Guidelines for the methodology of exercise challenge testing of asthmatics Peyton A. Eggleston, M.D., Richard R. Rosenthal, M.D., Chairmen, Sandra A. Anderson, Ph.D., Ross Anderton, M.D., C. Warren Bierman, M.D., Eugene R. Bleecker, M.D., Hyman Chai, M.D., Gerd J. A. Cropp, M.D., Ph.D., Jerry D. Johnson, Ph.D., Peter Konig, M.D., John Morse, M.D., Laurie J. Smith, M.D., Richard J. Summers, M.D., and Joseph J. Trautlein, M.D. Study Group on Exercise Challenge, Bronchoprovocation Committee. American Academy of Allergy
The purpose of these guidelines is to clarify and emphasize procedures for evaluating the airway response to exercise in asthmatics in clinical and laboratory settings. SELECTION AND PREPARATION THE SUBJECTS
OF
Prior to exercise, all subjects should be evaluated by a physician. The evaluation should include (1) a history with special attention to cardiovascular and pulmonary disease, musculoskeletal abnormalities, and current medication use, (2) a physical examination with special attention to heart, lungs, and blood pressure, and (3) appropriate laboratory tests. An electrocardiogram (EKG) may be limited to a rhythm strip but should include a stress EKG in subjects over 35 years of age who are at increased risk for cardiovascular complications of exercise, especially if there are other risk factors such as obesity, sedentary habits, or diabetes mellitus. In subjects suspected of having hypoxia or hypercarbia, resting arterial blood gasses should be determined. Certain conditions so increase the risks of an exercise challenge that subjects should be excluded from testing unless strong indications are present. These include a history of myocardial infarction or angina significant hypertension, pectoris, thyrotoxicosis, valvular heart disease, or any demonstrated electrocardiographic abnormalities. In subjects with resting arterial hemoglobin desaturation or hypercarbia, arterial blood gasses or oxygen saturation should be monitored during exercise. Medications that can influence the pulmonary re-
Reprint requests to: Peyton A. Eggieston, Virginia Medical Center, Charlottesville. Vol.
64, No. 6, Part 2, pp. 642-645
M.D., University VA 22908.
of
sponse should be withheld prior to exercise. Methylxanthines and beta adrenergic drugs should not be used for 8 hr, or for 12 hr in the case of extendedaction formulations. Cromolyn sodium should not be used for 24 hr. Anticholinergics should be excluded for 8 hr. Corticosteroids need not be excluded, but subjects should be receiving a stable dose. Prior to exercise, pulmonary functions should be within 80% of a subject’s usual values and I-set forced expiratory volume (FEV1) should be at least 65% of predicted values. For subjects whose pulmonary functions decrease below these values when medications are excluded, as indicated, the interval should be modified; these are then not appropriate subjects for most experimental protocols. EQUIPMENT A motor-driven treadmill is most appropriate for evaluation of exercise-induced asthma. However, a cycloergometer may be more appropriate where portability or more careful physiologic measurements during exercise are desirable. The subject’s response to work should be monitored with changes in either ventilation or heart rate. Since continuous assessment of ventilatory effort is cumbersome and electrocardiographic monitoring is a necessary precaution, continuous evaluation of heart rate is the usual method. Minimum equipment should provide for a continuous strip chart record of EKG, and ideally an oscilloscope to simplify continuous monitoring should be included. A cardiotachometer may also be helpful. Pulmonary function equipment will vary depending on the type of information required. In general, tests should be simple enough for frequent repetition and sensitive enough to detect small changes in airway obstruction. Minimal requirements can be met with a
0091-6749/79/130642+04$00.40/O
0
1979
The
C. V. Mosby
Co.
VOLUME NUMBEI?
64 6, PART 2
TABLE I. Suggested
Guidelines for exercise challenge in asthma emergency
equipment
and drugs (adapted
from the American
643
Heart Association)*
Epiptrw7t.
I. 2. 3. 1. 5. 6. 7.
Direct-writing EKG Delibrillator (synchronized direct-current preferable) Oxygenator, intermittent positive pressure capability E,sophageal airways, oral or tracheal Bag-valve-mask hand-operated respirator Sphygmomanometer Stethoscope
8. 9. 10. I I. 12. 13.
Drrrgs. I. 14orphine or meperidine 2. Nitroglycerin tablets and amyl nitrite pearls 3. Catecholamines Aramine Adrenalin Noradrenalin Isoproterenol 4. Methylprednisolone sodium succinate (Solu-Medrol or equivalent) 5. Aminophylline (intravenous) 6. lsuprel for inhalation 7. Bronkosol for inhalation
Cutdown tray (sterile) Syringes and needles Intravenous sets Intravenous stand Adhesive tape Laryngoscope (desirable)
8. Antiarrhythmics Lidocaine Procainamide Propranolol Digoxin Calcium chloride Sodium bicarbonate solution Dextrose, 555, in water Normal saline Oxygen
* Exerctse procedure should be supervisedby physician or attendanttrained in cardiopulmonary resuscitation TABLE
II. Guidelines
for stepped
exercise
challenge Treadmill
Step
I II 111
Duration
2 min 2 min 5-X min
Target
Rate
Incline
2.5 mph % Target conditions as determined by heightt Target conditions as determined by height
0% Determined by age-t Determined by age
heart rate
50% Predicted maximum* 70% Predicted maximum 90% Predicted maximum
*Predicted maximum heart rate determined from Fig. I. tTarget exercise of treadmill rate and incline from Fig. 2.
peak flowmeter or a positive displacement spirometer, provided the equipment meets the minimum standards set by the American Thoracic Society. ’ Safety equipment is listed in Table I.
EXERCISE PROCEDURE The level of stress to be used for the provocation must be determined by the subject’s response, as determined by some objective criteria such as heart rate or oxygen consumption (?O,). This response will depend on factors such as the subject’s age, size, and fitness. A stress that will increase heart rate to 90% of predicted maximum values (see Fig. 1) or increase oxygen consumption to 30 to 40 ml/min/kg is appropriate. In Fig. 2 are shown representative conditions that will increase heart rate to 90% of predicted maximum values. These are suggested conditions only, and must be adjusted to the subject’s observed response.
They were derived from the results of exercise by 35 persons of varying age, size, and fitness. The rate that produced a comfortable jogging mode varied with the subject’s height and stride. As the maximal heart rate declined with age, so did the incline needed to raise the observed heart rate to 90% of this figure. A stepped stress protocol should be used as the initial testing procedure for subjects undergoing testing for the first time, since it provides for learning, warm-up, and safe observation at low stress levels. As outlined in Table II, the subject exercises for 2 min under minimal conditions, an additional 2 min under more strenuous conditions, then 5 to 8 min under the target conditions. Progression between steps is contingent upon the absence of cardiovascular and pulmonary signs and symptoms. A 5- to 8-min period of steady-state exercise is most widely used for bronchoprovocation testing, providing maximal pulmonary response, good repro-
644
Eggleston
et al.
J. ALLERGY
CLIN. IMMUNOL DECEMBER 1979
TREADMILL SETTINGS TO RAISE HEART RATE TO 90 PERCENT OF AGE-ADJUSTED MAXIMUM
220 r
I,/
& a
/ / //’ /, / ////,/’ , , / / _1__1___ //
180
ii
I
,/
\ 150
//
69 IO
‘\ \
I
I
I
I
I
20
30
40
50
60
( 20-30
4-3
>30
2-3
L
J
AGE (years) FIG. 1. Maximum predicted heart rate at various broken lines encompass 1 SD.
ages. The
HEKiT (centimeters) I
1
I 60
ducibility, and an easily tolerated stress. Exercise begins with the subject slowly walking on the treadmill. Rate and inclination are then increased rapidly to target levels and maintained for the remainder of the test period. Heart rate and VO, should reach intended levels in 3 to 4 min. The subject’s EKG is monitored continuously throughout exercise. ASSESSMENT
OF PULMONARY
RESPONSE
Pulmonary functions are measured before exercise. They should be repeated until satisfactory reproducibility is demonstrated. These baseline measurements should be compared to those on other days. After exercise, measurements should be made at I- to 2-min and then at 5-min intervals until asthma subsides. Duplicate measurements are made within 1 to 2 min at each interval and the best value is recorded. Measurements of peak expiratory flowrate (PEFR) may be made during exercise to assess bronchial lability. Ambient temperature, barometric pressure, and relative humidity should be noted. There are several satisfactory methods of expressing the asthmatic response to exercise (see Table III). All are based on the comparison of preexercise pulmonary function measurements and the lowest postexercise pulmonary function measurements. Baseline pulmonary functions should always be reported in absolute terms and related to previously recorded values or to predicted values. The first method listed in Table III has the advantage of including baseline mea-
I
,
1
I
I
65
I
I
,
I
(inches)
I
1
70
I
,
I
,
,
I
I
I
75
FIG. 2. Regression graph based on exercise challenge by 30 young adults, 17 to 33 years old (y = 0.07 x -6.5; r = 0.93). Broken lines encompass 2 SD. Three overweight subjects, 167, 189, and 196 cm tall, required significantly lower speeds (4.6, 5.4, and 6 mph). Even when data from these subjects were included, correlation was still high (r = 0.83).
surements in both the numerator and denominator, and thus providing a unit that is unrelated to the level of baseline pulmonary function. In each case, but especially if the last 2 methods are used, baseline values should be reported separately; and in order to compare the results of several challenges, baseline values should be similar. Evaluation of exercise lability (the sum of the maximum rise in pulmonary functions during or after exercise and the maximum fall) may add significant information to the results of the exercise challenge. EXPERIMENTAL APPLICATIONS EXERCISE CHALLENGES Epidemiology
OF
When exercise challenges are used to evaluate the incidence of exercise-induced asthma, maximal sensitivity and specificity are required. Sensitivity can be increased by using exercise modes shown to induce most asthma, such as running in conditions of low ambient temperature and humidity. Specificity can be increased by designating some minimal response (for instance, 10% decrease in PEFR or
VOLUME NUMBEF
64 6, PART 2
Guidelines
FEV,) which is at least 2 SD beyond the mean response of nonasthmatics. Observational
for exercise
TABLE III. Methods
challenge
of expressing
Measurement
When physiologic correlates are to be assessedduring exercise and the subsequent asthma attack, it is most appropriate that protocols be based on these guidelines. Observations made with more extended protocols may not be comparable to those seen with the brief, intense exercise described here.
Lowest
level as % predicted
Manipulative
Lowest
level
Manipulative studies are those in which the response to exercise is modified by changing conditions or drug treatment. Prior to entry into these studies, several practice sessions are advisable for the subject to learn the procedure and to demonstrate a reproducible response. Subjects
should
be selected
who
are moderately
re-
sponsive (FEV, response of at least 20% from baseline) and whose intrachallenge variability is small. Intervals of no longer than 1 wk between challenges are preferable. If multiple exercise tests are performed in 1 day, a period of at least 2 hr should elapse between challenges. Active and placebo treatments, presented in a blinded, randomized fashion, should be included. Parallel studies with matched patients may be required where drug washout problems preclude crossover design. Twelve subjects are usually necessary in each treatment group to avoid sampling artifact. Treatments such as drugs, humidity, or ambient temperature, which might affect baseline heart rate or pulmonary functions, must be evaluated prior to exercise. Pulmonary function tests and heart rate must be measured before and after treatment as well as after exercise. Ambient temperature and humidity should be held constant for repeated determinations. If treatments affect heart rate, exercise conditions should not be changed from those established during practice sessions. Results of manipulative tests can be compared statistically with simple t tests. However, if baseline pulmonary functions prove to be statistically differ-
645
exercise
response
studies
studies
in asthma
Maximum
% fall
Maximum
fall as c/r predicted
Formula*
*x, Baseline function (e.g.,FEV,); y, lowest function; normal value of pulmonary function.
p. predlcted
ent, more complex methods are necessary, such as a repeated measures analysis of variance or the Grizzle or Koch method of analyzing crossover data. Results may be presented graphically using the mean and standard deviations of pulmonary functions. Alternatively, scattergrams can be constructed by plotting responses following test treatment and control treatment. CLINICAL APPLICATIONS Formal exercise provocation may be useful in screening for participation of asthmatics in activities where risk is involved, such as armed forces training programs or athletic competition, and in documenting work-related disability in asthmatics with active careers. It may be helpful in predicting response to a medication regimen, or in clarifying an indeterminate response to medications in patients with exerciseinduced asthma. Finally, it may be useful as a screening test for an unclear history of dyspnea, cough, or other related respiratory complaints, when related to exercise. In deciding whether a patient has asthma or not, a methacholine or histamine challenge may be the more appropriate procedure to demonstrate airflow lability, especially if the subject is sedentary or has a contraindication to exercise. In addition, a negative challenge in a laboratory setting may not necessarily exclude exercise-induced asthma.
The purpose of these guidelines is to clarify and emphasize procedures for evaluating the airway response to exercise in asthmatics in clinical and laboratory settings. SELECTION AND PREPARATION THE SUBJECTS
OF
Prior to exercise, all subjects should be evaluated by a physician. The evaluation should include (1) a history with special attention to cardiovascular and pulmonary disease, musculoskeletal abnormalities, and current medication use, (2) a physical examination with special attention to heart, lungs, and blood pressure, and (3) appropriate laboratory tests. An electrocardiogram (EKG) may be limited to a rhythm strip but should include a stress EKG in subjects over 35 years of age who are at increased risk for cardiovascular complications of exercise, especially if there are other risk factors such as obesity, sedentary habits, or diabetes mellitus. In subjects suspected of having hypoxia or hypercarbia, resting arterial blood gasses should be determined. Certain conditions so increase the risks of an exercise challenge that subjects should be excluded from testing unless strong indications are present. These include a history of myocardial infarction or angina significant hypertension, pectoris, thyrotoxicosis, valvular heart disease, or any demonstrated electrocardiographic abnormalities. In subjects with resting arterial hemoglobin desaturation or hypercarbia, arterial blood gasses or oxygen saturation should be monitored during exercise. Medications that can influence the pulmonary re-
Reprint requests to: Peyton A. Eggieston, Virginia Medical Center, Charlottesville. Vol.
64, No. 6, Part 2, pp. 642-645
M.D., University VA 22908.
of
sponse should be withheld prior to exercise. Methylxanthines and beta adrenergic drugs should not be used for 8 hr, or for 12 hr in the case of extendedaction formulations. Cromolyn sodium should not be used for 24 hr. Anticholinergics should be excluded for 8 hr. Corticosteroids need not be excluded, but subjects should be receiving a stable dose. Prior to exercise, pulmonary functions should be within 80% of a subject’s usual values and I-set forced expiratory volume (FEV1) should be at least 65% of predicted values. For subjects whose pulmonary functions decrease below these values when medications are excluded, as indicated, the interval should be modified; these are then not appropriate subjects for most experimental protocols. EQUIPMENT A motor-driven treadmill is most appropriate for evaluation of exercise-induced asthma. However, a cycloergometer may be more appropriate where portability or more careful physiologic measurements during exercise are desirable. The subject’s response to work should be monitored with changes in either ventilation or heart rate. Since continuous assessment of ventilatory effort is cumbersome and electrocardiographic monitoring is a necessary precaution, continuous evaluation of heart rate is the usual method. Minimum equipment should provide for a continuous strip chart record of EKG, and ideally an oscilloscope to simplify continuous monitoring should be included. A cardiotachometer may also be helpful. Pulmonary function equipment will vary depending on the type of information required. In general, tests should be simple enough for frequent repetition and sensitive enough to detect small changes in airway obstruction. Minimal requirements can be met with a
0091-6749/79/130642+04$00.40/O
0
1979
The
C. V. Mosby
Co.
VOLUME NUMBEI?
64 6, PART 2
TABLE I. Suggested
Guidelines for exercise challenge in asthma emergency
equipment
and drugs (adapted
from the American
643
Heart Association)*
Epiptrw7t.
I. 2. 3. 1. 5. 6. 7.
Direct-writing EKG Delibrillator (synchronized direct-current preferable) Oxygenator, intermittent positive pressure capability E,sophageal airways, oral or tracheal Bag-valve-mask hand-operated respirator Sphygmomanometer Stethoscope
8. 9. 10. I I. 12. 13.
Drrrgs. I. 14orphine or meperidine 2. Nitroglycerin tablets and amyl nitrite pearls 3. Catecholamines Aramine Adrenalin Noradrenalin Isoproterenol 4. Methylprednisolone sodium succinate (Solu-Medrol or equivalent) 5. Aminophylline (intravenous) 6. lsuprel for inhalation 7. Bronkosol for inhalation
Cutdown tray (sterile) Syringes and needles Intravenous sets Intravenous stand Adhesive tape Laryngoscope (desirable)
8. Antiarrhythmics Lidocaine Procainamide Propranolol Digoxin Calcium chloride Sodium bicarbonate solution Dextrose, 555, in water Normal saline Oxygen
* Exerctse procedure should be supervisedby physician or attendanttrained in cardiopulmonary resuscitation TABLE
II. Guidelines
for stepped
exercise
challenge Treadmill
Step
I II 111
Duration
2 min 2 min 5-X min
Target
Rate
Incline
2.5 mph % Target conditions as determined by heightt Target conditions as determined by height
0% Determined by age-t Determined by age
heart rate
50% Predicted maximum* 70% Predicted maximum 90% Predicted maximum
*Predicted maximum heart rate determined from Fig. I. tTarget exercise of treadmill rate and incline from Fig. 2.
peak flowmeter or a positive displacement spirometer, provided the equipment meets the minimum standards set by the American Thoracic Society. ’ Safety equipment is listed in Table I.
EXERCISE PROCEDURE The level of stress to be used for the provocation must be determined by the subject’s response, as determined by some objective criteria such as heart rate or oxygen consumption (?O,). This response will depend on factors such as the subject’s age, size, and fitness. A stress that will increase heart rate to 90% of predicted maximum values (see Fig. 1) or increase oxygen consumption to 30 to 40 ml/min/kg is appropriate. In Fig. 2 are shown representative conditions that will increase heart rate to 90% of predicted maximum values. These are suggested conditions only, and must be adjusted to the subject’s observed response.
They were derived from the results of exercise by 35 persons of varying age, size, and fitness. The rate that produced a comfortable jogging mode varied with the subject’s height and stride. As the maximal heart rate declined with age, so did the incline needed to raise the observed heart rate to 90% of this figure. A stepped stress protocol should be used as the initial testing procedure for subjects undergoing testing for the first time, since it provides for learning, warm-up, and safe observation at low stress levels. As outlined in Table II, the subject exercises for 2 min under minimal conditions, an additional 2 min under more strenuous conditions, then 5 to 8 min under the target conditions. Progression between steps is contingent upon the absence of cardiovascular and pulmonary signs and symptoms. A 5- to 8-min period of steady-state exercise is most widely used for bronchoprovocation testing, providing maximal pulmonary response, good repro-
644
Eggleston
et al.
J. ALLERGY
CLIN. IMMUNOL DECEMBER 1979
TREADMILL SETTINGS TO RAISE HEART RATE TO 90 PERCENT OF AGE-ADJUSTED MAXIMUM
220 r
I,/
& a
/ / //’ /, / ////,/’ , , / / _1__1___ //
180
ii
I
,/
\ 150
//
69 IO
‘\ \
I
I
I
I
I
20
30
40
50
60
( 20-30
4-3
>30
2-3
L
J
AGE (years) FIG. 1. Maximum predicted heart rate at various broken lines encompass 1 SD.
ages. The
HEKiT (centimeters) I
1
I 60
ducibility, and an easily tolerated stress. Exercise begins with the subject slowly walking on the treadmill. Rate and inclination are then increased rapidly to target levels and maintained for the remainder of the test period. Heart rate and VO, should reach intended levels in 3 to 4 min. The subject’s EKG is monitored continuously throughout exercise. ASSESSMENT
OF PULMONARY
RESPONSE
Pulmonary functions are measured before exercise. They should be repeated until satisfactory reproducibility is demonstrated. These baseline measurements should be compared to those on other days. After exercise, measurements should be made at I- to 2-min and then at 5-min intervals until asthma subsides. Duplicate measurements are made within 1 to 2 min at each interval and the best value is recorded. Measurements of peak expiratory flowrate (PEFR) may be made during exercise to assess bronchial lability. Ambient temperature, barometric pressure, and relative humidity should be noted. There are several satisfactory methods of expressing the asthmatic response to exercise (see Table III). All are based on the comparison of preexercise pulmonary function measurements and the lowest postexercise pulmonary function measurements. Baseline pulmonary functions should always be reported in absolute terms and related to previously recorded values or to predicted values. The first method listed in Table III has the advantage of including baseline mea-
I
,
1
I
I
65
I
I
,
I
(inches)
I
1
70
I
,
I
,
,
I
I
I
75
FIG. 2. Regression graph based on exercise challenge by 30 young adults, 17 to 33 years old (y = 0.07 x -6.5; r = 0.93). Broken lines encompass 2 SD. Three overweight subjects, 167, 189, and 196 cm tall, required significantly lower speeds (4.6, 5.4, and 6 mph). Even when data from these subjects were included, correlation was still high (r = 0.83).
surements in both the numerator and denominator, and thus providing a unit that is unrelated to the level of baseline pulmonary function. In each case, but especially if the last 2 methods are used, baseline values should be reported separately; and in order to compare the results of several challenges, baseline values should be similar. Evaluation of exercise lability (the sum of the maximum rise in pulmonary functions during or after exercise and the maximum fall) may add significant information to the results of the exercise challenge. EXPERIMENTAL APPLICATIONS EXERCISE CHALLENGES Epidemiology
OF
When exercise challenges are used to evaluate the incidence of exercise-induced asthma, maximal sensitivity and specificity are required. Sensitivity can be increased by using exercise modes shown to induce most asthma, such as running in conditions of low ambient temperature and humidity. Specificity can be increased by designating some minimal response (for instance, 10% decrease in PEFR or
VOLUME NUMBEF
64 6, PART 2
Guidelines
FEV,) which is at least 2 SD beyond the mean response of nonasthmatics. Observational
for exercise
TABLE III. Methods
challenge
of expressing
Measurement
When physiologic correlates are to be assessedduring exercise and the subsequent asthma attack, it is most appropriate that protocols be based on these guidelines. Observations made with more extended protocols may not be comparable to those seen with the brief, intense exercise described here.
Lowest
level as % predicted
Manipulative
Lowest
level
Manipulative studies are those in which the response to exercise is modified by changing conditions or drug treatment. Prior to entry into these studies, several practice sessions are advisable for the subject to learn the procedure and to demonstrate a reproducible response. Subjects
should
be selected
who
are moderately
re-
sponsive (FEV, response of at least 20% from baseline) and whose intrachallenge variability is small. Intervals of no longer than 1 wk between challenges are preferable. If multiple exercise tests are performed in 1 day, a period of at least 2 hr should elapse between challenges. Active and placebo treatments, presented in a blinded, randomized fashion, should be included. Parallel studies with matched patients may be required where drug washout problems preclude crossover design. Twelve subjects are usually necessary in each treatment group to avoid sampling artifact. Treatments such as drugs, humidity, or ambient temperature, which might affect baseline heart rate or pulmonary functions, must be evaluated prior to exercise. Pulmonary function tests and heart rate must be measured before and after treatment as well as after exercise. Ambient temperature and humidity should be held constant for repeated determinations. If treatments affect heart rate, exercise conditions should not be changed from those established during practice sessions. Results of manipulative tests can be compared statistically with simple t tests. However, if baseline pulmonary functions prove to be statistically differ-
645
exercise
response
studies
studies
in asthma
Maximum
% fall
Maximum
fall as c/r predicted
Formula*
*x, Baseline function (e.g.,FEV,); y, lowest function; normal value of pulmonary function.
p. predlcted
ent, more complex methods are necessary, such as a repeated measures analysis of variance or the Grizzle or Koch method of analyzing crossover data. Results may be presented graphically using the mean and standard deviations of pulmonary functions. Alternatively, scattergrams can be constructed by plotting responses following test treatment and control treatment. CLINICAL APPLICATIONS Formal exercise provocation may be useful in screening for participation of asthmatics in activities where risk is involved, such as armed forces training programs or athletic competition, and in documenting work-related disability in asthmatics with active careers. It may be helpful in predicting response to a medication regimen, or in clarifying an indeterminate response to medications in patients with exerciseinduced asthma. Finally, it may be useful as a screening test for an unclear history of dyspnea, cough, or other related respiratory complaints, when related to exercise. In deciding whether a patient has asthma or not, a methacholine or histamine challenge may be the more appropriate procedure to demonstrate airflow lability, especially if the subject is sedentary or has a contraindication to exercise. In addition, a negative challenge in a laboratory setting may not necessarily exclude exercise-induced asthma.
