BOSTON—Recent efforts to understand and treat asthma have often focused on its inflammatory aspects. Two new studies, however, highlight the importance of airway smooth muscle constriction in the disease.

In one of the studies, performed at the University of Sydney in Australia and the University of British Columbia in Canada, airway narrowing increased rapidly in a small group of asthma patients who refrained from deep inspiration during methacholine challenge—an effect previously thought to be limited to nonasthmatic subjects.[1] “That implies that deep inspiration protects against airway narrowing,” said Gregory G. King, MD, the lead author and a research fellow in the Institute of Respiratory Medicine at the University of Sydney.

The other study, done at Boston University, detected a highly heterogeneous pattern of near and complete airway closures at random sites throughout the lungs of asthma patients.[2] “The worse the asthma, the less the patient’s ability to break out of this pattern with a deep inspiration,” reported lead author Kenneth R. Lutchen, PhD, Chairman of the Department of Biomedical Engineering at Boston University.

PROTECTION FROM NARROWING

“Our study is unusual because we used set doses of methacholine rather than progressively increasing doses,” pointed out Dr. King in an interview with PULMONARY REVIEWS. The study included eight asthma patients ages 22 to 53 years; each patient was tested on six separate days. On the first day, the patients underwent methacholine challenge in increasing doses every five minutes until the dose that caused a 15% reduction in forced expiratory volume in one second (FEV1) was identified (PC15). On the second day, the patients were given five PC15-level doses, one every five minutes. Deep inspiration was permitted during these challenges, and spirometric measurements were obtained three times after each dose.

On the remaining four days, the patients were randomly given two, three, four, or five PC15 doses. Deep inspiration was prohibited during these challenges, and FEV1 was not measured until after the final dose.

There were no differences in mean baseline FEV1 between any of the study days. The geometric mean PC15 was 1.6 mg/mL.

Mean FEV1 measurements after methacholine challenge ranged from 78% to 84% of baseline when deep inspiration was allowed but only from 61% to 73% of baseline when they were prohibited. Furthermore, the declines in FEV1 leveled off after the third challenge when deep inspiration was permitted but continued to worsen when it was not. Measurements of forced vital capacity showed similar results.

The overall study findings are similar to those from an identical investigation of non-asthmatic subjects.[3] Thus, deep inspiration limits acute airway smooth muscle contraction in both healthy individuals and patients with asthma.

HETEROGENEOUS CONSTRICTION

The Boston University study included 12 asthma patients and seven healthy individuals ages 18 to 35 years. Airway constriction was classified as mild to moderate in eight asthma patients and as severe in four. All but one had airway hyperreactivity, and all received daily albuterol. Four also used salmeterol, fluticasone, or a leukotriene inhibitor.

Both the patients’ and the controls’ airway constriction patterns were assessed with dynamic resistance and elastance testing. The investigators used an optimal ventilation waveform (OVW) system to obtain these values, taking measurements from 0.1 to 8 Hz before and after a deep inspiration. Testing was performed at baseline as well as before and after two methacholine challenges: One used a standard protocol with deep inspiration; the other employed a modified protocol without such inspiration.

The subjects had two to five days of rest between the standard and modified challenges. During the standard challenge, progressively greater methacholine concentrations were given until the total amount reached 25 mg/mL or the FEV1 fell to 80% of baseline (PC20). Each dose was followed three minutes later by FEV1 and OVW measurements. During the modified challenge, the patients were given either the PC20 dose or 25 mg/mL (whichever limit had been reached during the standard protocol), and the OVW measurements were again obtained. After both challenges, subjects received aerosolized albuterol and the OVW measurements were repeated.

In all subjects, methacholine challenge increased airway resistance and elastance and produced heterogeneous airway constriction. Refraining from deep inspiration amplified this response. However, deep inspiration completely reversed the airway constriction in the healthy subjects and significantly improved it in the patients with mild to moderate asthma, although neither resistance nor elastance could return to baseline levels in the latter group until after albuterol was administered.

Heterogeneous airway constriction was already so extreme at baseline in the four patients with severe asthma that the investigators could perform the standard challenge in only three; only one of these patients could undergo the modified challenge. Those who were challenged with methacholine showed a high degree of constriction at the lowest dose (0.01 mg/mL).

Unlike the other subjects, the patients with severe asthma showed no residual bronchodilation with deep inspiration before or after methacholine challenge. In fact, deep inspiration sometimes produced paradoxical bronchoconstriction. Their resistance and elastance values fell when albuterol was given but still remained well above the values for healthy subjects.

The inability of deep inspiration to completely reverse heterogeneous airway constriction, particularly in patients with severe asthma, may result from increased stiffness of airway smooth muscle, Dr. Lutchen told PULMONARY REVIEWS. “Its molecular and cytoskeletal structure becomes such that it responds poorly [to] attempts to stretch it with deep inspiration,” he explained.

Thus, the patient is locked in a dysfunctional state that can be unlocked only with bronchodilators acting directly on airway smooth muscle, he and his colleagues stressed. Treatment should therefore focus on distributing bronchodilators to all airway smooth muscle, “including those subtended by closed airways,” they concluded.

—Timothy Begany

References
1. King GG, Moore BJ, Seow CY, Paré PD. Airway narrowing associated with inhibition of deep inspiration during methacholine inhalation in asthmatics. Am J Respir Crit Care Med. 2001;164:216-218.
2. Lutchen KR, Jensen A, Atileh H, et al. Airway constriction pattern is a central component of asthma severity: the role of deep inspirations. Am J Respir Crit Care Med. 2001;164:207-215.
3. King GG, Moore BJ, Seow CY, Paré PD. Time course of increased airway narrowing caused by inhibition of deep inspiration during methacholine challenge. Am J Respir Crit Care Med. 1999;160:454-457.

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