Hypoxic Pulmonary Vasoconstriction and Gas Exchange During Exercise in Chronic Obstructive Pulmonary Disease

Hypoxic Pulmonary Vasoconstriction and Gas Exchange During Exercise in Chronic Obstructive Pulmonary Disease* Alvar G. N. Agusti, M.D.; joan A. Barbera,• M.D.;t ]osep Roca, M.D.; Peter D. Wagner; M.D.; Raiman Guitart, Ph.D.;t. and Robert Rodriguez-Roisfn, M.D.

In patients with chronic obstructive pulmonary disease (COPD) studied at rest, oifedipine releases hypoxic pulmonary vasoconstriction (HPV) and worsens gas exchange. During exercise, this drug lowers pulmonary hypertension, but the effects of this lower pulmonary vascular tone on ventilation-perfusion (VAIQ) relationships are still poorly understood. To analyze them, we determined the VAIQ distributions in eight patients with stable COPD (FEV., 36 percent of predicted) at rest and during exercise (60 percent Vo.max), before and after nifedipine (20 mg sublingually). Nifedipine shifted to the right the pulmonary pressure-Sow relationship (p
I"ease patients with chronic obstructive pulmonary dis(COPD) studied at rest, nifedipine releases hypoxic pulmonary vasoconstriction (HPV), diverts blood Row to poorly ventilated lung units, and worsens gas exchange. 1 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

*From the Departments of Medicine, Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain, and the Section of Physiology, University of California, San Diego, La Jolla, Calif. Supported in part by Grant CCA 8309185 from the Joint US-Spain Committee, and CICYT PA 82-1787 and PA 86-0345. Presented in part at the American Thoracic Society Meeting, Las Vegas, May 8-11, 1988. tRecipient of a Postdoctoral Research Fellowship Award of the Fondo de Investigaciones de Ia Seguridad Social (FISss IIE/88), Spain. 1;Former Research Fellow, Universitat de Barcelona (FPIJ85). Manuscript received March 20; revision accepted July 13. Reprint requeats: Dr. Rodriquez-Roisin, Seroei de Pneurrwlogia, Hospital Clinic, Villarroell70, 08036 Barcelona. Spain

268

ment was not paralleled by a signi&cant decrease of P(A-a)01 • This apparent paradox could be explained by 20 percent of the actual P(A-a)O. 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 exchange during exercise in COPD. (Chat 1990: 97:268-75) HPV =hypoxic pulmonary vasoconstriction; VAIQ relationsbip=ventilation-perfusion relatipnships; shunt (inert~)=: percent ofQr.to lung units with VAf.Q tatios <0.005; low VAIQ =percent ol.Qr.to lung units ~th VAIQ ratios <0.1.(exelucliog shunt); bigh VAIQ =percent ofVE to Jung units with VAIQ I'JIIQ 10 to 100; ~ sppce:=percent of VE to lung units witli VAIQ ratios >100;..Q=VAIQ ratio at the mean Of the blood 8oW distribution; V =ratio at the mean of the ventilation distn'bution; Logso Q=dispersion (SD) of the blood flow distribution on a log scafe; Logso V=dispersion (SD) of the ventilation cJisttibution on a lOg seale; DISP R-E•=overall degree of VAIQ _mismatching clirectly obtained from the raw inert gas data; Ppa= pulmonary artery pressure; PFf=~ fun~ tion test;~= carbon monoxide diffusing capacity; Q,., canliac output; Pw = J?Uimonary capillary wedge pressure; TPVR =total pulmonary vascul&r resistance; RVSWI =right ventricular strqke. work index; f= respiratory rate; R =respiratory; Qs/QT =venous admixture; VoNT =dead space tidal volume ratio; BE= base excess

this lower pulmonary vascular tone on ventilationperfusion (VAIQ) relationships under exercise conditions are still poorly understood. This investigation was aimed at analyzing the role of hypoxic vasoconstriction in modulating pulmonary gas exchange during exercise in COPD. We used the multiple inert gas elimination technique5·6 to determine the VAIQ distributions of eight patients with COPD at rest and during exercise, before and after releasing HPV by nifedipine. 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 structural damage. 7 •8 METHODS

lbtients Eight male patients (x ± SEM, 62 ± 1 year) with the standard clinical criteria of COPD and with previous functional confirmation of nonreversible chronic airflow limitation (FEV,. 1.15±0.12 L VUOCOII8Irictlol • and Gas Exchange during Exllld8e (AQusfl et el)

[36±3 percent predicted]) were selected from the outpatient clinic institution. None ~them bad clinical evidence ~overt right heart failure. Type B COPD was present in 6ve patients whereas the three remaining patients bad predominantly type A COPD. Consent was obtained after the purposes and risks of the investigation were explained and understood by each patient. All were clinically stable (none bad required hospitalization during the previous two months) and none bad evidence of renal, liver, or intrinsic heart disease. None of them was receiving oxygen therapy at home. Pulmonary function test (PFI') evaluation included measurement~ static and dynamic lung volumes (H11.47804A Pulmonary System Desk; Hewlett-Pacbrd, Palo Alto, Calif), plethysmographic functional residual capacity and airway resistance (Body test, E. Jaeger, Wflrzburg, FRG). and single-breath carbon monoxide diffusing capacity (Dco) (Hesparameter model A, PK Morgan Ltd, Chatham, UK). The Dco values were corrected for hemoglobin.• Predicted values for PFI' were from our own laboratory.•u• ~our

Proceduru A transvenous balloon-tipped catheter (Swan-Ganz 7F, Edwards Laboratories, Santa Ana, 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 (95mA, Edwards Laboratories, Santa Ana, Calif). Intravascular pressures were continuously monitored (HP-7754 B) using HP-1290 A transducers and were read at end expiration over three respiratory cycles (the external zero reference level was positioned at midchest~ During esercise, the pronounced pleural pressure swings made the measurement of pulmonary capillary wedge pressure (Pw) difficult. Therefore, we elected to report Pw only at rest and to calculate total pulmonary vascular resistance (TPVR) as mean Ppa divided by Qr.• Right ventricular stroke work index (RVSWI) was derived as ([Ppa-PraJ.CI.0.0136)/ heart rate) (in g.mlm"), where cardiac index (CI) was Qr (L.min -•)1 body surface area (m"). 1 Minute ventilation eVE) and respiratory rate (f) 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, Wflrzburg, FRG~ Oxygen uptake (Vo.) and carbon dioxide output (Yeo.) were calculated from mixed expired fractions of 0 1 and C01 (Multi-gas MS2, Medixhield, Ohmeda-BOC UK), respectively, and the respiratory quotient (R) as Vco,/Vo1 • Po1 , Pco1 , and pH were analyzed in duplicate (IL 1302 pH blood gas analyzer; Instrumentation Laboratories, Milan, Italy). Hemoglobin concentration was measured (OSM-2 Hemo-oximeter, Radiometer, Copenhagen, Denmark) and oxygen saturation was computed through Kelman'S subroutines.• AlveolaJ'.arterial 0 1 pressure difference (P[Aa]O.) venous admixture (QstQr), dead space-tidal volume ratio {Vol VT, and systemic 0 1 delivery were calculated using standard

formulas. II

The VAJQ distributions were estimated by the multiple inert gas elimination technique. •.o Particular features of its set-up in our laboratory have been reported elsewhere. 11 Briefly, after infusing a 5 percent dextrose solution of six inert gases (SF,, ethane, cyclopropane, 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-Pacbrd 5880A). Solubilities of inert gases were measured for each patient and the VAJQ 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. 13 \'\\! defined shunt as. tht! percentage of Qr pe~sintt essentially unventilated alveoli (VAIQ <0.005), low and high VAIQ 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 VAJQ ratios higher than 100. The latter includes the anatomic dead space, unperfused alveoli, and instrument dead space. The position of the pulmonary blood flow (Q) and ventilation M distributions is described by the VAJQ ratio at their mean (Q, V, respectively), and their dispersion by their standard deviation on a log scale (log. 0 Q, Log. 0 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 of the overall amount of VAIQ 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 all oral or inhaled bronchodilators was withdrawn 24 hours before the study. Specifically, patients were not receiving additional medication that could have either vasoactive or bronchoactive 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 respiratory 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 FE02 and FECO.) was monitored in each of the steps of the present protocol (rest and exercise with and without nifedipine) by continuously monitoring electrocardiogram, minute ventilation, respiratory rate, and mixed expired 0 2 and C01 • 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 obtained 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 procedures included a continuous graphic recording of systemic and pulmonary arterial pressures as well as continuous electrocardiographic (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 of variance 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 used when appropriate. Comparison of the regression lines was done by CHEST I 97 I 2 I FEBRUARY, 1990

-

Table 1-GenertJIIJGIG and Lung Function Heault. FEV, Age, y

em

kg

L

1 2 3 4 5 6 7 8

fiT 64

161 175 171 172 164 170 158 162 lfi1:!:2

72 94 82 Iff 73 IKI 55 70 77:!:4

0.98 1.54 1.19 1.33 0.53 1.17 0.89 l.Sl 1.15:!:0.12

1U 58 65 61 64 59 i±SEM 62:!:1

11£

RV

Dco

FEV, Ratio,

Patient No.

Height, \\\light,

RVm..c,

percent pred percentFVC 35 43 34 38 18 35 33 52 36:!:3 39:!:3

34 39 35 48 24 39 34 56

L

percent pred

L

percent pred percent

7.13 7.11 7.78 8.1fl 9.38 7.37 6.39 7.45 7.69:!:0.35

106 88 103 117 135 98 100 112 108:!:5

4.14 3.12 4.35 5.99 7.17 4.19 3.77 4.51 4.66:!:0.46

139 94 147 001 239 137 134 165 1ST± 16

mVmiolmmHg percent pred

58 44 56 68 76 1U 59 61 60:!:3

24.46 17.42 19.46 tl.ai 14.30 18.46 19.94 24.55 00.21:!:1.28

105 61 69 81 58 fiT Iff 'It 78:!:6

FEV, indicates IOrced expiratory wlume during the 6nt second; FEV, ratio: FEV,Jrorced vital capacity ratio; 11£, tolallung capacity; RY, residual wlume; DI.,, single breath co di8Using capacity.

one-way analysis of covariance. Probability values lower than 0.05 were considered significant in all cases. .Results are expressed as meon±SEM. RESULTS

Airftow obstruction was severe in all but patient 8, and all but one subject (patient 2) showed marked air trapping ('Iable 1). Hyperinftation was noticed only in patient 5. The Dco was reduced in four subjects (patients 2, 3, 5, and 6) ('Iable 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 Nifedipine Oxygen uptake, heart rate, and Qr 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 !-Metabolic, Hemodynamic, and Gas &change IJGIG* Before Nifedipine

Vo1 , mllmin R J:lr, min-• Qr, Umin C1, Umin!m• Ppa, mm Hg TPVR, mm Hglllmin Ps, mm Hg VE, Umin f, min-• Pa01 mm Hg PaC01 , mmHg pH BE, mmol!L PV01 , mm Hg P(A-a)O, Vo/VT,% Shunt,% LowV_AIQ.% High VAIQ,% Dead Space, %

Q

Log.DQ

v

Log.D v DISPR-E*

Rest

p Value

259±20 0.81±0.02 75±4 5.4±0.3 2.9±0.1 19±1 3.6±0.3 106±4 9.4±0.7 19±2 76±2 39±2 7.40±0.02 -0.3±0.7 38±2 28±2 50±2 0.6±0.3 0.8±0.4 5.8±3.0 29.2±2.9 0.79±0.06 0.90±0.06 2.14±0.27 1.03±0.11 12.1 ± 1.0

0.001 0.001 0.001 0.001 0.001 0.01 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

0.005 0.05 0.001 0.001

After Nifedipine Exercise 872±94 0.80±0.03 106±6 10.6±0.8 5.8±0.3 44±3 4.2±0.3 135±10 24.2±2.8 29±2 68±4 43±2 7.35±0.02 -2.8±0.8 30±1 31±3 42±2 47±3 0.5±0.3 0.8±0.4 3.7±2.2 29.1±3.5 1.18±0.12 0.78±0.07 2.23±0.27 0.83±0.09 7.9±0.9

Rest

p Value

Exercise

269±15 0.82±0.02 83±6" 6.8±0.5< 3.7±0.2< 19±2 2.8±0.2" 88±5< 10.4±0.7• 20±2 71±3 37±27.41±0.02• -1±0.6 39±1 36±1·

0.001

843±57 0.80±0.03 116±5" 12.2±0.9" 6.6±0.3<' 36±1 8 3.1±0.2° 116±6" 25.9±2.4" 29±2 66±4 42±2" 7.36±0.02" -2.5±0.6 31±1 34±3" 47±38 0.5±0.3 2.7± 1.5 6.2±2.5 28.5±2.9 1.07±0.10" 1.00±0.10" 2.60±0.29" 0.92±0.09 10.9± 1.1°

0.7±0.4 2.5±1.5 6.1±3.5 28.2±3.2 0.64±0.04• 1.08 ± 0.08< 2.22±0.2& 1.06±0.09 15.2± 1.3d

0.001 0.001 0.001 0.001 0.01 0.001 0.001 0.001 0.001 0.001 0.001 0.001

0.005 0.05 0.001 0.001

For abbreviations, see text; p values relate to the significance of exercise-induced changes, while letters (a/A <0.05 biB <0.01; c/C <0.005; diD <0.001) denote statistical significance of differences between before and after nifedipine; lower case letters, resting measurements; capital letters, exercise measurements. *Values are x±SEM.

270

VIIIIOCOIIIIII'Iction

and Gas Exchange during Exercise {Agustl et Ill)

REST

EXERCISE

1.0

BEFORE N. ~

~

LL.

0 0

g

ID 0

~ ]:

1.0

z

AFTER N.

0

~....J

0.5

~

z

LIJ

>

0

0.1 1

10 100

0

01

1

10 100

VENTILATION- PERFUSION RATIO FIGURE 1. Recovered VAIQ distributions in a representative subject (patient 1). From left to right and from top to botton: rest and exercise beli>re nifedipine, and rest and exercise after nifedipine. Closed circles correspond to the distribution of pulmonary blood Row; open circles, the distribution of ventilation.

8.2 ± 0.5 g-m/m2) was within normallimits. 15 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 percent). None of the patients had C02 retention, but all had VoNT values higher than 40 percent. The inert gas data showed only small amounts of shunt and/or blood flow to lung units with VAIQ ratios lower than 0.1 (less than 1 percent of Qr, each) (Table 2). Seven of the eight patients !fhowed 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 Qr). Four patients (patients 1, 3, 5, and 7) had bimodal ventilation distributions with a substantial percentage ofVE distributed to high VAIQ areas (10 to 100) (Table 2 and Fig 1). The dispersion of the blood flow and ventilation distributions (Lo~ 0 Q and Lo~D V, respectively) (normal range, 0.3 to 0.6) and the overall amount of VAIQ mismatching estimated from raw retention and excretion values (DISP R-E*) were moderate to severely increased with respect to normal.14 Rest After Nifedipine (vs Rest Before Nifedipine) Neither Ppa nor Pw (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 ±0.5to9.1 ± 1.2 g-m/m 2). As previously reported, 3 VE increased slightly (9.4 to 10.4 L.min -I) but significantly (p<0.05) after nifedipine. As a result, PaC02 fell and arterial pH rose. The VoNT 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<0.05), and

0

5

10

15

QT,llmin FIGURE 2. Mean values (i( ± 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-Row relationship shifted to the right after nifedipine (p<0.01), indicating an active vasodilatory effect of the drug. CHEST I 97 I 2 I FEBRUARY, 1990

271

Qs/(>-r was higher (10± 1 to 15±2 percent, p<0.05). Because of the above-mentioned increase in (>-r 0 2 delivery improved (992 ± 85 to 1,228 ± 97 ml·min 1 , p<0.005). Ventilation-perfusion mismatching increased after nifedipine (higher DISP R-E*, p
mismatching as estimated either by the significant decreases in Log.;D Q and Logm V or DISP R-E* (Table 2 and Fig 1 and 3). The Q shifted toward higher values (p<0.005) hut V did not change. Arterial Po 2 was computed from the recovered VAI Q distributions6 to predict the Pa02 expected on the basis of VA!Q mismatch alone ("predicted Pa0 2 "). In this manner, diffusion limitation of 0 2 transfer from alveoli to the end-capillary blood is evident as a systematically higher predicted than measured Pa0 2 • 6 At rest, no significant difference was noticed between predicted and measured Pa02 • However, during exercise, predicted Po2 (74±5 mm Hg) was systematically higher than measured Pa0 2 (68 ± 4 mm Hg, p<0.002). In absolute terms, this difference was small (6 ± 1 mm Hg) and accounted for 20 percent of the actual P(A-a)0 2 • This observation suggests that pulmonary 0 2 transfer was partially diffusion limited in these patients with COPD during exercise . Exercise After Nifedipine (vs Rest After NifediiJine) The behavior of most of the hemodynamic and gas exchange variables during exercise after nifedipine was similar to that seen during exercise befi)re giving the drug (Table 2). However, the VnNT ratio showed a different response to exercise depending on tht: presence or absence of nifedipine: as expected , VnNT fell significantly during exercise before nifedipine, hut it did not change after giving the drug (Table 2 and Fig 3). Finally, it is of note that predicted and measured Pa0 2 values during exercise after nifedipine

12

c

10

.!0

08

~

0 .6

~

8' ..J

04 0.2

0

0

Oxygen

200

in:J

600

800

1000

Uptake, ml/min

Fl
272

Vasoconstriction and Gas Exchange during Exercise (Agusti et e/)

fell along the same direction as during exercise before nifedipine, but differences just failed to reach statistical significance (70 ± 4 vs 66 ± 4 mm Hg, respectively [p=0.09]). Exercise After Nifedipine (vs Exercise Before Nifedipine

Oxygen uptake during exercise was similar before and after nifedipine, but Qr increased following it (p
Our study documents that exercise can improve VAIQ 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 ofVAIQ 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 VAIQ 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 exchange at baseline (before nifedipine) and the role of HPV in modulating gas exchange during exercise will be discussed separately. Effects of Exercise on Gas Exchange at Baseline (Before Nifedipine) It has been well established that in patients with COPD Pa02 might increase, decrease, or remain unchanged during exerciseY·•s However, there is still a question regarding the effects of exercise on VAIQ maldistribution in COPD.t&-22 Wagner et al• 7 •18 and Dantzker and D'Alonzo22 used the multiple inert gas elimination technique to study patients with COPD during exercise. Even though VAIQ inequality did not change with exercise, Pa02 fell. 17 • 18 •22 This apparent discrepancy was explained by (1) a rise in PaC02 and (2) the effect of a lower PV02 on the end-capillary Po2 oflow VAQ units and shunt. 17 •18 •22 A subsequent study by Minh et al 19 disputed these conclusions. By comparing patients with COPD who improved Pa02 with those who showed a fall in arterial oxygenation with exercise, these authors concluded that the role ofPV02 in modulating such response was minimal, and that the increase in Pa02 with exercise was highly dependent on the reduction of Qs/Qr.t9 However, since the latter investigation used conventional gas exchange measurements, the authors could not separate the precise role of VAIQ mismatching, shunt, and 0 2 diffusion limitation as potential causes of hypoxemia. To our knowledge, our study is the first one to specifically demonstrate that VAIQ mismatching can improve during exercise in COPD. This is shown by the lower Log.; 0 Q (Fig 1 and 3), Log.; 0 V, and DISP R-E* (Table 2). It is tempting to speculate that differences from previous studies 17 • 18 •22 are related to the severity of COPD. For instance, both Minh et al 19 and Raffestin et al21 reported that those patients with COPD who developed exertional hypoxemia have a lower FEV 1 than those who did not. Further, the recent report by Dantzker and D'Alonzo22 showing no change in the VAIQ distributions with exercise included patients with much more severe airway obstruction than ours (FEV., 0.56 [in Dantzker and D'Alonzo22] vs 1.5 L [in our patients]) together with more C02 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 CHEST I 97 I 2 I FEBRUARY, 1990

273

those whose cases were reported by Dantzker and D'Alonzo, 22 reducing but not preventing the increase in PaC02 and shifting Q toward higher values. This higher Q would then minimize the impact of a lowered PV02 on the end-capillary blood of those units with very low VA!Q ratio 17 •111 •22 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 Bow (lower Log.; 0 Q). During exercise, P(A-a)02 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 VA!Q distributions definitely improved during exercise. The apparent paradox of a better VA!Q matching without any noticeable change in P(A-a)02 is explained by 20 percent of the P(A-a)02 due to diffusion limitation, as suggested by the higher predicted than measured Pa02 during exercise (p<0.002). 6 This would then limit the expected increase in Pa02 due to the improvement in VA!Q mismatching. This unexpected finding is at variance with previous reports. 17 •18 •22 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 Vo2 of our patients, compared with former reports, 11•18 •22 may well clarify it. Clearly, further studies are needed to confirm and explain this observation.

Role of HPV During Exercise At rest, nifedipine diverted blood Bow 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.t 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 -t To our knowledge, however, the effects of this lowered vascular tone on the adaptation of VA!Q mismatching to exercise in COPD have not been previously investigated. Our results show that the dispersion of the blood Bow distribution (Log.; 0 Q) was always higher after than before nifedipine, 274

either at rest or during exercise (Table 2 and Fig 3). Moreover, in contrast to before nifedipine conditions, the VoNT ratio did not fall with exercise after nifedipine (Table 2). As a result, VoNT 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 exerts its maximal vascular effect on those lung units with more alveolar hypoxia. 23 Therefore, it could be expected that during exercise after nifedipine, hypoxic areas would receive more blood Bow than those units with normal and high VA!Q ratios, making the latter less well perfused and, as a result, increasing their VA!Q ratio. Thken together, these two observations (higher Lo~ 0 Q, no change in VoNT 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 of blood Bow 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 VA!Q mismatching (DISP R-E*) improved with exercise even after the release of HPV induced by nifedipine (Table 2). Graphically, this is shown by the virtual disappearance of the low VA!Q mode in the blood Bow distribution in all of the patients in whom it had appeared at reast after nifedipine (Fig 1). Moreover, since exercise lowered the dispersion of the blood Bow distribution (Lo~ 0 Q) irrespective of nifedipine (ie, with or without modifying the pulmonary vascular tone) (Fig 3), we suggest that most of the VA!Q improvement seen during exercise is due to improvement 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, 23 we consider unlikely that it may have had any effect in our patients who have irreversible airflow limitation. Alternatively, nifedipine might have theoretically prevented the development of some bronchoconstriction induced by exercise. However we found that, before nifedipine, exercise improved VA!Q inequality, an observation that is at variance with the hypothesis of exercise-induced bronchoconstriction. Further, during exercise after nifedipine we showed more VA!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 \laaocor ISiriclion and Gas Exchange during Exercise (Agusti et 81)

in our patients. On the other hand, the potential effects of the slight changes in C02 during exercise on bronchomotor or vascular tone, although presumably negligible, cannot be quantified be design. To summarize, our study shows that exercise can improve VA/Q mismatching in COPD, although the type of response (ie, improvement or no change in the VA/Q maldistribution) is probably related to the severity of COPD. Further, it suggests that most of this improvement depends on a more homogeneous distribution of the inspired ventilation and that hypoxic pulmonary vasoconstriction probably plays a minor role in the modulation of such response. Nevertheless, our results also demonstrate that the release of hypoxic pulmonary vasoconstriction by nifedipine interferes with the ability of the pulmonary circulation to distribute blood flow more efficiently and worsens pulmonary gas exchange, not only at rest but also during exercise. Finally, this investigation highlights a limitation in the diffusion of 0 2 from the alveoli to the end-capillary blood during exercise of COPD. Undoubtedly, this observation requires further investigation. 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 her chromatographic work; F.A. Lopez, F. Burgos, T. Lecha, M. Simo, and C. Argai1a for their skillful technical assistance; A. Cobos (Department of Statistics, University of Barcelona) for his statistical advice; and the Medical Staff of our Service for their cooperation and care of the patients. REFERENCES

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