Methacholine challenge: test-shortening procedures.

STUDY OBJECTIVES: Validation of test-shortening procedures for the 2-min tidal breathing methacholine challenge method. DESIGN: Retrospective chart review. SETTING: Tertiary-care university clinical pulmonary function laboratory. PATIENTS: One thousand subjects aged 10 to 85 years (mean +/- SD, 44.5 +/- 16.0 years), 44.5% male, referred for methacholine challenge. INTERVENTION: Two-minute tidal breathing methacholine challenge was performed, with both physician and technician access to published test-shortening procedures. MEASUREMENTS AND RESULTS: There were 315 positive test results (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)] < or = 8 mg/mL) and 685 negative test results. The subjects with positive test results were less likely to be male (39.1 vs 47.5%; p < 0.02) and had lower FEV(1) (91.8 +/- 14.9% predicted vs 97.2 +/- 13.9% predicted; p < 0.001). The average starting PC(20) was between 0.5 mg/mL and 1.0 mg/mL; the most common PC(20) was 1 mg/mL (67%). There were 431 skipped concentrations in 380 subjects. The mean number of methacholine inhalations was 3.7 +/- 1.1 (3.9 +/- 0.1 for negative test results vs 3.3 +/- 1.2 for positive test results; p < 0.001). Eighteen subjects had a > or = 20% FEV(1) fall on the first inhalation, and 11 subjects had a > or = 20% FEV(1) fall after a skipped concentration. In only one case (0.1%) an FEV(1) fall > or = 40% on the first concentration was reported, compared with no cases after a skipped concentration and seven cases with a > or = 40% FEV(1) fall after a routine doubling dose step-up. CONCLUSIONS: The 2-min tidal breathing methacholine test in clinical practice can be safely shortened to an average of less than four inhalations using starting concentrations based on FEV(1), asthma medication, and clinical features, and by occasionally omitting concentrations.     

Airway resistance and atopy in preschool children with wheeze and cough.

The extent to which the measurement of airways resistance by the interrupter technique (Rint) distinguishes preschool children with previous wheeze from those with no respiratory symptoms and helps to classify subjects with persistent cough, was investigated. Rint was measured before and after salbutamol treatment in 82 children with recurrent wheeze, 58 with isolated cough and 48 with no symptoms (control subjects). Their mean age (range) was 3.7 yrs (2-<5 yrs). Median baseline Rint was higher (p<0.0001) in wheezers than in either coughers or control subjects (1.16, 0.94 and 0.88 kPa x L(-1) x s(-1) respectively); coughers did not differ significantly from control subjects (p=0.14). The median ratios of baseline to post-salbutamol measurements (bronchodilator response (BDR)) in the groups differed significantly (1.40, 1.27 and 1.07, p< or =0.01 for all), suggesting that coughers occupy an intermediate position. A BDR ratio of >1.22 had a specificity and sensitivity for wheeze of 80% and 76% respectively. Twenty-eight coughers had a BDR ratio >1.22. Wheezers' immunoglobulin E was inversely related to baseline Rint. It is concluded that measurements of airway resistance by the interrupter technique are useful for classifying preschool children with respiratory symptoms and could be used to monitor the effect of interventions. The relation between atopy and airways resistance suggests that they have separate roles in preschool wheezing. Coughers with a high bronchodilator response could represent "cough-variant" asthma in children who have baseline airway resistance by the interrupter technique measurements similar to control subjects. Whether these children develop classical asthma will only be known at follow-up later in childhood.     

Urinary leukotriene E4 in preschool children with acute clinical viral wheeze.

Cysteinyl leukotrienes (cystLTs) are important mediators of wheeze in atopic asthma, but the role of cystLTs in the pathogenesis of preschool viral wheeze (PVW) is unclear. Therefore, evidence for increased production of cystLTs in PVW was sought. Urinary leukotriene E4 (uLTE4) and serum total immunoglobulin (Ig)E were measured in children (1-5 yrs) with PVW during an acute attack (n=44) and in the convalescent phase (n=19), and compared with normal controls (n=15). The effect of atopic sensitisation was assessed in a separate group of atopic controls (n=6) in whom only uLTE4 was measured. The levels of uLTE4 were similar in normal and atopic controls and increased in acute PVW (median (interquartile range) 165 (101-285) versus 125 (82-163) ng x mM creatinine(-1)). Stratification by IgE showed that whereas uLTE4 was increased in 23 children with acute PVW and IgE > 95th percentile (median 211 (118-312) ng x mM creatinine(-1)), uLTE4 was not increased in the 21 children with acute PVW and IgE < or = 95th percentile. In the convalescent phase, uLTE4 fell in the subgroup with high IgE but not in the subgroup with low IgE. It is concluded that increased cysteinyl leukotriene production during acute preschool viral wheeze is associated with high serum immunoglobulin E.     

Randomized controlled trial of fluticasone in preschool children with intermittent wheeze

Previous studies have suggested that during non-rapid eye movement (NREM) sleep, neither large short-duration resistive loads nor sustained normoxic hypercapnia alone leads to increased genioglossus muscle activation. However, in normal individuals during stable NREM sleep, genioglossus activity rises above baseline as PCO2 rises and airway resistance increases. We therefore hypothesized that combinations of chemical (PCO2, PO2) and mechanical stimuli during NREM sleep would lead to increased genioglossal activation. We studied 15 normal subjects (9 males, 6 females) during stable NREM sleep, measuring genioglossus electromyogram, epiglottic/choanal pressure, and airflow under six conditions: (1) baseline, (2) inspiratory resistive loading (-5 to -15 cm H2O/ L/second), (3) increased PCO2 (5-10 mm Hg above baseline), (4) combined resistive loading and increased PCO2, (5 ) hypoxia (SaO2 80-85%), and (6 ) combined hypoxia/inspiratory resistive loading. Only the combined condition of hypercapnia and resistive loading led to significantly increased genioglossal activation, 3.91 +/- 0.77% to 9.64 +/- 1.96% of maximum. These data suggest that the genioglossus muscle is less responsive to either chemical stimuli (hypercapnia, hypoxia) or inspiratory resistive loading alone during NREM sleep at the degrees tested. When hypercapnia is combined with resistive loading, the muscle does respond. However, the possibility that higher levels of PCO2 or greater resistive loading alone could activate the muscle cannot be excluded.     

Methacholine challenge: comparison of two methods

BACKGROUND: Guidelines for the 2-min tidal-breathing and the five-breath dosimeter methods for methacholine challenge have recently been published by the American Thoracic Society (ATS). Although subjects are exposed to twice as much aerosol at any given concentration during the tidal-breathing method compared to the dosimeter method, they were thought to give equivalent results. OBJECTIVE: To compare the 2-min tidal-breathing and the five-breath dosimeter methacholine challenges. SETTING: Tertiary care university-based bronchoprovocation laboratory. PATIENTS: Forty subjects with currently symptomatic asthma. INTERVENTIONS: The two methacholine tests were done in random order on separate days at the same time of day at 1- to 7-day intervals. RESULTS: The dosimeter provocation concentration of methacholine causing a 20% fall in FEV(1) (PC(20)) was almost twice that of the tidal-breathing PC(20): 2.4 mg/mL vs 1.3 mg/mL (paired t test, p < 0.00005). The difference was greater in those with mild airway hyperresponsiveness (AHR) [PC(20) > 1.0 mg/mL; 3.2-fold] compared to those with moderate AHR (PC(20) < 1.0 mg/mL; 1.6-fold) [p = 0.04]. Three subjects with mild asthma and mild AHR (tidal-breathing PC(20), 1.9 to 4.3 mg/mL) had a nonmeasurable PC(20) (> 32 mg/mL) with the dosimeter. CONCLUSIONS: The tidal-breathing method, which exposes the subject to twice as much aerosol at each concentration, produced approximately twice the response. The total lung capacity maneuvers with breathhold during the dosimeter method may inhibit the response in some patients with asthma.     

Methacholine and adenosine 5'-monophosphate challenges in preschool children with cough-variant and classic asthma

Bronchial challenge with different stimuli provides different information and may be used as an adjunct to understand the pathophysiology of cough variant asthma (CVA) in young children in whom the mechanism of disease is still unresolved. This study was designed to investigate the hypothesis that airway hyperresponsiveness (AHR) to methacholine and adenosine 5'-monophosphate (AMP) is similar in preschool children with CVA and classic asthma. We examined airway response to methacholine and AMP in well-defined 3-6-year-old children with CVA (n = 18), classic persistent asthma (n = 31), and healthy controls (n = 10) by transcutaneous oxygen monitorization. The number of AMP responsive children was significantly lower in the group with CVA (38.9%) than classic persistent asthma (67.7%) (P = 0.049). Mean provocative concentration of AMP causing a 15% fall in transcutaneous oxygen tension (PC15PtcO2 AMP) in children with CVA and classic persistent asthma were 234.58 and 36.35 mg/ml, respectively (P = 0.001). None of the healthy children in the control group responded to AMP. The severity of methacholine responsiveness was found similar in CVA and classic persistent asthma groups (P = 0.738). Although both asthma groups showed a similar pattern in methacholine responsiveness, preschool children with CVA were found to differ from children with classic persistent asthma with regard to response profiles to AMP challenge which may point to different pathophysiologic mechanisms of CVA in the young age group.     

Feasibility of shortened methacholine challenge in preschool children

The aim of our study was to assess the feasibility and safety of a recently suggested tripling-dose methacholine (Mch) challenge in preschool children. Fifty-seven children aged 3-6 years were studied. Mch challenge was carried out using a tidal breathing method, with concentrations of 0.22, 0.66, 2.0, 6.0, and 18.0 mg/ml, at 5-min intervals, given by a Pari Turbo Boy compressor and Pari LC Plus nebulizer, for 1 min only. Oxygen saturation (SaO(2)) was monitored during the challenge. The challenge was terminated if there was wheeze, SaO(2) below 91%, or persistent cough. This final Mch dose was considered the provocative concentration inducing audible wheeze (PCW). Nine healthy children, 17 with cough and 25 with wheeze, completed the study. Mean output from nebulizers (SD) in these 51 children was 0.30 (0.05) ml/min. Geometric means for PCW in these groups were 2.88, 2.58, and 1.28 mg/ml Mch, respectively. The wheezing children were significantly more hyperresponsive than the coughing children (P < 0.05). A tripling-dose Mch protocol is safe and practicable in children over 3 years of age. A further reduction in nebulized dose may be needed for a more discriminatory test.     

Inhaled steroids compared with disodium cromoglycate in preschool children with episodic viral wheeze

In school children with atopic asthma the beneficial effects of disodium cromoglycate (DSCG) and beclomethasone dipropionate (BDP) are well-established. In preschool children, wheezing is quite common, and in the majority of cases the symptoms are episodic and reported to be associated with viral infections rather than atopy. We compared the efficacy of regular treatment with DSCG and BDP for prevention of wheezing in preschool children. We were interested to establish whether regular treatment with inhaled anti-inflammatory drugs could lead to a decrease in bronchial responsiveness. In 15 patients (median age, 56 months; range, 43–66 months) bronchial responsiveness was assessed by measuring specific airway resistance (sR_aw) during a histamine provocation test. The concentration of histamine eliciting a 100% increase in sR_aw (PC_100his) was determined. In a double-blind crossover study, patients inhaled either DSCG 10 mg three times a day or BDP 100 μg three times a day for 2 months. After a wash-out period, treatment was changed to BDP or DSCG, respectively. Daily peak flow measurements were carried out, and exacerbations were noted. PC_100his was measured at the start and end of each treatment period. No significant decrease in bronchial responsiveness was seen (PC_100his DSCG: before 1.3, after 1.66 mg/ml, P value not significant; BDP: before 1.1 after 1.22 mg/ml, P value not significant). Significantly higher morning peak flows were observed on BDP therapy (160 on BDP vs. 150 L/min on DSCG, P< 0.03). BDP treatment resulted in significantly fewer wheezing exacerbations (7 vs. 16, P< 0.005) compared with DSCG therapy. We conclude that in preschool children with episodic virally induced wheezing, BDP therapy was superior to DSCG aerosol treatments for the prevention of exacerbations of wheezing, although no significant effect on bronchial responsiveness was noted during either treatment protocol. Pediatr Pulmonol. 1998; 25:361–366. © 1998 Wiley-Liss, Inc.     

Methacholine inhalation challenge: a shorter, cheaper and safe approach.

Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre. All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) > or = 0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV1 >40%). When unavailable, provocative dose causing a 20% fall in FEV1 (PD20) values were obtained by linear inter- or extrapolation of the existing data. The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 151449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV1/FVCbl 0.7-0.8 reacted to inhalation up to 0.073 micromol. Four subjects (of 280, 1.4%) with FEV1/ FVCbl> or =0.8 reacted to inhalation up to 0.219 micromol. The authors suggest that: 1) an initial dose of 0.219 micromol (initial concentration= 0.21 mg.mL(-1)) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity > or =0.8 and 0.073 micromol (initial concentration=0.07 mg.mL(-1)) when the baseline ratio is <0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2%, faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.     

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler DPI.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) <4 mg x mL(-1)) were treated on separate days with 0, 100, 200 or 400 microg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney's bioassay to test for therapeutic equivalence of the inhalers. Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events). Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler.     

The use of transcutaneous oximetry in the noninvasive vascular laboratory.

Transcutaneous oximetry is gaining worldwide acceptance as a simple and effective means of evaluating the cutaneous circulation. Oximetry involves the use of Clark-type electrically heated oxygen-sensing electrodes that are attached to the skin; various protocols for the performance of studies (utilizing exercise, oxygen inhalation, leg elevation, and various other maneuvers) have been developed which may improve the accuracy when used in certain settings. Applications for transcutaneous oximetry are found in areas such as: (1) diagnosis of disease, (2) quantification of disease severity, (3) prediction of healing potential for skin ulcers or amputation sites, (4) assessment of microvascular disease, and (5) determination of cutaneous vasomotor status. Transcutaneous oxygen tension serves as an index of the adequacy of skin blood flow, and therefore yields valuable "functional" information not provided by noninvasive "anatomical" testing modalities such as echo-doppler ultrasound imaging.     

Methacholine inhalation challenge studies in a selected pediatric population

To determine bronchial reactivity patterns, 400 subjects, 5 to 21 yr of age, underwent a methacholine challenge in a Natural History of Asthma study. The diagnosis of asthma or allergy was based on a respiratory questionnaire. Subjects were nonsmokers and had had no respiratory infections for 1 month. Intradermal skin tests were done. The methacholine challenge response was expressed as the area beneath the dose-response curve (Area 35). Fifty-five asthmatics, 113 normal subjects from normal families, 103 normal subjects from asthma families, 60 normal twins, and 69 allergic subjects without asthma were studied. Overall, 52% of nonasthmatics and 47% of nonallergic subjects had an Area 35 less than 4,000 (800 breath units). There was a difference (p less than 0.05) in the distribution of methacholine Area 35 responses in normal subjects from that in normal families compared with normal subjects from asthma families. The age of the nonasthmatic subjects had an influence on the degree of bronchial reactivity. Methacholine challenge studies in pediatric patients must be interpreted with age, personal atopic status, and family asthma history in mind.