Interpretation of Pulmonary Function Tests A Practical Guide, 3. ed

5. Bronchodilators and Bronchial Challenge Testing

When a patient undergoes pulmonary function tests for the first time, itisalmostalwaysworthwhile to have spirometry performed before and after the administration of an inhaled bronchodilator.


Administering a β2 agonist is rarely contraindicated. Ipratropium bromide can be used if the β2 agonist is contraindicated. The major values of bronchodilator testing are as follows:

1. If the patient shows a positive response (see section 5C below), one is inclined to treat more aggressively with bron- chodilators and possibly with inhaled corticosteroids. The improvement can be shown to the patient, and compliance is thus often improved. However, even if no measurable improvement occurs, a therapeutic trial (2 weeks) of an inhaled bronchodilator in patients with obstructive disease may provide symptomatic and objective improvement.

2. Patients with chronic obstructive pulmonary disease (COPD) who acutely show a heightened response to a bronchodilator have been found to have an accelerated decrease in pulmonary function over time. In such cases, aggressive therapy of the COPD seems warranted.

PEARL: Some pulmonologists believe that a positive response to a bronchodilator in COPD warrants a trial of inhaled corticosteroid therapy. However, bronchodilator response does not predict response to inhaled corticosteroid. Inhaled corticosteroid therapy is indicated for patients with moderate to severe COPD (forced expiratory volume in 1 second [FEV1] <80% predicted) with frequent (more than once a year) or recent exacerbations. This therapy reduces the frequency of exacerbations and improves symptoms and quality of life [1,2].

3. Possibly the most important result is the detection of unsuspected asthma in a person with low-normal results on spirometry.


The agent can be administered either by a nebulizer unit or by use of a metered-dose inhaler. The technique for the inhaler is described in Figure 5-1.

FIG. 5-1. Technique for use of metered-dose inhaler. An inexpensive spacer of 5 to 6 inches is cut from disposable ventilator tubing. The patient is told to exhale toward residual volume, place the tubing in the mouth with lips around the tubing, and begin a slow, deep inspiration. The metered-dose inhaler is activated once at the start of inspiration, which continues to total lung capacity. The patient holds his or her breath for 6 to 10 seconds and then quietly exhales. After a few normal breaths, the procedure is repeated.

Ideally, the patient should not have used a bronchodilator before testing. Abstinence of 6 hours from the inhaled β2 agonists and anticholinergics and 12 hours from long-acting β2 agonists (salmeterol or formoterol) and methylxanthines is recommended. The technician should always record whether the medications were taken and the time at which they were last taken. Use of corticosteroids need not be discontinued.


The American Thoracic Society defines a significant bronchodila- tor response as one in which the FEV1 or the forced vital capacity (FVC) increases by both 12% and 200 mL.

PEARL: To evaluate whether the increase in FVC is merely the result of a prolonged effort, overlay the control and postdilator curves so that the starting volumes are the same, as in Figure 5-2B. If there is a slight increase in flow, then the increase in FVC is not due to prolonged effort alone.

The forced expiratory flow rate over the middle 50% of the FVC (FEF25_75) is a useful measure of airway obstruction. It is not a reliable indicator of an acute change in maximal expiratory flow, however, because of the way it is affected by changes in the FVC, as shown in Figure 5-2. Typical normal and abnormal responses to inhaled bronchodilator are shown in Figure 5-3.


In routine spirometry, changing effort can have a misleading effect on the FEV1 and flow-volume curve. In Figure 5-4 the same subject has made two consecutive acceptable FVC efforts. During one (curve a) the subject made a maximal effort with a high peak flow and sustained maximal effort throughout the breath. However, in another effort (curve b), the subject initially exhaled with slightly less than maximal force for less than a second and thereafter applied the same maximal effort as in curve a. The peak expiratory flow was slightly lower on curve b, but the flow on curve b exceeds that on curve a at lower volumes. In this situation, the slightly less forceful effort can produce an FEV1 that may be 15% higher

FIG. 5-2. By definition, the FEF25 - 75 (forced expiratory flow rate) is measured over the middle 50% of the vital capacity (A). The spirograms and flow-volume curves show an increase in both flow and volume after use of a bronchodilator. Yet the control FEF25-75 (0.67 L/s) is higher than the postdilator value (0.5 L/s). The reason for this apparent paradox can be appreciated from the flow-volume curves (B). The solid arrows indicate the volume range over which the control FEF25-75 is calculated. The dashed arrows show the volume range over which the postdilator FEF25-75 is calculated. The flows are lower at the end of the 25 to 75% volume range on the postdilator curve than those on the control curve. More time is spent at the low flows, which, in turn, causes the postdilator FEF25 - 75 to be lower than the control value. Recommendation: Do not use the FEF25 - 75 to evaluate bronchodilator response. Instead use the forced expiratory volume in 1 second and always look at the curves.

than the maximal effort. This result could be interpreted as a significant bronchodilator effect. Clearly, the subject's lungs and airways have not changed, however. The increase of FEV1 with less effort shown on curve b can be considered an artifact resulting from the slight difference in initial effort.

There is a physiologic explanation for this apparent paradox, and the interested reader is referred to Krowka and associates [3], but it is sufficient that one be alert to this potentially confusing occurrence, which can be very marked in patients with obstructive lung disease. The best way to avoid this problem is to require that all flow-volume curves have sharp peak flows, as in curve a on Figure 5-4, especially when two efforts are compared.

FIG. 5-3. Responses to inhaled bronchodilator. A. Normal response with -1% change in the forced vital capacity (FVC) and +2% change in the forced expiratory volume in 1 second (FEV1). B. Positive response with a 59% increase in the FVC and a 105% increase in the FEV1. The FEV1/FVC ratio is relatively insensitive to this change and therefore should not be used to evaluate bronchodilator response.

FIG. 5-4. Two consecutive flow-volume curves during which the subject exerted maximal effort (curve a) and then slightly submaximal effort (curve b). Note the slightly lower and delayed peak flow but higher flows over the lower volumes of curve b.

Short of that, the peak flows should be very nearly identical (<10-15% difference). The principle also applies to bronchial challenge testing (see below). This paradoxical behavior can easily be identified from flow-volume curves; it is almost impossible to recognize it from volume-time graphs.


The purpose of bronchial challenge testing is to detect the patient with hyperreactive airways. The classic example of hyperreactive airways occurs in the patient with bronchial asthma. Various insults, such as pollens, cold air, exercise, smoke, and dust, cause the smooth airway muscles to constrict and the mucosa to become inflamed. Wheezing, dyspnea, and cough are the classic symptoms, and the diagnosis is clear-cut. Not all patients with hyperreactive airways fit this classic clinical picture, however. For example, the patient may complain only of cough. In such patients, bronchial challenge testing can be extremely useful. Failure to recognize the existence of patients who do not have classic symptoms has contributed to the underutilization of bronchial challenge. The most common indications for this procedure are the following:

1. Normal results of spirometry and a normal response to bronchodilators but a history suggesting asthma.

2. Chronic cough that is often worse at night but not associated with wheezing. Asthma can present in this manner and can be detected by bronchial challenge testing. The response to therapy (inhaled bronchodilators and corticosteroids) can be gratifying.

PEARL: Asthma is often a nocturnal disease. According to some experts, if a subject does not have symptoms at night, then the subject does not have asthma. This principle does not necessarily apply, however, to the patient with exercise- or cold-air-induced asthma.

3. Episodic chest tightness often accompanied by cough and sometimes dyspnea. This is a common presentation of nonwheezing hyperreactive airways, a variant of asthma.

4. Occult asthma, which should always be in the differential diagnosis of unexplained dyspnea.

5. Recurrent episodes of chest colds, bronchitis, or recurrent pneumonia with infiltrates that do not occur in the same lung regions. This can occur with occult asthma. Detecting and treating hyperreactive airways in this situation can lead to substantial clinical improvement.

6. Unexplained decrease in exercise tolerance, not perceived as dyspnea and often occurring in cold air. Exercise and cold air are well-known triggers of asthma. Bronchial challenge testing is often positive in patients with allergic rhinitis, sarcoidosis (50% of cases), COPD, and cystic fibrosis.

PEARL: It is often wise to follow up a borderline or mildly positive bronchodilator response with a methacholine challenge. A 52-year-old woman had a history of cough and shortness of breath. Initial tests were normal in this nonsmoker, and there was only a 9% increase in the FEV1 after a bronchodilator. However, a methacholine challenge resulted in a 38% decrease in FEV1 associated with cough and dyspnea, both of which were reversed by a bronchodilator. The patient clearly had asthma.


The most commonly used agent for bronchoprovocation is inhaled methacholine, a cholinergic drug that stimulates muscarinic receptors and causes contraction of smooth muscle in the airway. The degree to which the smooth muscle contracts depends on its reactivity and is reflected in the magnitude of decrease in expiratory flow, usually quantified by measuring the FEV1.

On exposure to an allergen, a person with asthma may experience an initial (within a few minutes) decrease in expiratory flow, which is called the immediate response. This is what is measured in bronchial challenge testing. It can be blocked by bronchodilators and cromolyn sodium. In asthma, there may also be a late or delayed response, which usually occurs 4 to 12 hours after exposure; it reflects the airway inflammatory response. This response can be blocked by corticosteroids or cromolyn sodium and is not elicited by methacholine. Allergens such as pollens may elicit either response or both the early and the late responses. Although methacholine provokes only the early phase of the classic asthmatic hyperreactive airway response, it nevertheless is an excellent predictor of the presence of asthma. Thus, a positive result on methacholine challenge testing is predictive of asthma attacks provoked by, for example, cold air, exercise, pollens, or infection. An example of a positive methacholine challenge study is illustrated in Figure 5-5.



1 breath

5 breaths





FEV1 (L)




FEV1 (% decrease)




FEV1/FVC (%)




FIG. 5-5. Results of bronchial challenge testing in a 43-year-old woman who had a 3-year history of persistent cough, often at night. She denied wheezing but had mild dyspnea on exertion. One breath of methacholine produced a parallel shift in the flow-volume curve, no change in the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), a decrease of 11% in the FEV1, and mild chest tightness. She was given four additional breaths of methacholine, and cough and chest tightness developed, but there was no audible wheezing. This is a positive test result with a 36% decrease in the FEV1. Note that at five breaths, the flow-volume curve shows scooping and is no longer parallel with the control curve. The curve after one breath demonstrates that mild bronchoconstriction may produce only a mild decrease in FEV1 and no change in the FEV1/FVC ratio (see section 3E, page 36 and Fig. 3-8A, page 38). Further constriction (curve after five breaths) leads to a flow-volume curve that is classic for obstruction, with scooping, a low FEV1, and a decreased FEV1/FVC ratio.

Several protocols have been developed for bronchial challenge testing [4]. Clinically, the goal is to determine whether the patient has asthma. For this purpose, we favor a simple screening procedure such as that described by Parker and associates [5] in 1965. The procedure is as follows:

1. Five milliliters of a 25 mg/mL solution of methacholine chloride in normal saline is freshly prepared, and 2 to 3 mL

is placed in a standard nebulizer. It is not advisable to subject a patient to bronchial challenge if the baseline FEV1 is less than 65% of predicted. If the FEV1 is between 65 and 75% of predicted, the test is done with caution. If very hyperreactive airways are suspected, a concentration of 5 mg/mL or lower is used rather than 25 mg/mL. The low concentration is used in children, who often show a very severe response.

2. Baseline spirometry is performed to obtain a reproducible FEV1. The subject then inhales a deep breath of methacholine, holds the breath for 5 to 10 seconds, and then breathes quietly.

3. Spirometry is repeated in 1 minute to obtain two reproducible measurements of FEV1. If the FEV1 has decreased by 20%, the result is positive. If the FEV1 has decreased less than 15%, four more breaths of methacholine are inhaled. If the decrease is between 15 and 19%, only two more breaths are inhaled.

4. Spirometry is repeated in 1 minute.

A response is positive if the FEV1 decreases by 20% or more of control. In this case, a agonist is administered to reverse the effect of the methacholine.

Technicians should always note whether the methacholine causes symptoms, such as chest tightness, substernal burning, cough, or wheezing. If the patient's symptoms are reproduced but the decrease in FEV1 is less than but near to 20% (15-19%), we are inclined to consider that a borderline positive result.

Clinicians need to always be alert to the confounding effect of effort dependence on the FEV1 (see section 5D, page 53 and Fig. 5-4). For example, a control effort that is less than maximal may yield a value of FEV1 that is falsely high compared with the value on a truly maximal effort after the inhalation of metha- choline. A decrease in FEV1 in this situation could be due to varying effort and not hyperreactive airways.

There are, of course, modifications to this approach that can be considered. For example, in a patient who becomes dyspneic or has chest tightness when cross-country skiing, cold air may be the cause. Baseline spirometry needs to be performed. Then the patient should walk or jog outside in the cold to reproduce the symptoms, and retest is done immediately after the patient comes inside. The question of whether workplace exposure is causing symptoms can similarly be evaluated by testing before and immediately after work.

The following points need to be kept in mind:

1. Healthy patients may show a transient (for several months) increase in bronchial reactivity after viral respiratory infections, but they do not necessarily have asthma. This phenomenon is called the postviral airway hyperresponsiveness syndrome, and generally it responds well to inhaled bronchodilator and corticosteroid therapy.

2. In some persons with asthma, deep inspirations, such as occur with FVC maneuvers, can cause bronchoconstriction. This can lead to a progressive decrease in the FVC and FEVon repeated efforts during routine testing.

3. Patients with hyperreactive airways (that is, a positive result on methacholine challenge) may have an exacerbation of asthma or a severe asthma attack if given β-adrenergic blocking agent. For example, this situation has been reported with use of eyedrops for the treatment of glaucoma, in which the eyedrops contain β-adrenergic antagonist.

4. Many patients with COPD or chronic bronchitis have an increase in bronchial reactivity. Their results on metha- choline challenge will usually be between those of normal subjects and persons with asthma. The clinical history is usually sufficiently different in the two groups to permit distinction; however, there can be considerable overlap, leading to confusion in diagnosis and treatment.

5. Airway reactivity may vary over time. Airway responsiveness in asthma improves with long-term inhaled corticosteroid therapy. The degree of responsiveness correlates with the degree of airway narrowing because narrowed airways need to constrict only slightly to increase resistance and decrease the FEV1 markedly.


Asthma is recognized as a disease characterized by airway obstruction, airway hyperresponsiveness to contractile stimuli, and airway inflammation. The challenges in the laboratory assessment of asthma are to identify EV1dence of inflammation or airway hyperresponsiveness in patients without baseline airway obstruction and to distinguish asthma as a cause of airway obstruction from other causes. Spirometry is helpful for grading the degree of airway obstruction both at baseline and after bronchodila- tor administration. Bronchoprovocation, most commonly with methacholine, is not always used because there are safety issues for patients with moderate to severe obstruction and for certain other patients (for example, pregnant women and patients with other medical conditions). Measures of airway inflammation are even less commonly used. Bronchial mucosal biopsy is invasive, and quantification of sputum eosinophils is challenging to perform accurately, although it has been standardized.

For these reasons, an alternative assessment of airway inflammation could be helpful. Measurement of exhaled nitric oxide (NO) has been shown to correlate well with the presence of eosinophilic mucosal inflammation in patients with asthma [6]. NO was first described in exhaled breath in 1991. NO has been shown to be increased in most asthmatics and to be reduced by therapy with inhaled corticosteroids. It is also increased in viral respiratory tract infections, lupus erythematosus, hepatic cirrhosis, and lung transplant rejection. It is reduced or variable in COPD and cystic fibrosis and human immunodeficiency virus infection with pulmonary hypertension. It is decreased both acutely and chronically by cigarette smoking. Measurement of exhaled NO has been most widely applied for the diagnosis and management of asthma. The normal value for exhaled NO from the mouth is 3 to 7 parts per billion (ppb). The upper limit of normal, used to distinguish healthy persons from patients with asthma, has been variously reported between 15 and 30 ppb.

The method for measuring exhaled NO is somewhat complex and very dependent on a precise method for reproducible results. Care must be taken to maintain a stable airway pressure and expiratory flow rate and to avoid contamination with nasal air, which has a much higher concentration of NO. Methods also have been developed for measuring nasal exhaled NO as an indicator of allergic rhinitis. The American Thoracic Society and European Respiratory Society [7] published recommendations for standardized procedures for online and offline measurement of exhaled lower respiratory tract NO and nasal NO in 2005.

There are several manufacturers of equipment for measuring NO. All equipment is based on chemiluminescence, a photochemical reaction of NO with ozone under high-vacuum conditions. The dEV1ces cost $40,000 to $50,000. A new CPT code, 95012, was approved by the American Medical Association in 2007 for billing for procedures.

The role of measurement of exhaled NO in the diagnosis and management of asthma is evolving. The value should be clarified with ongoing studies.


1. GOLD: The global initiative for chronic obstructive lung disease [homepage on the Internet]. Bethesda (MD): National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization [cited 2007 Dec 17]. Available from:

2. COPD guidelines. New York: American Thoracic Society; c2007 [cited 2007 Dec 17]. Available from: sections/copd/.

3. Krowka MJ, Enright PL, Rodarte JR, Hyatt RE. Effect of effort on measurement of forced expiratory volume in one second. Am Rev Respir Dis 136:829-833, 1987.

4. Crapo RO, Casaburi R, Coates AL, et al. Guidelines for metha- choline and exercise challenge testing—1999. Am J Respir Crit Care Med 161:309-329, 2000.

5. Parker CD, Bilbo RE, Reed CE. Methacholine aerosol as test for bronchial asthma. Arch Intern Med 115:452-458,1965.

6. Payne DN, Adcock IM, Wilson NM, et al. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 164:1376-1381, 2001.

7. American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 171:912-930, 2005.

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