Methacholine Challenge

Bronchial challenge by inhalation of methacholine is performed by having the patient inhale increasing doses of the drug. All subjects will show a change in airway caliber with increasing concentrations of methacholine. Patients who have hyperresponsive airways demonstrate these changes at low doses of inhaled methacholine. This dose-response relationship permits the sensitivity of the airways to be quantified.

Spirometry, and sometimes sGaw, is measured after each dose. Most clinicians consider the test result positive when inhalation of methacholine precipitates a 20% decrease in FEV₁. The methacholine concentration at which this 20% decrease occurs is called the provocative concentration (PC₂₀). In some references it may be termed provocative dose (PD₂₀ ). In the doses usually used (Box 9-1), healthy subjects do not display decreases greater than 20% in FEV₁. Therefore, the methacholine challenge test is highly specific for airway hyperreactivity. Many patients who have asthma experience a 20% reduction in FEV₁ with doses of 8 mg/mL or less. However, bronchial hyperresponsiveness may also be seen in other pulmonary disorders such as COPD, cystic fibrosis, and bronchitis.

Patients to be tested should be asymptomatic, with no coughing or obvious wheezing. Recent upper or lower respiratory tract infections may alter airway responsiveness, so bronchial challenge testing may need to be deferred. Their baseline FEV₁ should be normal or at least greater than 60%–70% of their expected value. For patients with known obstruction or restriction, FEV₁ should be close to their highest previously observed value. Obvious airway obstruction (e.g., FEV_1% less than the lower limit of normal) is a relative contraindication. If the patient has an FEV₁ less than 1.0–1.5 L, there is a risk that a large drop in FEV₁ after a methacholine challenge might leave the individual with a compromised lung function. Bronchial challenge may be indicated in obstructed patients if the clinical question is related to the degree of responsiveness. Box 9-2 lists the absolute and relative contraindications to a methacholine challenge.

If the patient has been taking bronchodilators, they should be withheld according to the schedule listed in Table 9-2. Other medications or substances can affect the validity of the challenge as well. All medications being taken at the time of testing should be recorded to assist in the evaluation of the test results.

Baseline spirometry is performed to establish that the patient’s FEV₁ is greater than 60%–70% of predicted or the previously observed best value. Patients who demonstrate obstruction based on reduced FEV_1% or other flows typically do not require challenge testing. However, obstructed patients may be tested to establish the degree of hyperreactivity. Patients who have a restrictive process (i.e., reduced FEV₁, FVC [forced vital capacity], and TLC) may also be tested for coexisting airway hyperresponsiveness. If a patient is unable to perform acceptable and repeatable baseline spirometry (i.e., FEV₁), changes after an inhalation challenge may be impossible to interpret. In these situations, other parameters (such as sGaw or oscillatory resistance) that are less dependent on patient effort may be preferable as an endpoint.

Two methods of delivering methacholine to the airway have been recommended by the American Thoracic Society (ATS): the five-breath dosimeter method and the 2-minute tidal breathing method. A dosimeter can provide a true “quantitative” challenge test by delivering a consistent volume of the drug. The dosimeter (or nebulizer) is activated during inspiration, either automatically (by a flow sensor) or manually (by the technologist). A standardized driving pressure (typically 20 psi) and activation time (0.5–0.8 seconds) allows a fixed volume of aerosol to be generated for each breath. By limiting the period of aerosol production, the last part of the inhalation carries the aerosol into the lung. The tidal breathing method is somewhat simpler because only a nebulizer is used.

A small-volume nebulizer is used to generate the methacholine aerosol (Figure 9-2).

The nebulizer should generate an aerosol with a particle size in the range of 1.0–3.6 μm (mass median aerodynamic diameter). This particle range promotes deposition in the medium and small airways. For the tidal breathing method, the nebulizer output should be 0.13 mL/min; for use with a dosimeter (five-breath method), the output should be 0.009 mL for each 0.6-second actuation of the dosimeter. Because the output of each nebulizer varies by manufacturer and can change over time, it should be measured. This can be done by weighing the nebulizer on an accurate scale before and after a sham administration of the drug. The output should be measured with the protocol to be used for testing. For the five-breath dosimeter method, more breaths may be needed to measure the small output. The nebulizer should also be “primed” with an actuation before patient testing to alleviate the electrostatic properties of a plastic nebulizer or spacer. The delivered dose of methacholine is standardized by using a fixed number of breaths (5) or breathing for a fixed length of time (2 minutes).

Two dosing routines are commonly used for a methacholine challenge (see Box 9-2). One routine uses a quadrupling (4×) increase in methacholine concentration, and the other method uses a doubling dose (2×). For each of these regimens, the highest dose is 16 mg/mL, and the dilutions can be easily prepared from a stock solution, starting with 100 mg of dry methacholine (Table 9-3). The stock solution is prepared by dissolving the powdered drug in a saline diluent. A preservative (0.4% phenol) may be added to the solution but is not required. Methacholine concentrations from 0.025–25.0 mg/mL are stable after mixing and may be kept for 5 months if refrigerated at 2°C–8°C (36-46°F). An alternate dosing scheme is provided with the FDA-approved form of methacholine (Provocholine, Methapharm, Ontario, Canada). This dosing schedule uses methacholine concentrations of 0.025, 0.25, 2.5, 10, and 25 mg/mL and is designed for use with the five-breath dosimeter method. Methacholine should be prepared by a pharmacist or individual trained in preparing drugs using a sterile technique. Appropriate precautions should be taken when handling dry powdered methacholine. Vials of methacholine should be carefully marked with labels that clearly identify the concentration.

Two-Minute Tidal Breathing Method

In this method, normal relaxed breathing is used as the patient inhales the aerosol. Methacholine is usually prepared in 10 doses of doubling concentrations (see Box 9-1 and Table 9-3). If the methacholine has been refrigerated, it should be allowed to come to room temperature for 30 minutes. A nebulizer capable of delivering 0.13 mL/min (±10%) driven by compressed air should be used. An accurate flowmeter allows adjustment to the flow necessary to deliver the desired volume.

The patient should hold the nebulizer upright and breathe quietly through the mouthpiece with a noseclip in place. A facemask may be used in place of a mouthpiece, but the noseclip should not be omitted (noseclip may be placed over the mask). A filter may be placed on the expiratory limb of the nebulizer circuit to limit the amount of methacholine released in aerosol form in the testing area. A timer or stopwatch should be used to ensure that the breathing interval is exactly 2 minutes long.

As in the dosimeter method, spirometry is repeated at 30 and 90 seconds after the end of the 2-minute tidal breathing interval. If a diluent step is included, the target FEV₁ (for a positive response) is 80% of the largest value obtained after the diluent. If the diluent step is omitted, the target FEV₁ is 80% of the baseline value. Patients with highly reactive airways may have a positive response (e.g., a 20% decrease in FEV₁) to the diluent. The FVC maneuvers should be completed within about 3 minutes. If Raw or sGaw is to be measured, those measurements should be performed as quickly as possible after spirometry. If FEV₁ decreases less than 20%, the next highest dose should be administered. If FEV₁ decreases by 20% or more, the challenge is complete. A β agonist bronchodilator should be administered to reverse the bronchospasm and spirometry repeated after 10 minutes.

Spirometry or plethysmographic measurements are the most commonly used endpoints for bronchial challenge tests. For each parameter, the percent of decrease is calculated as follows:

< ?xml:namespace prefix = "mml" />V·maxFRCFRC

%  Decrease  =  x−yx × 100

where:

x = control FEV₁ (baseline or after diluent)

y = current FEV₁ after methacholine inhalation

This change is sometimes reported as a negative value (e.g., −20%) to indicate a fall in the FEV₁.

A 20% or greater decrease in the FEV₁ is considered a positive response. The decrease should be sustained. Additional spirometry efforts may be necessary to distinguish an actual decrease from variability in the maneuvers. The same equation may be used to calculate changes in airway resistance or specific conductance. A decrease of 35%–45% in sGaw is consistent with increased bronchial responsiveness. In patients suspected of having vocal cord dysfunction (VCD), complete flow-volume (F-V) loops may be helpful. VCD is sometimes mistaken for asthma in patients referred for bronchial challenge testing. Limitation of inspiratory flow (with little or no change in FEV₁) is usually observed in VCD.

Several methods of quantifying the results of the challenge are commonly used. The concentration of methacholine that results in a 20% decrease (PC₂₀) can be calculated from the last and second-to-last doses administered:

V·maxFRCFRC

PC20=antilog [logC1+(logC2−logC1)(20−R1)R2−R1]

where:

C₁ = second-to-last methacholine concentration

C₂ = final methacholine concentration (causing 20% or greater decrease)

R₁ = percent decrease in FEV₁ after C₁

R₂ = percent decrease in FEV₁ after C₂

PC₂₀ calculated this way provides a single index of bronchial responsiveness. PC₂₀ may also be identified directly from a graph in which change in FEV₁ is plotted against the log concentration of methacholine (Figure 9-3).

Provocative concentrations for other variables, such as sGaw, can be calculated similarly by substituting the appropriate percentage for 20 in the preceding equation and substituting the percent decrease for that variable for R₁ and R₂. Note that this calculation requires that at least two concentrations of methacholine have been given. If FEV₁ decreases 20% after the diluent or the first dose of methacholine, PC₂₀ should be reported as less than the lowest concentration administered. If FEV₁ does not decrease by at least 20% after the highest dose, PC₂₀ should be reported as “greater than 16 mg/mL.”

See Interpretive Strategies 9-1. Airway responsiveness to methacholine can be described using the PC₂₀. Most patients referred for bronchial challenge testing have a history or symptoms suggestive of asthma but not a definite diagnosis. For these patients, if FEV₁ decreases less than 20% at the highest dose (PC₂₀>16 mg/mL), bronchial responsiveness is probably normal and asthma is unlikely. For patients whose FEV₁ decreases 20% or more at low doses of methacholine (PC₂₀<1.0 mg/mL), the diagnosis of asthma is highly likely. For patients with PC₂₀ values from 1–16 mg/mL, the diagnosis of asthma must be considered, based on the pre-test probability of asthma, the history of symptoms, and other possible causes for bronchial hyperreactivity. In practice, patients who have a PC₂₀ greater than 8–16 mg/mL often do not have asthma. Patients who have a negative methacholine challenge (PC₂₀>16 mg/mL) may have asthma that has been suppressed by anti-inflammatory medications or occupational asthma that is triggered by a specific agent. Conversely, some individuals who have PC₂₀ values less than 8 mg/mL may not have asthma. Patients with allergic rhinitis and smokers with COPD often have bronchial hyperreactivity but not asthma.

Interpretive Strategies 9-1   Bronchial Challenge Tests

1. Was the challenge agent administered appropriately?

    For methacholine or histamine, were the doses of agonist appropriate?

    Were nebulizer output, inspiratory flow, and so on, consistent for each dose?

    For mannitol, was the proper inhalation technique using the DPI performed?

    For exercise, did the patient maintain an appropriate workload for 6–8 minutes?

    For hyperventilation, did the patient maintain the target level of ventilation?

2. Were there any pre-test factors that might influence results? Failure to withhold bronchodilators? Respiratory infection? If so, interpret cautiously or not at all.

3. Were spirometric efforts acceptable and repeatable before and during the challenge? If not, interpret very cautiously or not at all.

4. For methacholine or histamine challenge, was there a 20% decrease in FEV₁ after inhaling diluent? If so, test result is positive. Was there a 20% decrease in FEV₁ after inhalation of the agonist? If so, test result is likely positive, and PC₂₀ should be used to categorize the degree of hyperresponsiveness. Was there at least a 35% decrease in sGaw (preferably 50%)? If so, test result is likely positive.

    For mannitol, was there a 15% or greater decrease in the FEV₁ after inhalation or a 10% incremental fall in FEV₁ between two consecutive mannitol doses? If so, the test is positive. A PC₁₅ can be calculated if the former occurs.

5. For exercise or hyperventilation challenge, was there a 10%–15% decrease in FEV₁ after challenge? If so, test is positive.

6. Were there signs or symptoms of airway hyperreactivity (coughing, wheezing, and shortness of breath)? If so, test suggests bronchial hyperresponsiveness.

7. Were the results borderline? If so, consider repeat testing in the future.

8. Were symptoms present despite little or no change in FEV₁? Consider additional measurements such as sGaw, or related conditions such as vocal cord dysfunction.

PF Tip 9-2

Some patients whose FEV₁ drops 20% or more at low doses of methacholine may not have asthma. Hyperreactive airways are also found in some patients with COPD who smoke or in patients who have allergic rhinitis. A negative methacholine challenge (i.e., a decrease in FEV₁ <20% at the highest dose) may occur in patients who have asthma that has been suppressed by anti-inflammatory medications. Some asthma patients may have their asthma triggered by exposure to a specific agent such as cold, dry air.

A number of physiologic factors affect the sensitivity and specificity of methacholine challenge testing. Methacholine causes a constriction of bronchial smooth muscle. In healthy individuals, taking a deep breath before performing the FVC maneuver may cause bronchodilation for several minutes. In patients who have mild asthma, a similar response is sometimes observed. In patients who have severe asthma, the bronchodilating effect of a deep inspiration is reduced; a deep breath may actually cause bronchoconstriction. Because of this differing response, FEV₁ discriminates between those who have and those who do not have asthma.

Spirometry (i.e., FEV₁) may not detect a response in all patients. Raw or sGaw may be more sensitive in detecting hyperreactive airways in some individuals. Because Raw and sGaw are more variable than FEV₁ in healthy subjects, a larger change after the methacholine challenge is required to demonstrate hyperreactive airways. A decrease in sGaw of 35%–45% may be considered a positive methacholine response. Some individuals with asthma symptoms may have primarily large airway changes in response to methacholine. These changes may manifest themselves as a decrease in sGaw or blunting of the inspiratory limb of the F-V loop. Although PEF is useful for monitoring asthma, it is less reproducible and more effort-dependent than FEV₁ for detecting changes after a bronchial challenge.

Technical factors can also make methacholine challenge tests difficult or impossible to interpret (see Criteria for Acceptability 9-1). Changes in FEV₁ after a bronchial challenge are usually not diagnostic in patients who cannot perform acceptable and reproducible baseline spirometry. Variable efforts by the patient may produce a false-positive test result (apparent reduction in FEV₁ but not asthma). FEV₁ values obtained at 30 and 90 seconds after each dose of methacholine should be similar. The maneuvers should meet criteria for an acceptable effort (see Chapter 2). However, because the primary endpoint is the FEV₁, it may not be necessary for the patient to exhale for 6 seconds. Using a shortened exhalation requires that the patient inspires fully to TLC, and this may be difficult to determine unless a full FVC effort is performed. The usual repeatability criteria (FEV₁ efforts within 150 mL) may not be met because of the effects of methacholine. Additional maneuvers may be needed at 30 and 90 seconds to verify that a real decrease has occurred. The FEV₁ reported for each dose of methacholine should be the largest value obtained at that level.

Criteria for Acceptability 9-1   Bronchial Challenge Tests

1. The patient should withhold all bronchodilators before the test. Some long-acting bronchodilators may need to be withheld for up to a week.

2. The patient should also be free of upper or lower respiratory infection and not ingest any caffeinated beverages before the test.

3. Spirometric or plethysmographic efforts must meet standard criteria for acceptability and repeatability. For adults, the two largest FEV₁ measurements should be within 150 mL before the challenge (within 100 mL if the VC is 1.0 L or less). sGaw measurements should be within 10% before the challenge. During the challenge, acceptable efforts should be obtained; repeatability is desirable but may not be attained.

4. For methacholine and histamine challenges, a nebulizer that produces aerosol particles in the range of 1.0–3.6 μm should be used. Nebulizer output, inspiratory flow, lung volume, and breath-hold time should be consistent for all levels (doses) of challenge.

5. For mannitol, the medication and administration technique was performed according to the manufacturer’s instructions.*

6. For exercise challenges, the patient should attain at least 80%–90% of the predicted maximal heart rate (or o₂max, if measured). This level should be maintained for 4–6 minutes. Ventilation should increase to 40%–60% of the MVV (FEV₁ × 35). Measurement of _E is recommended.

7. For hyperventilation challenges (cold or ambient air), the target ventilation level should be maintained for the specified interval (dependent on protocol used). For EVH, a target ventilation of 30 × FEV₁ for 6 minutes is recommended. For all challenge protocols, clinical signs and symptoms (e.g., presence or absence of coughing, wheezing) should be documented.

---

^*Not included in the 1999 ATS recommendations.

Adapted from ATS Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med. 2000; 161:309-329.

The type of nebulizer and dosimeter affects the amount of agonist reaching the airways. Factors that should be controlled as much as possible include the type of nebulizer, nebulizer output, particle size, inhaled volumes, breath-hold times, and inspiratory flow. Nebulizer driving pressure or flow should be consistent throughout the test. If a single nebulizer is used, it should be thoroughly emptied between doses. If multiple nebulizers are used (one for each dose), they should be checked for similar output. Although the five-breath dosimeter and tidal breathing techniques deliver different volumes of methacholine, the sensitivity and specificity of the test are similar for both methods in adults and in children. The spirometer used should meet the minimal standards set by the ATS-ERS (see Chapter 12). It should provide spirometric tracings or F-V loops for later evaluation.

Methacholine challenge testing is a safe procedure. The main risk to the patient is that severe bronchospasm may occur, so a physician experienced in treating acute bronchospasm should be immediately available. The technologist administering the bronchial challenge test should be thoroughly familiar with the procedure and with the signs and symptoms of a bronchospasm. The technologist must know when to stop the test and how to administer bronchodilators to reverse an acute bronchospasm. Medications for reversal of the bronchospasm (e.g., epinephrine, atropine) and for resuscitation should be immediately available in the event of an adverse reaction. Because of the risks involved, some laboratories require written consent from the patient. The test should be administered in a well-ventilated room to protect other patients and the technologist from exposure. The addition of a filter to the exhalation port of the nebulizer may help reduce the volume of aerosolized methacholine in the room. Technologists with a known sensitivity to methacholine should not perform this procedure unless appropriate methods are used to avoid exposure to the drug.

Histamine Challenge

Aerosolized histamine extract (histamine phosphate) may be used for a bronchial challenge in a manner similar to a methacholine challenge. Histamine produces bronchoconstriction by an uncertain pathway. Antihistamines or H₁-receptor antagonists can block the response to histamine. Histamine-induced bronchospasm is also partially blocked by most classes of bronchodilators. Histamine differs from methacholine in its side effects, half life, and cumulative effects. Flushing and headache are two common side effects of histamine inhalation. The peak action of histamine occurs within 30 seconds to 2 minutes, which is similar to that observed in methacholine. Recovery of baseline function is significantly shorter for histamine than for methacholine. The action of histamine, unlike that of methacholine, is thought to be less cumulative.

Patient preparation for a histamine challenge is similar to that used for methacholine (see Table 9-3). Antihistamines and H₁-receptor antagonists should be withheld for 48 hours before testing.

Various dosing regimens for a histamine challenge have been proposed. Box 9-3 lists one dosing protocol for a histamine challenge. These increments approximately double the concentration of drug at each level. The same criteria as those used for baseline spirometry in a methacholine challenge are observed. Diluent may be administered first to determine a control value for FEV₁.

If FEV₁ does not decrease by more than 10%, then five breaths of the first dilution are administered. Spirometric measurements are performed immediately, and then repeated at 3 minutes. A response is considered positive if FEV₁ decreases by 20% or more below the control at 3 minutes. If there is a negative response (FEV₁ decreases <20%), the next dose is given and measurements are repeated.

The results of a histamine challenge are reported in a manner similar to that described for methacholine. The histamine concentration that produces a 20% decrease in FEV₁ is termed the PC₂₀. Response may also be reported by graphing the percentage of change in FEV₁ against the concentration (or its logarithm) of the drug. This type of plot is commonly called a dose-response graph. It permits interpolation of the precise concentration of drug that elicits the 20% decrease (see Figure 9-3).

Histamine, like methacholine, is relatively safe if testing follows the procedures described. Baseline and control values should always be established (see Criteria for Acceptability 9-1). Bronchial challenge should always begin with a low concentration of drug. The range of concentrations used should be appropriate for the patient tested. For adult patients in whom airway hyperreactivity is the suspected diagnosis, the dosing schedules previously described are recommended. Patients who have a positive response to a histamine challenge recover more quickly than those tested with methacholine. Histamine challenge can be repeated within 2 hours after the patient has returned to the baseline level of function.

Mannitol Challenge

Mannitol is a hypertonic stimulus, and inhalation increases the osmolarity of the airway that subsequently leads to the release of inflammatory mediators from mast cells and basophils. This leads to airway narrowing similar to that observed with hypertonic saline and exercise challenge tests. Mannitol is a sugar alcohol and is delivered by a special dry-powder inhaler (DPI). The DPI is trademarked as the Osmohale inhaler device and is a component of the testing kit (Aridol-Pharmaxis Ltd., Exton, PA) (Figure 9-4).

The testing kit includes the drug packaged in capsules, which contain the mannitol in the desired doses. These capsules load into the DPI device so there is not a need for additional specialized equipment or drug mixing. The dose scheme is listed in Table 9-4. Patient preparation for the mannitol challenge is similar to that used for methacholine (see Table 9-2). Mannitol is contraindicated in patients with known hypersensitivity to mannitol or to the gelatin used to make the capsules. According to the manufacturer’s package insert, it is for patients age 6 years or older who do not have apparent clinical asthma. The most common adverse reactions (rate ≥1%) were headache, pharyngolaryngeal pain, throat irritation, nausea, cough, rhinorrhea, dyspnea, chest discomfort, wheezing, retching, and dizziness. Special testing requirements are listed in Box 9-4; otherwise, the technique is similar to other challenge testing. Performance of acceptable spirometry with the largest FEV₁ at least 60% of predicted is required for test performance. Following the administration of 0 mg mannitol, FEV₁ is measured, and if it is not within 10% of the baseline, the test is terminated. The 0-mg dose FEV₁ then becomes the baseline value and the target FEV₁ is calculated:

V·maxFRCFRC

target  FEV1 = highest  baseline  value  (0mg)  ×  0.85

A positive response may be achieved in two ways; >15% fall in FEV₁ from the baseline (using the post 0-mg FEV₁ as the baseline) or a ≥10% incremental fall in FEV₁ (between two consecutive mannitol doses). A negative test is when a cumulative dose of 635 mg of mannitol has been administered and the patient’s FEV₁ has not fallen by ≥15% from the baseline.

Mannitol has been shown to have the same sensitivity and specificity as methacholine testing.

Exercise Challenge

Exercise-induced bronchospasm (EIB) is typified by a hyperreactive airway response (e.g., bronchospasm) during or immediately after vigorous exercise. Exercise-induced asthma (EIA) was at one time used to describe this hyperreactive response to exercise; however, asthma is a disease and not a sign or symptom. Therefore, EIB has been accepted recently as the more appropriate term. EIB is related to heat and water loss from the upper airway that accompanies increased ventilation during exercise. The exercise challenge is considered an indirect test because it depends upon the response of airway smooth muscle to bronchoconstricting mediators that are released from airway inflammatory cells. Evaluation of EIB may be helpful in the following instances:

Patients referred for exercise challenge should be evaluated by means of an appropriate history and physical examination. The evaluation should include a resting electrocardiogram (ECG) to ascertain potential contraindications to exercise testing (see Chapter 7). Certain medications should be withheld as for methacholine challenge testing (see Table 9-2). Before exercise, the patient’s FEV₁ should not be less than 65% of the predicted value. Patients with overt obstruction usually do not require an exercise challenge to demonstrate airway hyperreactivity. Patients should refrain from vigorous exercise for 4 hours before the test because there is a refractory period after exercise. Patients referred for EIB testing should be free from respiratory infections for 3–6 weeks before testing.

Either a treadmill or a cycle ergometer may be used, depending on the type of physiologic measurements being made. Exercise should be vigorous enough to elicit work rates of 80%–90% of the patient’s predicted heart rate (HR) for 6–8 minutes. The patient’s response to an increasing workload should be monitored through continuous ECG and blood pressure (BP). A pulse oximeter should be used to determine whether oxygen (O₂) desaturation occurs with exercise. Because pulse oximetry is not always accurate during exercise, an arterial line may be indicated if there is a high probability that exercise desaturation will occur. The pulse oximeter should be left in place in the post-exercise phase to detect desaturation that may occur with a bronchospasm.

Measurement of variables such as minute ventilation (_E) and tidal volume (V_T) may be helpful in assessing the ventilatory load imposed by the exercise. Measurement of F-V curves during exercise may be a useful adjunct in assessing the ventilatory response to increasing workloads (see Chapter 7). A spirometer that meets ATS-ERS requirements (see Chapter 11) is necessary. Resuscitation equipment, as described in Chapter 7, should be available.

Because EIB is related to heat and water loss from the upper airway, environmental conditions should be controlled. Room temperature should be less than 25°C (75°F) with relative humidity of 50% or less. The patient should wear noseclips, even if exhaled gas is not collected, to reduce gas conditioning by nasal airflow. Ambient temperature, relative humidity, and barometric pressure (P_B) should be recorded. The patient should breathe dry gas from a compressed air source using a reservoir bag (see section on EVH testing later in the chapter).

Low-intensity exercise for 1–2 minutes allows the evaluation of ventilatory and cardiovascular responses to work. As soon as a normal cardiovascular response is observed, workload should be increased until the patient attains 85% of predicted maximal HR or predicted maximal O₂ consumption (o₂). Alternately, the minute ventilation (_E) may be used as a target for exercise intensity if exhaled gas is collected. Ventilation should reach 40%–60% of the patient’s predicted MVV. The treadmill or cycle ergometer can be adjusted to increase or decrease the workload to maintain the correct intensity for the desired length of time.

In most instances, a short period of moderately heavy work is all that is required to trigger exercise-induced bronchospasm. The goal is to have the patient exercise at high intensity for 4–6 minutes, with total exercise duration of 6–8 minutes. Bronchospasm usually occurs immediately after the exercise, not during it, unless the test is extended over a longer interval (see Criteria for Acceptability 9-1). Repeated testing should be delayed for 4 hours because of a “refractory period” during which the severity of the bronchoconstriction lessens. This response is presumably caused by the release of catecholamines during exercise. An extended warm-up period before the actual exercise may also protect the airways and lessen subsequent bronchoconstriction (see section on EVH testing later in the chapter).

Baseline spirometry values are established before testing. The patient should be able to perform acceptable and repeatable FEV₁ measurements. Inability to perform acceptable spirometry will make interpretation of post-exercise changes difficult. The baseline FEV₁ value is also the control. After exercise, spirometry is performed at 1–2 minutes, then every 5 minutes as the selected variable (usually FEV₁) decreases to a minimum. For spirometry, the highest value of acceptable measurements is recorded; FEV₁ should be repeatable. The preferred method of reporting response to exercise is the following:

V·maxFRCFRC

%  Decrease = x−yx × 100

where:

x = baseline value (FEV₁)

y = lowest observed post-exercise value

As in methacholine challenge testing, the fall in FEV₁ is sometimes presented as a negative number (e.g., −10%) to indicate a decrease. Similarly, an increase in FEV₁ (as observed in healthy subjects after exercise) may be represented as a positive value, even though the preceding calculation produces a negative number if y is greater than x. Testing should be continued until the FEV₁ returns to the baseline. Maximal decreases are typically seen in the first 5–10 minutes after cessation of exercise. A decrease in FEV₁ of 10%–15% is consistent with increased airway sensitivity. Allowing the FEV₁ to fall to its lowest point provides an estimate of how severe the response to exercise has been. Spontaneous recovery usually occurs within 20–40 minutes. Some laboratories administer a β agonist to reverse the bronchospasm as soon as a threshold (e.g., 10%–15% decrease) has been reached. The FEV₁ should return to near baseline values whether or not a bronchodilator is administered.

Severe bronchospasm may occur following exercise, and the technologist performing the test should be prepared to manage it. If the bronchospasm is severe, it should be reversed using an inhaled bronchodilator. FEV₁ should return to within 10% of the pre-test baseline value. Administration of a bronchodilator may also be useful in assessing borderline decreases in FEV₁ (<10%) following the exercise challenge. Patients who show a minimal decrease after exercise may improve dramatically with an inhaled bronchodilator, suggesting increased airway responsiveness.

Patients who have VCD or other upper airway abnormalities are often referred for EIA tests. F-V curves (including maximal inspiratory flows) should be performed if the history or physical examination suggests these disorders. Measurement of tidal breathing loops during exercise (see Chapter 7) may also help define the pattern of ventilatory limitation.

One potential problem with using exercise to elicit EIB is that the level of exercise chosen may not mimic real-world triggers. Sedentary patients may not attain a level of ventilation high enough to trigger EIB when exercising at 85% of their maximal HR. Patients who are very fit (e.g., elite athletes) may require high workloads to reach 85% of their predicted HR or to increase their ventilation significantly. Measurement of _E during exercise may be needed to determine the level of ventilation attained. Patients whose asthma is triggered by cold, dry air may not show a maximal response if tested under standard laboratory conditions. Exercise-induced bronchospasm may be evaluated using hyperventilation with either cold or ambient temperature gas. These techniques eliminate the need for more complicated exercise testing. Hyperventilation (with a target ventilation level) may be more sensitive in detecting airway hyperreactivity than exercise testing.

Exercise testing with cold air can also be performed using the same exercise protocols as described earlier but requires specialized equipment to refrigerate and dry inspired gas (TurboAire Challenger, VacuMed, Ventura, CA). This equipment delivers cold, dry air to the airways (relative humidity 0% and temperature −20°C) and has been shown to be slightly more sensitive and specific than testing with room-temperature gas (Figure 9-5).

Eucapnic Voluntary Hyperventilation

Airway hyperreactivity may also be assessed by having the patient breathe at a high level of ventilation. The International Olympic Committee Medical Commission has expressed the viewpoint that, at present, eucapnic voluntary hyperpnea or hyperventilation (EVH) is the optimal laboratory challenge to confirm that an athlete has exercise-induced bronchoconstriction (EIB). In order to prevent respiratory alkalosis (i.e., true hyperventilation) during the test, carbon dioxide (CO₂) is mixed with inspired air. This gas mixture allows high levels of ventilation with little change in pH.

Patients to be tested with eucapnic voluntary hyperventilation (EVH) should withhold bronchodilators, as suggested in Table 9-2. Baseline spirometry is performed to ascertain that airway obstruction is not present. For ventilation challenges, the baseline FEV₁ is the control value with which subsequent measurements will be compared.

If cold air is to be used, the mixture is passed through a heat exchanger or over a cooling coil. These devices lower the temperature and remove water vapor from the gas. Gas temperatures are reduced to a subfreezing level in the range −10 °C to −20 °C. The relative humidity is usually near 0%.

The patient breathes the gas at an elevated level of ventilation. In one method, the patient breathes at a fraction of his or her maximal voluntary ventilation (MVV) (e.g., 30%–70% of the MVV). CO₂ is added to the gas to maintain a stable Petco₂. This is accomplished either by titrating CO₂ into the mixture or by using a gas composed of 5% CO₂, 21% O₂, and the balance nitrogen (N₂). The patient maintains the specified level of ventilation for 4–6 minutes. Spirometry or sGaw is then measured at fixed intervals after the hyperventilation (e.g., 1, 5, and 10 minutes). A second method has the patient breathe at increasing levels of ventilation up to the MVV (e.g., 7.5, 15, 30, 60 L/min, and MVV). Again CO₂ is added to the inspired gas to maintain isocapnia (i.e., Paco₂ of approximately 40 mm Hg).

EVH with gas at ambient temperature also provides a stimulus for bronchospasm. In this technique, the patient breathes a mixture of 5% CO₂, 21% O₂, and the balance N₂ at room temperature. The gas is used to fill a “target” bag or balloon of approximately 5 L (see Figure 9-6).

The patient breathes from the bag via a nonrebreathing valve (see Chapter 11) and large-bore tubing. The patient wears a noseclip. A high-output flowmeter is used to fill the target bag. The flowmeter is adjusted to deliver gas at approximately 30 times the patient’s FEV₁. The patient breathes from the bag and tries to match his or her ventilation to keep the bag partly deflated. The high level of ventilation is continued for 6 minutes. Spirometry is performed immediately after hyperventilation and then at 5-minute intervals (i.e., at 5, 10, 15, and 20 minutes). A commercial system is available, which uses a large reservoir bag for the hypercarbic gas mixture, gas analyzer, and pneumotach, which then gives feedback to the technologist and patient via the data acquisition screen on maintaining the predetermined ventilation (Figure 9-6).

For both the cold-air and room-temperature protocols, if no decrease in FEV₁ occurs within 20 minutes after hyperventilation, the test may be considered negative. The percentage decrease is calculated just as for methacholine challenge testing, as described previously. A decrease of 15% is consistent with some degree of airway hyperreactivity (see Criteria for Acceptability 9-1). EVH in healthy subjects usually results in bronchodilatation. Therefore, a 15% decrease is abnormal and highly specific for increased bronchial responsiveness. Some asthmatic patients may experience significant decreases in FEV₁ (20%–60%). Bronchospasm should be reversed with inhaled bronchodilators and the reversal documented with spirometry. The technologist performing the procedure should be prepared to manage severe bronchospasm if it occurs.

Raw and sGaw can be measured easily when hyperventilation tests are used. Because the airway challenge is applied once, the patient can remain in the body plethysmograph for measurements at defined intervals.

Both exercise testing and eucapnic voluntary hyperventilation techniques correlate well with the results of methacholine challenge tests, although they are slightly less specific. If multiple levels of ventilation are evaluated, a dose-response curve can be constructed. However, the single challenge is less complicated and can be used to evaluate patients with suspected asthma, particularly exercise-induced asthma.