Fig. 2, B and C) and because this mirrors the transmural pressure seen during a deep inspiration to TLC in humans (Scichilone et al., 2004; Allen et al., 2005). "
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    ABSTRACT: The airway response to deep inspirations (DIs) in asthmatics has been shown to be ineffective in producing bronchodilation and can even cause bronchoconstriction. However, the manner by which a DI is able to cause bronchoconstriction remains ambiguous. We sought to investigate the pathway involved in this stretch-activated contraction and whether this contraction is intrinsic to airway smooth muscle (ASM). In brief, intact bovine bronchial segments were dissected, and side branches were ligated and then mounted horizontally in an organ bath. Intraluminal pressure was measured under isovolumic conditions. Instantaneously opening and then closing the tap on a column of fluid 5 to 30 cm high evoked a sudden increase in intraluminal pressure (equivalent to the height of the column of fluid) followed by a stress relaxation response of the ASM. When tissues were stimulated with carbachol (10(-8) M) or serotonin (10(-7) M) for 10 min, and the consequent agonist-evoked pressure response was dissipated manually, the response to the same transmural stretch was accompanied by a slowly developing and prolonged increase in intraluminal pressure. This stretch-activated response was significantly diminished by the stretch-activated cation channel blocker gadolinium (10(-3) M), the L-type Ca2+ channel blockers nifedipine (2 x 10(-6) M), diltiazem (10(-5) M), and verapamil (10(-5) M), the sensory neurotoxin capsaicin (10(-5) M), and the neurokinin (NK)(2) receptor antagonists MEN 10376 ([Tyr(I),d-Trp(6,8,9),Lys(10)]-NKA(4-10)) (10(-5) M) and SR48968 (N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide) (3 x 10(-6) M). These results show the ability of isolated airways to exhibit stretch-activated contractions and suggest a role for stretch-activated cation channels, sensory afferent neurons, the neurotransmitter NKA, and L-type Ca(2+) channels in these isolated airway responses.
    Preview · Article · Sep 2008 · Journal of Pharmacology and Experimental Therapeutics
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