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J Appl Physiol 99: 1843-1852, 2005. First published July 21, 2005; doi:10.1152/japplphysiol.01399.2004
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Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects

H. C. Haverkamp,1 J. A. Dempsey,1 J. D. Miller,1 L. M. Romer,1 D. F. Pegelow,1 A. T. Lovering,1 and M. W. Eldridge1,2

Departments of 1Population Health Sciences and 2Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin

Submitted 21 December 2004 ; accepted in final form 14 July 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Twenty-one subjects with asthma underwent treadmill exercise to exhaustion at a workload that elicited ~90% of each subject's maximal O2 uptake (EX1). After EX1, 12 subjects experienced significant exercise-induced bronchospasm [(EIB+), %decrease in forced expiratory volume in 1.0 s = –24.0 ± 11.5%; pulmonary resistance at rest vs. postexercise = 3.2 ± 1.5 vs. 8.1 ± 4.5 cmH2O·l–1·s–1] and nine did not (EIB–). The alveolar-to-arterial PO2 difference (A-aDO2) was widened from rest (9.1 ± 6.7 Torr) to 23.1 ± 10.4 and 18.1 ± 9.1 Torr at 35 min after EX1 in subjects with and without EIB, respectively (P < 0.05). Arterial PO2 (PaO2) was reduced in both groups during recovery (EIB+, –16.0 ± –13.0 Torr vs. baseline; EIB–, –11.0 ± 9.4 Torr vs. baseline, P ≤ 0.05). Forty minutes after EX1, a second exercise bout was completed at maximal O2 uptake. During the second exercise bout, pulmonary resistance decreased to baseline levels in the EIB+ group and the A-aDO2 and PaO2 returned to match the values seen during EX1 in both groups. Sputum histamine (34.6 ± 25.9 vs. 61.2 ± 42.0 ng/ml, pre- vs. postexercise) and urinary 9{alpha},11{beta}-prostaglandin F2 (74.5 ± 38.6 vs. 164.6 ± 84.2 ng/mmol creatinine, pre- vs. postexercise) were increased after exercise only in the EIB+ group (P < 0.05), and postexercise sputum histamine was significantly correlated with the exercise PaO2 and A-aDO2 in the EIB+ subjects. Thus exercise causes gas-exchange impairment during the postexercise period in asthmatic subjects independent of decreases in forced expiratory flow rates after the exercise; however, a subsequent exercise bout normalizes this impairment secondary in part to a fast acting, robust exercise-induced bronchodilatory response.

exercise-induced bronchospasm; pulmonary resistance; airway inflammation; bronchodilation; alveolar-to-arterial oxygen difference

AIRWAY RESISTANCE INCREASES after whole-body exercise in the majority of individuals with bronchial asthma. This is primarily the result of bronchial smooth muscle contraction (4), but pulmonary vascular engorgement and airway wall edema (17) may also contribute to the postexercise airflow limitation. This increased airway resistance, known as exercise-induced bronchospasm (EIB), becomes apparent in the first few minutes after exercise and peaks between 5 and 15 min after exercise cessation (4).

The postexercise alterations in airway mechanics are associated with gas-exchange disturbance after the exercise, with greater amounts of alveolar ventilation-to-perfusion (A/) mismatch (15, 44), a widened alveolar-to-arterial oxygen pressure difference (A-aDO2), and arterial hypoxemia (5, 44). This is similar to the worsened gas-exchange efficiency in asthmatic subjects after inhalation of methacholine (12), allergen extract (26), and various inflammatory mediators (8, 11, 14). The worsened gas-exchange efficiency is probably due to several inflammation-based changes that affect the A/ distribution, including bronchial smooth muscle contraction, mucosal edema, luminal mucus and liquid accumulation, interstitial edema with "cuffing" of the small airways or pulmonary blood vessels, and small airway closure and air trapping (41).

We asked whether the pulmonary gas-exchange abnormality that occurs during an episode of EIB is further compromised during a subsequent exercise bout. Given the repetitive nature of many types of sporting events and occupations involving physical activity, this question has significance for the exercising asthmatic subject (also see DISCUSSION). Furthermore, because the physiological response to exercise is likely more complex and variable in asthmatic than in nonasthmatic subjects, it is difficult to predict the effects of previous exercise on the airway mechanics and pulmonary gas exchange of subsequent exercise in asthmatic subjects. On the one hand, any existing gas-exchange disturbance is likely to become more apparent during exercise for several reasons, all of which stress the lungs' ability to oxygenate mixed venous blood. Decreased mixed venous oxygen content in combination with a shortened pulmonary capillary transit time will magnify the effects of any A/ maldistribution on arterial oxygenation. Also, narrowed airways result in a high flow-resistive work of breathing and limit maximal expiratory airflow to values ultimately dictated by the maximal volitional flow-volume envelope. These mechanical constraints for ventilation might predispose asthmatic subjects to an insufficient ventilatory response during a subsequent exercise bout. Thus there is reason to believe that arterial blood-gas status will be compromised during exercise performed in close proximity with a previous exercise bout in asthmatic subjects.

On the other hand, exercise has been shown to cause bronchodilation in healthy and asthmatic subjects (10, 38, 42), and an increased airway caliber not only would improve A/ matching but would also minimize mechanical constraints on ventilation. However, the robustness of the bronchodilatory response is likely to be variable during exercise in asthmatic subjects for a variety of reasons. For example, many asthma patients have an irreversible component to their airway narrowing [i.e., airway remodeling (7)], and under certain conditions airway resistance may increase during the time course of exercise in asthmatic subjects (6, 38).

The purpose of this study was to determine the effects of a second exercise bout on the gas-exchange impairment caused by an initial EIB response in asthmatic subjects. We first hypothesized that exercise would cause an increased airway resistance and gas-exchange disturbance after the exercise in a group of habitually active, mild-to-moderate asthmatic subjects. We then hypothesized that the gas-exchange disturbance would be exacerbated further during a second exercise bout, resulting in worsened arterial blood gas status compared with the first bout.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This study was approved by the Institutional Review Board and the Human Subjects Committee of the University of Wisconsin-Madison. Subjects were recruited by poster and newspaper advertisement and by contact with university, community, and regional running, triathlon, and cycling clubs. Potential subjects were provided a detailed description of all study procedures and risks, and they agreed to further study after signing an informed consent for participation in human research.

Subject Selection

Subjects with a known history of asthma or suspected asthma underwent several screening studies to determine eligibility for study participation. All subjects were required to meet at least one of four inclusion criteria: 1) at least a 12% increase in the forced expiratory volume in 1.0 s (FEV1.0) after inhalation of a {beta}-agonist, 2) at least a 10% decrease in the FEV1.0 after a maximal incremental exercise test to exhaustion, 3) at least 2% eosinophils, as a percentage of white blood cells, in the induced sputum, and 4) a provocative concentration ≤ 4.0 mg/ml of methacholine causing a 20% decrease in FEV1.0 (PC20). Only those subjects that met these inclusion criteria requirements were invited to complete the exercise study reported in this manuscript. Three of the 21 subjects met only one of the four inclusion criteria. Of these three subjects, one had greater than a 12% increase in FEV1.0 after bronchodilator inhalation (15.5%), one had a PC20 less than 4.0 mg/ml (0.30 mg/ml), and one had a 28% decrease in FEV1.0 after the incremental exercise test. There were no subjects in the study that met only the eosinophil criteria for study inclusion. Complete results from the screening studies can be found in a separate publication (19).

Lung Function Measurements

Forced vital capacity (FVC), the FEV1.0, expiratory flow at 50% of the FVC (FEF50%), and inspiratory capacity (IC) were determined in agreement with American Thoracic Society recommendations (2) by use of a commercially available system (Jaeger). FEF50% was measured at 50% of the FVC maneuver from which it was taken, rather than at an isovolume from the baseline FVC. Functional residual capacity was measured in a body plethysmograph, and total lung capacity was calculated as the sum of functional residual capacity and IC. Forced oscillation was performed at a fixed breathing frequency (12 breaths/min) and duty cycle (0.35) and was used to determine total respiratory resistance (Rrs) (Jaeger, MS-IOS) and frequency dependence of resistance, calculated as the difference in Rrs between 5 and 25 Hz (Rrs 5–25 Hz).

Arterial Blood Measurements

Samples of arterial blood were drawn anaerobically over 10–20 s during exercise from a percutaneously inserted radial artery catheter (Cook, Bloomington, IN). Measurement of arterial PO2 (PaO2), arterial PCO2 (PaCO2), and pH were made with a blood-gas analyzer (ABL505, Radiometer, Copenhagen), and oxyhemoglobin saturation (SaO2) and Hb were measured with a CO-oximeter (OSM-3, Radiometer, Copenhagen). The ideal alveolar partial pressure for O2 was calculated using the ideal alveolar gas equation (31). Blood gases were corrected for body temperature changes during exercise as measured continuously with a Mon-a-therm nasopharyngeal temperature probe (Mallinckrodt Medical, St. Louis, MO). Arterial blood lactate concentration was measured with an electrochemical analyzer (YSI, model 1500 Sport, Yellow Springs, OH).

Induced Sputum and Inflammatory Mediator Measurements

Fifteen minutes after inhalation of two actuations of albuterol, nebulized 3% hypertonic saline (Ultra-Neb, Devilbiss, Somerset, PA) was breathed for periods of ~5 min with a nose clip in place. Subjects then coughed forcefully and expectorated lung sputum into a sterile specimen container, which was placed on ice until analysis. This process was repeated until an acceptable volume of sputum was obtained or FEV1.0 fell by >20%, at which time albuterol was immediately inhaled. Mucus plugs were manually selected and processed as previously described (1). The same laboratory technician completed all sputum processing and cell counts. Induced sputum supernatant was analyzed for histamine by using a commercially available competitive enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI). Urine samples (unextracted) were analyzed for 9{alpha},11{beta}-PGF2 using a commercially available competitive enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI).

Exercise Apparatus

Subjects breathed through a low-resistance, two-way valve (model 2400, Hans Rudolph, Kansas City, MO), and expired gases were sampled at the mouth and after an 8.64-liter mixing chamber via a mass spectrometer (Perkin-Elmer, model 1100, Norwalk, CT). Inspiratory and expiratory flow rates were measured separately with heated pneumotachographs, and integration of these signals provided tidal volume. Signals were displayed on a chart recorder, sent through an analog-to-digital board, and sampled on a computer at 75 Hz. Room air was used as the inspirate for the first eight subjects to complete the study (laboratory temperature = 24.0 ± 1.2°C; humidity = 47.6 ± 13.2%), whereas the remaining 13 subjects inspired compressed, dry air from a gas cylinder (laboratory temperature = 24.0 ± 1.0°C). The same inspirate was used for the first and second exercise tests in any given subject.

Exercise Breathing Mechanics Measurements

A nasopharyngeal 10-cm latex balloon-tipped catheter (Ackrad Laboratories, Cranford, NJ) connected by polyethylene tubing to a differential pressure transducer (Validyne) was used to measure esophageal pressure. Inspiratory pulmonary resistance (RLi), expiratory flow limitation, exercise lung volumes, and calculated maximal ventilatory capacity (ECap) were determined as previously described (21, 29, 38). Subjects performed several maximal volitional flow-volume loops (MFVL) before the exercise while standing on the treadmill, and the resting and spontaneous exercise flow-volume loops were placed within the largest of these MFVLs.

Protocol

A schematic of the exercise protocol is shown in Fig. 1. After baseline lung function testing and expired gas and arterial blood collection, subjects performed two submaximal workloads for 3 min each [60.0 ± 7.5 and 73.0 ± 8.6% of measured maximal O2 uptake (O2 max)], and blood was collected during the final 30 s of each workload. Results for the submaximal workloads are presented in a separate publication (19). Subjects then rested in a standing position on the treadmill for 3–5 min, at which time expired gases and arterial blood were collected. Constant work rate exercise was then performed at ~90% measured O2 max until exhaustion (EX1). Arterial blood was collected, and IC maneuvers were performed at regular intervals and also at the end of exercise. Subjects remained on the mouthpiece for 4 min after exercise, and arterial blood and expired gases were collected at 3 min postexercise (early recovery). Pulmonary function tests were completed at 5, 10, and 20 min after exercise. Approximately 35 min after EX1, expired gases and arterial blood were again collected (late recovery). A second exercise bout to exhaustion (EX2) then began with 3 min of exercise at the previous EX1 workload, after which time the speed and/or grade was increased to elicit O2 max. Arterial blood was collected and an IC was performed during the final minute of exercise. Finally, expired gases and arterial blood were collected 3 min after EX2 and lung function was assessed at 5, 10, and 20 min after EX2. A urine sample and an induced sputum sample were collected at 45 and ~60 min after exercise, respectively.



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  		Fig. 1. Schematic of the exercise protocol. Subject preparation included placement of arterial catheter, nasopharyngeal esophageal balloon, and nasopharyngeal esophageal temperature probe. Baseline data included lung function tests, expired gas collection, arterial blood collection, and repeated inspiratory capacities (IC) and maximal volitional flow-volume loops. Subjects then completed 2 successive submaximal workloads for 3 min each (Sub1 and Sub2). A 3- to 5-min rest period was then followed by expired gas and arterial blood collection. Next, the first exercise test to exhaustion (EX1) was performed and included collection of arterial blood just before exhaustion. This was followed by collection of expired gas and arterial blood at 3 and 35 min after exercise, and lung function tests at 5, 10, and 20 min after exercise. Exercise was then recommenced and performed for 3 min at the same workload used during EX1, after which time the treadmill workload was increased and exercise was performed to exhaustion at the maximum workload achieved during a previous incremental exercise test (EX2). Arterial blood was collected before exhaustion. Arterial blood was collected 3 min after exercise, and lung function was assessed at 5, 10, and 20 min postexercise. Ventilation and expired gases were collected continuously during all exercise bouts, and ICs were performed near the end of each bout for placement of the spontaneous exercise tidal flow-volume loops. O2 max, maximal O2 uptake. Arrows denote arterial blood collection.

 
Statistical Analyses

All exercise metabolic, ventilatory, breathing mechanics, and arterial blood data were analyzed by repeated-measures ANOVA with one between-subjects factor (Group: EIB+ and EIB–) and one within-subject factor (Time: baseline, EX1, early recovery, late recovery, EX2). Pulmonary function measured at baseline and after exercise was analyzed in the same manner, except that the Time factor consisted of baseline, 5, 10, and 20 min postexercise. Significance was set at the P ≤ 0.05 level, and a Tukey's post hoc was used to determine which values were significantly different from each other. Relationships between variables were determined using Pearson's correlation coefficients. The statistical software program SAS, version 8.0, was used to analyze all data.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
On the basis of the decrease in FEV1.0 between 5 and 20 min after EX1, subjects were divided into two groups: 1) those with greater than a 10% decrease in FEV1.0 were classified as EIB+ (mean ± SD = –24.0 ± 11.5%; range = –10.0 to –51%; n = 12), and 2) those with less than a 10% decrease were classified as EIB– (mean ± SD = –4.7 ± 4.8%; range = +6.0 to –9.9%; n = 9).

Baseline Lung Function Characteristics

Anthropometric and baseline lung function characteristics from the screening studies for the EIB+ and EIB– subjects are summarized in Table 1. Subjects in the EIB+ group were on average ~5 yr older than the EIB– subjects (P = 0.045). The two groups had similar values for O2 max, baseline lung volumes and flow rates, and airway resistance. The PC20 was not different between groups, and 10 of 12 subjects in the EIB+ group and 5 of 7 in the EIB– group had a PC20 < 4.0 mg/ml.


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  		Table 1. Anthropometric characteristics, maximal O2 uptake, and lung function in subjects with and without exercise-induced bronchospasm

 
Airway Resistance and Pulmonary Function in EIB– and EIB+ Groups

Mean results for RLi at baseline, during EX1, during recovery from EX1, and during EX2 are shown in Fig. 2, and pulmonary function data at baseline and after EX1 are shown in Table 2.



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  		Fig. 2. Inspiratory pulmonary resistance (RLi) at baseline, during EX1, every 30 s during the first 4 min of recovery after EX1, 35 min after EX1, and during EX2. Data are included for subjects with (EIB+), and without (EIB–) ≥10% decrease in the forced expiratory volume in 1.0 s after EX1. EIB, exercise-induced bronchospasm. *Significant difference from the baseline value (P < 0.05). {dagger}Significant difference between EIB+ and EIB– groups (P < 0.05). Values are group means ± SD.

 

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  		Table 2. Pulmonary function and airway resistance at baseline and after the first exercise bout in subjects with and without significant exercise-induced bronchospasm

 
In the EIB– subjects, RLi did not change significantly from baseline during EX1 or during the recovery period, although it was increased slightly but nonsignificantly (+1.4 ± 1.2 cmH2O·l–1·s–1) from the baseline value at 4 min of recovery (Fig. 2). Airway resistance at 5 Hz was significantly increased by ~30% at 20 min after EX1, and the FVC was significantly decreased by ~300 ml at all measurement times after EX1. There were no changes in FEV1.0, in FEF50%, or in the IC after exercise. During EX2, RLi was not different from the values during EX1 or during recovery from EX1.

In the EIB+ group RLi did not change from baseline during EX1. During recovery from EX1, RLi increased progressively over time, was significantly increased compared with baseline beginning at 120 s after exercise, and remained increased during all subsequent recovery measurements (Fig. 2). Pulmonary resistance reached a peak of +4.2 ± 3.2 cmH2O·l–1·s–1 from the baseline value at the fourth minute of recovery (range = +63 to 454%). Significant and sustained decreases occurred in the FVC, FEV1.0, FEF50%, and the IC at all measurement times after EX1, whereas significant increases were seen in Rrs 5 Hz and 5–25 Hz (Table 2). During EX2, RLi decreased significantly from the recovery values and was not different from the EX1 value or the baseline value obtained before EX1.

In summary, the EIB+ group had marked increases in RLi and decreases in maximal expiratory flow-rates during recovery from EX1, whereas the EIB– group had a slight but nonsignficantly increased RLi and no changes in expiratory flow-rates during the same recovery periods. During EX2, RLi decreased significantly from recovery in the EIB+ group, and RLi was not different from the EX1 value in either group.

Gas Exchange

Arterial PO2.   In the EIB– group, PaO2 remained unchanged from rest during EX1 (see Fig. 3A). It increased at 3 min postexercise but then decreased significantly by –10.9 ± 9.4 Torr from baseline during late recovery. During EX2, PaO2 increased by 13.6 Torr from the late recovery value (P = 0.005) and was identical to the value during EX1. In the EIB+ group, PaO2 decreased from baseline during EX1 (–9.9 ± 11.6 Torr), increased to baseline levels 3 min postexercise, but then decreased by 15.8 ± 13.0 Torr from baseline during the late recovery period (P < 0.0001). During EX2, PaO2 increased from the late recovery value and was not different from the EX1 value. In summary, both groups had significant arterial hypoxemia during the late recovery time after EX1; however, PaO2 increased during EX2 to the same values seen during EX1 in both groups.



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  		Fig. 3. Group mean pulmonary gas-exchange responses for subjects with (EIB+) and without (EIB–) ≥10% decrease in the forced expiratory volume in 1.0 s after EX1. Data are presented for baseline, during EX1, during early (3 min) and late (35 min) recovery from EX1, and during EX2. A: arterial PO2. B: alveolar-to-arterial PO2 difference (A-aDO2). C: arterial PCO2. D: oxyhemoglobin saturation (SaO2). *Significant difference from baseline value (P < 0.05). {dagger}Significant difference from 3-min recovery value (P < 0.05). {Psi}Significant difference from 35-min recovery value (P < 0.05). Values are group means ± SD.

 
Alveolar-to-arterial PO2 difference.   The A-aDO2 increased from baseline during EX1 in both groups (see Fig. 3B). In the EIB– group the A-aDO2 returned to baseline levels during early recovery but then increased substantially to 18.1 ± 9.1 Torr during late recovery. During EX2, it remained unchanged from the late recovery value and was identical to the A-aDO2 during EX1. In the EIB+ group, the A-aDO2 remained greater than baseline at 3 min after exercise and widened further during late recovery, at which time it was 14.1 Torr greater than baseline (P < 0.001). During EX2, it did not change from the late recovery value and was not different from the value during EX1. The A-aDO2 thus exhibited the usual increase during exercise in both groups. It was widened during both recovery times in the EIB+ group but only during late recovery in the EIB– subjects. During EX2 the A-aDO2 was not different from the EX1 value in either group.

Arterial PCO2.   In the EIB– subjects, PaCO2 decreased by 5.1 Torr from baseline during EX1 (P = 0.002) and remained low during both recovery periods (see Fig. 3C). During EX2 it was not different from the PaCO2 during EX1. In the EIB+ subjects, PaCO2 did not change from baseline during EX1 but was significantly decreased during the recovery period. During EX2, PaCO2 increased from recovery to equal the value seen during EX1. In summary, both groups hyperventilated during recovery from EX1, PaCO2 was not different between EX1 and EX2 in either group, and the EIB– group showed a nonsignificant tendency to have a lower PaCO2 than the EIB+ group during both exercise bouts.

Correlations Between Pulmonary Function, Airway Resistance, and Gas Exchange

All subjects from both groups were combined, and linear regression was performed between three measures of airway resistance after EX1 (predictor variables: maximum percent decrease in FEV1.0 after EX1, maximum Rrs 5–25 Hz after EX1, and peak RLi measured after EX1) and several indexes of gas exchange (criterion variables: PaO2, PaCO2, and the A-aDO2) measured during EX1 and during both recovery times after EX1. PaO2 during EX1 was significantly correlated with postexercise Rrs 5–25 Hz (r = –0.478, P = 0.028). PaO2 and the A-aDO2 during early recovery were significantly correlated with postexercise FEV1.0 (PaO2, r = 0.577, P = 0.008; A-aDO2, r = –0.684, P = 0.002), postexercise Rrs 5–25 Hz (PaO2, r = 0-.526, P = 0.017; A-aDO2, r = 0.644, P = 0.005), and postexercise RLi (PaO2, r = –0.534, P = 0.019; A-aDO2, r = 0.576, P = 0.02). There were no significant correlations between any of the three predictor variables and PaO2, PaCO2, or the A-aDO2 during the late recovery time.

Exercise O2, Ventilation, Breathing Mechanics, and Acid-Base Status

Exercise metabolic rate was not different between the two groups (Table 3). The ventilatory equivalent for CO2 production was significantly greater in the EIB– subjects compared with the EIB+ subjects during EX1 (consistent with the tendency for a lower exercise PaCO2 in the EIB– group) but not during EX2. Expiratory flow limitation was similar between the two groups during EX1 but was 27.3% higher during EX2 in the EIB+ subjects. This difference, however, did not reach statistical significance because of the large variability in the EIB– group. The E/ECap and operating lung volumes as a percentage of total lung capacity were similar between the two groups during the exercise bouts. Figure 4 depicts group mean preexercise MFVLs, resting flow-volume loops, and spontaneous exercise tidal flow-volume loops for the EIB+ and EIB– groups during EX1 and EX2. The MFVL was smaller in the EIB+ group relative to the EIB– group before the exercise, and this resulted in a decreased ventilatory capacity and greater expiratory flow limitation during the exercise bouts in the EIB+ group.


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  		Table 3. Metabolic rate, ventilation, breathing mechanics, and acid-base results for the first and second exercise bouts

 


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  		Fig. 4. Group mean resting flow-volume loops and spontaneous exercise tidal flow-volume loops plotted within the maximal volitional flow-volume loops for subjects with (EIB+) and without (EIB–) ≥10% decreases in the forced expiratory volume in 1.0 s after EX1. A: spontaneous exercise tidal flow-volume loops from EX1 (EIB+, n = 12; EIB–, n = 9). B: spontaneous exercise tidal flow-volume loops from EX2 (EIB+, n = 10; EIB–, n = 8). Note the greater baseline airflow limitation in the EIB+ subjects as revealed by the "scooped" expiratory boundary of the maximal volitional flow-volume envelope. The increased airflow limitation resulted in a smaller ventilatory capacity and greater expiratory flow limitation during exercise in the EIB+ subjects.

 
Inflammatory Mediators

Results for sputum eosinophils, sputum supernatant histamine, and urinary 9{alpha},11{beta}-PGF2 are contained in Table 4. Baseline and postexercise sputum eosinophils tended to be greater in the EIB+ than the EIB– group, but the differences were not statistically significant. Sputum histamine and urinary 9{alpha},11{beta}-PGF2 were increased significantly after exercise in the EIB+ group, but not in the EIB– group. Furthermore, in the EIB+ group postexercise sputum histamine was significantly correlated with PaO2 (r = –0.68, P = 0.02), the A-aDO2 (r = 0.68, P = 0.02), and SaO2 (r = –0.65, P = 0.03) during EX1. Additionally, the exercise-related changes in sputum histamine (i.e., postexercise – baseline) were significantly correlated with the changes in PaO2 (r = –0.70, P = 0.02), the A-aDO2 (r = 0.63, P = 0.04), and SaO2 (r = –0.67, P = 0.02) between rest and the end of EX1 in the EIB+ group. None of these correlations were significant in the EIB– group.


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  		Table 4. Induced sputum and urinary inflammatory mediator results

 
Pulmonary Function After EX1 vs. EX2

Figure 5 is an identity plot comparing the changes in FEV1.0 after EX1 and EX2 for the EIB– and EIB+ subjects. Of the 20 subjects who completed both EX1 and EX2, 55% had slightly less EIB after EX2 (4 EIB– and 7 EIB+ subjects), whereas 25% had slightly worse EIB after EX2 (2 EIB– and 3 EIB+ subjects) compared with EX1. The decrease in FEV1.0 between EX1 and EX2 was not significantly different in the EIB+ subjects (–23.7 ± 11.5 vs. –21.3 ± 11.6%, P > 0.05) or in the EIB– subjects (–4.7 ± 4.8 vs. –4.2 ± 6.7%, P > 0.05). Thus refractoriness to EIB was not a significant finding in this study, and the majority of subjects remained in the same group (EIB– or EIB+) after EX2.



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  		Fig. 5. Identity plot showing the maximum percent change in the forced expiratory volume in 1.0 s (FEV1.0) after the first and second exercise bouts to exhaustion. Eleven subjects (7 EIB+ and 4 EIB–) had a smaller decrease in FEV1.0 after EX2 compared with EX1 (i.e., less exercise-induced bronchospasm, above the line of identity). Conversely, 9 subjects (4 EIB+ and 5 EIB–) had either no change or a greater fall in FEV1.0 after EX2 compared with EX1.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Summary of Findings

Pulmonary gas exchange and breathing mechanics were assessed before, during, and after two high-intensity endurance exercise bouts to exhaustion (performed within ~40 min of each other) in a group of habitually active asthmatic subjects. Gas exchange was significantly impaired after the first exercise bout in subjects with (EIB+) and without (EIB–) significant decreases in forced expiratory flow-rates after the exercise, resulting in a widened A-aDO2 and arterial hypoxemia during the recovery period. However, the EIB+ group had large increases in pulmonary resistance and developed the gas-exchange disturbance by 3 min postexercise, whereas the gas-exchange disturbance took a longer time to develop in the EIB– subjects (~35 min after the exercise). Another difference between the two groups was that inflammatory mediators in the sputum and urine were increased after exercise in the EIB+, but not EIB–, subjects. The second exercise bout was accompanied by profound decreases in pulmonary resistance from the recovery values in the EIB+ group and a return of the A-aDO2, PaO2, and PaCO2 to the values obtained during the first exercise bout in both groups. Accordingly, exercise caused a normalization of the gas-exchange impairment. Finally, significant correlations were found between postexercise sputum histamine levels and the exercise A-aDO2 and PaO2, suggesting that airway inflammatory mediator release during exercise in asthmatic subjects may have a negative impact on gas exchange during exercise.

Gas-Exchange Impairment After Exercise

Our subjects developed modest gas-exchange disturbance after exercise; the A-aDO2 was widened to mean values of 20 Torr and PaO2 decreased to 80 Torr at 35 min after exercise despite a continued hyperventilation that drove PaCO2 down to well below baseline levels during recovery. Previous studies have also shown a widened A-aDO2 and decreased PaO2 after exercise in asthmatic subjects (5, 9, 15, 44). Additionally, the multiple inert-gas elimination technique has shown that the A/ distribution becomes more nonuniform after exercise in asthmatic children and adults (15, 44) and that this is primarily due to perfusion of poorly ventilated lung regions. Thus it is most likely that the postexercise arterial hypoxemia seen in our subjects was due to increased A/ mismatch.

An important new finding from the present study is that gas-exchange disturbance occurs after exercise even in asthmatic subjects who do not exhibit decreases in spirometric measures of expiratory airflow or increased pulmonary resistance after exercise. Thus subjects without evidence of EIB, as defined by a <10% decrease in FEV1.0 after exercise, also showed the exercise-induced gas-exchange impairment. However, the EIB+ subjects had already developed the gas-exchange impairment by 3 min after exercise, whereas the EIB– subjects did not show the impairment until the late recovery time. In the EIB+ subjects the gas-exchange disturbance during early recovery was likely due to an uneven ventilation distribution resulting from decreased caliber of the medium and large airways, as RLi in these subjects had already increased substantially by this time. Accordingly, the gas-exchange disturbance during the early recovery period did correlate with the airflow limitation developed after the exercise.

In contrast, the gas-exchange impairment seen in both groups of subjects during the late recovery period did not correlate with the exercise-induced airflow limitation. This is likely due to the fact that standard tests of pulmonary function are indicative of central airway caliber whereas gas exchange takes place in the terminal airways. Thus the gas-exchange disturbance during late recovery was likely caused by peripheral airway ventilation distribution heterogeneity due to a combination of factors, including bronchial smooth muscle contraction, airway wall edema, luminal mucus and fluid accumulation, and a heterogeneous peripheral airway closure and gas trapping (22, 24, 25, 35, 41). Recent evidence in animals (39, 40) and humans (22, 24, 25, 35) suggests that airway closure is a vital feature of asthma and also that this closure occurs commensurate with ventilation distribution heterogeneity (3, 35). Airway closure can occur through formation of liquid bridges across narrowed airways (32) and may be further exacerbated by the tendency of airways to transition between two states, one open and the other nearly closed (3). Additionally, two of the alleged determinants of airway closure, including airway wall thickness and luminal fluid content, are likely to be increased after exercise in the asthmatic subject. Finally, several components of plasma exuded into the airways during or after the exercise might interfere with surfactant function, creating an unstable airway that is more likely to close (40, 43).

Presumably, it takes time for these peripheral airway abnormalities to develop after exercise and indicates that peripheral airway dysfunction can occur after exercise in asthmatic subjects even in the absence of changes in forced expiratory flow rates and thus in airways of medium- and large-sized caliber. The sustained decreases in FVC after exercise in both groups of subjects provide indirect evidence for the development of peripheral airway pathology after the exercise bout (16). Also, the EIB– subjects did have a small but significant increase in Rrs 5 Hz after exercise, suggesting further that peripheral airways dysfunction occurred even in the absence of marked changes in the central airways. Thus we propose that the EIB+ subjects had both a decrease in central airway caliber and peripheral airway dysfunction after exercise, whereas the EIB– subjects had only peripheral airway dysfunction after the exercise. This difference likely explains the faster onset and slightly worse gas-exchange impairment after exercise in the EIB+ subjects.

Gas Exchange During Repeat Exercise

Arterial blood gases and the A-aDO2 during the second exercise bout were virtually identical to the values seen during the first exercise bout, which was not preceded by increased airway resistance and gas-exchange impairment. Thus the exercise-induced gas-exchange disturbance during the recovery period was normalized by the subsequent exercise. Similar findings were reported in a study by Katz et al. (23), in which asthmatic children (~14 yr) performed 6-min exercise stages of increasing intensity with 10-min rest periods separating each stage. The children either maintained or showed gradually increasing values for PaO2 during the subsequent exercise stages. Unfortunately, recovery values for the A-aDO2 and PaO2 were not reported. Similarly, the effects of high-intensity exercise on gas exchange during a second exercise bout have been studied previously in healthy nonasthmatic endurance-trained men and women (18, 36) and in Thoroughbred horses (27). In each of these studies, gas exchange was not impaired further during the second exercise bout and PaO2 was either unchanged or increased compared with the first exercise bout. Importantly, however, gas exchange was not impaired and PaO2 was not decreased during recovery from the first exercise bout in these previous studies, whereas a markedly widened A-aDO2 and decreased PaO2 were seen during the recovery period in our asthmatic subjects.

What are the potential contributors to the improvement in gas exchange upon resumption of exercise after recovery? The second exercise bout was accompanied by a profound bronchodilation in the EIB+ subjects, as shown by a marked decrease in RLi from the recovery values (see Fig. 2). Furthermore, the decrease in RLi appears to occur at the immediate onset of exercise. For example, Fig. 6 depicts RLi measured before, and, on a breath-by-breath basis, during the first 1 min of EX1 in five subjects with the highest values for RLi before the exercise. In each subject, RLi decreased rapidly within the first 30 s of exercise commencement. Stirling and colleagues (37) showed a more gradual decrease in pulmonary resistance during treadmill exercise performed 3 min after a previous 12-min exercise bout in asthmatic subjects, and bronchodilation in asthmatic subjects during the steady state of exercise has been shown by multiple investigators (10, 28, 38). Moreover, the exercise bronchodilatory effect is often so strong that it abolishes the bronchoconstricting effects of inhaled histamine (37) and substantially reduces the reactivity to inhaled methacholine in asthmatic subjects (20) when inhaled during exercise. The bronchodilation also occurs during exercise performed at the time of the late asthmatic reaction (when airflow limitation is pronounced) after inhaled antigen challenge (10). The airway narrowing due to bronchial smooth muscle contraction is heterogeneous (24); thus any relief of that bronchospasm should improve the uniformity of alveolar ventilation and the A/ distribution. Similarly, the increased airway closure and gas trapping after exercise (35) surely contribute to A/ maldistribution, and the increased tidal volumes during exercise should help to open closed airways and improve the ventilation distribution.



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  		Fig. 6. RLi measured immediately before EX1 and on a breath-by-breath basis during the first minute of EX1 in 5 subjects with the highest values for RLi preceding the exercise. The RLi measured before EX1 was generally increased from the baseline value, because it was measured ~3 min after subjects completed the submaximal exercise workloads. Note the immediate and sustained reduction in RLi at the onset of exercise in all 5 subjects. Note also that in spite of the dramatic decreases in RLi, it was still between 3 and 5 cmH2O·l–1·s–1 at the end of the first minute of exercise, much higher than that seen in healthy nonasthmatic subjects, in which RLi during exercise is between 1–2 cmH2O·l–1·s–1. *Data collection did not begin until treadmill speed and grade were set to the correct workload, which takes ~20–30 s. Thus breath 1 during exercise was actually collected after subjects had been exercising for ~20–30 s.

 
Refractory Period

The extent of bronchospasm after a second exercise bout (when performed within ~2 h of an initial exercise bout) is sometimes less than that seen after the first bout (13). This phenomenon has become known as the "refractory period." In the current study, the submaximal exercise bout may have caused some refractoriness to EIB after EX1. We were able to obtain RLi measurements 3–5 min after submaximal exercise (i.e., immediately before commencement of EX1) in 14 subjects, and these were compared with the values for RLi measured 3 min after EX1. In these subjects, RLi was 5.6 ± 3.7 and 6.6 ± 4.5 cmH2O·l–1·s–1 after submaximal exercise and EX1, respectively. Thus, in this group of subjects under the present protocol, it does not appear that the submaximal bout caused refractoriness to EIB.

Our subjects also showed minimal refractoriness to EIB after EX2 (see Fig. 5). Other data also show that refractoriness does not occur in all asthmatic subjects (13, 30, 33), is variable within a subject over the course of days (13), is dependent on the exercise protocol (13, 33), and might be affected by fitness level (34). Moreover, the mechanism for refractoriness is unknown. Given these uncertainties, we cannot implicate any refractoriness to EIB as being related to our findings. The important point in the present study is that a second exercise bout reversed the increases in airway resistance that occurred after an initial exercise bout and at the same time caused a normalization of gas-exchange efficiency.

Practical Considerations

There are several practical issues regarding these findings. Many professions require periods of intense physical activity interspersed with periods of rest (e.g., firefighting, law enforcement, life guarding). Our finding that all but two subjects were able to resume and complete the second exercise bout to exhaustion, even when immediately preceded by an increased airway resistance, increased work of breathing, and altered mechanical lung function, suggests that the ability to perform multiple "bouts" of physical activity is not compromised in most asthmatic subjects. This also applies to contests in which athletes compete multiple times in 1 day (e.g., swimming, track and field, wrestling).

We also emphasize that the subjects included in this study represent habitually active individuals with mild-to-moderate levels of asthma severity and airway dysfunction and for the most part were able to initiate and complete the second exercise bout with minimal discomfort. However, the two subjects with the largest declines in FEV1.0 and two of the three highest values for RLi after EX1 (9.1 and 10.5 cmH2O·l–1·s–1) were not able to complete the second exercise bout (one was unable even to initiate the exercise) because of extreme dyspnea. Beck et al. (6) also reported on a subject with a significant increase in airway resistance during exercise, forcing him to discontinue the exercise protocol. Thus there are "mild-to-moderate" asthma patients with more severe airway hyperresponsiveness to exercise who are not able to complete successive exercise bouts, at least without the benefit of inhaled {beta}-agonists or other pharmacological therapy. Accordingly, the results from this study cannot be generalized to all asthmatic patients of mild-to-moderate severity.


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Funding was provided by the National Heart, Lung, and Blood Institute (RO1-HL015469 and T32-HL007654 for H. C. Haverkamp, J. D. Miller, and A. T. Lovering) and by a grant from the Veterans Affairs/Department of Defense.


   ACKNOWLEDGMENTS
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We thank our subjects for their time, patience, and enthusiastic participation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. C. Haverkamp, Univ. of Vermont, Vermont Lung Center, 149 Beaumont Ave., HSRF 226, Burlington, VT 05405 (e-mail: hans.haverkamp{at}med.uvm.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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