hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary...

DOI 10.1378/chest.97.2.268 1990;97;268-275Chest

A G Agustí, J A Barberá, J Roca, P D Wagner, R Guitart and R Rodriguez-Roisín pulmonary disease.exchange during exercise in chronic obstructive Hypoxic pulmonary vasoconstriction and gas

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HPV = hypoxic pulmonary vasoconstriction; i7A/Q relation-shipventilation-perfusion relatipnslsips; shunt (inert gascs)�percent ofQr.to lung units with VA�Q ratios <0.005; low VA/Q

percent ofQr.to lung units iyith VA/Q ratios <0.1,(excludingshunt); high V1t/Qpercent OfVE tojung units with VA/Q r$ios10 to 100; deadsp�cepercent ofVE to lung units with VA/Qratios >100�QVu/Q ratio at the mean of the blood flowdistribution; V ratio at the mean of the ventilation distribu-tion; LOgSD Qdispersion (SD) of the blood flow distributionon a log scale; LOg5D Vdispersion (SD) of the ventilation4istdbution on a log scale; DISP R-E overall degree of‘h/Qjnismatching direcdy Obtained from the raw inert gasdata; Ppa = pulmonary artery pressure; PFT pulmqnary func-

tion test; Dco carbon monoxide diffusing capacity; Q�, cardiac

output; Pwpulmonary capillary wedge pressure;TPVR = total pulmonary vascular resistance; RVSWI rightventricular strQke . work index; f respiratory rate;R = respiratory; Qs/QT venous admixture; VDIVT deadspace tidal volume ratio; BE base excess

268 Vasoconstriction and Gas Exchange during Exercise (Agust! at a!)

Hypoxic Pulmonary Vasoconstriction andGas Exchange During Exercise in ChronicObstructive Pulmonary Disease*Alvar G. N. AgustI, M.D.; Joan A. Barberd,4 M.D.;t Josep Roca, M.D.;

Peter D. Wagner� M.D.; Raim#{243}n Guitart, Ph.D.;� and

Robert Rodriguez-RaisIn, M.D.

In patients with chronic obstructive pulmonary disease

(COPD) studied at rest, nifedipine releases hypoxic pul-monary vasoconstriction (HPV) and worsens gas exchange.During exercise, this drug lowers pulmonary hypertension,

but the effects of this lower pulmonary vascular tone onventilation-perfusion (V��/Q) relationships are still poorlyunderstood. To analyze them, we determined the VA/Q

&sfributions in eight patients with stable COPD (FEy1, 36

percent ofpredicted) at rest and during exercise (60 percent

Vo�max), before and after nifedipine (20 mg sublingually).Nifedipine shifted to the right the pulmonary pressure-flow

relationship (p<O.Ol) and increased the dispersion of theblood flow distribution at rest and during exercise(p<O.005). These observations strongly suggest that nifedi-pine released HPV under both conditions. However, evenafter releasing HPV by nifidipine, exercise distributed

blood flow more homogeneously than at rest (p<O.05).

Besides, exercise greatly decreased the overall degree ofi’A/Q mismatching (p<O.OOl) not only before but also afternifedipine. Thus, we postulate that most of the VA/Q

improvement that exercise may induce in patients withCOPD, as it is shown here, is due to improvement in theventilation distribution. Interestingly, this VA/Q improve-

I n patients with chronic obstructive pulmonary dis-

ease (COPD) studied at rest, nifedipine releases

hypoxic pulmonary vasoconstriction (HPV), diverts

blood flow to poorly ventilated lung units, and worsens

gas exchange.’ During exercise, release of HPV in

COPD by nifedipine blunts the increase in pulmonary

artery pressure (Ppa) and lowers the severity of

pulmonary hypertension.2”� However, the effects of

*Fmm the Departments of Medicine, Servei de Pneumologia,

Hospital Clinic, Universitat de Barcelona, Barcelona, Spain, andthe Section of Physiology, University ofCalifornia, San Diego, LaJolla, Calif.Supported in part by Grant CCA 8309185 from the Joint US-SpainCommittee, and CICYT PA 82-1787 and PA 86-0345.Presented in part at the American Thoracic Society Meeting, LasVegas, MayS-11, 1988.

tRecipient of a Postdoctoral Research Fellowship Award of theFondo de Investigaciones de Ia Segundad Social (FISss IIE/88),Spain.

tFormer Research Fellow, Universitat de Barcelona (FP1185).Manuscript received March 20; revision accepted July 13.Reprint requests: Dr. Rodriquez-RoLrin, Servel de Pneunwlogia,

Hospital Clinic, V’mllarroel 170, 08036 Barcelona, Spain

ment was not paralleled by a significant decrease ofP(A-a)02. This apparent paradox could be explained by 20

percent of the actual P(A-a)02 during exercise due to

diffusion limitation, as assessed through the inert gas

approach. Taken all together, these results help to better

understand the mechanisms that govern pulmonary gas cx-

change during exercise in COPD. (Chest 19%: 97:268-75)

this lower pulmonary vascular tone on ventilation-

perfusion (‘��A/Q) relationships under exercise condi-

tions are still poorly understood. This investigation

was aimed at analyzing the role of hypoxic vasocon-

striction in modulating pulmonary gas exchange dur-

ing exercise in COPD. We used the multiple inert gas

elimination technique5’6 to determine the VA/Q distri-

butions ofeight patients with COPD at rest and duringexercise, before and after releasing HPV by nifedi-

pine. We elected to include subjects with advanced

COPD but without overt clinical cor pulmonale on

the assumption that HPV might predominate in these

patients more than in those with end-stage vascular

disease, who presumably have more irreversible struc-

tural damage.7’8

Patients

M

Eight male patients (�± SEM, 62 ± 1 year) with the standard

clinical criteria ofCOPD and with previous functional confirmationof nonreversible chronic airflow limitation (FEy,, 1.15±0.12 L



CHEST I 97 I 2 I FEBRUARY, 1990 269

[36±3 percent predicted]) were selected from the outpatient clinic

ofour institution. None ofthem had clinical evidence ofovert right

heart failure. Type B COPD was present in five patients whereas

the three remaining patients had predominantly type A COPD.

Consent was Obtained after the purposes and risks ofthe investiga-

tion were explained and understood by each patient. All were

clinically stable (none had required hospitalization during the

previous two months) and none had evidence of renal, liver, or

intrinsic heart disease. None ofthem was receiving oxygen therapy

at home. Pulmonary function test (PFT) evaluation included meas-

urement ofstatic and dynamiclung volumes(HP.47804A PulmonarySystem Desk; Hewlett-P�kard, Palo Alto, Calif), plethysmographic

functional residual capacity and airway resistance (Body test, E.

Jaeger, Wurzburg, FRG), and single-breath carbon monoxide dif.fusing capacity (Deo) (Resparameter model A, PK Morgan Ltd.

Chatham, UK). The Dco values were corrected for hemoglobin.�

Predicted values for PET were from our own labory.b0h1

&ocedures

A transvenous balloon-tipped catheter (Swan-Ganz 7F, Edwards

Laboratories, Santa Ann, Calif) was placed into the pulmonary

artery under pressure wave monitoring (HP.78303 A), and a

polyethylene catheter (Seldicath, Plastimed, France) was inserted

in the radial artery. Cardiac output (Qr) was determined by the

thermodilution technique (9520A, Edwards Laboratories, Santa

Ana, Calif) Intravascular pressures were continuously monitored

(HP-7754 B) using HP1290 A transducers and were read at endexpiration over three respiratory cycles (the external zero reference

level was positioned at midchest). During exercise, the pronounced

pleural pressure swings made the measurement of pulmonary

capillary wedge pressure (Pw) difficult. Therefore, we elected to

report Pw only at rest andto calculate total pulmonary vascular

resistance (TPVR) as mean Ppa divided by Qr.� Right ventricular

stroke work index (RVSWI) was derived as ([Ppa-Pra].CI.0.0136)/

heart rate) (in g.m/rn2), where cardiac index (CI) was Qr (L.min’�

body surface area (rn’).1

Minute ventilation (VE) and respiratory rate (1) were recorded

minute by minute using a calibrated Wright spirometer. Low dead

space, low resistance, and nonrebreathing valves were used to

collect the expired gas through a heated-mixing box, either at rest

(No. 1500, Hans Rudolph, Kansas City Mo) or during exercise (E.

Jaeger, Wurzburg, FRG). Oxygen uptake (Vo,) and carbon dioxide

output (Vco,) were calculated from mixed expired fractions of 0,

and CO, (Multi-gas MS2, Medishield, Ohrneda..BOC UK), respec-

lively, and the respiratory quotient (R) as Vco,/Vo,. Po,, Pco,, and

pH were analyzed in duplicate (IL 1302 pH blood gas analyzer;

Instrumentation Laboratories, Milan, Italy). Hemoglobin concentra-lion was measured (OSM-2 Hemo-oximeter, Radiometer, Copen-

hag en, Denmark) and oxygen saturation was computed through

Kelman’s subroutines.’ Alveolar-arterial 0, pressure difference (PEA-

alO,) venous admixture (Qs/Qr), dead space-tidal volume ratio (VD/

VT, and systemic 0, delivery were calculated using standard

formulas.”

The �‘A/Q distributions were estimated by the multiple inert gas

elimination technique.” Particular features of its set-up in our

laboratory have been reported elsewhere.” Briefly, after infusing a

5 percent dextrose solution of six inert gases (SF,, ethane, cyclo-

propane, enflurane, ether, and acetone) through a peripheral vein

for about 30 minutes at a constant rate, duplicate samples of

heparinized arterial and mixed venous blood and mixed expired gas

were simultaneously withdrawn. Inert gas concentrations in mixed

expired samples and the gas phase of equilibrated arterial and

mixed venous samples were measured by gas chromatography

(Hewlett-Packard 5880A). Solubilities ofinert gases were measured

for each patient and the VA/Q distributions were estimated from

the inert gas data using a least-square fit to the data by a

multicompartmental model with enforced smoothing in the usual

manner.’3 %%�s defined shunt as � the percentage of Qr perfusing

essentially unventilated alyeoli (VAJQ <0.005), low and high VAJQ

regions as those with VAJQ ratios between 0.005 and 0.1, and 10

and 100, respectively, and dead space as the percentage of VE to

lung units with VA/Q ratios higher than 100. The latter includes the

anatomic dead space, unperfused alveoli, and instrument dead

space. The position ofthe pulmonary blood flow (Q) and ventilation

cy) distributions is described by the VA/Q ratio at their mean (Q,V, respectively), and their dispersion by their standard deviation

on a log scale (log,0 Q, I�#{176}�s�V). The inert gas results are also

reported as the dispersion directly obtained from retention (R)

minus excretion (E) (corrected for the acetone excretion, E*) of

each inert gas (DISP R-E�), which is an index ofthe overall amount

ofV��JQ mismatching.”

Protocol

The protocol was approved by the Hospital Clinic-Facultat de

Medicina Research Committee on Human Investigations. Patients

were allowed to continue taking their usual steroid regimen (if any),

but treatment with alloral or inhaled bronchodilators was withdrawn

24 hours before the study. Specifically, patients were not receiving

additional medication that could have either vasoactive or bron-

choactive effects. After the patient had fasted overnight and without

premedication, pulmonary and systemic arterial catheterization

were performed. Forty-five minutes after starting the inert gas

infusion, measurements of pulmonary and systemic hemodynamic

variables and respiratory and inert gas exchange parameters were

taken at rest. Then, exercise was begun on a cycle ergometer

(E. Jaeger) at a power output (33 ± 8 W) equivalent to 50 to 60

percent of their maximal tolerated work load (which had been

quantified on a previous day), and a second set of hemodynamic

and gas exchange measurements was obtained approximately ten

minutes later. The patients were allowed to rest for 15 to 30 minutes

until pulmonary and systemic hemodynamic variables and respira-

tory gas exchange parameters had returned to resting conditions.

Nifedipine (20 mg) was then given sublingually, and resting and

exercise measurements were repeated as before (at 45 minutes and

1 h after nifedipine, respectively). All measurements were taken in

a semirecumbent position. A steady state condition (as defined by

variations of less than ± 5 percent in heart rate and minute

ventilation and ofless than ±0. 1 percent in FEO2 and FECO,) was

monitored in each of the steps of the present protocol (rest andexercise with and without nifedipine) by continuously monitoring

electrocardiogram, minute ventilation, respiratory rate, and mixed

expired 02 and CO,. The hemodynamic measurements were

obtained before and after blood sampling for respiratory and inert

gas analysis. Given that there were no significant differences

between these two hemodynamic measurements, only values oh-

tamed after blood sampling are reported.

Safety Measures

Our primary concern at all times during the study was the safety

of the patient. Consequently, improvement in monitoring proce-

dures included a continuous graphic recording of systemic and

pulmonary arterial pressures as well as continuous electrocardio-

graphic (HP.7830A) and ear oximetry (Biox II; Ohmeda-BOC, UK)

monitoring. Patients were instructed to stop exercise should unusual

symptoms (other than discomfort) develop, but none of them did.

Three physicians were present at all times, with one directing his

attention exclusively to the patient.

Statistical Analysis

An analysis ofvariance for repeated measures (MANOVA, SPSS)

was used to compare measurements at rest and during exercise,

before and after nifedipine. Interaction between exercise and

nifedipine was specifically checked. Linear regression was usedwhen appropriate. Comparison of the regression lines was done by



Patient Age, Height, V�ight, ‘

FEY

. FEY Ratio, ‘- UC� �‘ -�

BY

- - RV!I’LC,

Dco

-

No. y Cal kg L percent pred percent FYC L percent pred L percent pred percent mL/mia/mm Hg percent pred

1 67 161 72 0.98 35 34 7.13 106 4.14 139 58 24.46 105

2 64 175 94 1,54 43 39 7.11 88 3.12 94 44 17.42 61

3 57 171 82 119 34 35 7.78 103 4.35 147 56 19.46 69

4 58 172 87 1,33 38 48 8.87 117 5.99 �l 68 23.05 81

5 65 164 73 0,53 18 24 9.38 135 7.17 239 76 14.30 58

6 61 170 80 1.17 35 39 7.37 98 4.19 137 57 18.46 67

7 64 158 55 0.89 33 34 6.39 100 3.77 134 59 19.94 87

8 59 162 70 1.57 52 56 7.45 112 4.51 165 61 24.55 97

i±SEM 62±1 167±2 77±4 1.15±012 36±3 39±3 7.69±0.35 108±5 4.66±0.46 157±16 60±3 20.21±1.28 78±6

FEY indicates forced expiratory volumeduringthe first seurnd; FEY, ratio: FEY,/forced vital capacity �6o;TLC,totallungcapuity; BY, residual volume; � single breath codiffusing

Table 1-General Data and Lwsg FUnCtIOn Results

270 Vasoconstriction and Gas Exchange during Exercise (Agust! et at)

one-way analysis of covariance. Probability values lower than 0.05

were considered significant in all cases. . Results are expressed as

mean±SEM.

RESULTS

Airflow obstruction was severe in all but patient 8,

and all but one subject (patient 2) showed marked air

trapping (Table 1). Hyperinflation was noticed only in

patient 5. The Deo was reduced in four subjects

(patients 2, 3, 5, and 6) (Table 1). Table 2 provides the

metabolic, hemodynamic, and gas exchange data at

rest and during exercise, before and after nifedipine.

Nifedipine was well tolerated by all the patients and

did not produce any symptomatic adverse side effect.

Rest Before N(fedipine

Oxygen uptake, heart rate, and (�r were normal.

Mean pulmonary artery pressure (Ppa) was slightly

increased (19 ± 1 mm Hg; range, 14 to 25 mm Hg)

but right ventricular stroke work index (RVSWI,

Table 2-Metabolic, HemOdywimiC, and Gas Exchange Data�

Before Nifedipine After Nifedipine

Rest p Value ExerciseRest p Value Exercise

Vo,,ml/min 259±20 0.001 872±94 269±15 0.001 843±57

R 0.81±0.02 . . . 0.80±0.03 0.82±0.02 . . . 0.80±0.03

Hr. min’ 75±4 0.001 106±6 83±6” 0.001 116±5’

QT, lJmin 5.4±0.3 0.001 10.6±0.8 6.8±0.5’ 0.001 12.2±0.9c

C,, Iimin/m2 2.9±0.1 0.001 5.8±0.3 3.7±0.2’ 0.001 6.6±0.3c

Ppa,mmHg 19±1 0.001 44±3 19±2 0.001 36±P

TPVR, mm HgfLJmin 3.6±0.3 0.01 4.2±0.3 2.8±0.2d 0.01 3.1±0.2’�

Ps,mmHg 106±4 0.001 135±10 88±5’ 0.001 116±6c

VE, Lfmin 9.4±0.7 0.001 24.2±2.8 10.4±0.7’ 0.001 25.9±2.4”

f,min’ 19±2 0.001 29±2 20±2 0.001 29±2

PaO,mmllg 76±2 . . . 68±4 71±3 . . . 66±4

PaCO,,mmHg 39±2 0.001 43±2 37±2’ 0.001 42±2”

pH 7.46±0.02 0.001 7.36±0.02 7.41±0.02� 0.001 7.36±0.02A

BE, mmolJL -0.3±0.7 0.001 -2.8±0.8 -1±0.6 0.001 -2.5±0.6

P�O,,mmHg 38±2 0.001 30±1 39±1 0.001 31±1

P(A-a)O. 28± 2 . . . 31 ±3 36± 1’ . , . 34 �3A

VD/VT,% 50±2 0.001 42±2 47±3 . . . 47±3’Shunt, % 0.6±0.3 . . . 0.5±0.3 0.7±0.4 ‘ ‘ ‘ 0.5±0.3

LowV��JQ,%

HighVA/Q, %

0.8±0.4

5.8±3.0

. . .

. . .

0.8±0.4

3.7±2.2

2.5±1.5

6.1±3.5

. ‘ ‘

. . .

2.7±1.5

6.2±2.5

Dead Space, % 29.2±2.9 . . . 29.1±3.5 28.2±3.2 . . . 28.5±2.9

0.79±0.06 0.005 1.18±0.12 0.64±004” 0.005 1.07±0.10’

Log,0 Q 0.90±0.06 0.05 0.78±0.07 1.08±0.08W 0.05 1.00±0.10’�

V 2.14±0.27 . . . 2.23±0.27 2.22±0.28’ ‘ ‘ . 2.60±0.29”

b�0V 1.03±0.11 0.001 0.83±0.09 1.06±0.09 0.001 0.92±0.09

DISP R.E* 12.1 ± 1.0 0.001 7.9±0.9 15.2± 1.3d 0.001 10.9± 1.1’�

For abbreviations, see text; p values relate to the significance of exercise-induced changes, while letters (a/A <0.05 b/B <0.01; c/C <0.005;

d/D <0.001) denote statistical significance of differences between before and after nifedipine; lower case letters, resting measurements;

capital letters, exercise measurements.*Values are �±SEM.



BEFORE N.

EXERCISE

0z4

0

z

0

-J

zU>

0 01 1 10100 0 0.1 1 XHOO

a’IEEa

IQ.

50

40

30

20

10

0

I- �,2E -�

�

ib

OT, L/min

FIGURE 2. Mean values (� ±SEM) of cardiac output (Qr) and mean

pulmonary artery pressure (Ppa) at rest (bottom) and during exercise(top), before (continuous line) and after nifedipine (dashed line).

The pressure-flow relationship shifted to the right after nifedipine(p<O.Ol), indicating an active vasodilatory effect of the drug.


AFTER N.

C

E

0-J

000-j

REST

VENTILATION- PERFUSION RATIO

FIGURE 1 . Recovered �A/Q distributions in a representative subject (patient 1), From left to right and from

top to b()ttofl: rest and exercise before nifedipine, and rest and exercise after nifedipine. Closed circles

correspond to the distribution of pulmonary blood flow; open circles, the distribution of ventilation,

8.2 ± 0.5 gm/m2) was within normal �5 Capillary

wedge pressure was normal (4 ± 1 mm Hg). Gas

exchange was mildly impaired with some degree of

arterial hypoxemia (range, 67 to 83 mm Hg) and mild

increases in both the P(A-a)o2 (Table 2) and the

percentage of venous admixture (Qs/Qr, 10 ± 1 per-

cent). None of the patients had CO2 retention, but all

had VDNT values higher than 40 percent. The inert

gas data showed only small amounts of shunt and/or

blood flow to lung units with �TA/Q ratios lower than

0. 1 (less than 1 percent of Qr, each) (Table 2). Seven

of the eight patients showed a broad unimodal blood

flow distribution without shunt (Fig 1); patient 7

showed a bimodal blood flow distribution. Only patient

5 had a noticeable amount of shunt (2.6 percent of

Q’r). Four patients (patients 1, 3, 5, and 7) had bimodal

ventilation distributions with a substantial percentage

of�E distributed to high VA/Q areas (10 to 100) (Table

2 and Fig 1). The dispersion of the blood flow and

ventilation distributions (Log,�0 Q and Logs,) V, re-

spectively) (normal range, 0.3 to 0.6) and the overall

amount of �TA/Q mismatching estimated from raw

retention and excretion values (DISP R�E*) were

moderate to severely increased with respect to nor-

mal. ‘�

Rest After Nifedipine (vs Rest Before Nifedipine)

Neither i�pa nor i�w (4 ± 1 to 3 ± 1 mm Hg) changed

but Qr increased (Table 2). Consequently, TPVR fell.

Besides, for a given flow Ppa was always lower after

nifedipine (Fig 2). The RVSWI did not change

(8.2 ± 0.5 to 9. 1 ± 1 .2 g’m/m2). As previously reported,3

VE increased slightly (9.4 to 10.4 L.min ‘) but signif-

icantly (p’(O.05) after nifedipine. As a result, PaCO2

fell and arterial pH rose. The VD/VT did not change

(Table 2). Oxygen exchange worsened: Pa02 showed a

trend to be lower (76 to 71 mm Hg, p = 0.06),

P(A-a)o2 was larger (28 to 36 mm Hg, p<O.O5), and



12 -10

08 -

C

0

-I

06

04

60

0.2 -

I-50 >

‘ I � I � � � � �

0 200 400 600 800 1000

40

272 Vasoconstriction and Gas Exchange during Exercise (Agusti et a!)

QS/QT was higher (10 ± 1 to 15 ± 2 percent, p<O.O5).

Because of the above-mentioned increase in Qr O�

delivery improved (992 ± 85 to 1 ,228 ± 97 ml’min � I,

P<O.005). Ventilation-perfusion mismatching in-creased after nifedipine (higher DISP R�E*, p<0.O0l)

(Table 2). Specifically, the blood flow distribution

shifted toward a lower VA/Q ratio (Q decreased,p�zzO.0l) and l)ecaflle wider (Logs,) Q increased,

p<O.005) (Table 2). A separate low ‘�AJQ mode of

blood flow appeared in five subjects (patients 1, 2, 4,

6, and 8) (Fig 1). These changes are in keeping with

�)reviot�s results and strongly suggest release of HPV.’Despite the increase observed in the dispersion of the

ventilation, distribution (Logs,) V) was not modified

l)y nifedipine. However, this increase in �TE probably

exI)laiflS the significantly higher V observed at rest

after giving the drug (Table 2).

Exercise Befiwe Nifedipine (vs Rest Before Nifedipine)

Exercise Vo: (872 mI/mm) averaged 53 ± 5 percent

of maximal predicted . “ This represented a substantial

level of exercise for these patients, as it is shown bythe significant decrease in arterial pH and base excess

(BE) (Table 2). During exercise, pulmonary hyperten-

slim became severe and both TPVR (Table 2) and

RVSWI increased (8.2 ± 0.5 to 23.0 ± 1 .7 gm/m,

P<O.O�)l). Even though PaO� showed a trend to fall(76 to 68 ,i�ni Hg, p = 0.07), because PaCO2 increased

simultaneously (39 to 43 nim Hg, p<O.OOl), P(A-a)02

did flot change (28 to 31 mm Hg). The VDNT fell from

50 to 42 iercent (p<O.OOl). Exercise reduced ‘�A/Q

mismatching as estimated either by the significant

decreases in Logs,) Q and Logs,) V or DISP R�E*

(Table 2 and Fig 1 and3). The � shifted toward higher

values (p<O.005) but V did not change.

Arterial Po2 was computed from the recovered �/

Q distributions6 to predict the PaO2 expected on the

l)asis of ‘$;�A/Q mismatch alone (“predicted Pa02”). In

this manner, diffusion limitation of O� transfer from

alveoli to the end-capillary blood is evident as a

systematically higher predicted than measured PaO2.6

At rest, fl() significant difference was noticed between

predicted and measured Pa02. However, during ex-

ercise, predicted Po2 (74 ± 5 mm Hg) was systemati-

cally higher than measured Pa02 (68 ± 4 mm Hg,

p<O.002). In absolute terms, this difference was small

(6 ± 1 mm Hg) and accounted for 20 percent of the

actual P(A-a)02. This observation suggests that pul-

monary 02 transfer was partially diffusion limited in

these patients with COPD during exercise.

Exercise After Nifedipine (vs Rest After Nifedipine)

The behavior of most of the hemodynamic and gas

exchange variables during exercise after nifedipinewas similar to that seen during exercise before giving

the drug (Table 2). However, the VDNT ratio showed

a different response to exercise depending on th�

presence or absence of nifedipine: as expected,

VIIVT fell significantly during exercise before nifedi-

pine, but it did not change after giving the drug (Table

2 and Fig 3). Finally, it is of note that predicted and

measured PaO� values during exercise after nifedipine

Oxygen Uptake,mI/minFIctIIF: 3. Mean ( ± SEM) values of oxygen uptake plotted against the (lispersioll of the blood flow

(listriln,tion (L()g�,) Q) (left panel) and the dead space/tidal volume ratio (V1/VT) (rig/it ;xinel) at rest and

(l1,nng exercise, before (c�ontinnou,s line) and after nifedipine (dashed line). Stars denote significance (for

exact p val,,,’, see Table 2). The shaded area corresponds to the expected limits of r�ormalit)� Left panel:

Note that, after nifedipine, the dispersion ofthe blood flow distribution increased, both at rest and duringexercise. lh)wever, irrespective of nifedipine, exercise (higher � uptake) distributed blood flow ITh)�C

homogeneously (lower L4)g�,, Q). Rig/it paru’l: Befre nifedipine, the VoATT ratio decreased with exercise

as expected. however, after nifedipine, this ratio did not change with exercise. As a result, Vo/VT was

higher (luring exercise, after than before nifedipine. For further explanatiotis, see text.




fell along the same direction as during exercise before

nifedipine, but differences just failed to reach statis-

tical significance (70 ± 4 vs 66 ± 4 mm Hg, respectively

{p=O.09]).

Exercise After Nzfedipine (vs Exercise Before

Nifedipine

Oxygen uptake during exercise was similar before

and after nifedipine, but Qr increased following it

(p<0.005) (Table 2). Moreover, during exercise, Ppa,

TPVR (Table 2), and RVSWI (20.3± 1.6 gm/m2,

p<O.05) were all lower after nifedipine. The pulmo-

nary pressure-flow relationship was displaced toward

higher flows in each patient (Fig 2). Although Pao2

during exercise was similar irrespective of the drug,

P(A-a)02 was higher after nifedipine because the

higher VE lowered PaCO2 (Table 2). Oxygen delivery

was increased during exercise after nifedipine

(2, 182 ± 187 vs 1 ,931 ± 159 mI/mm, p<O.002). Inter-

estingly, since VD/VT did not change during exercise

with nifedipine, it was higher after than before giving

the drug (Table 2). Accordingly, the percentage of

ventilation distributed to high ‘1A/Q areas (10 to 100)

increased almost twofold during exercise after nifedi-

pine (3.7 to 6.2 percent), but differences failed to

reach statistical significance. Overall, there was more

�;‘A/Q mismatching during exercise after than before

nifedipine (higher DISP R�E*, p<O.00l). The perfu-

sion distribution was shifted to the left (lower Q) and

the ventilation distribution was shifted to the right

(higher V) (Table 2). The higher Log�� Q during

exercise after nifedipine probably reflects release of

HPV and subsequent interference with the ability of

the pulmonary circulation to distribute blood flow

during exercise in a more efficient manner (Fig 3).

The dispersion of the ventilation distribution (Log�1)

V) during exercise was not modified by nifedipine

(Table 2).

A synergistic effect between exercise and nifedipine

could be demonstrated only for VD/VT. The physio-

logic significance of this interaction has already been

discussed above.

DIScUSSIoN

Our study documents that exercise can improve

‘s;�AJQ mismatching in COPD. In addition, it confirms

that nifedipine releases HPV in these patients’ and

lowers right ventricular afterload during exercise.24

To our knowledge, however, no previous information

regarding the role of HPV in modulating gas exchange

during exercise in COPD has yet been raised. Our

results show that the release of HPV induced by

nifedipine clearly interferes with the ability of the

pulmonary circulation to distribute blood flow more

efficiently both at rest and during exercise (Fig 3).

However, the latter has a small functional effect since,

even after nifedipine, exercise reduced the overall

amount of ‘:I�A/Q mismatch. This observation suggests

that the role of HPV in modulating gas exchange

during exercise in COPD is probably minor, and that

most of the ‘/A/Q improvement seen under these

conditions is due to improvement in the ventilation

distribution. To clarify the more relevant aspects of

this investigation, the effects of exercise on gas ex-

change at baseline (before nifedipine) and the role of

HPV in modulating gas exchange during exercise will

be discussed separately.

Effects ofExercise on Gas Exchange at Baseline

(Before Nifedipine)

It has been well established that in patients with

COPD PaO2 might increase, decrease, or remain

unchanged during �7�18 However, there is still

a question regarding the effects of exercise on VA/Q

maldistribution in COPD.’� Wagner et alh7,18 and

Dantzker and D’Alonzo� used the multiple inert gas

elimination technique to study patients with COPD

during exercise. Even though ‘$�A/Q inequality did not

change with exercise, PaO2 � This apparent

discrepancy was explained by (1) a rise in PaCO2 and(2) the effect of a lower NO2 on the end-capillary Po2

oflow VAQ units and shunt.’7”8’� A subsequent study

by Minh et al’s disputed these conclusions. By com-

paring patients with COPD who improved Pa02 with

those who showed a fall in arterial oxygenation with

exercise, these authors concluded that the role of P�O2

in modulating such response was minimal, and that

the increase in Pa02 with exercise was highly depend-

ent on the reduction of Qi’’9 However, since the

latter investigation used conventional gas exchange

measurements, the authors could not separate the

precise role of VA/Q mismatching, shunt, and 02

diffusion limitation as potential causes of hypoxemia.

To our knowledge, our study is the first one to

specifically demonstrate that �‘A/Q mismatching can

improve during exercise in COPD. This is shown by

the lower Log�� Q (Fig 1 and 3), Log8,) V, and DISP

R�E* (Table 2).

It is tempting to speculate that differences from

previous studies’7”8’� are related to the severity of

COPD. For instance, both Minh et al’s and Raffestin

et al2’ reported that those patients with COPD who

developed exertional hypoxemia have a lower FEy,

than those who did not. Further, the recent report by

Dantzker and D’Alonzo� showing no change in the

‘;;�A/Q distributions with exercise included patients

with much more severe airway obstruction than ours

(FEy,, 0.56 [in Dantzker and D’Alonzo�9 vs 1.5 L [in

our patients]) together with more CO2 retention at

rest (56 vs 39 mm Hg, respectively). Thus, we suggest

that the less advanced disease of our patients enabled

them to hyperventilate during exercise more than



274 Vasoconstriction and Gas Exchange during Exercise (Agusti et a!)

those whose cases were reported by Dantzker and

D’Alonzo,� reducing but not preventing the increase

in PaCO2 and shifting Q toward higher values. This

higher Q would then minimize the impact ofa lowered

P�O2 on the end-capillary blood of those units with

very low ‘�‘A/�:! ratio’7”8’� which, on the other hand,

would have been reduced by exercise itself (Table 2).

In summary, we postulate that the less severe lung

structural derangement of our patients may have

facilitated a more homogeneous distribution during

exercise of both the alveolar ventilation (lower Log�0

V) and the pulmonary blood flow (lower LOgSD Q).During exercise, P(A-a)O2 did not change (Table 2).

At first glance, this suggests that exercise did not

modify the efficiency of the lung as a gas exchanger.

However, as it has been already pointed out, the inert

gas elimination technique showed that the �A/Q

distributions definitely improved during exercise. The

apparent paradox of a better “A/Q matching without

any noticeable change in P(A-a)02 is explained by 20

percent of the P(A-a)O2 due to diffusion limitation, assuggested by the higher predicted than measured

PaO2 during exercise (p<O.002).6 This would then limit

the expected increase in PaO2 due to the improvement

in �A/Q mismatching. This unexpected finding is at

variance with previous po7’8’� In our laboratory,

the accuracy of Po2 and Pco2 electrodes is checked

daily with tonometered blood, and reported Po2

values are systematically corrected for body

temperature6 which, in the present study, was obtained

through the thermistor of the Swan-Ganz catheter.

Using the same methodology, this difference was not

seen at rest. Moreover, during exercise after nifedipine

(1 h after the first exercise measurements were taken),

we observed a similar trend (p 0.09). Thus, under

these circumstances, a technical error seems most

unlikely. We lack a precise explanation for this finding,

but we would suggest that the higher exercise �#{176}2 of

our patients, compared with former reports,’7”8’� may

well clarify it. Clearly, further studies are needed to

confirm and explain this observation.

Role ofHPV During Exercise

At rest, nifedipine diverted blood flow to poorly

ventilated lung units (Fig 1 and 3). This observation

strongly suggests release of HPV and is in keeping

with previous reports in COPD.’ After releasing HPV,

the increase in Ppa seen during exercise was blunted

and the severity of pulmonary hypertension was

lowered (Fig 2), again in accordance with former

investigations.2� To our knowledge, however, the ef-

fects of this lowered vascular tone on the adaptation

of ‘/A/Q mismatching to exercise in COPD have not

been previously investigated. Our results show that

the dispersion of the blood flow distribution (Log��

Q) was always higher after than before nifedipine,

either at rest or during exercise (Table 2 and Fig 3).

Moreover, in contrast to before nifedipine conditions,

the VDNT ratio did not fall with exercise after nifedi-

pine (Table 2). As a result, VD/VT during exercise was

higher after than before nifedipine (Fig 3). The reason

for this latter finding is not evident but a possible

explanation is as follows. Nifedipine theoretically ex-

erts its maximal vascular effect on those lung units

with more alveolar hypoxia.� Therefore, it could be

expected that during exercise after nifedipine, hypoxic

areas would receive more blood flow than those units

with normal and high �iA/Q ratios, making the latter

less well perfused and, as a result, increasing their

‘;/A/Q ratio. Taken together, these two observations

(higher ‘-‘#{176}�SD Q� no change in VD/VT with exercise

after nifedipine) indicate that the release of HPV

induced by nifedipine certainly interferes with the

ability of the pulmonary circulation to efficiently

control the distribution ofblood flow during exercise.

However, it also appears from our results that this has

a small effect in modulating the gas exchange response

to exercise in COPD. Note that the overall amount of

�;�AJQ mismatching (DISP R�E*) improved with exer-

cise even after the release of HPV induced by nifedi-

pine (Table 2). Graphically, this is shown by the virtual

disappearance ofthe low ‘�A/Q mode in the blood flow

distribution in all of the patients in whom it had

appeared at reast after nifedipine (Fig 1). Moreover,

since exercise lowered the dispersion ofthe blood flow

distribution (Lo�D Q) irrespective of nifedipine (ie,

with or without modifying the pulmonary vascular

tone) (Fig 3), we suggest that most of the ‘IAJQ

improvement seen during exercise is due to improve-

ment of the ventilation distribution.

For example, the increase in the end-inspiratory

volume that follows exercise may have facilitated a

better ventilation of airways that were partially closed

at rest. We cannot exclude that nifedipine has some

effect on the bronchomotor tone. However, given that

nifedipine has no bronchodilator effect at rest in

asthmatic patients,� we consider unlikely that it may

have had any effect in our patients who have irreversi-

ble airflow limitation. Alternatively, nifedipine might

have theoretically prevented the development of some

bronchoconstnction induced by exercise. However we

found that, before nifedipine, exercise improved

�;�A/Q inequality an observation that is at variance with

the hypothesis of exercise-induced bronchoconstric-

tion. Further, during exercise after nifedipine we

showed more �TA/Q mismatch than before nifedipine.

If we speculate that nifedipine really has either a

bronchodilator or a protective effect on the bronchial

tone, then it would be conceivable to observe a better

VA/Q matching after its administration, which was not

shown. In summary, it seems highly unlikely that

nifedipine had any effect on the bronchomotor tone




in our patients. On the other hand, the potential

effects of the slight changes in CO2 during exercise on

bronchomotor or vascular tone, although presumably

negligible, cannot be quantified be design.

To summarize, our study shows that exercise can

improve ‘c�A/Q mismatching in COPD, although the

type ofresponse (ie, improvement or no change in the

VA/Q maldistribution) is probably related to the sever-

ity of COPD. Further, it suggests that most of this

improvement depends on a more homogeneous distri-

bution of the inspired ventilation and that hypoxic

pulmonary vasoconstriction probably plays a minor

role in the modulation ofsuch response. Nevertheless,

our results also demonstrate that the release of hypoxic

pulmonary vasoconstriction by nifedipine interferes

with the ability of the pulmonary circulation to dis-

tribute blood flow more efficiently and worsens pul-monary gas exchange, not only at rest but also during

exercise. Finally, this investigation highlights a limi-

tation in the diffusion of 02 from the alveoli to the

end-capillary blood during exercise of COPD. Un-

doubtedly, this observation requires further investi-

gation. Taken all together, these results help to better

understand the mechanisms that govern pulmonary

gas exchange during exercise in COPD.

ACKNOWLEDGMENTS: The authors thank C. Gistau for herchromatographic work; F.A. Lopez, F. Burgos, T Lecha, M. Simo,and C. Arga#{241}a for their skillful technical assistance; A. Cobos(Department ofStatistics, University ofBarcelona) for his statisticaladvice; and the Medical Staff of our Service for their cooperationand care of the patients.

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DOI 10.1378/chest.97.2.268 1990;97; 268-275Chest

A G Agustí, J A Barberá, J Roca, P D Wagner, R Guitart and R Rodriguez-Roisínchronic obstructive pulmonary disease.

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