Intermittent dobutamine therapy in patients with advanced congestive heart failure

Archives of Gerontology and Geriatrics 23 (1996) 313-327

ELSEVIER

ARCHIVES OF GERONTOLOGY AND GERIATRICS

Intermittent dobutamine therapy in patients with advanced congestive heart failure Claudio Ferroni*, Aureliano Fraticelli, Enrico Paciaroni Cardiology Department, LN.R.C.A.--LR.C.S.S., Via della Montagnola, 164, 1-60131 Ancona, Italy Received 8 May 1996; revised 25 July 1996; accepted 27 July 1996

Abstract Congestive heart failure is an increasingly common condition carrying a poor prognosis and a decay in the quality of life. Usually frequent and lengthy hospitalizations are required with heart failure, with obvious discomfort for the patient and increase in health costs. Heart transplantation is rarely possible due to shortage of donors. Thus, improvement of pharmacological strategies for the management of these patients is desirable. The present study evaluated the effects of intermittent dobutamine infusion in elderly patients (mean age 75.9 years), hospitalized for advanced (NYHA, 1973, class IV) congestive heart failure of ischemic etiology. Dobutamine infusions of 2, 4 and 6/~g/kg/min for 36 h every 2 - 4 weeks were randomly prescribed to 24 subjects, who were then followed up every three months for an average of ten months. Data on mortality, cardiovascular events and N Y H A (1973) functional classifications were systematically collected. Our study shows that while in this series of patients mortality remained high (50% at 12 months), there was an improvement in the NYHA-classification during the follow-up, and a decrease in the need for hospitalization. In addition, side effects were relatively rare, with only two patients interrupting dobutamine treatment. We conclude that intermittent dobutamine infusion is a reasonable treatment option in elderly patients with congestive heart failure unresponsive to conventional treatments. Copyright © 1996 Elsevier Science Ireland Ltd Keywords: Congestive heart failure; Dobutamine therapy in elderly

* Corresponding author. 0167-4943/96/$15.00 Copyright © 1996 Elsevier Science Ireland Ltd. All rights reserved PI! S0167-4943(96)00739-X

314

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327

I. Introduction

The effectiveness of thrombolytic and antiarrhythmic therapy in acute myocardial infarction, of coronary revascularization in patients with moderate to severe left ventricular dysfunction, and of surgical correction of valvular and congenital heart defects has prolonged survival of many patients with heart disease. However, the number of heart patients who progress to a dilative phase, with moderate to severe manifestations of heart failure, has increased concomitantly (Sacher et al., 1992). Heart transplantation can restore functional efficiency and a good quality of life for some of these patients, who would otherwise have a poor short-term prognosis. However, this option is precluded to patients older than sixty-five because the low number of donors limits the availability of transplants, and because it has been demonstrated that the benefits of heart transplantation are greater in the younger than in the older subjects. Cardiac insufficiency is a complex entity, arising from a marked depression of myocardial contractility and from the subsequent reduction in cardiac output which in turn causes a series of neurohormonal responses directed at restoring a balance compatible with the conservation of the main vital functions. The responses, however, are often exaggerated, thus bringing about a series of functional and anatomical changes within the cardiovascular system, which differ in the acute and in the chronic phases. Drugs improving cardiac output in heart failure patients, through vasodilation and neurohormonal changes, have significantly reduced long term mortality (Cohn et al., 1986; The CONSENSUS Trial Study Group, 1987). Instead, available trials on the chronic oral administration of positive inotropic agents have obtained contrasting results. In fact, the majority but not all of these studies have documented that after initial improvement of the clinical signs of heart failure and of the quality of life, there was an increase in mortality in the treated groups, probably due to arrhythmias (Packer et al., 1991; Feldman et al., 1993). However, a recent study in which vesnarinone was used in two different dosages, demonstrated a reduction in the mortality in the group treated with the lower dose (Feldman et al., 1993). In summary, novel drugs have provided effective therapy for previously incurable patients, who would rapidly progress to general deterioration and death. Unfortunately, however, there remains a category of patients who, despite optimal therapy with beta-blockers (in the stages of minor hemodynamic impairment), digitalis, diuretics and vasodilators, taken in combination or separately, are prone to repeated episodes of decompensation of heart failure and serious manifestations of low cardiac output, requiring hospital admission for the intravenous administration of medications that would be poorly absorbed orally. Dobutamine, a synthetic catecholamine with an interesting mechanism of action, could be useful in the correction of several manifestations of heart failure: in fact, it can improve hemodynamics in both the acute and the chronic phase. The

C. Ferroni et al. / Arch. Gerontol. Geriatr. 23 (1996) 3 1 3 - 3 2 7

315

duration of these beneficial effects, the onset of tolerance to prolonged use and its side effects are the subject of studies still in progress, aiming at better defining the indications and administration modalities.

2. Mechanism of action of dobutamine

Dobutamine is a synthetic catecholamine with agonist activity on the alpha-l, beta-1 and beta-2 receptors, thus capable of modifying myocardial inotropism, chronotropism and vascular smooth muscle tone (Table 1) (Lawless and Loeb, 1989). The increase in cardiac inotropism is strictly correlated with the stimulation of the beta-1 receptors, which in chronic heart failure are already overstimulated by the augmented production of local and circulating endogenous catecholamines. With time this brings about a downregulation phenomenon, that is a decreased availability of receptors, with a consequent reduction in the efficiency of the agonists and onset of tolerance (Cohn et al., 1986). The further increase in the blood levels of endogenous catecholamines would cause excessive stimulation of the beta-2 receptors, with subsequent augmentation of the chronotropism and peripheral vasodilation, responsible for the increase in oxygen consumption together with a reduction in perfusion pressure. Instead, dobutamine produces an inotropic effect also through the stimulation of the cardiac postsynaptic alpha-I receptors, preserving the presynaptic deposits of noradrenaline (Lejemtel et al., 1989). More over, peripheral vasodilation, mediated by the beta-2 receptors, causes a reduction in afterload. Thus, hemodynamically a significant increase in cardiac output is observed, in addition to a significant reduction in filling pressure (Goldstein, 1989). Several studies, many of which have focused on cardiogenic shock complicating myocardial infarction, have shown that dobutamine can, in the majority of patients, utilize residual energy reserves to increase cardiac output and consequently peripheral perfusion pressure, reducing the ventricular filling pressure and without substantially changing vascular resistance. Advantages are considerable compared with other alpha and beta agonists that overly increased oxygen consumption, by an excessive augmentation of vascular resistance or heart rate (Goldstein, 1989).

Table l P h a r m a c o d y n a m i c effects o f d o b u t a m i n e Dose/~g/kg/ rain

<2 2 5 5 10 10 15

Receptors

beta-1

beta-2

alpha-I

+ + ++ ++

+ + +

± + + +

lnotropism

Chronotropism

Bathmotropism

R e n a l flow

+ + ++ +++

-± ++ +++

-+ + ++

+ + ++ ++

316

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Arch. GermTto/. Geriatr. 23 (1996) 313 327

According to Tan and Littler (1990) an incremental-dose dobutamine test in patients with cardiogenic shock can identify those with high probability of survival, based on peak systolic work ( < 0.25 J/m 2) and peak heart power ( > 1.0 W). Some authors (Richard et al.~ 1983) recommend combined use of dobutamine with other catecholamines, lbr example low dose dopamine, as it would favorably improve heart performance without excessive increase in energy demand. In addition, this combination would enhance oxygen supply and peripheral perfusion of essential organs such as the kidneys. Dobutamine also causes a reduction in pulmonary vascular resistance which is rarely emphasized, although it is of extreme importance for the majority of patients with refractory heart failure, often associated with pulmonary hypertension. In a recent work (Oliva et al., 1994a) cardiac catheterization was performed in 32 patients with relapsing congestive heart failure and secondary pulmonary hypertension. Seventeen patients underwent a complete series of pharmacological tests aimed at assessing the reversibility of pulmonary hypertension, in view of inclusion in the heart transplant program. Drugs used in incremental doses were: dobutamine, sodium nitroprusside, prostacyclin, enoximone and the combination of dobutamine and sodium nitroprusside. Table 2 lists the effects on the main hemodynamic parameters. In particular, it can be noted that dobutamine alone is able to achieve a significant increase in cardiac index (CI) from 2.0 + 0.41/mm/m ~ to 3.4 + 0.81/min/m -~ and a significant reduction in the systemic vascular resistance (SVR) from 22.7_+ 8 to 1 4 + 4 (Wood units) and in pulmonary vascular resistance (PVR) from 4.8 _+ 2 to 3 _+ 1 (Wood units). The combination of dobutamine and sodium nitroprusside obviously obtained the best results, with CI, SVR and PVR, respectively were equal to 3.5 _+0.81,,' min/m 2, 12.5_+4 Wood units, and 1 . 9 + 0 Wood units, Thus, the reversal of pulmonary hypertension according to commonly accepted criteria (CI >2.51,,' min/m 2, PVR <2.5 Wood units and transpulmonary pressure gradient < 12 mmHg) was achieved by dobutamine alone in six patients out of 17 (35.2%), and by the combination of dobutamine and sodium nitroprusside in 10 out of 17 patients (58.8%) (Oliva et al., 1994a). However, controlled trials strictly evaluating the survival of patients with dilative cardiomyopathy and cardiogenic shock treated with dobutamine are lacking. The group of Mauri (Oliva et al., 1994a) treated 32 patients of the 90 admitted for dilative cardiomyopathy and symptoms of low cardiac output from June 1989 to February 1992. Five of these received dobutamine alone. Twelve patients died (37.5%) while ot" the remaining 20, 10 were discharged (31%), four (13%) implanted with ventricular assist devices, and six (19%) underwent heart transplantation. The overall survival rate was 63%, an excellent result compared with the series of patients with cardiogenic shock treated conservatively.

80.2 71.7 28.5 6.0 16.3 12.1 2.6 15.1 2.5

(1.0) (9.0)* (l.O)* (3.4)* (8.0)* (6.0)* (l.O)* (4.0)* (0.5)*

95.7 77.8 28.1 5.8 5.8 12.6 1.9 12.5 3.5

(2.0)* (1.0) (l.O)* (5.0)* (5.0)* (5.0)* (0.9)* (4.0)* (0.8)*

Na-nutroprusside

cardiomyopathy + dobutamine

83.9 71.9 34.6 6.7 6.7 13.3 2.5 12.8 3.1

PGI, (9.0)* (8.0)* (l.O)* (4.0) (4.0) (4.0)* (l.O)* (4.0)* (0.8)*

86.9 82.3 31.9 5.0 5.0 14.9 3.3 17.7 2.6

(l.O)* (1.0) (l.o)* (4.1)* (4.1) (7.0)* (l.o)* (5.0)* (0.6)*

Enoximone

MAP: mean arterial pressure; P-MAP: pulmonary mean arterial pressure; RAP: gradient; PVR: pulmonary vascular esistence; SVR: systemic vascular resistance;

with dilative

Na-nutroprusside

in 17 patients

( ): standard deviation; * PcO.05; HR: heart rate; bpm: beats per minute; right atrial pressure; MCP: mean capillary pressure; TPG: tram-pulmonary CI: cardiac index; PGI,: prostacyclin

(l.O)* (1.0) (l.o)* (4.0)* (8.0)* (5.0) (l.o)* (4.0)* (0.8)*

91.6 85.7 37.4 5.8 20.0 17.4 3.0 14.0 3.4

(2.0) (9.0) (1.0) (5.0) (8.0) (5.0) (2.0)* (8.0) (0.4)

78.2 86.4 42.9 78.8 26.2 16.7 4.8 22.7 2.0

treatments

HR (bpm) MAP (mmHg) P-MAP (mmHg) RAP (mmHg) MCP (mmHg) TPG (mmHg) PVR (Wood units) SVR (Wood units) CI (l/min/m’)

by various Dobutamine

induced Basal

changes

Treatment

Table 2 Hemodynamic

31g

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Arch. Gerontol, Geriatr. 23 (1996) 313 3 2 7

3. Dobutamine in the treatment of chronic heart failure

The pathophysiological picture is definitively more complex in chronic than in acute heart failure. In t:act, the persistent low cardiac output promotes and sustains a series of neurohormonal changes, affecting various systems (neurovegetative, surrenal, renin-angiotensin and natriuretic systems) which in turn leads to an increase in cardiac inotropism and vasoconstriction on one hand, and to metabolic changes involving both cells, extracellular space and its hydroelectrolytic balance (Cohn et al., 1981) on the other hand. The ideal drug should not only eliminate the primary cause of heart failure, increasing cardiac output, but also correct the above mentioned biohumoral alterations. Unfortunately, to date trials on long-term oral administration of positive inotropic drugs have been disappointing (Packer et al., 1991). The available main studies have documented an increase in mortality, for which various explanations have been provided. However, therapeutic strategies which selectively interact with one of the above mentioned systems have obtained positive results in terms of surviwll, even in large trials, as has occurred with Angiotensin Converting Enzyme (ACE)-inhibitors or other vasodilators (Cohn et al., 1986: The CONSENSUS Trial Study Group, 1987). In clinical practice, treatment strategies involving beta-blockers, ACE-inhibitors and diuretics are common. Studies that clarify the respective advantages and possible synergy, however, are still not available. In addition, the appearance of side effects often limits the use of vasodilators or anti-adrenergic drugs, a typical example being hypotension due to ACE-inhibitors or beta-blockers. In these cases the therapeutic role of positive inotropic drugs and in particular, of intravenous beta agonists such as dobutamine must be considered. Despite the down-regulation of beta-1 receptors present in all patients with a long-standing dilative cardiomyopathy, dobutamine increases the cardiac index up to 20 50% of baseline values during acute tests: at the same time a reduction in pulmonary and systemic vascular resistances and in the filling pressure is observed. without a decline in arterial pressure, which actually increases in some cases. This type of action is comparable in many ways to that of phosphodiesterase inhibitors, at least in as much as cardiac output and peripheral resistance (Tsukahara, 1989) are concerned. Miller et al. {1990) described a group of 11 patients with dilative cardiomyopathy in NYHA (1973) class I V these were not considered candidates for a heart transplant and discharged on dobutamine therapy since they were strictly dependent on it. In seven patients dubutamine was suspended gradually after an average 2.3 months, while in the remaining four it was prolonged for the entire follow-up period (13 -37 months). In the former group no hospital admission for heart failure was required while on dobutamine therapy. Collins et al. (1990) reported that in three patients awaiting heart transplant, treatment was prolonged for an average of 27 days, resulting in marked improvement in the quality of life and functional capacity, without the need for further hospital admissions. Contradictory observations on the effects of dobutamine on quality of life are rare (Krell et al., 1986).

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Improvement in cardiac performance achieved with prolonged ( > 4 8 - 7 2 h) treatment appears to be sustained for weeks. Liang et al. (1984) reported that in a placebo controlled study individuals treated with dobutamine for 72 h, belonged to a better functional class after four weeks and exhibited a higher ejection fraction and an improved tolerance to physical exercise. According to Unverferth et al. (1983), dobutamine could improve not only cardiac output, but also metabolism, both at the myocardial (enhanced coronary flow and consequently greater oxygen supply) and at the systemic level (higher blood sodium and lower blood urea). Histologically, a reduction in mitochondrial swelling could be observed. These positive changes, achieved with infusion of dobutamine for 72 h, are considered responsible for the subjective and objective (echocardiographic) improvements. Unverferth et al. (1980) also reported that with prolonged ( ___72-96 h) dobutamine infusion, the acute hemodynamic response was gradually attenuated up to 40-50%. This reduction is similar to that observed after other treatments acting through the beta receptor-adenylate cyclase-cAMP system, and it may be contrasted by a dose increment. However, this would tend to provoke an excessive positive chronotropic response with an undesirable increase in oxygen consumption. For this reason it seems appropriate to test the effect of intermittent administration-48-72 h each week or 4 h a day (Applefeld et al., 1983). Table 3 shows the main results of available clinical studies of this latter type. These were mainly small and uncontrolled series, in which dobutamine was judged beneficial by most authors, taking into account the clinical severity of the heart failure in the majority of patients. In particular, an improvement in the quality of life and a reduction in hospital readmissions were observed. Dies et al. (1986), who carried out a randomized study on 60 patients, found that in addition to a clear benefit for the quality of life, there was an excessive mortality rate (probably due to arrhythmias) in the group treated with dobutamine. Consequently, this study was prematurely terminated. However, their conclusions cannot be considered definitive for two reasons, one being of clinical and the other of statistical origin. In fact in their work, the clinical severity of the two treatment groups was not clear, at least in terms of arrhythmic risk. Thus it is simply reported that, in subjects with more than four episodes of ventricular tachycardia in 24 h, dobutamine therapy carries a greater risk of death. Furthermore, two patients initially assigned to the placebo group were switched to dobutamine because of persistence of heart failure symptoms. From a statistical point of view, the wide confidence intervals due to the low number of patients do not allow their results to be considered conclusive. In addition, Sacher et al. (1992), who reviewed 24 trials with dobutamine, emphasized that in 67% of them there is no mentioning of arrhythmic problems. In the remaining ones, arrhythmias complicating dobutamine treatment correlate with the dose administered and with the previous presence of major arrhythmias. Goldenberg et al. (1989) point to a potassium lowering effect of dobutamine, undoubtedly crucial for patients taking diuretics in high doses. Based on these potentially dangerous adverse effects, some authors suggest direct medical surveillance throughout the period of dobutamine infusion. Recently an observational multicenter study has been carried out on intermittent dobutamine therapy (Oliva

3 4 3-4

3 4

31 (29) 19 (2)

32

h:w, hours

w. weeks; CHF.

48

3 4

10 (I)

per week; mo. months:

48

4

I

Oliva et al., 1994b

4x

4

1

deterioration

56

48

48

48

3-m4

13

Infusion duration (h w)

Krell et al.. 1986 Hodgson et al. 1984 Berger et al.. 1985 Roffman et al. 1985 Dies et al.. 1986 Applefeld et al 1987

class

NYHA

with dobutamine

No. of patients

treatment

Study

Table 3 Studies on ambulatory

of congestive

4.5

7.1

X.1

9.4

5

6

7.5

heart

Dose(mcgkg min)

failure:

HT. heart

6 mo

8.1 mo

8 U

9.8 mo

8 mo

II u

6 mo

follow-upmo

class

2

median NYHA

NYHA 3.X-2.6

= 2

from

NY HA from 3.7- 2.5 interrupted

NYHA

improved in 54% NYHA 3

NYHA changes

transplant

w

pump

malfunction

and adverse

16 deaths; IO infections (4 in hospital): 2 pump malfunctions 8 deaths, 5 HT, 16 CHF: 3 infections: 2 pump malfunctions

18 CHF: 8 deaths; 9 infections; pump malfunctions Ii deaths

I death:

10 deaths

Deaths events

C. Ferroni et al. / Arch. Gerontol. Geriatr. 23 (1996) 313-327

321

et al., 1994b) In five participating centers 32 patients (30 male and 2 female, aged between 31-72 years) with drug-refractory congestive heart failure, despite optimal medical therapy, were infused with dobutamine doses ranging between 2.5-5.0 pg/kg/min for periods of 24-120 h a week (average of 65.6 h a week). Infusion by portable pumps allowed patients to return home and continue their limited daily activities. Etiology of heart disease was coronary disease in 20, idiopathic dilated cardiomyopathy in nine patients and valvular disease in three patients. Ten patients were in NYHA (1973) functional class III and 22 in class IV (median IV). Ejection fraction was between 15 and 32% (average 21 + 5%) Cardiac index varied from 1.1-2.81/min/m 2 (average 1.8 ± 0.4); pulmonary capillary pressure ranged between 12 and 45 mmHg (average 23 _+9). All patients were given a weekly check-up, that included symptoms evaluation, physical examination, and laboratory tests, in particular electrolytes and the main biohumoral markers. At the end of the observation period (25-412 days, average 160 ± 97), the median NYHA (1973) class had become II. During the follow-up, 16 patients required 27 hospital admissions (16 for heart failure, two for sustained ventricular tachycardia associated with severe hypokalemia, two for atrial fibrillation, three for sepsis due to central venous catheter, two for infusion system malfunction and two for extracardiac disease unrelated to dobutamine treatment). Eight patients (25%) died (six from cardiogenic shock and two from sudden deaths). In five patients treatment was suspended (in four for heart transplant and in one for other causes). In two patients mechanical malfunctions of the infusion system occurred but were repaired out of hospital. It must be emphasized that the first studies were carried out on patients so seriously compromised that they were excluded from heart transplant programs because of either age limits or coexistent diseases. In spite of this, intermittent ambulatory dobutamine treatment proved feasible for a period _>4 months in 62% of cases. An improvement in symptoms and functional class was observed, together with a reduction in health costs as a result of fewer hospital admissions.

4. The present study Elderly subjects with dilated cardiomyopathy, usually of ischemic etiology, and severe refractory heart failure, form a large share of hospitalized patients, due to high prevalence and frequent relapses of this highly unstable condition. They are usually not eligible for heart transplant because of advanced age and because coronary revascularization procedures have already been carried out or are not recommended. When hospital admission is needed, they present with congestive failure, at times anasarca, with dyspnea at rest and even pulmonary edema, in spite of full dosages of conventional treatment (digitalis, diuretics, ACE inhibitors). Usually high dose diuretics, intravenous nitrates and, in refractory cases, combination of dobutamine and dopamine, can achieve negative water balance, symptoms control and mobilization of the patient within a few days, enabling a slow recovery of daily activities. However, within a few months, these patients often return to the

322

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Arch. Gerontol. Geriatr. 23 (1996) 313 327

Table 4 Clinical and echocardiographic features of the study population Total no. of patients Sex (male/female) Mean age (years) lschemic heart disease Coronary artery bypass graft Permanent pacemaker Chronic atrial fibrillation NYHA class 4 LVTDD (mm) EPSS (mm) Mean follow-up (mouths) Days in hospital per year*

24 18:6 75.9 24 6 6 8 24 70.0 (55 83) 23.2 (11 35) 10 (2 18) 66.8

*Average of the previous three years; LVTDD. letl ventricular tele diastolic diameter; EPSS, E-point septum separation Numbers in brackets represent ranges attention of the physician with increased body weight, tibial edema, dyspnea at rest and a typical suffering face, requiring assistance. With time, intervals between hospital admissions become progressively shorter, with a dramatic deterioration in the quality of life of the patient and a parallel increase in health costs. The above described subjects were enrolled in the study conducted in the Cardiology division of I.N.R.C.A. in Ancona from March 1994 - - August 1995 (Table 4). All 24 patients (18 male and six female; age ranging from 60-87 years, average age 75.9 years) had ischemic dilated cardiomyopathy, six had already undergone coronary artery bypass surgery, six had permanent pacemakers and eight had chronic atrial fibrillation. All patients belonged to N Y H A (1973) functional class I V at the beginning of the study. During echocardiographic examination, left ventricular telediastolic diameter (LVTD) was on average 70 m m (range 55 83 mm). The distance between the E point and the interventricular septum (IVS) according to some authors (Wong et al., 1993) represents an important prognostic index for survival, averaged 23.2 mm (range 11 35 mm). Dobutamine was intermittently administered in doses of 2. 4 and 6 #g/kg/min for 36 h every 2 4 weeks. Doses were assigned to each patient according to a randomization table. The drug was dispensed during a hospital stay of two days. During the 36 h spent in hospital, attached to the infusion device, some patients brought with them a television, some a pile of newspapers or a book, others a Walkman. At each session, patients answered a questionnaire about their symptoms. They underwent a careful physical examination which included measurement of body weight, blood pressure and heart rate: routine blood tests; evaluation of water balance: and a walking test (measuring the distance in meters walked in 6 min at a normal pace). At the first session ambulatory (Holter) E C G was applied for 24 h to detect possible major arrhythmias and at every third session, Color Doppler Echocardiography was carried out for the morphodynamic evaluation of the cardiac chambers. The follow-up lasted on average 10 months (range 2 18 months). It was established retrospectively that during the previous 3 years each patient had spent in hospital an average of 66.8 days/year.

GG SA PM RM CA BE BB

BN MM MV PN CF LA RL CI RE

AA LE LL TI RM BP UI BE

2 2 2 2 2 2 2

4 4 4 4 4 4 4 4 4

6 6 6 6 6 6 6 6

86 80 65 68 86 75 65 84

72 69 84 76 60 76 78 69 87

70 76 76 79 82 84 75

Age(years)

M M M M M F M M

M M F M M M F F M

M M F M M M F

Sex

73 68 69 73 75 70 72 66

55 57 65 68 73 67 65 68 68

83 72 68 76 64 76 70

LVTTD(mm)

25 25 24 26 25 27 25 28

14 19 13 18 21 11 16 22 20

35 25 25 37 25 25 26

EPSS(mm)

4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4

0 mo

4 (R) 3 3 3 3 3 3 4 (R)

3 3 3 SE (VEB) 3 D (ARF) 2 3 4

2 2 3 4 D (CS) 3 3

3 mo

D (CS) 3 2 3 (R) 3 3 3 D (CS)

2 3 3

2

2 3 3

3 (R) 2

2 2 SE (flushing) 3

6 mo

3 2 3 3 2

2 D (PO)

•2

2 D (PO) 3

3

2

2 D (MI)

9 mo

N Y H A class and clinical events during follow-up

3 3 3

2

3 2 3

2

2 (CRF)

3

3 (R) 2

2

D (MI)

15 m o

2

D (CS)

2

12 m o

*itg/kg/min; mo, months; D, death; MI, myocardial infarction; SE, side effects; CS, cardiogenic shock; R, re-hospitalization; PO, post-operative; VEB, ventricular ectopic beats; C R F , chronic renal failure; A R F , acute renal failure

Patient

Dose*

Table 5 Follow-up

"q

L

.~

~.

~'

~"

~-

.~

324

('. Ferroni eta/.

,.h'ch. Gcronml. Gertatr. 23 (1996)313

327

Table 6 Causes of death Dose*

No. treated

No. died

Cause

2 4 6

7 9 {4

4

Sudden death (2); cardiogenic shock (2) Post-operative (2): acute renal failure (1) Cardiogenic shock (2)

2 6

24

2 9

*/@kgmin

Table 5 shows the results of tile study. For each patient we have indicated age, sex, LVTD and the E-point-septum separation (EPSS), both in millimeters, and the NYHA (1973) class at the beginning of the study and then every three months. Of all patients enrolled, two (8%) were withdrawn because of dobutamine side effects, one for flushing and headache and the other for enhanced ventricular ectopic activity. Nine patients died (37.5%). One of acute renal failure, two of sudden death, two of cardiogenic shock which occurred following major abdominal surgery and four of cardiogenic shock complicating deterioration of heart failure (Table 6). Thus, 12 months survival was 50% (Fig. 1). A marked improvement in NYHA (1973) class and in quality of life were observed during follow-up (Table 7). At three months of the 21 patients remaining in the study, only four were still in NYHA (1973) class IV, 14 were in class III and three in class I1. Only five patients required traditional hospitalization for clinical deterioration of heart failure during the study period. The estimated number of days spent in EFFECT OF DOBUTAMINE ON SURVIVAL

24•24 100

21/23

80

60 i~

40

20

0 0

3

6

9

12

15

MONTHS

Fig. 1. Survival ill C H F patients treated with intermittent dobutamine infusion. Numbers upon columns represent absolute ligures of survivors all patients followed-up.

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325

Table 7 Effect of dobutamine on N Y H A functional class N Y H A class

4

Months 0

3

XXXXX XXXXX XXXXX XXXXX XXXX

XXXX

6

9

12

15

3

XXXXX XXXXX XXXX

XXXXX XXXXX X

XXXX

XXXX

XXX

2

XXX

XXXXX XX

XXXXX XX

XXXX

XXXX

21

18

11

8

7

2-4

24

hospital per year by each patient for intermittent dobutamine therapy was 33% lower compared with the average during the previous 3 years (66.8 versus 45%), with a yearly saving estimated around 10 million Italian lire per patient.

5. Conclusions

In our series, intermittent dobutamin treatment in average doses of 4/ag/kg/min infused in hospital for 36 h every 2nd-4th week did not prove to be effective in prolonging survival of elderly patients with refractory chronic heart failure in NYHA (1973) class I V (one year survival was 50%). On the other hand, this treatment was able to reduce symptoms and improve clinical signs and quality of life in these patients, besides reducing (by 33%) the number of days of hospital stay per person per year. At the doses used in this study, dobutamine showed a good tolerability (only two out of 24 patients interrupted the treatment because of adverse reactions) with few proarrhythmic effects. In our opinion, intermittent dobutamine treatment according to the protocol in this study, should be started in a hospital setting to evaluate tolerability, but it can be continued with reasonable safety at the patients' homes. However, further studies and larger trials are necessary to optimize the dose, duration and frequency of intermittent dobutamine administration, in order to reduce the risk/benefit ratio and, above all, to identify the subgroup of patients with refractory chronic heart failure who would benefit the most from this therapeutic approach.

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