Relationship between ultrasonically nebulized distilled water–induced bronchoconstriction and acetic acid–induced cough in asthmatic children

doi:10.1016/S0091-6749(95)70008-0

Journal of Allergy and Clinical Immunology

Volume 96, Issue 2, August 1995, Pages 193-199

https://doi.org/10.1016/S0091-6749(95)70008-0 Get rights and content

Abstract

Background: Although wheezing and cough are the most common complaints in asthmatic persons, the mechanisms of hyperresponsiveness to bronchoconstriction and cough are nevertheless still unclear. Objective: To investigate the common mechanisms between them, we studied the relationship between ultrasonically nebulized distilled water (UNDW) inhalation challenge and acetic acid (AA) inhalation challenge. In addition, we evaluated the effect of inhaled furosemide on both provocation tests by means of a placebo-controlled study. Method: In study 1 the UNDW, AA, and histamine inhalation challenges were performed in 40 asthmatic children (26 boys, aged from 7 to 16 years; mean ± SD, 11.2 ± 2.0 years). In study 2, 12 of the study 1 subjects (9 boys, 11.3 ± 2.4 years) were subjected to each challenge test after inhalation of furosemide (10 mg/body square meters), or placebo (0.9% saline solution) on separate days. Results: There was a good correlation between the provocative dose causing a 20% fall in forced expiratory volume in 1 second in the UNDW inhalation challenge (UNDW-PD₂₀) and threshold dose causing cough in the AA inhalation challenge (r = 0.527; p < 0.001). There was no relationship either between UNDW-PD₂₀ and the provocative concentration causing a 20% fall in the histamine inhalation challenge (histamine-PC₂₀)(r = 0.384; p > 0.1), or between histamine-PC₂₀ and the cough threshold (r = 0.308; p > 0.05). In study 2 neither bronchoconstriction nor bronchodilatation after inhalation of furosemide was observed. Inhaled furosemide exerted a protective effect on UNDW-PD₂₀ and cough threshold of the AA inhalation challenge (p < 0.01 and p < 0.01, respectively), but did not attenuate histamine-PC₂₀ (p > 0.1). Conclusion: These data suggest that a common mechanism may cause hyperresponsiveness against both UNDW-induced bronchoconstriction and AA-induced cough in asthmatic children. (J ALLERGY CLIN IMMUNOL 1995;96:193-9.)

Section snippets

Subjects

Forty asthmatic children (26 boys, 14 girls; mean age ± SD 11.2 ± 2.0 years) were enrolled in study 1. Twelve of the study 1 children (9 boys, 3 girls; 11.3 ± 2.4 years old) were also enrolled in study 2 (Table I). The clinical diagnosis of bronchial asthma was based on a characteristic history of recurrent attacks of dyspnea with perceptible wheezing, with the diagnosis having been established after more than 2 years of follow-up. All subjects had been free of upper respiratory tract

Relationships between acetic acid inhalation challenge, UNDW inhalation challenge, and histamine inhalation challenge

Fig. 1 shows the results of study 1 (n = 40). The mean value and standard error of the mean of UNDW-PD₂₀, histamine-PC₂₀, and threshold of cough in AA inhalation challenge were 4.50 ± 0.47 (ml), 2.54 ± 0.09 log(mg/ml), and 0.67 ± 0.07 log(concentration %), respectively.

. A, Relationships between UNDW-PD₂₀ and threshold dose causing cough in AA inhalation challenge. There was a good correlation between them (n = 40; r_s = 0.527; p < 0.001) B, Relationships between histamine-PC₂₀ and threshold dose

DISCUSSION

In persons with asthma wheezing, which is mainly dependent on bronchoconstriction, and cough are the most common complaints.²¹ However, the mechanism of hyperresponsiveness to bronchoconstriction and cough in these patients is still unclear. Accumulating data suggest that the two airway reflexes of cough and bronchoconstriction have separate afferent neural pathways,²² and they may have a differing sensitivity to inhibitory drugs.23, 24 In the recent report of Eschenbacher et al.,⁶

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Cited by (19)

Relationship between sodium transmembrane fluxes and methacholine-provoked bronchoconstriction
2002, Revue Francaise d'Allergologie et d'Immunologie Clinique
Sodium transmembrane flux modifies cell membrane potential by changing intracellular ion concentration and amino-acid balance, thereby influencing cell reactivity. Diminished activity of Na⁺-K⁺ -2Cl^- co-transport is a cause of primary hypertension. Furosemide is known to prevent methacholine-induced bronchoconstriction and inhibit Na⁺-K⁺-2Cl^- co-transport. A possible mechanism of this protective effect is furosemide-dependent inhibition of ion transport in cell membrane, but data from previous studies are contradictory. We therefore investigated the correlation between the sodium flux in lymphocytes of asthmatics and the results of methacholine challenge. Fifteen patients with mild asthma, (seven males, eight females, age: 18–52, mean: 30.67 years), were included in the study. Patients underwent two methacholine challenge tests on two separate occasions. The second methacholine nebulisation was preceded by nebulisation with 20 mg of furosemide. The in vitro Na⁺-K⁺-2Cl^- co-transport activity was investigated in peripheral blood lymphocytes using ²²Na. There was no statistically significant difference between methacholine-induced bronchoconstriction (PC20) with and without furosemide nebulisation (P = 0.73) . The value of PC20 without furosemide prenebulisation correlated with both Na⁺-K⁺-2Cl^- co-transport activity (R = 0.684 ; P = 0.005) and total sodium flux (R = 0.618 ; P = 0.014). When methacholine challenge was preceded by inhalation with furosemide, there were no correlations between methacholine PC20 and either Na⁺-K⁺-2Cl^- co-transport activity (R = 0.104 ; P = 0.719) or total sodium flux (R = 0.062 ; P = 0.826). In conclusion, methacholine-induced bronchoconstriction is not prevented by prenebulisation with furosemide; methacholine-induced bronchoconstriction is interrelated with transmembrane sodium ion fluxes, both total sodium flux and furosemide-dependent sodium flux (Na⁺-K⁺-2Cl^- co-transport). The nature of this relationship remains unclear.
Le flux transmembranaire du sodium modifie le potentiel de la membrane cellulaire en changeant la concentration intracellulaire des ions et l’équilibre aminoacidosique en influençant la réactivité de la cellule. L’activité diminuée du cotransporteur Na⁺-K⁺-2Cl^– est une cause d’hypertension essentielle. Le furosémide prévient la bronchoconstriction induite par la métacholine et inhibe le cotransporteur Na⁺-K⁺-2Cl^–. Le mécanisme de cet effet protecteur pourrait être l’inhibition du transport du furosémide dépendant des ions, mais les données de nombreuses expériences sont contradictoires. Nous avons étudié la corrélation entre le flux de sodium et les résultats du test de provocation à la métacholine. Quinze patients avec un asthme persistant léger (sept hommes, huit femmes, âgés de 18 à 52 ans, moyenne : 30,67 ans) ont subi deux tests de provocation à la métacholine en deux occasions distinctes. La seconde inhalation a été précédée par l’inhalation de 20 mg de furosémide. L’activité du cotransporteur Na⁺-K⁺-2Cl^–- dans les lymphocytes a été étudié in vitro en utilisant le ²²Na. Il n’y avait pas de différence statistiquement significative entre la métacholine avant et après le traitement par PC20 (p = 0,73). La valeur de la PC20 sans furosémide est dépendante de l’activité du cotransporteur Na⁺-K⁺-2Cl^– (R = 0,684 ; p = 0,005) et du flux total de sodium (R = 0,618 ; p = 0,014). Quand le test de provocation à la métacholine est précédé par l’inhalation de furosémide, il n’y a pas de corrélation entre la PC20 métacholine, l’activité du cotransporteur Na⁺-K⁺-2Cl^– (R = 0,684 ; p = 0,005) et le flux du sodium total (R = 0,618 ; p = 0,014). En conclusions, d’une part la bronchoconstriction induite par la métacholine n’est pas prévenue par l’inhalation de furosémide et, d’autre part, la bronchoconstriction induite par la métacholine est également liée au flux du sodium total et du cotransporteur Na⁺-K⁺-2Cl^–. La nature de cette relation reste peu claire.
Inadvertent administration of nebulized acetic acid [9]
2001, American Journal of Emergency Medicine
Citation Excerpt :
Acetic acid (CH3 COOH) has many uses, including: a manufacturing component of various acetates and plastics, a preservative in foods, a solvent for gums and oils, and a pharmaceutical acidifier.1 Inhalation of acetic acid has caused reactive airway disease, pulmonary edema, pneumonitis, asthma exacerbation, and other respiratory problems.2-4 We report a case where inhaled acetic acid produced relatively significant respiratory effects (respiratory acidosis, hypercapnea, tachypnea, and increased respiratory effort) in a 10-month old girl.
Cough induced by low pH
1999, Respiratory Medicine
Citric acid has been used as a tussive agent in the investigation of the cough reflex. The mechanism of cough stimulation remains unclear. We conducted studies to compare the cough response of citric acid to an organic (acetic acid) and an inorganic acid (phosphoric acid). We also compared the cough response of citric acid to capsaicin, a non-acid tussive stimulus. In study 1, 26 subjects inhaled equimolar concentrations of citric and acetic acid. In study, 2, 22 subjects inhaled citric acid and phosphoric acid in concentrations of similar pH. Eighteen subjects from study 2 completed a capsaicin cough challenge test. The cough response was recorded and the concentration causing two coughs, the cough threshold, calculated (D2). The correlation of cough thresholds between both citric and acetic acid (r=0·79, 95% CI 0·37−0·90, P<0·0001) and citric acid and phosphoric acid (r=0·68, 95% CI 0·37−0·86, P=0·0005) were significant. There was no correlation between the citric acid and capsaicin cough thresholds. These results show that an individual's cough response to acetic and phosphoric acid are similar to that caused by citric acid. Thus these acids may cause cough by a common mechanism such as disturbance of the pH of the airway surface liquid. Capsaicin does not appear to share this common pathway.
Cough Hypersensitivity Syndrome: Why Its Use Is Inappropriate in Children
2023, Journal of Clinical Medicine
Antitussive drugs-past, present, and future
2014, Pharmacological Reviews
Clinical cough III: Measuring the cough response in the laboratory
2009, Handbook of Experimental Pharmacology

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^☆: From the Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.

^☆☆: Reprint requests: Hiroyuki Mochizuki, MD, Department of Pediatrics, Gunma University School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma, Japan 371.

^★: 0091-6749/95 $3.00 + 0 1/1/63284

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Relationship between ultrasonically nebulized distilled water–induced bronchoconstriction and acetic acid–induced cough in asthmatic children☆,☆☆,★

Abstract

Section snippets

Subjects

Relationships between acetic acid inhalation challenge, UNDW inhalation challenge, and histamine inhalation challenge

DISCUSSION

Lancet

Gen Pharmacol

Respir Med

Lancet

Chest

J ALLERGY CLIN IMMUNOL

Jpn J Pharmacol

The experimental production of cough in human subjects induced by citric acid aerosol

Am J Med Sci

Capsaicin inhalation in man and the effects of sodium cromoglycate

Br J Pharmacol

Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone

Am Rev Respir Dis

The role of titratable acidity in acid aerosol–induced bronchoconstriction

Am Rev Respir Dis

Inhaled furosemide inhibits cough induced by low chloride content solutions but not by capsaicin

Am Rev Respir Dis

Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions

N Engl J Med

Inhaled furosemide is highly effective in preventing ultrasonically nebulised water bronchoconstriction

Pulm Pharmacol

Effect of inhaled furosemide on metabisulfite- and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects

Am Rev Respir Dis

Inhaled furosemide does not attenuate the bronchial response to methacholine in asthmatics [Abstract]

Eur Respir J

Hyperresponsiveness of cough receptors in patients with bronchial asthma

Pediatrics

Evaluation of ultrasonically nebulized solutions for provocation testing in patients with asthma

Thorax

Comparison of ultrasonically nebulized distilled water and hyperventilation with cold air in asthma

J ALLERGY CLIN IMMUNOL