Variability of the Pulmonary Vascular Response to Acute Hypoxia in Chronic Bronchitis

Variability of the Pulmonary Vascular Response to Acute Hypoxia in Chronic Bronchitis· Emmanuel Weitzenblum, M.D.; Francine Schriien, M.D.; Thekkinkattil Mohan-Kumar, M.D.; Yeronique Colas des Francs, M.D.; and Alain Lockhart, M. D.

Hypoxic pulmonary vasoconstriction is considered as one of the factors leading to pulmonary hypertension in patients with chronic bronchitis, but the magnitude and the variability of the pulmonary vascular response to hypoxia in these patients have not been weD established. We investigated the pulmonary hemodynamic changes induced by breathing two hypoxic mixtures (FIo.=O.15 and 0.13) in 26

patients with chronic bronchitis with airway obstruction (FEV1NC=49±14 percent), Results show that there is a wide variability of the pulmonary vascular response to acute hypoxia in chronic bronchitis patients, but it is not possible to say whether such differences play a role in the natural history of the disease. (Chat 1988; 94:772-78)

I t has long been observed that acute alveolar hypoxia induces in man, as well as in several other species, a rise in pulmonary artery mean pressure (PPA) which is accounted for by hypoxic vasoconstriction. 1.2 In fact, the response of the pulmonary circulation to acute alveolar hypoxia, in mammals, varies considerably according to interspecies or intraspecies differences. 3.4 Some species, and in a given species some races, appear to be good "responders" to hypoxia, which can be explained by either structural factors, eg, the quantity of smooth muscle in the media of the small pulmonary arteries, 5 by genetic factors, 6 by differences in the release of mediators induced by acute hypoxia, 7 and (or) by a restricted collateral ventilation. 8,9 In normal men, the interindividual differences observed in the level of PPA at high altitude are not completely accounted for by differences in Pa0 2 , which suggests an interindividual difference in the pulmonary vascular response to hypoxia.'? Clinical observations have indicated that some subjects exhibit a marked hyperreactivity of the pulmonary circulation to acute hypoxia, in particular, those with a previous history of high altitude pulmonary hypertension'! and those suffering from high altitude pulmonary edema. 12 In patients with chronic bronchitis, the variability of the pulmonary vascular response to hypoxia could explain the marked differences in PPA and pulmonary vascular resistance observed in patients exhibiting the

same degree of functional impairment and hypoxemia.P The aim of our study was to investigate the degree of variability of the pulmonary hemodynamic response to an acute hypoxic challenge in a series of 26 patients with chronic bronchitis and mild to moderate hypoxemia.

*From the Pulmonary Function Laboratory Pavilion Laennec, University Hospital, Strasbourg; Inserm U14, Nancy; and the Department ofPhysiologj; H6pital Cochin, Paris, France. This study has been partially supported by a grant of the "Fonds special des comites d~partementaux contre la tuberculose et les maladies respiratories" (Paris, France) No 84-MRlI5. Manuscript received October 26, 1987; revision accepted March 8.

Reprint reque8t8: Dr. Weitzenblum, Pavillon Laennec, HopitalCivil, BP 427, 67091 Strasbourg, France

772

METHODS

Patients Twenty six patients with chronic bronchitis defined according to the criteria of the American Thoracic Societyl4 were included in the study They all had chronic airway obstruction defined by a ratio FEVivital capacity <65 percent They were investigated in a stable state of the disease: no acute exacerbation for at least two months; stability of arterial blood gas levels, FEV l and weight during a control period of three weeks. Patients with asthma or whose FEV1 improved markedly (>30 percent) after inhalation of a P2 agonist were excluded as were those with systemic hypertension (diastolic brachial pressure >95 mm Hg) and left heart diseases. In six patients, the ECG indicated right ventricular hypertrophy and seven patients had experienced in the past, one or more episodes of right heart failure. Age, body surface area, and pulmonary function data are shown in Table 1. Airway obstruction was generally moderate to severe, and hypoxemia at rest was mild to moderate. Most patients had no hypercapnia and the average PaCo. of the group was not elevated. The decision to perform right heart catheterization was made by

Table l-CharClCteriatics of Patients· Age, yr BSA, m2 vc, % pred TLC, % pred FEVl.c/VC, % RVrrLC, % PaCO~bmmHg

Pa02, mm Hg

*Mean ± 1 SD;

BSA is body surface area; total lung capacity; R~ residual volume.

52±7.5 1.80±O.21 88±16 121±26 49±14 45±11 41.0±5.3 59.8±6.4

ve,

vital capacity; TLC,

variability of PulmonaryvascularResponse(WeItzenbium et 81)

the clinical stafffor diagnostic purposes. The patients gave informed consent to the examination. When routine measurements had been completed, the patients were asked if they agreed to prolong the examination while breathing air with less than usual oxygen. Most of them gave their consent, but a few refused because of tiredness or because they felt uneasy with the facial mask; in these patients, the procedure was not carried out further, and they could not be included in the study

Analytic Techniques Patients were studied in the morning, fasting but without premedication. A Coumand or a plastic needle was inserted in one brachial artery and a Swan-Ganz catheter was introduced in a basilic or external vein in the other arm, and advanced under fluoroscopic and ECG control until it reached a branch of the pulmonary artery where good wedge pressure tracings could be obtained upon balloon inflation. Minute ventilation, oxygen uptake, and carbon dioxide output were measured with a closed circuit spirometer which provides a graphic display of these three variables every minute, thus enabling verification of a steady state of ventilation and gas exchange. The spirometer included a gas reservoir in which a nitrogen-air mixture was prepared. The opening of a switch valve between the reservoir and the closed circuit results in a quick mixing of the gas in the circuit and in establishing a new inspired oxygen concentration. This does not interfere with the measurement of oxygen uptake, which is purely volumetric. Thus, it was possible to administer to the patient either room air or a hypoxic mixture of 15 or 13 percent O. in Nt. The patient was connected to the spirometer via an air tight mask and the inspired 0 1 concentration was continuously monitored with a polarographic electrode. Cardiac output was calculated according to the Fick equation, and pulmonary vascular resistance (PVR) as (PPA-Pw)/Q, where PPA is the mean pulmonary artery pressure, Pw the wedge pressure, and Q the cardiac output Blood gas values were measured with ABL or semi-automated apparatus. The O. concentration of the arterial or mixed venous blood was computed from hemoglobin concentration and oxygen saturation determined by spectrophotometry (OSM I, radiometer), or was directly measured with the Lex O, CON apparatus. Vascular pressures were measured with inductance manometers. The zero reference level for the pressure transducers was at the midthoracic plane. Mean pressures were obtained by electronic integration over five respiratory cycles. Protocol

When the catheter was in the proper position, the patient was connected to the spirometer via a tightly fitting facial mask. After

ten minutes of room air breathing, a set of measurements was obtained, including VE, VOl' Vcas, over three minutes during which vascular pressures were recorded and blood was simultaneously withdrawn from the brachial and the pulmonary artery After the measurements in room air hadbeen completed, Flo. was decreased to 0.15. After 15 minutes, when ventilation and vascular pressures were again stead~ measurements were repeated. The patients were then disconnected from the spirometer. The study was interrupted, at this moment, in seven patients either because they declined to complete the investigation or because their SaO. hadfallen to less than 70 percent and it was not felt safe to carry out a second more severe hypoxic period. The remaining 19 patients were allowed to rest for 20 minutes. Next, a second period on room air was carried out during ten minutes followed by a second hypoxic period with Flo, of 0.13. A complete set of measurements was repeated during the last minutes of breathing the different gases. Patients were systematically questioned about subjective feelings but none of them could tell when they breathed hypoxic air. There were no untoward effects of hypoxia in any of the subjects.

Statistical Methods Statistical evaluation was performed using Students t-test on paired data for comparisons of differences between periods, and on unpaired data for comparisons between groups of patients. A twoway analysis of variance was also performed in the 19 subjects who were studied at two levels of hypoxia. Relationships between variables were tested by correlation coefficients. RESULTS

Changes in arterial blood gas values, ventilatory and circulatory variables are shown in Tables 2 and 3. All the variables, except the VAlVE ratio, returned to the control level after the first hypoxic period (n = 19 patients). The difference in VAlVE between the two control periods was, however, of small magnitude. Thus, the first hypoxic period had almost no residual effects detectable after the "wash-out" free interval of 20 minutes. On average, ventilation increased significantly during hypoxic breathing (p
Table I-Ventilation and Blood GaB Valua* Flo.

VE (Umin)

( (b/min) Vas (mllmin)

R

VAlVE (%)

[H+] nmollL PaCO I (mm Hg) PaOs(mm Hg) PAOI(mm Hg) SaOI (%) & (a-v)OI (vol %)

0.21 (1)

0.15

Diff 0.21-0.15

9.0± 1.8 16.3±4.4 278±59 0.85±0.12 55±8 38.3±3.0 41.0±5.3 59.8±6.4 110±8 89.9±3.7 4.7±0.8

10.2±2.2 17.3±5.3 278±65 0.95±0.15 6O±9 35.9±2.1 37.8±4.6 43.0±7.4 74±5 77.9±10.4 4.5±0.8

1.2±1.1 1.0±3.3 0.6±31 0.10±0.11 4±7 -2.4± 1.7 -3.2±2.3 -16.8±5.5 -36±6 -12.0±8.1 -0.2±0.6

p

0.21 (2)

0.13

Diff 0.21-0.13

B

8.9±2.1 16.8±5.3 281±68 0.89±0.12 63±7 37.9±2.9 39.1±5.3 61.2±8.1 113±8 9O.6±3.0 5.0±0.7

10.6±2.7 17.4±5.6 286±70 0.97±0.14 64±9 35.2±2.3 36.2±4.8 37.9±5.1 59±6 72.7±7.1 4.3± 1.0

1.7±1.3 0.6±2.7 5.4±2.7 0.08±0.10 1±7 -2.7± 1.6 -2.9±2.1 -23.3±4.9 -52±5 -17.9±4.9 -0.7±0.5

B A

B B

B B B

P

B

A

B B

B

B

B B

*Mean values ± 1 SD for 26 patients at Flo, =0.15, 19 patients at FIOt =0.13. R is respiratory quotient; VAlVE, alveolar/overall ventilation; &(a-v)O., arterio-venous oxygen concentration difference. Statistical significance of changes (t on paired data): A is p
773

Table 3-Circulatory VGriGblea* FI<>s

Q, Umin

HR, hlmin S\! ml PPA, mm Hg Pw, mm Hg PRVED, mm Hg Pha, mm Hg PVR, dynesecm-5

0.21 (1)

0.15

0.21-0.15

6.0± 1.1

6.3± 1.5 84.6±16.1 76.4±17.6 24.3±8.4 6.5±2.6 4.9±2.8 102±9 228±84

0.3± 1.0 4.3±6.3 0.1±12.9 3.2±5.0 0±2.7 0.9±1.5 2±6 31±50

BO.3±14.4

76.3±14.7 21.1±6.1 6.5±2.4 4.0±2.2 l00±10 197±80

p B B B B

0.21 (2)

0.13

0.21-0.15

p

5.6± 1.2 79.4±15.9 72.1± 14.3 21.1±7.0 6.6±2.4 4.1±2.1 99±13 208±78

6.9± 1.8 87.4±17.4 81.7±26.2 25.6±9.1 6.4±2.0 5.0±2.7 101±9 231±99

1.3± 1.2 8.0±6.2 9.7±14.7 4.6±3.7 -0.2±1.4 0.9±1.5 1±9 24±46

C C A C A A

*Mean values± 1 SD for 26 patients at FIo.=0.15, 19 patients at FI<>t= O. 13. Qis cardiacoutput; fPA, mean pulmonary pressure; Pw, mean wedge pressure; PIlVEDJ right ventricular end-diastolic pressure; Pba, mean systemic (brachial) artery pressure; PVR, pulmonary vascular resistance. Statistical significance of differences (paired data): A is p
in PaC02 and hydrogen ion concentration (p
Arteriovenous oxygen concentration difference decreased at Flo, of 0.13 (p20 percent PFA increase ranged between 1 and 17 mm Hg. The PPA increased slightly but significantly (p<0.01) at Flo, of 0.15 and more at Ffo, of 0.13 (p
n= 26

r

FI02 .21

-

----- FlO, .15 ......... Flo, .13

20

=-0.665

p
• -30

10

-20

i

-10 %

6 5002 FICURE 1. Changes in f pA as a function of changes in SaO. from FIo.=0.21 to FI<>s 0.13 in 19 subjects and to Flo. 0.15 in seven subjects. The regression line is shown. The subdivision between. and. is based on the level of SaO. at FIo1=0.21.

774

%

30

10

-40

60

•

15

o

n

50

6 PPA

+5

average increase of PPA was only 3.2±5.0 mm Hg at Flo2 of 0.15 and of 4.6±3.7 mm Hg at rro, of 0.13. The brachial artery pressure did not change signifleantly The larger increase in PPA at FIo2 of 0.13 compared to Flo, of 0.15 was associated with a concomitant rise in cardiac output (p
o

~r---~

.

:L_ - _.~.,:.::,::,::r :i , :w

5

a

5

10

,

.,

- --,

,,

1SmmHg

d PPA

FICURE 2. Histogram of :PPA changes between the two control periods at FI<>s=0.21 (-~ between 0.21 and 0.15 Flo. (-~ and between 0.21 and 0.13 FIOt (. . . ~ The number of patients is expressed as percent of the total. Yariablltty of Pulmonary Vascular Response (WeItzenbium et III)

PPA -PW 40

Fio 2 0.21- 0.13

mmHg

30

20

10

i

90

,

80

,

,

70

60 ,.

FIGURE 3. Individual changes of pressure drop in pulmonary circulation (hA-Pw) as a function of changes in SaO. from 0.21 to 0.13 FIOt (n == 19~

0.15). There was a slight but significant correlation between PPA changes at Flo, of 0.15 and 0.13 (r = 0.52, p5 mm Hg, "poor responders" or "nonresponders" were defined by a PPA increase <5 mm Hg provided that the drop in Sa02 was > 10 percent There were 12 responders and 11 poor or nonresponders, and three patients could not be classified because the PPA change was <5 mm Hg but the drop in Sa02 was <10 percent. When responders were defined by a 25 percent PPA increase from baseline value, we obtained the same subdivision in 12 responders and 11 poor or nonresponders and the patients were similarly classified using either definition of responders, with only two exceptions. From Table 4, it can be seen that there were no major differences between responders and poor or nonresponders with regard to arterial blood gas values, functional, and pulmonary hemodynamic data. The average PaC02 was slightly higher in the responders (p<0.01). The magnitude of the drop in Sa02 during the hypoxic challenge was higher in the responders, but the difference was hardly significant (p = 0.05). The PPA and PVR were generally higher in the responders, but the difference did not reach the level of statistical significance. A previous history of right heart failure was noted in four responders, in one nonresponder, and in two patients who could not be classified.

Hg). The histogram of changes in PPA caused by the change in Flo, from 0.21 to 0.15 was skewed towards higher increases in pressure. However, the most frequent change in pressure was still of + 0 to 2.5 mm Hg. With changes of Flo, from 0.21 to 0.13, the frequency of high positive values for changes in PPA was increased, but the most frequent change was again +0 to 2.5 mm Hg. The pressure drop across the pulmonary circulation (FPA-Pw) has been plotted against arterial O2 saturation during normoxia and hypoxia on Figure 3. The rise in PPA per unit change in Sa02 did not depend upon the level of basal pulmonary pressure, but the O 2 saturation drop was more pronounced in patients DISCUSSION with pulmonary hypertension. The results of this study suggest the following: (1) There was no significant correlation between the change in PPA during hypoxia and the initial level of the pulmonary vascular response to hypoxia is rather PPA (r=0.37 for Flo, of 0.13, r=0.17 for Flo, of modest, as a mean, in chronic bronchitis patients; (2) Table 4-CompGrison of Main FunctiontJl and Hemodynamic DGttJ BetweenBapondera to Hf/PODtJ and Poor or Nonreaponden

Age,yrs

FEVh ml

FEV1NC, % PaO., mm Hg PaC01, mm Hg SaO., % Hematocrit, %

VAlVE, %

hA, mmHg PVR, dynesesecm- 5 4SaO. hypoxia, % 4Pp'/4SaOI, mm Hw'%

Responders

(n== 12)

Poor or Nonresponders (n == 11)

52±8 1460±680 42.9±12.3 59.8±5.7 42.8±5.5 89.4±3.9 48.7±9.7 54±7 23.4±8.4 242±105 21.8±8.4 0.47±0.95

53±5 1900±730 54.4± 14.5 62.0±9.9 37.1±3.3 90.9±3.3 47.6±7.5 60±8 18.3±4.1 172±54 16.2±3.4 0.13±0.09

Students t-test

NS

NS NS NS

p
p==O.05 p
CHEST I 94 I 4 I OClOBER. 1988

775

the magnitude of the response is related to the degree of acute hypoxia; and (3) there is a wide variability of the pulmonary vascular response ranging from no response at all to a marked elevation of PPA, driving pressure, and PYRe The response to acute hypoxia was rather modest if one considers the average figures: with the lowest FIo2 (13 percent); the mean increase in PPA was of 4.6 mm Hg, which represents an average increase of26 percent from baseline; the mean increase in PVR was of only 16 percent, whereas the change in cardiac output was of + 23 percent. Our results are in agreement with those of Abraham et al15 who observed in 12 patients with a more severe airway obstruction than ours, marked hypoxemia and moderate pulmonary hypertension, an average increase in PPA of22 percent when the patients breathed acutely a 13 to 14 percent O2 mixture; this change was explained by a simultaneous rise of PVR (+ 26 percent) and cardiac output (+ 11 percent). Indeed, more pronounced responses to short-term hypoxic challenges have been observed in healthy subjects at sea level. In the 23 so-called "normal" subjects investigated by Westcott et al,16 a short hypoxic challenge (FIo2 = 0.13) increased PVR by 48.5 percent. In the eight healthy subjects studied by Doyle et al,17 breathing a 10 percent O 2mixture during ten minutes increased PPA by 50 percent. In the 32 healthy young subjects (mean age of 25 years) investigated by Naeije et al,18,19 breathing 12.5 percent O2 during ten minutes caused an increase in PFA from 13.3±0.5 (mean ± SEM) to 19.7±0.8 mm Hg, in cardiac index from 3.8±O.1 to 4.6±O.2 Lsmin-rrrs, and in PVR by about 120 percent. It must be emphasized that the drop in Pa02 during hypoxia was larger than in our patients whose initial Pa02 during hypoxia was indeed lower (61.8±8.1 vs 91.5± 1.1 mm Hg), although the final value was the same (37.9±5 in our patients vs 40.3±0.8 mm Hg). The magnitude of the pulmonary vascular response probably depends not only on the alveolar or arterial P02 reached during the hypoxic challenge but also on the magnitude of the fall in Sa02 or Pa02 from baseline. In the present study the mean increase in PPA was of 3.2 mm Hg with 15 percent O 2 (average decrease in Pa02 = 16.8 mm Hg), while it was of 4.6 mm Hg with 13 percent O2 (average decrease in Pa02=23.3 mm Hg). This "dose-effect" relationship is further illustrated by the correlation that we found between the changes in Sa02 and those in PPA: r = - 0.665, p
tween the hemodynamic effects of the two hypoxic mixtures were mainly due to the fact that breathing 15 percent O 2 did not induce a rise in cardiac output, whereas breathing 13 percent O 2 did (Table 3). Conversely the rise of PVR was identical with 15 percent and 13 percent 02. It thus appears that the hypoxic "threshold" could be different for vasoconstriction and for the increase of cardiac output. The combination of elevated PVR and increased cardiac output has also been observed during sleep-related episodes of severe nocturnal hypoxemia in COPD patients." The most striking result of our study is probably the high variability of the pulmonary vascular response to acute hypoxia in chronic bronchitis patients. Nearly 50 percent of the patients appeared to be nonresponders or poor responders to hypoxia. Fishman et alm have stated that a Sa02 of 85 percent was the critical threshold for the pulmonary vascular response to hypoxia. In our subgroup of 11 nonresponders or poor responders, Sa02 fell regularly below 85 percent except in one patient where it reached 86 percent. Thus, the poor vascular response to hypoxia in these patients could not be attributed to an insufficient drop of arterial O 2 saturation. Such a variability of the hemodynamic response to acute hypoxia has not been observed by Naeije et al18.19 in their healthy subjects since all were responders to hypoxia and PPA increased in all individual cases. Similarly Fishman et al2 observed a rise of PFA in all their COPD patients, but their series was limited to six patients. In the more important series (n = 12) of Abraham et al,15 the individual results were not given, and we do not know whether all patients "responded" to hypoxia. Our classification between responders and poor or nonresponders was based on the absolute change in PPA, responders being defined by an increase of >5 mm Hg. This criterion is rather arbitrary but it is of interest to note that we have observed the same classification of the patients (with only two exceptions) when using as a criterion a proportional change in PPA>25 percent, or an increase of PVR >25 percent. Since our series was limited to 26 subjects, it was difficult to describe precisely the distribution of patients according to the level of the pulmonary vascular response to hypoxia. Is the distribution a continuous one from nonresponders to responders, or is there, on the contrary a clear-cut separation between these groups with a bimodal distribution? We cannot answer satisfactorily this question even though the distribution of PPA changes shown on Figure 2 might evoke a bimodal aspect (at least for FIo2= 0.13) with a main peak of frequency for PPA changes between 0 and +5 mm Hg (nonresponders or poor responders) and a less prominent peak for PPA changes between + 10 and + 15 mm Hg (responders). We need results in large variabilityof Pulmonary vascular Response(WeItzanbium at 8/)

series of COPD patients exhibiting various degrees of severity and we also need to know the distribution of the pulmonary vascular response to hypoxia in healthy subjects covering a large range of age, which was not the case in the important series of Naeije et al. 18 , 19 The clinical situation which bears the closest analogy with acute hypoxic challenges is probably the sleeprelated worsening of hypoxemia, particularly during rapid-eye movement sleep, which frequently occurs in cOPO patients. Hemodynamic investigations have rarely been performed during sleep,2l,22-14 and the series are limited to short numbers of co PO patients, but these data suggest that, although a majority of patients can be considered as responders to nocturnal hypoxemia,2l,23 poor and nonresponders can also be found representing one third of the patients in one stud~24 However, there is a major difference between acute hypoxic challenges and sleep-related episodes of hypoxemia. In the former, PaC02 decreases as a consequence of hyperventilation. In the latter, PaC0 2 is either stable when the worsening of hypoxemia is explained by ventilation/perfusion mismatching or does increase in case ofhypoventilation. Toour knowledge, there has not yet been any study comparing the results of acute hypoxic challenges and the hemodynamic effects of sleep-related episodes of severe hypoxemia. We found no relationship between the magnitude of the rise in PPA and the baseline value of:PPA ' which is in good agreement with the data of Fishman et al2 but markedly differs from the results of Abraham et al. IS Such a relationship could be expected, since the hemodynamic consequences of acute pulmonary vasoconstriction should be greater in those patients in whom the internal diameter of the small pulmonary arteries is reduced; and the patients with the highest PPA should be those with a marked vascular response to hypoxia. In fact, we have noticed similar responses to acute hypoxia in patients with pulmonary hypertension (PH) (six responders out of 11 patients) and without pulmonary hypertension (six responders out of 12 patients), pulmonary hypertension being defined by a resting PPA >20 mm Hg. Similarly the comparison between responders and poor or nonresponders showed no significant difference for baseline PPA and PVR (Table4). The majority of patients with a previous history of right heart failure was responders (four out of five patients who could be classified), but the number of the cases was too small to allow any firm conclusion. The difference between our results and those of Abraham et allS could be explained by differences in the frequency and severity of PH: all the patients included in the series of Abraham et allS had PH and some had severe hypertension, PPA ranging from 23 to 50 mm Hg, whereas half of our patients had no pH

and no patient had severe hypertension (range of PPA: 12 to 33 mm Hg). The level of PPA in patients investigated in a stable state of the disease is probably related to structural changes induced by chronic hypoxia and by the disease itself: more than to acute vasoconstriction. In this respect, it is not surprising to observe a lack of correlation between the baseline level of PPA and the magnitude of the response to hypoxia. Is there a relationship between the level of the pulmonary vascular response to acute hypoxia and clinical situations such as the development of pulmonary hypertension or the degree of reversibility of PH under various treatments including long-term oxygen and vasodilators? The present data do not allow us to answer this question. As mentioned above, there are probably marked differences between the pulmonary hemodynamic effects of acute hypoxia and those of long-standing hypoxia. In COPO, chronic hypoxia is probably the determining factor but the effects of acute hypoxia are not negligible since they may occur during exercise, sleep,21.21-24 and episodes of acute respiratory failure.25-27 Ashutosh et allS have demonstrated that there is a rather good correlation between the hemodynamic improvement under 02' administered continuously during 24 hours, and prognosis in patients receiving long-term O2 therapy Similarly it would be worthwhile to know whether there is any relationship between the vascular reactivity to hypoxia and the development of pulmonary hypertension, or the pulmonary hemodynamic changes under longterm 02. Further studies are needed in this field. ACKNOWLEDGMENT: The writers wish to thank F. Poincelot for technical assistance, B. Clement for typing the manuscript, and M. C. Rohrer for drawing the figures.

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Yariabillty of Pulmonaryvascular Response(WeItzenblwn et 81)