hemodynamic effects of intravenous diltiazem in patients treated chronically with propranolol

Hemodynamic effects of intravenous diltiazem in patients treated chronically with propranolol

In the search for any deleterious hemodynamic effects of the acute administration of intravenous diltiazem (0.25 mg/kg), in patients on beta blockers, studies were performed in two comparable groups of eight patients with chronic coronary heart disease without clinical signs of heart failure. In the first group, with no previous treatment, the only significant variations observed were a decrease in systemic vascular resistance (p < 0.01) and an increase in cardiac index (p < O.Ol), which were noted only at 5 minutes. In the second group, receiving long-term oral doses of 120 to 240 mg/day of propranolol, at 5 minutes, despite a slight decrease in peak positive first derivative of left ventricular pressure (p < 0.05) cardiac index and systolic index increased (p < 0.05 and p < 0.01) with decreases in systemic vascular resistance (p < 0.01) and mean blood pressure (p < 0.05); at 15 minutes, systemic vascular resistance was still decreased (p < 0.05) and cardiac index and systolic index were still increased (p < 0.05). In conclusion, intravenous administration of diltiazem (0.25 mg/kg) to patients with chronic coronary heart disease and no evidence of congestive heart failure, who were receiving propranolol, was safe and prevented, in these patients, the potential deleterious effects of beta blockers, that is, increased peripheral vascular resistance and decreased cardiac output. (AM HEART J 111:62, 1986.)

Paulo Rocha, M.D., Bernard Baron, M.D., Alain Delestrain, M.D., Michel Pathe, M.D., Jean-Louis Cazor, M.D., and Jean-Claude Kahn, M.D. Poissy, France

Calcium antagonists have been shown to induce a reduction in myocardial contractility in vitro.ls2 However, this negative inotropic effect has not been observed in intact animals or humans3s4 and could be counteracted by the secondary sympathetic response to the systemic hypotension commonly observed with these drugs.5-s The use of calcium antagonists in patients presenting signs of heart failure may be limited by the negative inotropic effect, particularly when combined with beta blockers. Furthermore, the negative inotropic, dromo- tropic, and chronotropic effects of calcium antagonists were found to be cumulative to those of beta blockers combined with nifedipineg* lo or verapamil 11*12 However, some authors, with the use of a . nifedipine-beta blocker combination, found that this was not only safe but therapeutically more effective.‘3-17

From the Department of Cardiology, Centre Hospitalier Intercommunal de

Poissy. Faculty of Medecine Paris-Ouest-Universitk Ren& Descartes.

Received for publication Jan. 25, 1985; revision received June 10. 1985; accepted July 8, 1985.

Reprint requests: J. C. Kahn, M.D., Department of Cardiology, Centre Hospitalier Intercommunal, 10, rue du Champ Gaillard, 78303 Poissy, France.

Hung et a1.17 were the first to study the association between diltiazem and propranolol, which was shown to be clinically safe. However, their study provided no hemodynamic data. The aim of our study was to determine the safety and hemodynamic effects of diltiazem, with a single intravenous dose which had a supraventricular antiarrhythmic effect,ls in two comparable groups of patients with proved coronary heart disease. The first group received no treatment prior to diltiazem and the second was treated chronically with propranolol. We compared the hemodynamic variations induced by diltiazem in the two groups.

METHODS

Patients. Sixteen maIe patients, sent to the hemodynamics department for investigation of thoracic pain, agreed to participate in the study. Patients with clinical signs of heart failure, bradycardia of less than 50 bpm, atrioventricular block, or myocardial infarction within the previous month were all excluded from the study. Other criteria for exclusion were the impossibility of stopping all treatment for a period of at least 3 days and the absence of sinus rhythm.

These 16 patients were divided into two groups of eight patients with similar pathologies. Each group consisted of

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Number 1 Hemodynamics of combined diltiazemlpropranolol 63

four cases of effort myocardial angina, three cases of inferior myocardial infarction, and one case of anterior myocardial infarction. The patients in the first group (diltiazem) had a mean age of 52 years (range: 39 to 60) and showed one or two stenoses of more than 70 % luminal narrowing of a major coronary artery, with a mean of 1.25. All previous treatment was stopped prior to the study for more than five times the half-life of the drugs, except for propranolol in the propranolol group. The patients in the second group (propranolol + diltiazem) had a mean age of 51 years (range: 35 to 69) and a mean of 1.5 stenoses of more than 70% luminal narrowing of a major coronary artery. They received 120 to 240 mg/day of propranolol for at least 1 week prior to the study with the last intake 2 hours before the examination. Propranolol plasma levels were a mean of 125 mg/ml (range: from 67 to 157) at the time of the measurements.

Protocol. Patients were examined in the morning, in the supine dorsal position, after fasting, and without premeditation. Ten minutes after the catheters had been inserted control measurements were made, including right and left intracavitary pressures, cardiac output, and left ventricular volumes by angiography. Ten minutes after ventriculography and during continuous recording of left ventricular, aortic, pulmonary capillary wedge, and right atria1 pressures, a bolus of 0.25 mg/kg of diltiazem was injected in 15 seconds vi.a an intravenous catheter. Five minutes later, cardiac output was measured. At 15 minutes after the bolus injection of diltiazem, all measurements were repeated and a second left ventriculography was performed.

Materials. Right intracavitary pressures were measured via a Swan-Ganz 7F catheter with one lumen in the right atrium and the other in the pulmonary artery. Cardiac output was measured by thermodilution. Left ventricular pressures were collected by a high-fidelity micromanomet- er, Millar 6F model PC 360, inserted through an introducing sheath into the femoral artery. Mean aortic pressure was measured by the lateral approach to the introducing sheath. Angiography was, performed via a “pigtail” 7F catheter inserted into the other femoral artery. The left ventricular pressure tracing was recorded and also fed to a differential amplifier (Electronics for Medicine) to pro- vide the peak positive first derivative of left ventricular pressure averaged over 15 cardiac cycles. The other catheters were connected to a Statham 23 ID transducer and intracavitary pressures were transmitted via liquid col- umns. The signals were analyzed by an Electronics for Medicine electromanometer and recorded on a VR 12 polygraph (Electronics for Medicine) with four ECG leads. Left ventriculography was performed in the 30- degree right anterior oblique position. Ventricular volumes were measured in end systolic and end diastolic according to the method of Dodge.lg

Data measured. The following were measured: mean right atria1 pressure (RAP), mean pulmonary arterial pressure (MPP), pulmonary capillary wedge pressure (PWP), mean blood pressure (MBP), left ventricular

Table I. Control hemodynamic data in the two groups before diltiazem

Data D P P+D

HR (bpm) 68 +- 5 <O.Ol 58 k 6 RAP (mm Hg) 6.6 k 1.9 NS 6.4 T 1.0

MPP (mm Hg) 18.3 f 3.9 NS 17.1 * 3.4 PWP (mm Hg) 11.5 f 3.5 NS 12.1 i 2.7 LVEDP (mm Hg) 17?6 NS 17 I? 6 SBP (mm Hg) 127 k 11 NS 132 ” 19

MBP (mm Hg) 93 f 7 NS 97 k 7 CI (L/mm/m2) 3.43 2 0.54 <0.05 2.79 k 0.16 SI (ml/cycle/m2) 51 f 10 NS 49 f 6 LVSWI (gmlcycle/m2) 72 k 18 NS 71 * 11 SVR (dynes set .cmmS) 1106 + 150 <0.05 1444 k 277 PVR (dynes set .sec-’ 86 + 18 NS 79 + 17 dLVP/dt (mm Hg .sec -‘) 1281 + 173 NS 1426 t 287 V,,, (set-‘) 1.03 k 0.07 NS 1.07 k 0.13 Angiographic

EDV (ml/m’) 102 k 27 NS 97 k 16 ESV (ml/m’) 47 r 28 NS 45 Yc 12 SI, (ml/m2) 55 k 14 NS 53 _t 6 EF t II, ) 58 k 15 NS 55 k 6 ACS ((‘(8 ) 15 k 15 NS 14 -c 11

CI, (L/mn/m2) 3.63 f 0.79 NS 3.05 f 0.47

Abbreviations: D = diltiazem; P + D = propranolol + diltiazem; ACS = ex-

tent of akinetic or dyskinetic abnormally contracting segments expressed as a percentage of end-diastolic perimeter of the left ventricle; CI = cardiac

index; Cl,a = angiographic cardiac index; dLVP/dt = peak positive first derivative of left ventricular pressure; EDV = end-diastolic volume index; EF = ejection traction; ESV = end-systolic volume index; HR = heart rate; LVEDP = left ventricular end-diastolic pressure; LVSWl = left ventricular stroke work index: MBP = mean aortic blood pressure; PVR = pulmonary vascular resistance: PWP = pulmonary wedge pressure; RAP = right atria1 pressure; SBP = systolic blood pressure; SI = stroke index; SI, = angiographic stroke index; SVR = systemic vascular resistance: V,,, = maximal shortening speed of the myocardial fiber.

end-diastolic pressure (LVEDP), systolic blood pressure (SBP), peak positive first derivative of left ventricular pressure (dLVP/dt), cardiac output (Q), and heart rate U-W.

Data calculated. The following were calculated: systemic vascular resistance (SVR), where SVR = 80 (MBP - RAP)/Q; pulmonary vascular resistance (PVR), where PVR = 80 (MPP - PWP)/Q; peak dLVP/dt; maxi- mum shortening speed of myocardial fibers (V,,,) accord-

ing to the method of Grunk-emeier et al.*O cardiac index (CI), where CI = Q/body surface; systolic index (SI), where SI = CI/HR; left ventricular stroke work index (LVSWI), where LVSWI = (left ventricular systolic mean pressure - LVEDP) x SI x 0.0144. On ventriculography were calculated: left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) indices, both in relation to body surface; angiographic stroke index @I,), where SI, = LVEDV - LVESV; left ventricular ejection fraction (EF), where EF = SI,/ LVEDV; angiographic cardiac index (CI,), where CI, = SI, X HR.; the akinetic perimeter of the left ventricle (ACS) for patients who had presented with.a myocar-

64 Rocha et al. January. 1986

American Heart Journal

RAP ImmHgl

LVEDP lmmtigl

IP+Dl 150 r T

MPP ImmHgi PWP immHgl IDi lP+Ol

SBP (mmtigl IO1 IP+Oi 150 T. r MEP ImmHgl

iDI IP+Di

Fig. 1. Right atria1 pressure (RAP), mean pulmonary pressure (MPP), pulmonary wedge pressure (PWP), left ventricular end-diastolic pressure (LVEDP), systolic blood pressure @BP), and mean aortic blood pressure {MBP) in the first group, without previous treatment (D), and in the second group, treated with propranolol (P + D), during a control period (C), 5 minutes after diltiazem infusion, and 15 minutes after diltiazem infusion. p < 0.05; p < 0.01 (both compared to the control period).

HR (BEATSIMIN1 Cl lllmdl

100 r lOI iP+OI r

(01 lP+OI **

4

50 2

0 0 c 5' 15' c 5' 15' c 5' 15' c 5' 15'

SI ImllCYCLElm21 LVSWIIgmlCYCLElm2I

im IP+Ol

80 80

40 40

0 0 c 5' 15' c 5' 15' c 5' 15' c 5' 15'

Fig. 2. Heart rate (HR), cardiac index (CI), stroke index @I), and left ventricular stroke work index (LVSWI) in the first group, without previous treatment (D), and in the second group, treated with propranolol (P + D), during a control period (C), 5 minutes after diltiazem infusion, and 15 minutes after diltiazem infusion. *p < 0.05; **p < 0.01 (both compared to the control period).

dial infarction, where ACS = the extent of akinetic or dyskinetic “abnormally contracting segments” expressed as a percentage of the end-diastolic ventricular perimeter.21

Statistical analysis. Data were expressed as mean +

standard deviation during the control period and 5 and 15 minutes after drug administration. Comparisons during the control period between the two groups were done by t test for independent data. Hemodynamic effects of diltiazem were analyzed by analysis of variance for repeated measures between the two groups. In the event of significance, t test was used to determine significant differences. Statistical significance of the variations observed within each group at the 5% level was evaluated by means of analysis of variance and Student’s t test. Comparisons of data and variations observed between the two groups relied on analysis of variance.

RESULTS

Hemodynamic control values in the two groups of patients. Values for hemodynamic parameters before injection of diltiazem are shown in Table I.

In the diltiazem group (without previous treatment) usual values for coronary patients were found, with a slightly increased LVEDP to 17 -t 6 mm Hg. Vascular resistances and data related to contractility were .also normal. Left ventricular angiography showed that the LVEDV index was 102 -C 27 ml/m2. Left ventricular EF was 58 f 15 9%. The mean percentage of ACS of the left ventricle was 15 k 15%.

In the propranolol + diltiaxem group, previously treated with propranolol, initial values were similar to those of the diltiazem group, except for those parameters influenced directly by propranolol. Thus HR was 68 -+ 5 and 58 + 6 bpm in the diltiazem and propranolol + diltiazem groups, respectively

“cllwne 111

Number 1

SVR IDYNES-cm-51 PVR (DYNES-cm-51

Hemodynamics of combined diltiazemlpropranolol 65

EDV Imlim2i ID1 lP+OJ

TT IP+CIl 2000

T *

1000 100

(P+DI

100

50

15' c 5' 15'

dlVPfdt hnmHglSi v max (S-11 ID1 lP+Di 0 !

-r * - (P+Dl

r

1000 1 100

0.5

50

0 0

c 5' 15 c 5' 15' c 5' 15' c 5' 15

0 1 Fig. 3. Systemic vascular resistance (SW, pulmonary vascular resistance (PVR), peak positive first derivative of the left ventricular pressure (dLVP/dt), and maximal shortening speed of the myocardial fiber (V,,,) in the first group, without previous treatment (D), and in the second group, treated with propranolol (P + D), during a control period (C), 5 minutes after diltiazem infusion, and 15 minutes after diltiazem infusion. *p < 0.05, **p < 0.01 (both compared to the control period).

ESV Imllm2)

Sla lmllm2l 1OOr EF 1%)

IP + 0)

50

n 1 c 15' c 15'

Fig. 4. End-diastolic volume index (EDV), end-systolic volume index (ESV), angiographic stroke index (SIJ, and ejection fraction (EF) in the first group, without previous treatment (D), and in the second group, treated with propranolol (P + D), during a control period (C), 5 minutes after diltiazem infusion, and 15 minutes after diltiazem infusion. *p < 0.05; **p < 0.01 (both compared to the control period).

(p < 0.01); the CI was 3.43 -t 0.54 L/min/m” in the diltiazem group and 2.79 f 0.16 in the proprano- 101 + diltiazem group, 0, < 0.05); and SVR was 1106 + 150 dynes . set . cmm5 in the diltiazem group and 1444 f 277 in the propranolol + diltiazem group (p < 0.05).

Hemodynamic effects of diltiazem (within 15 minutes) in both groups of patients (Figs. 1 to 4). In the diltiazem group, without previous treatment, the modifications induced by diltiazem were moderate. Pressures remained stable. At 5 minutes the CI increased from 3.43 ? 0.54 to 3.90 _+ 0.55 L/min/m2 (p < 0.01) and SVR fell from 1106 f 150 to 919 + 130 dynes . set . cm+ (p < 0.01). At 15 minutes

these differences were no longer significant. Fifteen minutes after injection of diltiazem, the LVESV index increased from 47 + 28 to 51 f 28 ml/m* tp < 0.05) and left ventricular EF decreased from 58 +. 15 to 55 4 14 ml/m” (p < 0.05). These minor variations suggest a slight negative inotropic effect, but the other indices of contractility remained stable. The mean diltiazem plasma level after 15 minutes was 89 f 18 rig/ml.

In the propranolol + diltiaxem, previously treated with propranolol, 5 minutes after injection of diltia-

zem the PWP increased from 12.1 f 2.7 to 14.5 f 3.3 mm Hg (p < 0.05) and the MPP increased from 17.1 f 3.4 to 20.5 f 4.3 mm Hg (p < 0.05), with the appearance of a “v” wave on the PWP in two of these patients; LVEDP, however, remained unchanged. MBP fell from 97 +- 17 to 85 ? 13 mm Hg @ < O.Ol), CI increased from 2.79 f 0.16 to 3.38 -t 0.46 L/min/m* (p < 0.05), and SVR fell from 1444 f 277 to 1034 rt 172 dynes - set . cmm5 (p < 0.01). The interpretation of the evolution of the data linked to the inotropism is not obvious, since dLVP/dt decreased from 1426 * 287 to 1296 -t 281 mm Hg/sec (p < 0.05), but V,, remained unchanged and the SI increased from 49 & 6 to 57 f 6 ml/ systole (p < 0.01).

After 15 minutes three parameters remained dis- turbed by diltiazem. MBP was further decreased, having passed from 97 +- 17 initially to 88 k 13 mm Hg (p < 0.05), SVR also remained decreased at 1210 f 240 dynes . set . cmF5 from 1444 & 277 initially (p < 0.05), and the SI was increased, passing from 49 + 6 ml/systole initially to 55 + 8 ml/systole (p < 0.05). The angiographic parameters were

66 Rocha et al. January, 1986

American Hear1 Journal

PATIENTS WITHOUT PREVIOUS TREATMENT

PATIENTS CHRONICALLY TREATEO BY PROPRANOLOL

I

p<oo5 p<o.o5 RAP MPP PWP LVEOP SBP MBP Cl Sl LVSWI SVR PVR dLVEDP Vmax

Fia. 5. Comnarison of nercentapres of change from the control period to 5 minutes after diltiazem infusion (aGbreviatio& as in Figs. 1 to 3).

unchanged. Diltiazem showed no obvious negative inotropic effect in the patients on beta blockers. The mean diltiazem plasma level at 15 minutes was 79 +- 26 rig/ml in the propranolol + diltiazem group.

Differences between the hemodynamic variations observed with diltiazem: Comparison of the two groups (Figs. 5 and 6). Hemodynamic changes were identical in both groups with three exceptions. At 5 minutes, SVR fell at 17% in the diltiazem group and by 28% in the propranolol + diltiazem group; this drop was statistically greater in the beta blocker group (p < 0.05). dLVP/dt increased by 4% in the diltiazem group and fell by 9% in the propranolol + diltiazem group; these variations were statistically significant @ < 0.05).

At the 16 minutes, the LVESV index increased by 9 % in the diltiazem group and decreased by 7 % in the propranolol + diltiazem group; these variations were also statistically significant (p < 0.05). What was observed primarily at 5 minutes in the patients treated with propranolol was a slight decrease in dLVP/dt. However, since the SVR was lower in this group, it was in the beta blocker group that the SI was most increased (NS). The angiographic data confirmed these results: LVESV remained unchanged in the beta blocker group but increased slightly in the group without previous treatment.

DISCUSSION

The hemodynamic effects of the association of diltiazem with beta blockers are not well known.

Other calcium antagonists have been studied hemo- dynamically in patients on beta blockers, and deleterious effects on left ventricular function have been revealed.15’22 The present study focuses on the potential deleterious negative inotropic effects of the diltiazem plus propranolol association in two groups of patients with similar pathologies. Only the data influenced directly by propranolol differed between the two groups. Thus CI and HR were lower and SVR was higher in the propranolol + diltiazem group. These effects of propranolol have been well known since 196623 and have been confirmed by several authors.24-26

Hemodynamic effects of diltiazem in the diltiarem group. In this group of previously untreated patients are those effects normally found in the literature when this drug is used intravenously in vivo and at therapeutic doses.27.28 These effects are centered on a reduction in SVR and an early and fleeting reduction in inotropism. Data in the literature refer- ring to left ventricular volumes are discordant; for example, left ventricular EF increased from 50% to 54% in one study5 but remained unchanged in another.%

In our study, the EF decreased slightly in the untreated group. This decrease was secondary to an increase in LVESV, which is in contrast to the findings of Just et aIzg who reported a decrease of 9% in left ventricular end-systolic diameter. All these variations in left ventricular volume with diltiazem are close to the sensitivity limits of the measurement methods used: echocardiography

Volume 111

Number 1 Hemodynamics of combined diltiazemlpropranolol 67

L -40

HR RAP MPP PWP LVEDP SBP MBP Cl SI LWSWi SJR PWR dLVPldt Vmax ELIV ESV Sla EF

Fig. 6. Comparison of percentages of change from the control period to 15 minutes after diltiazem infusion (abbreviations & in Figs. 1 to 3).

time motion (TM)% or radionuclide ventriculogra- phy6 compared to contrast ventriculography for our patients.

Hemodynamic effects of diltiazem in patients treated chronlcally with propranole!. These effects are similar to those observed in the group of patients without previous treatment. However, the patients on beta blockers presented a drop in dLVP/dt up to 5 minutes and a greater and more lasting decrease in SVR, which was still significant at 15 minutes. This different response suggests that the sympathetic reflex resulting from the initia,l hypotension pro- voked by the calcium antagonist could not develop fully under propranolol. The greater fall in SVR masked the supplementary negative inotropic effect of propranolol, and the SI increased and remained increased for 15 minutes without any modification in filling pressure. Moreover, the decrease in systemic vascular resistance allows the left ventricular systolic volume index and the ejection fraction to return to control values.

Nifedipine is the calcium antagonist most commonly studied in association with beta blockers. Some authors find this association to be dangerous,10 but other@ believe it is safe and even advantageous as an antianginal treatment. The hemodynamic effects of this association are similar to those observed with nifedipine used alone, that is, a clear reduction in SVR with stable filling pressure and a decrease in mean systemic arterial pressure. Howev- er, when beta blockers are combined with nifedipine, the reduction in SVR is smaller. The increase in the CI, previously lowered by the beta blockers, is also

inferior to the increase in this parameter induced by nifedipine alone.

The hemodynamic effects of intravenous verapamil have been studied in patients treated chronically with propranolol.30 The hemodynamic changes observed were minim& SVR dropped by 7% as did MBP. In this instance propranolol obliterates the beneficial hemodynamic effects of verapamil used alone.32

The present study reinforces prior observations.17 The combination of diltiazem plus propranolol is safe in patients without important left ventricle impairment. Furthermore, this calcium antagonist counteracts two potentially deleterious effects of propranolol: the increase in SVR and the decrease in the CI. The improvement of the “pump” activity of the left ventricle with this combination is particular to diltiazem, since the other calcium antagonists do not counteract the effects of beta blockers as effec- tively. The clinical implications are that in patients treated with propranolol and without important left, ventricle impairment, the intravenous infusion of 0.25 mg/kg of diltiazem, an antiarrhythmic dose,18 is safe and without measurable evidence of left ventricle contractility depression.

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hemodynamic effects of intravenous diltiazem in patients treated chronically with propranolol

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