Reduction of Nocturnal Asthma by an Inhaled Anticholinergic Drug

The mechanism of nocturnal asthma is still uncer-tain. In both normal and asthmatic subjects, anticholinergic drugs cause bronchodilatation, thus indicating a degree of resting cholinergic tone in human airways. There is some evidence that vagal tone may be greater in asthmatic subjects than in normal subjects, since the sinus arrhythmia gap, which reflects cardiac vagal tone, is more prolonged. There is no direct evidence for circadian variation in cholinergic regulation of airway tone, but several studies have indicated that indices of vagal activity, such as heart rate and sinus arrhythmia gap, are significantly enhanced at night in both normal and asthmatic subjects. In asthmatic subjects, there may be a close association between the fall in peak expiratory flow (PEF) at night and the fall in heart rate, which supports the idea that increased cholinergic airway tone may be at least a contributory factor in the pathogenesis of nocturnal asthma. If this is so, anticholinergic drugs may have a beneficial effect in preventing nocturnal asthma.

In a previous report, ipratropium bromide appeared to reduce the early morning fall in PEF, but the study was not placebo-controlled, and only a single dosage was studied. We have now examined the effect of another anticholinergic drug, oxitropium bromide, given in different dosages at night, on early morning bronchoconstricdon in a double-blind placebo-controlled study.

Nocturnal asthma

Materials and Methods


Eighteen patients (Table 1) with documented nocturnal asthma, defined as a difference of more than 20 percent in peak expiratory flow (PEF) between evening and early morning readings on 50 percent of the occasions over a two-week run-in period, were investigated. The study was approved by the Ethical Committee of Hammersmith Hospital, London, and all of the patients gave informed consent. No subjects were taking either anticholinergic treatments or oral steroids.

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Experimental Protocol

The effect of oxitropium bromide, given as a single dose at night, was examined in a double-blind, randomized crossover study over a period of six weeks, comprising three separate two-week periods of treatment During each period of treatment, patients received either 200μg of oxitropium bromide (two 100μg puffs), 400μg of oxitropium bromide (two 200μg puffs), or placebo (two puffs) by inhalation at night. Subjects were instructed in correct usage of the inhalers before commencing the study.

PEFThe response to each treatment was assessed by measurement of PEF using a Wright peak flow gauge and the patients assessment of symptoms. On waking each morning, patients performed three PEF maneuvers, recording the highest score on a diary card. The PEF was also measured ten minutes after inhaling 200μg of albuterol (salbutamol). The same routine was followed before retiring last thing at night, followed by the inhalation of the studied drug. In addition, records of PEF were made if the patient awoke during the night due to their asthma. Patients also kept a daily record of daytime and nocturnal use of extra inhalations of albuterol (one of the known albuterol –, together with symptom scores of daytime and nocturnal cough and wheeze and early morning cough and wheeze, which were graded on a scale of severity from zero to three. No change was made in concurrent antiasthmatic medication.

At the end of each two-week period of treatment, patients were required to attend the clinic to exchange inhalers and diary cards, record any side effects, and complete self-assessment of that period of treatment using a 10-cm visual analog scale.

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Statistical Techniques

The effect of oxitropium on nocturnal asthma was assessed by statistical analysis of the group mean percentage of foil in PEF from evening to morning using two-way ANOVA, and the level of significance was tested by paired t-test.

Table 1—Clinical Details cf Subjects

Subject, Sex, Age (yr) AtopicStatus* Duration of Asthma, yr FEVl percent of predicted Respondert
1, F, 65 7 36.8
2, F,43 13 87.3
3, F, 34 12 44.4
4, M, 71 4 90.0
5, F, 48 23 37.7
6, F, 59 20 71.7
7, F, 56 4 32.5
8, M, 71 2 42.6
9, M, 76 70 29.4
10, F, 24 5 87.9
11, F, 26 19 68.2
12, M, 22 1 35.9
13, M, 18 16 67.6
14, M, 27 27 45.1
15, F, 48 20 38.3
16, M, 34 14 83.9
17, F, 44 42 93.4
18, F, 58 58 59.6