PULMONARY ADAPTATION TO EXERCISE: EFFECTS OF EXERCISE TYPE AND DURATION, CHRONIC HYPOXIA AND PHYSICAL TRAINING* J. A. Dempsey, N. Gledhill, W. G. Reddan,

H.V. Forster, P. G. Hanson, and A. D. Claremont Pulmonary Physiology Laboratory Department of Preventive Medicine University of Wisconsin Madison, Wisconsin 53706

A precise, efficient response of the pulmonary system to the increased energy demands imposed by rhythmic muscular work is well recognized as a necessary first line of defense in ensuring adequate systemic oxygen transport. We shall describe some critical aspects of this response in short-term muscular work and then examine how this response might be altered-both acutely by varying types of exercise and chronically by physical training and hypoxic environments. Short-term exercise in healthy man at sea level may be used as the criterion response for purposes of comparison with other states. Some essential features of this pulmonary response are shown in TABLE 1. Note that arterial oxygen tension (Po,) is maintained near resting levels even to exhaustion and that arterial Pco, is maintained through moderate exercise levels and only falls as hyperventilation responds to the metabolic acidosis of heavy work. The efficiency with which this blood gas and acid-base homeostasis is achieved is remarkable, as evidenced by the absence of dyspneic sensations until exhaustive work levels are approached and the fact that the pulmonary vasculature is capable of receiving the entire cardiac output with minimal changes in right- or left-sided pressures and no accumulation of pulmonary extravascular water. The only significant sign of any “inefficiency” in pulmonary gas transport during exercise is the progressive widening of the alveolar to arterial Po, difference [(A - a)Do,l (see below). Several key mechanisms or characteristics underlie this homeostatic pulmonary response to short-term exercise. To name a few: (1) the complex combination of primary and feedback input to medullary neurons (see FIGURE 5 for details) ensures an isocapnic hyperpnea and high alveolar Po,; (2) a portion of this feedback system, i.e., that from respiratory muscle and lung stretch receptors to brain and spinal motor neurons, dictates a combination of breathing frequency and tidal volume that ensures a near ideal “minimum work” generation by the chest wall; and (3) the large reserve capabilities of the lung are such that the metabolic capacity of respiratory muscles, the mechanical limits of the lungs, airways, and parenchyma for gas flow and volume expansion, and the expansion capabilities of the pulmonary capillary network are barely taxed in exhaustive short-term work.

* This work was supported by the National Heart, Lung and Blood Institute Grant

17540 and Career Development Award 00149, by the Wisconsin Heart Association and by the University of Wisconsin Graduate School.

243

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Annals New York Academy of Sciences

Pulmonary gas transport or the magnitude of the alveolar to arterial Po, difference [(A - a)Do,I is critically dependent upon ventilation (r',)to perfusion (Q) relatjonshipsTboth the overall V.,:Q for the lung and the relative distributions of V , and Q throughout the lung. Gledhill ei a!.' have studied the effects of exercise in health on the steady-state elimination of inert gases,' a technique that-ynlike conventional radioactive tracer methods-permits the quantitation of VA:Q distribution throughout the lung. An example of these findings during mild exercise (TABLE 2) revea!s the following pertinent conclusions: (1) Overall, V9 increases more than Q during exercise, resulting in a higher overall V.*:Qwith increasing exercise intensity (e.g., V , : Q 5 5 in maximum work). Hence, during exercise, the low V , : Q compartments are elirninated from participation in gas exchange-an adjustment that is critical to avoiding arterial hypoxemia and CO, retention in the face of increased metabolic demand and declining mixed venous Po, and rising Pco2. (2) Unexpectedly, vA4:Q dispersion or distribution did not become more uniform during

TABLE1 ARTERIAL BLOOD GAS HOMEOSTASIS: HEALTHY MAN IN SHORT-TERM WORK (4-8 MINUTES)AT SEA LEVEL Alveolar to

Arterial Blood VO*rn..

%

Rest Light work Moderate work Heavy work Maximum work

20-3 0 40-60 65-85 100

Po,

Pco,

(mmHg) 90 88 90 90 93

40 42 40 35 30

PH 7.40 7.38 7.38 7.34 7.29

Arterial [HCO;] Po, (meqll) (mmHg) 25 25 23 19 14

10 12 15 18 25

exercise.. In view of the more uniform topographical (or interregional) distribution of VA or Q found during exercise using radioactive tracers,: our findings point to an exercise-induced [ntraregional inhomogeneity in VA:Q distribution. (3) The quantitation of V , :Q distribution permits calculation of end-capillary blood gases and hence a partitioning of factors causing the observed (A - a) Do,. Note that the increased (A - a)Do, during exercise is attributable mostly to the contribution from an anatomical shunt of mixed venous blood (-1% of cardiac output). We will now examine a variety of conditions which may alter the pulmonary response to exercise. The effects of short-term work in varying body postures and during tethered crawl swimming were tested in healthy subjects (FIGURES 1 & 2). We postulated an improve$ pulmonary gas exchange secondary to a more homogeneous topographical V A:Q distribution with supination and immersion. At rest, (A - a)Do, was narrowed and DLco significantly higher in the supine posture, but during exercise and particularly heavy exercise no clear effects of posture or immersion were evidenced other than small differences in ventilatory response at moderate workloads. These data confirm the idea ex-

Dempsey et al. : Pulmonary Adaptation

245

TABLE 2 PULMONARY VENTILATION TO PERFUSION RATIO ( +A: DURINGEXERCISE: RESULTSOF MULTIPLEINERTGAS ANALYSIS

8)

Rest

(

Mild Work ( V o , = 1.1 literdmin)

GI,, =0.27

liters/min ) Mixed-i.enous blood gus IYllves

(rllrllHg)

31 52

39 45

PO,

5.4 5.8

.Q.

25.6 11.7

V.1:Q

Mean Dispersion 'i: Range PO? (rl7rflHg) Alveolar

0.93 20.34 0.49-2. I

2.3 20.46 0.93-6.6

100.

I08

}9 -i.

93 ) - 7 t

End pulmonary capillary

99

13t Arterial Alveolar to arterial difference, ( A -n)D,,, ::

90

1.8 % 91 J

f -

-

10

17

Log of standard deviation (SD).

f Portion of the (A--n)D,,, due to k:Q inhomogeneity. % Portion of the ( A -n)D,,, due to anatomical shunt. We assume that limitations to alveolar capillary diffusion contribute nothing to the ( A -u)Dll,.

100

PaO,

(mmHql

P

T

90

(ml.min. mm Ha-')

85

7.40

7.30

35 I

I

I

10 .

1

1

2.o

I

1

I

I

1.0

1

I

2 .o

1

FIGURE 1. Effects of posture on pulmonary response to short-term (4-6 min) workloads (r7=6). Exercise diffusion capacity ( D L , . , , )was measured with the singlebreath method at rest and steady-state method during exercise. Postural effects were negligible in moderate to heavy work.

Annals New York Academy of Sciences

246

40

L 4 ’

OOZ (I,min, STPD)

I$

1

1

I

2 .o

1

1

3.0

FIGURE2. Effects of tethered swimming (4-5 min per load) on ventilation and DLCO (steady-state method) in trained swimmers ( n = 9 ) . Swimming effects were limited to a relative underventilation and mild COaretention in moderate work. eressed above that intraregional rather than only topographical differences in V , :Q distribution determine alveolar to arterial gas exchange during exercise and demonstrate that it is difficult to improve upon an already near-ideal gas exchange system in the exercising healthy upright man. We emphasize that steady-state exercise in laboratory conditions may not mimic the pulmonary response to the unsteady states encountered under competitive conditions. For example, the sprint crawl is often preceded by 20 or more minutes of volitional hyperventilation, with the swimmer beginning the race at high lung volume, which he maintains while apneic throughout the 20+ seconds of a 50-yard sprint. Note below the changes in alveolar (end-tidal) gases obtained immediately before and the first breath after practice time trials in a highly trained sprinter (mean of four trials) . Quiet Rest Alveolar Pco2 (mmHg) Alveolar Po, (mmHg)

41

96

50-yd. Sprint (21.0 sec) Before 23 124

After 68 47

Dempsey et al. : Pulmonary Adaptation

247

The pulmonary response. to prolonged heavy exercise at constant workload of maximum Vo,) in the fit but not highly trained individual is most notably characterized by a progressive, time-dependent tachypneic hyper3). This “ventilatory drift” is analogous ventilation and hypocapnia ( FIGURE to the well-known progressive tachycardia or “cardiovascular drift” in prolonged work and is accompanied by, gradually rising intravascular temperatures and a

(60%-75%

-0-

--

-*----a

3.0 METAB. RATE

WORK TIME (min)

1.0 1

REST

I

1

20

I

I

40

I

I

60

1

I 80

FIGURE3. Pulmonary respoFse to long-term work (66% Vo,,.. at sea level in fit but untrained subjects ( n = 6 , V 0 ~ , ~ ~ ~ = 5ml/kg). O f 2 All blood gases were corrected

to qbserved vascular temperatures. During the prolonged heavy work phase increases in V E ,breathing frequency, and heart rate (148 to 175) were 40%, 70%, and 18%,

respectively. near-perfect regulation of arterial [H+]. In the sea-level native after 2-5 weeks sojourn at high altitudes, this ventilatory drift is similar in nature to that seen at sea level but is markedly accentuated (FIGURE 4 ) . Alveolar to arterial O2 transport is well maintained during prolonged work, i.e., at sea level and even at 3100 m arterial Po, remains at or above resting levels and (A - a)Do, narrows slightly with exercise duration. There are, of course, limits to even the healthy lung’s capability for alveolar-capillary diffusion and blood gas

248

Annals New York Academy of Sciences

homeostasis, as may be noted at 4300 m where arterial hypoxemia worsens with intensity and duration of work despite the extreme levels of hyperventilation. The potential mediators o f “hyperventilatory drift” in prolonged exercise are outlined in FIGURE5. They are viewed as overriding stimuli-superimposed on the basic system of primary and feedback stimuli which operate in combina-

so 40

30 20

25 20 7.50

K

PHa

X

P-

X 8

9oz

7.40 3.0

/===

(I min,STPD)

21.-00 1 1

REST

1

I

20

1

1

40

1

1

60

I

FIGURE 4. Pulmonary response to long-term work (70% V O , ~ . . )after 10 days to 3 weeks at high altitudes in the same subjects as in FIGURE 3 ( V O ~ , ,at , . ~3100 m=45 +2 ml/kg). Vascular temperature changes were similar to those at sea level (FIGURE 3). At 3100 m during the prolonged heavy work phase, increases i n V E ,breathing frequency, and heart rate (157 to 179) were 35%, 67%, and 15%, respectively.

tion to ensure a fairly precise eucapnic hyperpnea in short-term moderate work. While we are as yet unable to determine precisely which of these overriding stimuli are responsible for ventilatory drift, the evidence to date points to three possibilities: (1) The [H+] stimulus, although a dominant factor in the hyperventilation of short-term heavy exercise, must play a small or negligible role in prolonged work-simply because a metabolic acidosis is not incurred in arterial

/

'

t FEEDBACK (FINE CONTROL (

(HYPOXEMIA)

t METABOLIC

( ACIDOSIS

@

OVERRIDING STIMULI

,miMEDULLARY

CIRCULATING (NOR-EPINEPHRINE)

PRIMARY (GROSS CONTROL 1

0.

t

EUCAPNIC

TACHYPNEIC HYPOCAPNIC HYPERVENTILATION

IY PERPNEA

FIGURE5 . Schema for regulation of exercise hyperpnea and hyperventilation. Eucapnic hyperpnea is maintained (in short-term work) by a precise combination of 1 or 2 "primary" drives originating in working muscle ' with both chemical and mechanical feedback or "error" control. During prolonged heavy work in normoxia o r hypoxia a number of stimuli override this basic control system resui'ting in a progressive tachypneic, hypocapnic hyperventilation.

I \

CHEST- WALL [ MECHANO RECEPTORS]

\o

P

h)

Y

c

3

0

z

cd C

Annals New York Academy of Sciences

250

'"r \

1

STEADY-STATE VENTILATORY RESPONSE TO HYPOXIA (A.P.)

0

FIGURE6. Mild exercise (treadmill walking) combined with hypoxemia causes a multiplicative effect on steady-state ventilatory response. Each point represents 15 min of breathing a hypoxic, normoxic, or hyperoxic gas with continuous adjustment of inspired Conso as to maintain a steady arterial Pco,. blood (FIGURES 3 & 4). We do not, however, know if [H+] homeostasis at the level of intracranial chemoreceptors is similarly maintained. (2) A thermal drive to ventilation has been documented in man under conditions of increased ambient and core temperature 6. and may be important during prolonged work as evidenced by the absence of hyperventilation when skin temperature was cooled sufficiently to prevent most of the rise in core temperature.' However,

25 1

Dempsey et al. : Pulmonary Adaptation TABLE3 EFFECTSOF EXERCISE, HYPOXIA, AND THEIRCOMBINATION ON CATECHOLAMINE EXCRETION (27 EXPERIMENTS IN 3 SUBJECTS) Work Normoxia Light Moderate

Rest Hypoxia Vo, (liter/min)

0.27 56

Paoz (mmHg)

Epinephrine + norepinephrine urinary excretion (% of resting control values) *

I00

1.6 110

1.1 55

1.6 56

100%

182%

200%

467%

1.1

168%

Work + Hypoxia Light Moderate

* Each experimental condition consisted of 20 min of exercise and/or hypoxia. Urine catecholamine excretion was obtained from samples collected 5 min after each of these conditions and compared to control samples obtained in the resting normoxia state at 20-min intervals over the 60 min preceding each condition and at 30-40 min following each condition of hypoxia and/or exercise. These control excretion values averaged 0.024 pg/min (range 0.020 to 0.03 1). we emphasize the preliminary nature of these data and the fact that the site or mode of action of this proposed thermal drive remains unknown. (3) Circulating norepinephrine acting via carotid body chemoreceptors may be a key mediator of hyperventilatory response-particularly in hypoxic exercise. Supportive, circumstantial evidence is shown from the work of Jackson et al. in our laboratory: ( a ) hypoxemia and even mild exercise produce multiplicative effects on ventilation (FIGURE 6) ; (b) these same conditions in combination have an interactive effect on norepinephrine excretion (TABLE 3); and (c) infused norepinephrine, like mild exercise, potentiates the ventilatory response to hypoxia (FIGURE 7). We suspect, because of the substantial magnitude of

9~ (I,min,BTPS) At Rest, (iso-PET =42mmHg) co2 Nor-epinephrine Infusion ( 0 ) (.12-.18pg, kg, min)

30 20 10

Saline lnfurion 1

1

60

80

I

100

1

110

,.

1

(0)

.' 160

1

180

1 200

FIGURE7. Norepinephrine intravenous infusion causes a multiplicative effect on steady-state ventilatory response to hypoxia at rest. Each point represents 25 min of isocapnic hypoxia, or normoxia plus saline (control), or norepinephrine infusion

Annals New York Academy of Sciences

252

20:.

;

-’ !.

ARTERIAL e

w

Note venous O2 contents falling to < 2 mV100 ml, as C ( U - V ) ~ ,

’“\ 1’

A

0

the hyperventilatory drift, that its mediation would require a combination of these stimuli acting simultaneously. Of what significance is this substantial hyperventilatory drift to systemic 0, transport and tissue metabolism? During exercise at sea level the effects on arterial O2 content are negligible; however, at 3 100 m, hyperventilation is essential to maintaining arterial O2 content (Cu,) near resting levels and this adaptation may be critical in view of the very low levels of femoral venous Co, and Po, achieved in long-term work (FIGURE 8 ) . On the other hand, additional data suggests (FIGURE 9) that, so long as blood flow is high and H+ concentration reasonably well regulated, end-capillary Po, in working skeletal muscle must reach extremely low levels (-