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Department of Preventive Medicine, John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, Madison, Wisconsin 53705
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Seventeen fit women ran to exhaustion (14 ± 4 min) at a constant speed and grade, reaching 95 ± 3% of maximal O2 consumption. Pre- and postexercise lung function, including airway resistance [total respiratory resistance (Rrs)] across a range of oscillation frequencies, was measured, and, on a separate day, airway reactivity was assessed via methacholine challenge. Arterial O2 saturation decreased from 97.6 ± 0.5% at rest to 95.1 ± 1.9% at 1 min and to 92.5 ± 2.6% at exhaustion. Alveolar-arterial O2 difference (A-aDO2) widened to 27 ± 7 Torr after 1 min and was maintained at this level until exhaustion. Arterial PO2 (PaO2) fell to 80 ± 8 Torr at 1 min and then increased to 86 ± 9 Torr at exhaustion. This increase in PaO2 over the exercise duration occurred due to a hyperventilation-induced increase in alveolar PO2 in the presence of a constant A-aDO2. Arterial O2 saturation fell with time because of increasing temperature (+2.6 ± 0.5°C) and progressive metabolic acidosis (arterial pH: 7.39 ± 0.04 at 1 min to 7.26 ± 0.07 at exhaustion). Plasma histamine increased throughout exercise but was inversely correlated with the fall in PaO2 at end exercise. Neither pre- nor postexercise Rrs, frequency dependence of Rrs, nor diffusing capacity for CO correlated with the exercise A-aDO2 or PaO2. Although several subjects had a positive or borderline hyperresponsiveness to methacholine, this reactivity did not correlate with exercise-induced changes in Rrs or exercise-induced arterial hypoxemia. In conclusion, regardless of the degree of exercise-induced arterial hypoxemia at the onset of high-intensity exercise, prolonging exercise to exhaustion had no further deleterious effects on A-aDO2, and the degree of gas exchange impairment was not related to individual differences in small or large airway function or reactivity.
exercise-induced arterial hypoxemia; arterial blood gases; esophageal temperature; respiratory resistance; histamine
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXERCISE-INDUCED
ARTERIAL hypoxemia (EIAH), defined as an inability to maintain
resting levels of arterial O2 partial pressure (PaO2) and arterial O2 saturation
(SaO2) of Hb, occurs in many trained subjects during
incremental exercise tests to maximum (13, 18, 37). This
condition is primarily due to an excessive alveolar-to-arterial
O2 difference (A-aDO2) and
inadequate compensatory hyperventilation but also to increasing
temperature and metabolic acidosis, which cause a rightward shift in
the Hb-O2 dissociation curve (14). In
susceptible individuals, during brief, high-intensity exercise,
PaO2 falls in the first minute of exercise and stays relatively constant over the ensuing 2-4 min, whereas, at the same
time, %SaO2 continues to fall as pH decreases
(13, 21, 32). Furthermore, EIAH begins to occur even in
submaximal exercise in some subjects and often worsens as work rate is
further increased (13, 18, 40). During long-term,
high-intensity exercise, these influences on pulmonary gas exchange
might be altered. For example, in moderate-intensity [65% maximum
O2 consumption (
O2 max)], prolonged exercise, ventilation-perfusion
(A/
) inequality was shown to increase with
time, and although A-aDO2 did not widen much
beyond resting levels and did not worsen over time in this study
(20), this might not be the case in higher intensity
endurance exercise. On the other hand, EIAH may be lessened in
prolonged exercise because hyperventilation is progressive and arterial pH may remain near normal or actually shift in an alkaline direction over time (17).
Airway inflammation and narrowing, leading to abnormal ventilation distribution, could contribute to the widened A-aDO2 seen during incremental exercise. The condition of asthma is characterized by some degree of airway inflammation, and high rates of ventilation result in a drying of airway mucosal cells and can lead to increases in bronchoconstrictor mediator release (8). Whereas asthmatic subjects typically respond to exercise with large and small airway constriction, perhaps in subjects with EIAH the large airways are protected from bronchoconstriction but smaller peripheral airways are not. Histamine is one inflammatory mediator that has been shown to increase during heavy exercise and that could cause bronchoconstriction at the level of the small airways and/or increase microvascular permeability (2). Both factors could contribute to gas exchange abnormalities. In addition, increases in peripheral airway resistance could constrain ventilation and contribute to the inadequate alveolar hyperventilation seen in subjects with EIAH. The differences in susceptibility to EIAH among fit subjects may also be related to differences in airway smooth muscle reactivity. To date, a role for exercise-induced changes in airway resistance has not been evident, as decreases in the maximal flow-volume loop after maximal exercise have not been demonstrated in subjects with EIAH (23). However, this does not rule out a significant role for increased airway reactivity, inflammation, and narrowing of the smaller airways in EIAH (26).
We were interested in the effects of prolonged, constant-speed,
high-intensity exercise to exhaustion on EIAH and its components, as
this type of exercise bout is more typical of a racelike situation than
a progressive, incremental exercise test. We also wondered whether
changes in large or small airway resistance or interindividual differences in resting (preexercise) airway resistance or airway reactivity might be implicated as causes of an excessively widened A-aDO2. We, therefore, characterized the
development of EIAH and its components over the course of a ~15-min
constant-speed treadmill exercise bout to exhaustion (mean of 93%
O2 max) in fit women runners. We also
compared pre- with postexercise changes in lung function, including
total respiratory resistance (Rrs) at 5-35 Hz and general airway
reactivity to methacholine challenge, with the degree of gas exchange
impairment. We hypothesized that EIAH, especially during prolonged,
high-intensity exercise, would in part be due to enhanced airway
reactivity and exercise-induced changes in airway caliber and resistance.
We used women as our test subjects because 1) less exercise
data, including blood-gas data, have been collected in women; 2) EIAH has been observed in some active women with a much
lower absolute O2 max than in men with
EIAH, and some of these women show significant EIAH even during
submaximal exercise, possibly due to smaller relative lung and airway
size (18, 27, 29); 3) there is some
epidemiological evidence that women have greater general airway
reactivity compared with men (35, 47).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Seventeen healthy women (nonsmoking) were recruited to participate in this study. Informed consent was obtained in writing from each subject, and all procedures were approved by the Institutional Review Board of the University of Wisconsin-Madison. All subjects were nonelite runners; however, most competed in local road races. Fourteen considered running their primary physical activity, two were cyclists, and one was a triathlete. Nine of the subjects were on oral contraceptives, and the other eight were tested during the follicular phase of their menstrual cycle. Based on a detailed questionnaire, all subjects were free from cardiopulmonary disease. Two subjects had used bronchodilators (last usage was >2 mo before the study); however, at the time of the study, none was taking medication with the exception of one subject taking allergy medication.
Resting pulmonary function tests. Vital capacity (VC), inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1), functional residual capacity, and total lung capacity (TLC) were determined as previously reported (28). Lung diffusing capacity for carbon monoxide (DLCO) and residual volume were determined by a single-breath, breath-holding technique (33). Briefly, seated subjects made a maximal inspiration from residual volume of a gas mixture containing 20.9% O2, 0.5% Ne, 0.4% CO, balance N2. The breath was held for 10 s and then expired. The first liter of expired gas was discarded, then ~50% of the VC was collected, and Ne and CO concentration was analyzed by gas chromatograph. Measurements were made in triplicate, separated by 5 min, and the average value was recorded. Closing volume was measured by using a standard single-breath N2 washout procedure (42). Total Rrs was measured by using the forced oscillation technique (Jaeger, MS-IOS), and both room air (all subjects) and helium (11 subjects) were used as the inspired gas (9). Frequency dependence of resistance (Rrs, 5-25 Hz) was calculated as the change in Rrs from 5 to 25 Hz, and resonant frequency was the frequency at which reactance equaled zero. In 13 of the subjects, exhaled nitric oxide (NO) concentration was measured at a constant expiratory airflow rate, as previously described (45). These tests were all performed both before and after exercise.
Exercise protocols. 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 a 8.64-liter mixing chamber via a Perkin-Elmer (Norwalk, CT) mass spectrometer (model 1100). Inspiratory and expiratory flow rates were measured separately by heated pneumotachographs (23). Signals were displayed on a chart recorder, sent through an analog-to-digital board, and sampled on a computer at 75 Hz. Subjects wore a heart rate monitor (Polar Electro, Kempele, Finland).
Initially, subjects completed an incrementalO2 max exercise test on a treadmill. At
a later date, a second treadmill test was conducted at a constant speed
and a slight grade, which combined to elicit ~90-95%
O2 max and could be sustained for ~15
min. DLCO tests were conducted on this day both
pre- and ~30 min postexercise. This treadmill test served to
familiarize the subjects with the exercise protocol to be conducted
while drawing arterial blood. The exercise protocol on the day of blood collection (third exercise test) is depicted in Fig.
1. A 20-gauge arterial catheter (Arrow)
was inserted percutaneously in the radial artery of the left arm under
local 1% lidocaine anesthesia, and a Mon-a-therm nasopharyngeal
temperature probe (Mallinckrodt Medical, St. Louis, MO) was placed
intranasally in the lower one-third of the esophageal lumen. After
preexercise lung function tests, resting arterial blood samples were
collected while subjects breathed on the mouthpiece. After a brief
warmup, subjects ran for 3 min at 50 and 75%
O2 max, and blood samples were
collected during the final 30 s of each workload. The speed and
grade of the treadmill were then increased over 30 s to the
predetermined high-intensity (~90%
O2 max) constant work rate (speed 8.0 ± 0.5 mph, grade 2.6 ± 0.8%). Subjects were instructed
and encouraged to run as long as possible. Arterial blood was collected every 2 min beginning at minute 1 and also at exhaustion
(minutes 1, 3, 5, ... , final
30 s of exercise). After an ~30-min rest, during which time
postexercise pulmonary function tests were performed, subjects again
ran for 3 min at the same constant ~90% workload, after which time
the grade was increased by 2-4% to bring the subjects to
O2 max, and they ran until exhaustion
(time at final workload = 95 ± 30 s).
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Blood gas, body temperature, blood lactate, and plasma histamine
measurements.
Samples (3-5 ml) of arterial blood were drawn anerobically over
10-20 s during each trial for measurement of
PO2, PCO2, and pH with
a blood-gas analyzer calibrated with tonometered blood (ABL300,
Radiometer), and samples of O2 saturation and Hb were measured with a CO-oximeter (OSM 3, Radiometer). Calculated
SaO2 values (based on measured PaO2
and changes in body temperature and pH) were essentially identical to
measured SaO2 [r = 0.96; where
calculated SaO2 = 0.998 (CO-oximeter
%SaO2) + 0.048]. Blood gases were corrected for
body temperature changes during exercise. The alveolar O2
partial pressure (PAO2) was estimated by
using the ideal alveolar gas equation (34). Blood lactate
concentration was analyzed by means of a Yellow Springs Instruments
lactate analyzer (model 1500 Sport). Hematocrit was determined by
microcentrifuge. Blood samples for histamine were drawn into tubes with
EDTA and immediately placed on ice until centrifugation. Plasma was
harvested and stored at 
70°C until analysis with an enzyme
immunoassay kit (Immunotech, Marseille, France).
Methacholine challenge test. A methacholine challenge test (MCT) was done to test for an association between general airway reactivity to a bronchoconstrictor agent and exercise-induced changes in airway function or the development of EIAH or a widened A-aDO2. This test was done on a separate day in 16 of the subjects following American Thoracic Society guidelines (3). A DeVilbiss nebulizer (model 646) and Rosenthal dosimeter were used to administer methacholine chloride (Provocholine, Methapharm). A five-breath dosimeter protocol was used, and doses of saline that were 0.0625, 0.25, 1, 4, 16, and 32 mg/ml of methacholine were administered. Output of the nebulizer was 0.009 ml/breath with a 0.6-s activation. Subjects breathed in to TLC and held each breath for ~5 s. The time interval between doses was kept at 5 min. At baseline and between each dose, measures of Rrs were made first, as this method has been shown to be a more sensitive test compared with FEV1 to measure changes in bronchial tone (36, 43) and avoids a lung volume history, which might reverse a bronchoconstriction effect. This was followed by the conventional FEV1 measure and then IC measurement as an indication of the functional significance of the bronchoconstriction (i.e., changes in end-expiratory lung volume). Exhaled NO was measured last. If and when a >20% fall (from the saline dose) in FEV1 occurred, the FEV1 maneuver was repeated one to two times. If the FEV1 fell more than 20%, the dosing protocol was stopped, a bronchodilator (albuterol) administered, and tests repeated to ensure recovery from bronchoconstriction.
Statistical analysis.
Subjects were divided into two groups based on the
PaO2 maintained during the high-intensity prolonged
exercise bout to exhaustion (the mean PaO2 value of
minute 1 through the end value was calculated for each
individual) and labeled according to low PaO2 (
80
Torr; Lo-PO2, n = 8) and high
PaO2 (>80 Torr; Hi-PO2,
n = 9). This categorization is similar to the >10-Torr
fall in PaO2 from resting values used previously
during an incremental maximal exercise test (18) but is
less influenced by hyper- or hypoventilation at rest. Seven of eight
subjects in Lo-PO2 and none in
Hi-PO2 had a mean PaO2 decrease of >10 Torr from rest during the exercise bout.
Repeated-measures two-way ANOVA was used to compare mean values for
each group across time. If a main effect (group or time) or interaction
(group × time) was observed, Tukey's post hoc analysis was used
to determine where the differences existed. For analysis of data
conducted at different exercise intensities, intensity replaced time as the factor. Linear regression was used to establish correlations. Significance was set at P < 0.05. Data are presented
as means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General data.
Subjects' physical and resting lung function characteristics
are shown in Table 1.
O2 max was ~30% above predicted values, whereas DLCO was ~9% lower
(P = 0.003) than predicted. Maximal voluntary
ventilation in 15 s was also ~30% above predicted using a
prediction equation based on age and body surface area (BSA); however,
with the use of another common predictor (FEV1 × 40),
this fell to 95 ± 15% of predicted.
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Prolonged exercise data.
Individual and group mean data collected at rest and during the
high-intensity exercise bout to exhaustion are presented in Figs.
2-4.
Blood-gas data revealed a rapid fall in PaO2, a
widening of A-aDO2, and a progressive decline
in arterial PCO2 (PaCO2) on
initiation of exercise. Throughout the duration of exercise, PaO2 increased slightly as
PAO2 rose (107 ± 3 Torr at
minute 1 to 112 ± 3 Torr at exhaustion), and
PaCO2 fell and A-aDO2 remained relatively unchanged over the duration of the exercise. Overall mean
SaO2 declined by 2.5 ± 1.9% at minute
1 and fell further throughout exercise to a nadir of 92.5 ± 2.6% at exhaustion (range 86.2-95.6%). In subjects with lower
mean PaO2 values (Lo-PO2), differences in SaO2, PaO2, and
A-aDO2 from Hi-PO2 were
apparent early in the exercise bout (by 1-3 min), but the patterns
of change over time were similar, although subjects in
Lo-PO2 had a reduced rise in
PaO2 from minute 1 to exhaustion. Although
mean PaCO2 did not differ between groups, the decrease
over time was greater in Hi-PO2 as was the
increase in minute ventilation/O2 consumption (O2).
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O2 max (r = 0.02, P = 0.93) in this group of runners with a narrow range of O2 max values (44-56
ml · kg
1 · min1).
Metabolic and heart rate data were similar between
Lo-PO2 and Hi-PO2, both
in terms of absolute values and changes over exercise time (Figs. 3 and
4). O2 increased throughout the first 7 min of exercise, peaked at 95 ± 3% of
O2 max, and then remained stable until
exhaustion (range 87-99% of
O2 max).
O2 did not differ between groups.
CO2 production also increased from 2.46 ± 0.35 l/min
at minute 1 to 2.93 ± 0.42 l/min at exhaustion. Heart
rate increased from 60 ± 12 beats/min at rest to 171 ± 15 beats/min at minute 1 and 189 ± 12 beats/min at
exhaustion. The increase in minute ventilation over time was due
predominantly to increased breathing frequency as tidal volume reached
a maximum of 51 ± 8% of VC (range 33-71%) during
minute 7 before decreasing slightly over the remaining time
to exhaustion.
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1.3°C at all exercise time points.
The amount of hemoconcentration from rest to exhaustion was 1.4 ± 0.2 g/dl with the majority (1.0 ± 0.2 g/dl) occurring by minute 1 (no difference between
Hi-PO2 and Lo-PO2). As
a result of this and the decrease in %SaO2, arterial
O2 content increased from 17.4 ± 1.5 and 18.0 ± 1.6 g/dl at rest to 18.0 ± 1.2 and 19.2 ± 1.5 g/dl at
exhaustion in Lo-PO2 and
Hi-PO2, respectively.
Plasma histamine was significantly increased from rest to minute
3 and further increased at end exercise (137 ± 96% above resting values). Values ranged between 2 and 8 nmol/l at exhaustion, and all returned toward resting levels during recovery (Fig.
6). The mean PaO2
maintained during exercise was positively correlated to end-exercise
histamine level (Fig. 5C), and this relationship was of
borderline significance (P = 0.051) when the changes in PaO2 and histamine from rest to end exercise were
correlated (Fig. 5D).
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Causes of O2 desaturation during exercise. For the Lo-PO2 group, we partitioned the amount of the total fall in SaO2 from rest at 3 min (4.7 ± 1.8%) and at exhaustion (6.7 ± 2.7%) due to the effects of PaO2, pH, and temperature. For the initial (rest to minute 3) fall in SaO2, the 21 ± 8 Torr drop in PaO2 was the most significant factor, accounting for 65 ± 7% of the decrease in SaO2. From 3 min to end exercise, the contributions due to increasing temperature and decreasing pH accounted for the entire remaining decrease in SaO2 that occurred over time. At the end point of prolonged exercise, 54 ± 11% of the Hb-O2 desaturation from resting values was caused by the combination of metabolic acidosis (decrease of 0.14 ± 0.08 pH units) and a 2.5 ± 0.5°C rise in temperature, and the remainder (46 ± 11%) was due to a 17 ± 9 Torr decrease in PaO2.
Effects of exercise intensity on EIAH.
Figure 7 shows mean
SaO2, PaO2,
A-aDO2, PaCO2, pH, and
esophageal temperature at 3 min of exercise at 50, 75, and 90%
O2 max and during a shorter bout
(95 ± 30 s) of exercise at 100% of
O2 max in
Lo-PO2 and Hi-PO2
groups (categorized based on PaO2 during 90%
prolonged exercise bout). The most notable findings were that, by 75%
of O2 max, PaO2 was
already significantly lower and A-aDO2 wider in
those subjects who showed the most EIAH during prolonged exercise
(i.e., Lo-PO2 group).
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Changes in lung function after exercise and correlation to EIAH.
Pre- and postexercise lung function tests are shown in Table
2. Preexercise Rrs varied considerably
among subjects (2-9
cmH2O · l1 · s), and
individual changes in Rrs after exercise were highly variable. Rrs at
all frequencies fell in four subjects and was unchanged (changes of 1
cmH2O · l1 · s) in the
others. The higher the preexercise Rrs, the greater the fall in Rrs
after exercise (r = 0.699, P = 0.002), but this was primarily due to large decreases in two subjects
with high preexercise Rrs values. Neither pre- nor postexercise Rrs was correlated with the exercise A-aDO2,
PaO2, or PaCO2; however, there was a
trend for an increase in Rrs after exercise to be related to a wide
A-aDO2 (r = 0.42;
P = 0.096) and low PaO2
(r = 0.41; P = 0.105). It was not
related to differences in PaCO2. The frequency
dependence of Rrs was also not affected by exercise and did not
correlate with exercise blood-gas variables. Substituting helium for
room air caused Rrs to fall by ~1
cmH2O · l1 · s (at 5 Hz), and
frequency dependence of Rrs tended to be greater (0.96 helium vs. 0.75 air), but this helium effect was not significant and also did not
differ pre- to postexercise. None of the lung volumes, maximal flow
rates, or DLCO changed significantly pre- to
postexercise (see Table 2).
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0.736; P = 0.002) and positively with A-aDO2
(r = 0.550; P = 0.034). VC
(%predicted) was negatively associated with the A-aDO2 (r = 0.485;
P = 0.048), and forced VC (%predicted) with PaO2 (r = 0.511; P = 0.036). No other resting lung function measures correlated with the
degree of hypoxemia.
Airway reactivity to methacholine.
Individual values for FEV1, Rrs, and IC during the MCT are
presented in Fig. 8. With the use of the
clinical definition of the concentration of methacholine causing a 20%
fall in FEV1 (PC20), 2 of 16 subjects would be
classified as having a positive MCT (PC20 < 4 mg/ml),
and three additional subjects would be considered to have borderline
bronchial hyperresponsiveness (PC20 = 4-16 mg/ml). The rest had normal bronchial responsiveness
(PC20 > 16 mg/ml). We also calculated 95% confidence
intervals for both Rrs and FEV1 values in each subject
based on repeated baseline measurements conducted on the various test
days (n = 4-12 values). We then determined the
dose of methacholine that caused a significant change in Rrs or
FEV1 (i.e., one that exceeded the 95% confidence interval). Seven subjects had a measurable change in Rrs before (at a
lower dose) FEV1 changed; in four, Rrs and FEV1
changed at the same dose; and in five, FEV1 changed at a
lower dose. Rrs of 5-25 Hz changed in response to the MCT in a
similar manner across subjects as did Rrs at 5 Hz.
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0.1, P > 0.6). In addition, exercise-induced
changes in Rrs and FEV1 were not related to bronchial
hyperresponsiveness to methacholine in our group of subjects. Five
subjects had a >1
cmH2O · l1 · s increase in
Rrs at a methacholine dose of 4 mg/ml; in these same subjects, the
change in Rrs pre- to postexercise was a fall of between 0.3 and 2.0 cmH2O · l1 · s.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to determine the time course of SaO2 and gas exchange during prolonged, constant work rate, high-intensity running exercise to exhaustion and to evaluate baseline and changes in pre- to postexercise lung function, including airway resistance, in relation to EIAH. At the first minute of exercise, PaO2 fell 14 Torr from rest and A-aDO2 widened to 27 Torr; at the same time, PaCO2 was nearly unchanged from rest. After the initial fall, PaO2 rose slightly as PAO2 increased with the onset of hyperventilation, and there was no further worsening of pulmonary gas exchange (as evidenced by a constant A-aDO2) over the exercise time. SaO2 continued to fall throughout the exercise bout, indicating the importance of a time-related decrease in pH and increasing temperature at any given PaO2. Changes in large or small airway function with exercise and airway responsiveness to methacholine were not related to the development or degree of EIAH or gas exchange impairment. This lack of correlation existed despite the fact that several subjects had high baseline airway resistance and/or bronchial hyperresponsiveness to methacholine.
Comparison with previous "prolonged" constant-workload studies. Many studies have examined EIAH by using an incremental exercise protocol or very short-term heavy exercise; however, there have been relatively few studies that have examined the time course of EIAH or gas exchange during a constant-workload exercise bout lasting >5 min, and none of these has been conducted with female subjects. The studies that have been done were conducted at lower intensities and over a longer exercise time than the present study (17, 20, 46, 48). In each of these studies, arterial desaturation was generally absent as PaO2 did not fall >5 Torr on initiation of exercise and typically rose slightly across the exercise time, whereas A-aDO2 ranged between 10 and 25 Torr, and in only one of the studies (48) did it worsen over time. Interestingly, most of the subjects in the Dempsey et al. study (13) who showed no EIAH during long-term, moderate-intensity exercise did desaturate significantly during short-term maximal exercise. In the present study, high-intensity, prolonged exercise elicited significant gas exchange impairment and EIAH in approximately one-half of the subjects.
Relative contributions of PaO2, pH, and temperature to the fall in SaO2. The fall in PaO2 that occurred in the rest-to-exercise transition accounted for the majority of the decreased SaO2 early in the exercise bout. However, in most subjects, PaO2 then rose slightly over the course of exercise, and the further fall in SaO2 was completely due to decreasing pH and increasing temperature and the resultant rightward shift of the Hb-O2 dissociation curve.
Individual variations in temperature, pH, and PaO2 can greatly affect SaO2. Esophageal temperature increased to39°C in all subjects and in two reached 40.0°C at
exhaustion. This temperature increase is higher than what is typically
seen during an incremental exercise test (38.2°C in Ref.
18) and is likely the result of a greater amount of time
spent near maximal effort. Changes in the pH of arterial blood were
more varied, falling only slightly in some and to <7.20 in several
others. What is the effect of differences in pH and temperature in
subjects with similar PaO2 and
A-aDO2 values on SaO2? Two
subjects maintained an A-aDO2 of ~28 Torr and
a PaO2 of ~80 Torr, but their pH fell to 7.20 and body temperature rose to 40°C. In these subjects,
SaO2 decreased to 90% at exhaustion. In contrast,
two other subjects with a wider A-aDO2 (~34
Torr) and a lower PaO2 (~77 Torr), but whose pH
remained >7.33 and temperature rose to only 39.5°C, had an SaO2 at end exercise of 93-94%. Thus, whereas
PaO2 remains the primary determinant of
SaO2, the influence of individual differences in
changes in pH and body temperature during exercise and the importance
of changes in these variables over exercise time should not be
overlooked. The effects of pH on desaturation in rowers during
high-intensity exercise have been stressed previously
(32).
Correlation of EIAH with resting lung function.
Our resting spirometry values were within normal ranges.
DLCO was slightly below predicted values based
on equations by Knudson et al. (24) and also by Crapo and
Morris (11). The absolute values for
DLCO and for
DLCO/A of our female
subjects were nearly identical to those found in similar groups of fit
female subjects (18, 19).
A/ inequality during exercise (as measured by
the log SD of distribution during the multiple inert-gas
elimination technique) was significantly correlated with the ratio of
TLC to BSA (TLC/BSA) and hypothesized that perhaps people with a
smaller relative lung size would have smaller airways and blood vessels
and that this could accentuate any regional inhomogeneities in the
distribution of air and blood flow (20). We found no
relationship between A-aDO2 and TLC/BSA (r = 0.166; P = 0.525), nor was a
relationship found in the study by Harms et al. (18),
which included 29 female subjects with a wide range of EIAH at
O2 max. Despite this, in the present
study, several other measures of lung size or function (VC, FVC, and
FEV1) were weakly (r < 0.6; see
RESULTS), but significantly, correlated with the
A-aDO2 or PaO2 during
exercise. Therefore, it is unclear what, if any, role lung size has in
explaining EIAH in healthy subjects. We emphasize that a lack of
correlation between lung size and EIAH does not contradict the positive
correlation reported of lung size to exercise
A/ uniformity, because overall mean
A/ rises substantially during exercise,
thereby negating much of the effect of A/
nonuniformity on arterial oxygenation.
Airways and EIAH.
Our rationale for studying the role of small airway reactivity and
small airway resistance in EIAH was threefold. First, we reasoned that
A/ maldistribution was a potential
contributor to the widened A-aDO2 in persons
with EIAH because, in both fit men (13, 41) and especially
in female subjects (18), an excessive
A-aDO2 was already obvious, even in
mild-to-moderate-intensity exercise. These changes are unlikely to be
attributable to diffusion limitation at these lower metabolic
requirements; however, we wish to emphasize that diffusion limitation
is a very likely contributor to EIAH and excessive
A-aDO2 during high-intensity and maximal exercise intensities (41). Second, a recent study using
pharmacological blockade also pointed to airway inflammation as a
potential cause of the widened A-aDO2 in EIAH,
at least in older, fit subjects (38). Thus airway
resistance changes may be involved. However, in normal subjects, tests
of large airway resistance, namely the expiratory flow-volume loop or
FEV1, show no effect of maximum exercise; in fact
bronchodilation is most often observed both during and after exercise
(8), even in the presence of severe EIAH
(23). Therefore, we reasoned that small or peripheral
airway diameters might be compromised with heavy exercise, thereby
creating a maldistribution of mechanical time constants and of inspired ventilation (26). Finally, we also suspected that even
relatively small increases in airway resistance may be especially
important in women who, in general, have smaller airway diameters and
lung volumes relative to men of similar age and stature (4,
29). This hypothesis was tested by using the forced oscillation
technique to measure Rrs under physiological conditions with tidal
breathing. The frequency dependence of Rrs (5-25 Hz) has been
shown to be sensitive to selective increases in small airway resistance
and to correlate highly with frequency dependence of compliance,
especially when He-O2 is used as an inspirate
(9). Change in the phase III of the single-breath
N2 test was also used to document any exercise-induced
changes in the distribution of inspired gas (10). On the
other hand, there are several limitations to these methods. These tests
were conducted postexercise, and, therefore, any changes apparent
during exercise may have resolved in the recovering, resting subjects.
MCT. Five of sixteen subjects had a positive MCT or were classified with borderline hyperresponsiveness. These responses to methacholine, whether measured in terms of Rrs or FEV1, did not correlate with changes in Rrs or FEV1 that occurred pre- to postexercise. In addition, the bronchoconstriction associated with the MCT did not correlate with the amount of hypoxemia present during exercise. As none of our subjects had any significant amount of bronchoconstriction (measured either with Rrs or FEV1) after exercise, this lack of correlation is not surprising. The finding that subjects with hyperreactive airways did not respond to exercise in a similar manner as they did to methacholine has also been reported by others (1) and may reflect the fact that even exhaustive exercise (at least in the nonasthmatic subject) does not involve sufficient bronchoprovocation via release of inflammatory mediators to cause measurable changes in central or peripheral airway diameter.
Histamine and EIAH. Histamine is an inflammatory mediator that can induce airway bronchoconstriction via effects on smooth muscle but also is known to increase vascular permeability (7). Plasma histamine has also been found to be significantly higher in athletes compared with sedentary controls at the end of a maximal exercise bout (2). Furthermore, a significant correlation between histamine release (%H = plasma histamine as a percentage of whole blood histamine) and the degree of hypoxemia implicates a possible role for this inflammatory mediator in the exercise-induced fall in PaO2 (2, 31). Because histamine in the circulation likely reflects basophil release to a much greater extent than lung mast cell release, is complicated by a very short half-life, and is possibly released during centrifugation, it is unclear whether histamine is causal or only indirectly related to EIAH (7, 22, 30, 39).
In our subjects, mean plasma histamine concentration increased with time over the course of the constant work rate exercise bout, and the absolute concentration and change from rest was similar (2) or slightly higher (31) at exhaustion to values found in athletes at the end of an incremental maximal exercise test. In contrast to previous studies, subjects in the present study with the greatest amount of hypoxemia tended to have a lower, not higher, plasma histamine concentration (see Fig. 5, C and D). A confounding factor may be differences in subject selection; all subjects in the present study were athletes of comparable fitness levels, whereas Anselme et al. (2) compared highly trained athletes with sedentary subjects. Thus the corresponding work rates (and potentially other factors such as time of exercise, body temperature, pH, etc.) at maximal exercise were different between those two groups. Both previous studies did find significant correlations with the change in %H from rest to maximal exercise and the drop in PaO2 in their highly trained athletes. The meaning of %H is unclear as changes in %H from rest to maximal exercise are primarily due to changes in plasma histamine because whole blood histamine remains relatively unchanged (31) or increases during exercise (2). Furthermore, %H remained unchanged across exercise intensities of 50-100% ofO2 max
(31). Given this, it is unclear why %H correlates with
EIAH. Perhaps %H is simply a marker for "leaky basophils," which
in turn is correlated with an increased permeability of the pulmonary
vasculature. The association between a reduction in %H and a reduction
in the widening of the A-aDO2 and fall in
PaO2 during exercise with the administration of
nedocromil sodium provides indirect evidence for at least a partial
causative role for histamine in EIAH (38); however, other
possibilities exist. Because nedocromil sodium acts as a general mast
cell stabilizer, it does not only block histamine release. Reduction of
other potential inflammatory mediators (e.g., leukotrienes or
prostaglandins) could have been responsible for the improvement in EIAH.
Finally, the findings of the present study show a rapid widening of the
A-aDO2 immediately on onset of high-intensity
exercise, with no further widening over the remaining exercise time to
exhaustion. These data cast doubt on an inflammatory mechanism for EIAH
simply because of the speed and stability of the occurrence of EIAH. Certainly, the role of histamine or other inflammatory mediators in
EIAH remains in question, at least those mediators whose release would
be influenced by increased flow and shear rates in both the airways and
the pulmonary vasculature.
In summary, we demonstrated that continuing, high-intensity exercise,
beyond the initial few minutes, has little further effect on gas
exchange and that a continued fall in SaO2 is due to
the combined effects of decreasing pH and increasing body temperature. We also confirmed that subjects with the greatest degree of EIAH during
high-intensity exercise begin to show significant gas exchange abnormalities even during moderate-intensity exercise. We found that
several of these fit subjects had high baseline airway resistance and
hyperreactive airway responses to bronchoprovocation; however, airway
resistance or its frequency dependence was not increased by prolonged,
high-intensity exercise, nor was EIAH correlated with airway resistance
or its reactivity. The reason why gas exchange impairment during
exercise occurs in some subjects remains unanswered; whatever the
cause, it becomes apparent early during high-intensity exercise and
does not worsen over time.
| |
ACKNOWLEDGEMENTS |
|---|
We thank our subjects for enthusiastic participation in this study. Special thanks to Matt O'Brien for technical assistance with methacholine dosing, Dr. Keith Meyer for medical assistance, and Zhuzai Xiang for analysis of histamine samples.
| |
FOOTNOTES |
|---|
Support for this project was provided by National Heart, Lung, and Blood Institute (NHLBI) Grant RO1 HL-15469 and jointly by the US Departments of Veterans Affairs and Defense. T. J. Wetter was supported by a NHLBI training grant.
Address for reprint requests and other correspondence: T. J. Wetter, PO Box 53056, Medford, MA 02153 (E-mail: tjwetter{at}yahoo.com).
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.
Received 18 December 2000; accepted in final form 10 April 2001.
| |
REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, Data for
Lo-PO2 group (n = 8);
, data for Hi-PO2 group
(n = 9); both are connected by thick solid lines. For
individual data, thin solid lines represent subjects in
Lo-PO2 and dotted lines represent subjects in
Hi-PO2. Values are means ± SD.
* Significant difference between groups (P < 0.05).
G, significant main effect of group; G × T, group × time
significant interaction. Time effect was significant (P < 0.001) for all variables except A-aDO2
(P = 0.015).
