Asthma has historically been challenging to diagnose due to the non-specific nature of symptoms characteristic of the disease. Bronchoprovocation testing is a useful method to evaluate airway hyperresponsiveness and establish an initial diagnosis. Also, bronchoprovocation testing can be used to quantify the severity of airway dysfunction in patients with asthma. Methacholine challenge testing is the most common form of bronchoprovocation testing, utilizing the longer-acting acetylcholine derivative methacholine to induce bronchoconstriction. Direct bronchial challenge testing, chemically triggering airway smooth muscle receptors. The dose or concentration is escalated in small increments while monitoring airway hyperreactivity, via the resultant decreased forced expiratory volume in one second (FEV1), recording the provocative dose (PD20) or concentration (PC20) resulting in 20% decrease in FEV1 in a positive test. Methacholine is preferable to other pharmacologic bronchoprovocation agents, such as histamine, due to its limited systemic side effects.
Methacholine is a non-selective muscarinic receptor agonist that acts directly on airway smooth muscle receptors to induce bronchoconstriction. However, methacholine has also been linked to indirect mechanisms of airway response as well, including stimulation of mucous cell secretion. The mechanism of action of derivative methacholine is longer than acetylcholine, thus useful in bronchial challenge testing to allow time for assessment of reactivity.
Indications for testing include evaluating symptoms clinically suggestive of asthma and response to therapy. It is important to note that although the test is highly sensitive, the positive predictive value has limitations due to the high incidence of false positives results seen in several other conditions, including allergic rhinitis, chronic obstructive pulmonary disease (COPD), bronchitis, and cystic fibrosis. This situation renders the test more useful in terms of exclusion due to high negative predictive value when presenting with clinical symptoms suggestive of asthma, such as in patients with vocal cord dysfunction, central airway obstruction due to tumors or polyps, and certain cases of occupational exposure.
In addition to general limitations if unable to tolerate inhalation of the challenge agent, contraindications include airflow limitations in FEV1 less than 60% predicted or 1.5L, inability to consistently reproduce quality spirometry, recent myocardial infarction within past three months, uncontrolled hypertension, known aortic aneurysm, recent ophthalmologic surgery or patients at risk for intracranial pressure elevation. In younger patients with smaller airway caliber, hypoxemia is a concern. However, testing can safely be performed utilizing pulse oximetry (SaO2) and transcutaneous oxygen pressure. Methacholine is a pregnancy category C drug and it is not known whether it is excreted in breast milk or is associated with fetal abnormalities. 
Spirometry, nebulization apparatus to administer aerosolized methacholine, and preparations of varying concentrations of methacholine are required to perform methacholine challenge testing.
The appropriate personnel plays a critical role in methacholine challenge testing, as patient breathing maneuvers must be coached properly to obtain reliable and accurate results when performing spirometry and measuring FEV1. The patient must be able to reproduce the spirometric maneuvers, otherwise the quality of the test will not be useful to interpret. Staff trained in treatment of acute bronchospasm as well as rescusitation equipment should be present with emergency rescusitation equipment and bronchodilators/administration equipment available.
Before performing the test, the patient must discontinue certain medications that decrease bronchial hyperresponsiveness. Several half-lives may be required for these drugs to be eliminated and not interfere with the testing. These drugs include inhaled bronchodilators (6 to 48 hours or 1 week in long-acting muscarinic antagonists), oral albuterol (12 to 24 hours), inhaled and oral glucocorticoids (two to three weeks), leukotriene modifying agents (48 hours), theophylline (12 to 24 hours), cromolyn (8 hours), and anti-histamines due to their anticholinergic effect. Solutions and nebulizers require preparation in a standardized fashion. Increasing doses or concentrations of methacholine are administered via nebulization with subsequent spirometry performed at each adjustment to reproduce a dose-response curve. Also, advanced cardiopulmonary resuscitation medications and equipment should be available, as well as personnel capable of treating severe bronchospasm and/or cardiac arrest.
For this technique, it is essential to define the breathing maneuver, as the duration of "quiet," or tidal volume, breathing must be specified; this duration is typically at least one minute. An alternate method of five vital capacity breaths followed by a breath-hold is another option. However quiet breathing technique has shown higher sensitivity likely due to false negatives due to the protective and bronchodilator effects seen at higher vital capacity breathing. Submaximal inhalation, limiting total lung capacity, can be implemented in the vital capacity method to limit these effects, thereby increasing sensitivity.
Methacholine is administered sequentially in increasing concentrations ranging from 0.016 to 16 mg/m, prepared in two to four-fold dilutions. The tester should perform spirometry before establishing a baseline. Then methacholine is given via nebulization starting with the lowest (most diluted) concentration. FEV1 then gets measured at 30, then 90 seconds post aerosol inhalation, during which the patient must be adequately coached to ensure quality measurements. If vocal cord dysfunction is under evaluation, the tester should implement full vital capacity breathing maneuvers with inspiratory and expiratory phase analysis. Otherwise, expiratory time can be decreased from six seconds to about two seconds if FEV1 is measured alone. The dose or concentration is increased in a stepwise fashion until FEV1 drops by more than 20%, or 35 to 40% specific airway conductance (SGaw) is achieved, and PD20 or PC20 is determined.
A test is considered positive if PD20 is less than or equal to 200mcg or PC20 is less than or equal to 8mg/mL. If using SGaw, 100mcg, or 4mg/mL or less indicates a positive test. A test is considered negative if PD20 is greater than 400mcg or PC20 is greater than 16mg/mL.
Furthermore, the degree of bronchial hyperresponsiveness can be categorized based off of PC20 as normal (>16mg/mL), borderline (4.0-16mg/mL), mild (1.0-4.0mg/mL), or moderate to severe (<1.0mg/mL).
Methacholine challenge testing is a form of non-specific bronchoprovocation and is useful in patients with a questionable diagnosis of asthma. Baseline spirometry should be normal, and an atypical history that may be suggestive of asthma should prompt evaluation for testing. The test has high sensitivity and a strong negative predictive value, helpful in excluding a diagnosis of asthma. Positive test results may suggest asthma. However, other conditions that may produce false-positive test results merit consideration. Positive testing in otherwise asymptomatic patients can be seen in up to 7% of the population and is believed to be normal with hyperreactive airways, which may also be indicative of the future development of clinical asthma and requires followup. In patients with a clinical history suggestive of asthma, with negative testing, alternate diagnoses should be considered, such as vocal cord dysfunction, occupational asthma, or central airway obstruction (i.e., tumor, polyp, or foreign body) as these conditions may clinically imitate asthma. Full inspiratory and expiratory phase flow volume loop analysis is important when paradoxical vocal cord motion is suspected. In patients with a history suggestive of asthma with positive testing, response to therapy merits close observation. Baseline spirometry that shows pattern of airway obstruction (i.e. low FEV1/FVC ratio and low FEV1) may be difficult to interpret as hyperresponsiveness strongly correlates to the baseline level of obstruction, and strong bronchodilator response of >12% and 200mL in either FEV1 or FVC likely establishes the diagnosis without need for methacholine challenge.
Proper administration of methacholine challenge testing requires an interprofessional team approach, beginning with the physician prescribing the test based on clinical history with failure to establish or eliminate the diagnosis after careful consideration of contraindications. Optimal performance during testing is reliant upon proper assistance and coaching of patient breathing maneuvers by registered respiratory therapists. Nursing may assist in preparing the patient for the test as well as counseling them on what to expect with the respiratory therapist, as dealt with in further detail in the following sections. Additionally, pharmacist preparation of varying concentrations of methacholine is needed to ensure accurate data. Although the test is low risk with the proper exclusion of contraindicated patient populations with diminished baseline FEV1, assessment of vital signs and patient symptoms is also essential to prevent and recognize wheezing or bronchospasm. Health care professionals should assess the need for bronchodilators for the treatment of severe bronchospasm. Resuscitation equipment and personnel should be readily available. Guidelines provided by the American Thoracic Society established in 1999 outline step-by-step protocols, safety measures, patient preparation and procedures, and cohesion between care team members is required to safely and accurately assess patients.
All these factors combine to demonstrate that the methacholine challenge test is most effective when part of an interprofessional healthcare team approach, where multiple disciplines (clinicians, specialists, nursing, respiratory therapists) collaborate to administer testing and use the results to direct patient management most effectively. [Level 5]
The methacholine challenge should take place with assistance from a nurse. The nurse should ensure that the patient understands the procedure and that the consent is signed and also ensure that resuscitative equipment is in the room prior to the procedure. Additionally, the nurse should closely monitor the vital signs of the patient during and post-procedurally. Bronchodilators must be available in the room at all times.
Besides monitoring the patient's vital signs and oxygenation, the nurse should document the test; when it started, what was injected and when the tested was terminated. Also, the respiratory status of the patient during and after the test requires full documentation by the nurse.
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