Dose Dependency of Aminophylline Effects on Hemodynamic and Ventricular Function in Patients With Chronic Obstructive Pulmonary Disease

Dose Dependency of Aminophylline Effects on Hemodynamic and Ventricular Function in Patients With Chronic Obstructive Pulmonary Disease* Pierre Mol&, M.D.; Chi H. Huynh, M.D.; Phaippe Dechamps, M.D.; Nicole Naeije, M.D.; and Hamphrey R. Ham, M.D. The effects of aminophylline on pulmonary vascular tone, systemic hemodynamics, and ventricular ejection fractions reported in the literature show some discrepancies. We therefore studied in COPD patients the effects of amin0phylline on hemodynamics, on ventricular ejection fractions, andon systolic and diastolic functions of each ventricle, and we measured simultaneously the blood level of the drug. The analysis of the data revealed a relationship between the blood level of aminophylline andthe variations of right ventricular ejection fraction (RVEF) (r=O.83, p = 0.005), left ventricular ejection fraction (LVEF) (r=0.76, p=O.OI7), pulmonary vascular resistance index (PVRI) (r= -0.58, p=O.(96), systemic vascular resistance index (SVRI) (r= -0.60, p=0.08), and right ventricular

peak systolic pressure/end-systolic volume index (RVPSPI ESVI) (r = 0.75, p = 0.02). Modi&catiODS of ejection fractions and vascular resistance indices were correlated for both ventricles (RVEF vs PVRI, r= -0.77, p=O.OI; LVEF vs SVRI, r = - 0.76, p = 0.02). Finally, RVEF modi&cation was also correlated to RVPSPIESVI variation (r = 0.78, p = 0.01). These results suggest that even within the therapeutic range (10 to 20 mg/L), the effects of aminophylline seemed to depend on its blood level. This dose dependency could explain the contradictory data reported in the literature concerning the effects of aminophylline on pulmonary and systemic hemodynamics and on ventricular function. (Chat 1993; 103:1725-31)

For several decades, aminophylline has been widely used to treat chronic obstructive pulmonary disease (COPD). In this abnormality, it has been shown to cause a modest subjective improvement of dyspnea scores, and a slight objective improvement of expiratory volume in 1 SI as well as a cardiovascular benefit with improved left and right ejection fractions.2--' Some authors suggest that a systemic and a pulmonary vasodilation and an improved myocardial contractility might induce the improvement of ventricular performances. Others show the absence of effect of aminophylline on pulmonary vascular tone or on ventricular ejection fractions both at rest and during exercise."? To elucidate these discrepancies we measured, in COPD patients, the effects of aminophylline at rest and during exercise, on hemodynamics, on ventricular ejection fractions, and on the systolic and diastolic function of each ventricle. Blood levels of aminophylline were also measured.

catheterization and radionuclide ventriculography to measure the degree of pulmonary arterial hypertension and to appreciate the right ventricular (RV) and left: ventricular (LV) functions. There were eight men and one woman aged 49 to 69 years (mean, 58 years). No patient had any clinical or ECG evidence of systemic hypertension, valvular heart disease, coronary artery disease, or primary myocardial disease. Five had been hospitalized previously for acute respiratory failure. Two had already presented clinical signs of RV failure. At ECG examination, incomplete right bundle branch block was found in two subjects, and right atrial hypertrophy was found in five of them. Patient characteristics and lung function data are given in 'Iable 1. All the patients gave informed consent to the study which was approved by the ethical committee of our institution.

METHODS ltJtIents

Nine patients with stable severe COPD underwent right-sided

*From the Departments of Internal Medicine (Drs. Mols, Huynh, and Dechamps) and Radioisotopes (Dr. Ham), Saint-Pierre University Hospital, Brussels, and the Institut Georges Brugmann (Dr. Naeije), A1semberg, ULB, Belgium. This work has been supported by FNRS grant 3.4528.88. Manuscript received November 11, 1991; revision accepted September 15. Reprint requests: Dr. Mol&, Service des Urgences, HopItal Univer-

sitaire St Pierre, lOOO-Brussel&, Belgium

Study Protocol The right heart catheterization was performed with the patient in the supine position, after an overnight fast, without any premedication. No drug had been administered for at least 24 h. In the three patients with long-term O. therapy, the O. administration was stopped 2 h before the investigation. The patients were allowed to rest after the insertion of the catheters. When respiratory rate, heart rate, and vascular pressures were stable, hemodynamic measurements were started. Right and LV ejection fractions and peak expiratory flow rate were measured simultaneously All these measurements were performed twice, at basal condition. During the cycloergometric exercise in each patient, the load was adjusted to allow a constant, nearly maximal exercise during 6 to 8 min. The level of the load was determined as follows: the patient performed the exercise at about 30 cycles per minute. The load was then progressively increased and the patient was asked to determine the maximal level he could tolerate. At the end of the exercise, all the patients complained of dyspnea and exhaustion. All the measurements, excepted peak respiratory flow rate, were started after 3 min of constant exercise. Aminophylline was then infused into the jugular vein; a bolus dose of 5.6 mg/kg was infused over 20 min and followed by a CHEST I 103 I 6 I JUNE, 1993

1725

constant infusion of 0.9 mWkglh. One hour later, measurements were performed again at rest and during an identical cycloergometric exercise. Blood levels of aminophylline and lactic acid were measured.

Hemodynamic and Blood Gas Determinations A Swan-Ganz catheter (Paceport, Edwards Laboratories, Santa Ana, Calif) was introduced into the right internal jugular vein, using the Seldinger technique, and advanced under constant pressure wave and Huoroscopic control into the right pulmonary artery. A small polyethylene catheter was inserted in a radial artery for systemic pressure measurements. Pressures were measured using physiologic pressure transducers (AE 840, Akbjebelskapet Mikro Elektronikk, Norway) and recorded on a thermal writing recorder (Visicorder 1858, Honeywell). The zero reference was placed at midchest level and values for pressures were averaged for three successive respiratory cycles. Heart rate was determined from a continuously monitored ECG lead. Cardiac output was measured in triplicate by the thermodilution method using a computer (9520A, Edwards Laboratories). Arterial and mixed venous blood gases were measured using a pHlblood gas system (Corning 175, Corning Medical Products, Medfield, Mass). Hemoglobin concentrations and oxygen saturations were determined by a hemoximeter (OSM2, Radiometer, Copenhagen, Denmark). The following formulas were used for hemodynamic calculations: cardiac index (Izmin -Iem-2)= cardiac output (L-min-I)/body surface area (m!); oxygen transport (ml/min/m') = arterial oxygen content (mIldl) X cardiac index X 10, where arterial oxygen content = hemoglobin (g/dl) X 1.39 X oxygen saturation + arterial P0 2X 0.0031; alveolar-arterial Po! gradient (mm Hg) = (inspiratory P0 2- arterial Pco/R + (Flo! X arterial Pco, X [(1- R)/R])- arterial POI' where Flo, is the fraction of oxygen in the inspired air and R the respiratory exchange ratio assumed to be 0.8; venous admixture (percent of total blood How) = (capillary O 2 content - arterial O 2 content)/(capillary O! content - mixed venous 0 1 content), where capillary O 2 content is estimated using the calculated ideal alveolar POI and the corresponding saturation determined using the subroutine of Kelman," systemic vascular resistance index (dyne-s-cm -5. m2) = 80 X (mean systemic arterial pressure - right atrial mean pressure)/cardiac index; LV stroke work index (g-m-m -I) = stroke volume index (ml-m-2) X (mean systemic arterial pressure - pulmonary arterial wedge pressure) X 0.0136, where

Table 1-Patienta CharacterUticl and Lung Function Data· Case No.1 Age, y/ Sex

lJ53IM 2/69/M

3I63IM 4I56IF

5149/M 6I6O/M 71561M 8I59/M 9I54/M

FEVhL

FVC,L

0.76 0.80 0.92 0.50 1.65 0.90 1.61 1.30 0.88

4.78 1.80 3.04 1.60 2.62 2.61 3.33 3.26 2.42

%

PaOI, mmHg

PaCO I, mmHg

16 44 30 31 63 34 48 40 36

65 50 77 46 73 70 62 83 50

40

FEV/FVC,

54

44 60 41 40 44 34 46

*M = male; F = female; FEVI = forced expiratory volume in 1 s: FVC = forced vital capacity; PaO. = arterial POI; PaCO I = Pco., stroke volume index = 1,000 X cardiac index/heart rate; pulmonary vascular resistance index (dyne-s-em -Semi) =80 X (mean pulmonary arterial pressure - pulmonary wedge pressure) X cardiac index; RV stroke work index (g-m-m -2)= stroke volume index X (mean pulmonary arterial pressure - right atrial mean pressure) X 0.0136.

RadionuclideTechnique Concomitantly to hemodynamic measurements, RV and LV ejection fractions were measured, using multi-gated radionuclide ventriculography. This technique used the in vivo method of red blood cell labeling. A commercial kit was provided for (Amerscan R, Amersham, UK) containing 4 mg of stannous fluoride and 6.8 mg of sodium medronate in 6 ml, and 0.03 mllkg was injected intravenously After 30 min, 20 mCi of 99m technetium pertechnetate was injected into the right atrium. After 5 min to allow equilibration in the blood pool, the multiple gated study was performed (using an LFOV-Searle and Informatek Simis-3 computer). The patient remained as supine as possible with the camera angled ur caudally and 4:)0 left anterior oblique. In each patient the angle was adjusted to obtain maximum separation of the ventricles. Sixteen frames per cycle were acquired during 3 min. Fourier phase and amplitude functional images were used to help trace the regions of interest, and RVand LV ejection fractions were calculated.v'"

Table 2-Effecta oflntravenouB AminophyUine on Blood Gases in Nine COPD lbtienta at BeBt and During Subrnaximal Exercise·

Arterial pH Arterial P0 2, mm Hg Arterial Pcol , mm Hg Arterial S02, % Venous POI' mm Hg Alveolar-arterial POIgradient, mm Hg Venous admixture, % Peak 80w rate, Irmtn " 0 1 consumption, ml-min - l em- 2 0 1 transport, ml-min v-m ? 0 1 extraction, % Lactate, mmollL Blood level of aminophylline, mg/L Workload, W Duration of exercise, s

Baseline

Aminophylline

Exercise

Exercise Aminophylline

p 1.2

p 1.3

p 3.4

p 2.4

7.41±0.02 64±4 45±3 9O±2 36±1 33±2 22±4 135± 13 147±5 568±29 25.8± 1.1 0.95±0.11 2.9±0.3

7.43±0.12 64±4 42±3 92±2 34±1 35±2 19±3 149±14 140±5 483±24 29.2± 1.4 1.33±0.35 15.7±1.8

7.36 ± 0.02 67±6 46±2 89±3 31±1 29±5 18±7

7.38 ± 0.02 70±5 44±2 91±2 3O±1 29±3 13±3

<0.01 NS NS NS <0.001 NS NS

NS NS NS NS NS NS NS

0.001 NS NS NS <0.001 NS NS

385±37 891±78 43.2±2.7 3.08±0.41

390±36 856±66 45.6±2.4 3.68 ± 0.29

<0.001 <0.001 <0.01 <0.001

NS NS 0.001 NS

<0.001 <0.001 <0.001 <0.001

39±7 414±17

4O±6 442±25

NS NS <0.05 NS NS NS NS NS NS <0.05 <0.001 NS <0.001

NS NS

*Results are expressed as mean values ± SEM; RV= right ventricular; LV = left ventricular; P 1.2 = comparison between baseline and aminophylline; P 1.3 = comparison between baseline and exercise; P 3.4 = comparison between exercise and exercise aminophylline; P 2.4 = comparison between aminophylline and exercise aminophylline.

1726

Dose DepetldetICY of Aminophylline (Mols st 81)

Table 3-Effecta oflratrooenoua AminophyUine on SfI'Iemic and Pulmona'll Hemodynamics, and on Left and Bight Ventricular Function in Nine COPD IbtientB at Bat and During a SulmaaDmal Exercise-

Heart rate, bpm Cardiac index, Izmin-I·m-I Stroke volume index, ml"lll-I Mean arterial pressure, mm Hg Mean pulmonary arterial pressure, mm Hg Pulmonary arterial wedge pressure, mm Hg Mean right atrial pressure, mm Hg Ppa-Ppw, mm Hg Pulmonary vascular resistance index, dynes-s-cm -s.ml Systemic vascular resistance index, dynes-s-cm -5.m 2 RV end-diastolic pressure, mm Hg RV end-diastolic volume index, ml-m" RV end-systolic volume index, ml-m? RV peak dP/dt, mm Hg-S-I RV peak systolic pressure/end-systolic volume, mm Hg-ml-l·ml RV stroke work index, g-m-m? RV ejection fraction, % RV peak filling rate, oounts-s " LV end-diastolic volume index, ml-m? LV end-systolic volume index, ml-m ? LV stroke work index, g-m-m ? LV ejection fraction, % LV peak filling rate, eounts-s"

Baseline

Aminophylline

Exercise

Exercise Aminophylline

p 1.2

p 1.3

p 3.4

80±4 3.33±0.16 42±2 89±2 22±3 5±1 1±1 17±2 418±58 2135± 148 3±1 99±10 57±9 255±36 0.71±0.11

88±5 2.78±0.10 33±2 89±3 17±2 4±1 1±1 13±1 390±42 2532±97 1±1 75±11 42±9 216±20 0.90±0.14

102±3 5.23±0.32 51±3 110±6 37±3 12±2 7±1 24±3 386±48 1591±74 8±1 111±8 59±8 418±52 1.10±0.12

107±3 4.91±0.28 46±2 110±5 31±3 9±1 5±1 22±2 367±43 1715±62 4±1 96±10 5O±10 398±38 1.37±0.24

NS <0.05 <0.001 NS 0.05 NS NS 0.05 NS <0.05 <0.05 <0.001 <0.05 NS NS

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 NS <0.01 <0.05 NS NS <0.01 <0.05

NS NS <0.05 NS <0.05 <0.05 NS NS NS NS <0.05 <0.05 NS NS NS

12±1 44±3 2.09±0.22 80±7 29±6 5O±3 61±5 3.20±0.57

8±1 47±4 2.43±0.37 55±6 22±4 39±3 63±3 3.40±0.48

21±2 48±4 3.44±0.30 80±6 28±5 72±7 66±4 4.85±0.39

17±1 51±4 4.07±0.52 68±5 22±5 67±5 70±4 5.52±0.65

<0.01 NS NS <0.001 <0.05 <0.001 NS NS

<0.001 <0.01 NS NS 0.05 NS <0.01 <0.01 NS <0.05 NS <0.001 NS NS NS <0.01

*Results are expressed as mean values±SEM; RV=right ventricular; LV=left ventricular, Ppa-ppw=driving pressure. Systolic and Diastolic &nction

To assess RV contractility, RV peak systolic pressure/end-systolic volume index ratio was calculated. This parameter is independent of preload and afterload modifications" and it has been shown, for the L~ that pressure/volume ratio calculated when using either peak or end-systolic pressures is closely correlated. U Diastolic properties of the ventricles were assessed by measuring the peak ventricular filling rate13 for both ventricles, using radionuclide method. If

Respiratory &nction

Peak expiratory flow rate was measured in triplicate, by a peak

flow meter (mini-Wright), at the same time as the hemodynamic measurements. Only the best value was considered. Statistics

Results are expressed as mean values ± SEM. Statistics consisted of analysis of variance, and comparison of mean values was performed using modified t test with the Bonferroni adjustment for multiple comparisons. RESULTS

All the patients had severe airflow limitation (Table 1). Mean values showed mild hypoxemia and hypercapnia and moderate pulmonary hypertension at rest (Tables 2 and 3). After J-h of intravenous infusion, aminophylline blood levels increased from 2.9±O.3 mg/L (range, 0 to 4.5) to 15.7 ± 1.8 mg/L (range, 9.3 to 23.7). Arterial blood gases hardly varied during the aminophylline infusion. At rest, PaC02 decreased from 45 ± 3 to 42 ± 3 mm Hg (p
but not significantly whereas the arterial Po2 , the venous admixture, and the alveolar-arterial P02 gradient remained unchanged. Oxygen transport decreased and O2 extraction increased. Peak expiratory Howrate remained unchanged during the aminophylline infusion. During exercise, the arterial blood gas values remained unchanged.

Systemic and Pulmonary Hemodynamics At rest, during the aminophylline infusion, heart rate, mean arterial pressure, pulmonary arterial wedge pressure, and pulmonary vascular resistance index remained unchanged. End-diastolic volume of both ventricles, RV end-diastolic pressure, pulmonary Table 4-Correlatioraa Between the Blood Level of Aminophylline and the Variation of Different Parameters-

RV ejection fraction

Pulmonary vascular resistance index RV peak systolic pressure/end-systolic volume RV peak filling rate LV ejection fraction Systemic vascular resistance index LV peak filling rate Cardiac index Stroke volume index Oxygen transport Oxygen uptake

r

p

+0.83 -0.58 +0.75 +0.25 +0.48

0.005 0.096 0.02 0.54 0.17 0.08 0.43 0.50 0.84 0.22 0.17

-0.60 +0.32 +0.26 +0.08 +0.39 -0.48

*RV= right ventricular; LV= left ventricular. CHEST I 103 I 6 I JUNE, 1993

1727

4LVEI'

ARVEl'

....

15~~~~

~

<~~t;:~~ig~~:;,.>· II ::·::• .::e:::~':r

•

5

, 5

·11

1' ......_~

..

--..~~_-...

I

•

.-----...----....------1 20 II o 30

•

•

·104---.........-.._...._ ....._ ...........,.----._.... • 0.6 • 0.4 • 0.2 0.0

AMINOPHYLLINE BLOOD LEVEL

0.2

0.4

0.6

0.8

1.0

4SVRI

FIGURE 1. Relationship between the blood level of aminophylline and right ventricular ejection fraction (RVEF).

FIGURE 3. Relationship between the modifications of left ventricular ejection fraction (LVEF) and those of systemic vascular resistance index (SVRI).

arterial pressure, cardiac index, and stroke volume index decreased, whereas systemic vascular resistance index increased (Table 3). During exercise, similar variations of parameters were observed except the decrease in cardiac index and the increase in systemic vascular resistance were no longer signi6cant. In addition, pulmonary arterial wedge pressure decreased (Table 3). The analysis of individual data revealed that the modifications of pulmonary and systemic vascular resistance index were related to the blood level of aminophylline (Table 4). These indices decreased or increased in relationship to the blood level of the drug. The infusion of aminophylline did not cause any modification of the mean value of RVand LV ejection

fractions, either at rest or with exercise (Table 3). However, as shown in Figure 1 and Table 4, there was modification of the individual value that varied in relation to the aminophylline blood level. At a low therapeutic blood level, the drug tended to decrease ejection fraction, whereas at a high therapeutic blood level, an increase of ejection fraction was observed. This tendency was more pronounced for the R'V: After aminophylline administration, there was also a correlation between the modifications of ejection fractions and the vascular resistance indices (Fig 2 and 3). Increased ejection fractions were observed concomitantly to a vascular vasodilation, whereas decreased ejection fractions appeared when vasoconstriction occurred. Finally, RV ejection fraction modifications were correlated to RV peak systolic pressure! end-systolic volume index variations (Fig 4). Increased

ARVEl'

ARVEl'

Ejection Fraction

20.....

--.._ _

~

........

~

18

,

o

.-

·10 +-...... ~_._-

·100

......-

- .- - - - -

......__.-.....-....___I

o

4PVRI

101

FIGURE 2. Relationship between the modifications of right ventricular ejection fraction (RVEF) and the pulmonary vascular resistance indexes (PVRI).

1728

·11 +-................-......- - . _ . . -......- . . _...........--1

o

ARV PSPIESVI

FIGURE 4. Relationship between the modifications of right ventric-

ular ejection fraction (RVEF) and the right ventricular peak systolic pressure/end-systolic volume index (RVPSPIESVI).

Dose Depetdel K:Y of AmInophylline (Mois et 81)

4 RV PSPIESVI ... -~-~-: ;:r)~~i:~+.·O.75:;·: : .......

-

'-

>~f...:.... :;~;~I{!.0:::2·:?.......•..< ?;<

.....--------...

..

•

...:.

200

•

o

----.-------1

-200 +-..-.-----.....

o

10

20

30

AMINOPHYLLINE BLOOD LEVEL FIGURE 5. Relationship between the blood level of aminophylline and right ventricular peak systolic pressure/end-systolic volume index (RVPSPIESVI).

RV ejection fraction was observed concomitantly to an increase of this contractility parameter. Ventricular Systolic and Diastolic Function

During the aminophylline infusion, the mean value of RV peak systolic pressure/RV end-systolic volume index remained unchanged both at rest and during exercise (Table 3), although a significant positive correlation was observed between the variation of this parameter and the blood level of the drug (Fig 5). Concerning the diastolic function, aminophylline did not change the peak filling rate at rest or during exercise (Table 3). Also, no correlation was observed between this parameter and the blood level of aminophylline (Table 4). DISCUSSION

Our work presents the effects of aminophylline in patients with a severe but stable COPD on systemic and pulmonary hemodynamics and on RV and LV functions. Systemic and Pulmonary Hemodynamics

At rest and during exercise, aminophylline causes a decrease in the end-diastolic volume of both ventricles, in the RV end-diastolic pressure, and in the stroke volume index. At rest, it also causes a decrease of cardiac index, and, during exercise, of pulmonary arterial wedge pressure (Table 3). The concomitant decrease in filling pressure and in end-diastolic volume of both ventricles suggests a decrease in venous return caused by a vasodilating effect of aminophylline on the peripheral venous system. 15 Aminophylline-induced cardiac index modifications in COPD patients are variable,I6-18 and the result of the interaction between a decreased preload, a de-

creased stroke volume index, and a variable chronotropic effect. In our study, the significant decrease in stroke volume index is not compensated by a significant increase in heart rate. Cardiac index therefore decreases. The effect of aminophylline on the peripheral arterial bed depends on two opposed mechanisms: on one hand, a vasoconstricting effect involving an a-adrenergic mechanism (which can be abolished by phentolamine), and on the other hand a direct vasodilating effect. 19 The relationship between the aminophylline blood level and the modification of systemic vascular resistance index observed in our work suggests that at a low therapeutic blood level, a-adrenergic effects induced by an important decrease of preload prevail. In contrast, at a high therapeutic level, the direct vasodilating effects of aminophylline predominate. The discrepant hemodynamic responses to aminophylline observed in different studies in the literature could be due to a variation of the blood levels of the drug, which usually have not been measured. 16-18 The aminophylline doses reported in the studies of Parker et al,t6,17 for instance, are largely higher than those recommended for clinical use. 20 As for the discrepancies in the hemodynamic response between the two studies of Parker et al, in spite of the same study protocol and aminophylline dose, they may be due to changing drug clearances related to cor pulmonale and hypoxemia.21 ,22 Data in the literature concerning pulmonary vascular resistances are conflicting, showing either the absence of effect of aminophylline or aminophyllineinduced vasodilation. 16,17,23 Our study indicates that even within the therapeutic range, the effects of aminophylline on pulmonary arterial vessels are related to the blood level of the drug. As with the peripheral arterial bed, there might also be a competition between the proper vasodilating effect of aminophylline" and its indirect a-adrenergic constriction on the pulmonary arterial bed. Pulmonary vasodilation has been observed only in relation to a high therapeutic blood level. Tissue oxygenation appreciated by the mixed venous P02 in this work was not modified by the decreased in O2 transport at rest thanks to the increased in tissue O2 extraction. Ventricular Systolic and Diastolic Function

A positive correlation is observed between the blood level of aminophylline and RV peak systolic pressure! end-systolic volume index suggesting that the inotropic effect of aminophylline I9 ,25-27 is also dose dependent. The positive inotropic effect of aminophylline probably depends on several mechanisms. The infusion of aminophylline in man has been shown to increase plasma levels of adrenaline and noradrenaline. 26 In CHEST I 103 I 6 I JUNE. 1993

1729

conscious dogs or on isolated rat papillary muscle, propranolol and reserpine diminish without suppressing the aminophylline-induced positive inotropic response. Those data suggest that the acute positive inotropic effects of aminophylline are mediated partly by a sympathetic nervous system stimulation and partly by a direct action on cardiac muscle fibers. This last mechanism is not entirely clear yet. A theophylline-induced inhibition of the cyclic nucleotide phosphodiesterase with an increase in cyclic 3'·5'-AMP seems unlikely Indeed, drugs like noradrenaline. glucagon, and dibutyril cyclic AM~ which increase decrease the time required to reach cyclic 3'·5'-AM~ peak isometric tension, whereas theophylline increases it. z:T However, interference of methylxanthines with the intracellular calcium metabolism might explain the positive inotropic cardiac effects partly by inhibition of calcium sequestration by the sarcoplasmic reticulum and partly by an effect on cell membrane leading to increased calcium entry 28 Finally, a drug-induced antagonism of cell surface receptor for adenosine to explain the improvement of myocardial contractibility has also been advanced." Ventricular relaxation, assessed by the peak filling rate for both ventricles, is not modified by aminophylline. This observation is in keeping with that of Gomez et aI,25 who have shown, in dogs with maintained constant preload, that aminophylline under normoxic condition does not modify the end-diastolic dimension of the L\I: Ventricular Ejection Fraction

The ventricular ejection fraction is a parameter that reflects ventricular performance. It is influenced by modifications of heart rate, afterload, contractility, and ventricular compliance. Based on group data, aminophylline seems not to modify the ventricular ejection fractions. Individual data, however, indicate that an increase of ejection fraction does occur for high therapeutic blood levels of the drug. For the R\; the increase of ejection fraction is observed concomitantly with a decreased pulmonary vascular resistance index and an increased myocardial contractility As for the L\; a similar phenomenon probably occurs: systemic resistance index progressively decreases and the LV ejection fraction progessively increases for an increasing blood level of aminophylline. Unfortunately, LVcontractility was not measured in our study. In summary, even within the therapeutic range (10 to 20 mgIL), the effects of aminophylline seem to depend on the blood level of the drug. This dose dependency could explain the contradictory data reported in the literature concerning the effects of aminophylline on pulmonary and systemic hemodynamics and on ventricular function. Finally, it should be noted that in this study; a single dose of amino1730

phylline was used. Whether the same dose dependency is observed during long-term administration of this drug is still to be determined. The appropriate target blood level(s) for aminophylline in COPD patients depends probably on the effects sought. The lowest aminophylline blood level that induces effective bronchodilation and increases respiratory muscular tone is ideal. However, at low therapeutic blood levels, a decrease in preload occurs inducing a decrease in cardiac index and a pulmonary and systemic vasoconstriction. Only a slight or even no positive inotropic effect is observed on the myocardium and ventricular ejection fraction remained unchanged. If the blood level needed to improve the pulmonary function is rather high, it will induce a vasodilation in the systemic and pulmonary circulation. A positive inotropic effect is observed on the myocardium and the ejection fraction increases. ACKNOWLEDGMENT: The authors express their gratitude to A. Malcorps, C. Tassenoy, and C. Cuerit for their excellent technical assistance. REFERENCES

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