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European Journal of Heart Failure 2001 3(5):601-610; doi:10.1016/S1388-9842(01)00165-9
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© 2001 European Society of Cardiology

Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome

Soccorso Capomollaa,*, Oreste Feboa, Cristina Opasichb, Giampaolo Guazzottia, Angelo Caporotondia, Maria Teresa La Roverea, Marco Gnemmia, Andrea Mortarac, Margherita Vonaa, Gian Domenico Pinnaa, Roberto Maestria and Franco Cobellia

a Fondazione S. Maugeri, Clinica del Lavoro e della Riabilitazione, IRCCS Istituto scientifico di Montescano Pavia, Italy
b Istituto scientifico di Pavia Pavia, Italy
c Policlinico di Monza Milano, Italy

* Corresponding author. Tel.: +39-0385-2471; fax: +39-0385-61386. E-mail address: scapomolla{at}fsm.it (S. Capomolla)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
Background: in patients with severe heart failure additional therapeutic support with intravenous inotropic or vasodilator drugs is frequently employed in an attempt to obtain hemodynamic and clinical control. No data comparing the use and efficacy of chronic intravenous inotropic and vasodilator therapy in patients with advanced heart failure are available.

Aims: we evaluated, in a group of patients with advanced heart failure undergoing chronic infusion with dobutamine or nitroprusside, in addition to optimized oral therapy, (1) the safety of chronic infusion, (2) the efficacy of both drugs in managing unloading therapy and (3) clinical outcome of the two therapeutic strategies.

Methods: one hundred and thirteen patients receiving optimized oral therapy, in functional class III/IV with symptoms and signs of refractory heart failure and requiring additional pharmacological support with either intravenous dobutamine or nitroprusside were evaluated. Clinical and therapeutic management and clinical outcome of the two groups were considered.

Results: dobutamine was administered for 12 h/day for 20 ± 23 days at a dosage of 7 ± 3 µg/kg/min to 43 patients. The mean dose of nitroprusside was 0.76 ± 0.99 µg/kg/min. The mean duration of use of this drug, administered as a 12-h/day infusion was 22 ± 38 days. Nitroprusside infusion allowed greater doses of short-term ACE-inhibitors to be used compared to pre-infusion (ACE-inhibitor dose: 55 ± 30 mg/day vs. 127 ± 30 mg/day P < 0.0001) and during dobutamine infusion (ACE-inhibitor dose: 85 ± 47 mg/day vs. 127 ± 30 mg/day P < 0.002). Nitroprusside unlike dobutamine significantly improved the NYHA functional class. Of the 113 patients, 109 (97%) had a cardiac event during a mean follow-up of 337 ± 264 days. Forty-four patients required hospitalization for worsening congestive heart failure, 45/113 (39%) patients died during the follow-up and 27/113 (24%) patients had a heart transplant in status one. Hospitalization, because of worsening heart failure was less frequent in the nitroprusside than in the dobutamine subgroup [29/51 (57%) vs. 19/22 (86%) P < 0.02]. The overall mortality was 28% (20/70) in the nitroprusside group and 58% (25/43) in the dobutamine group (odds ratio 0.33 CI 0.16 to 0.73 P < 0.006). In the group treated with nitroprusside, heart transplantation in status one was performed in 16/33 patients (48%), while in the dobutamine group this was done in 11/14 patients (78%) (odds ratio 0.25 CI 0.06–1.02 P < 0.06). There was a significant reduction in the combined end-point of mortality/heart transplantation in status one in patients treated with nitroprusside compared to those treated with dobutamine (36/70 (51%) vs. 36/43 (84%) — (odds ratio 0.34 CI 0.14–0.80 P < 0.01). The incidence of adverse events in the patients treated with nitroprusside was similar to that in those treated with dobutamine (20% vs. 17% P = ns).

Conclusions: for patients awaiting heart transplantation chronic intermittent nitroprusside infusions are more effective and safer than dobutamine in relieving symptoms, facilitating unloading therapy management and improving survival. Whether chronic intermittent infusion of nitroprusside could represent a feasible medical strategy in out-patients with severe heart failure remains to be investigated.

Key Words: Severe heart failure • Chronic infusion • Nitroprusside • Dobutamine

Received December 15, 2000; Revised February 28, 2001; Accepted April 26, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
Despite improvements in therapy for congestive heart failure, this syndrome is a major and growing clinical problem associated with high rates of mortality and morbidity [1]. Several therapeutic strategies have been proposed for the management of severe heart failure [2]. Beta-blockers have consistently produced clinical benefits [3]. However, their use is difficult and often impossible in patients with severe heart failure. In advanced stages of disease conventional oral therapy is often inadequate to control the heart failure syndrome and additional pharmacological support with either intravenous inotropic or vasodilator agents is often needed [4].

Previous studies have shown that both dobutamine [5,6] and nitroprusside [7] induce significant improvement in left ventricular performance when given to patients with low cardiac output and severe symptoms of heart failure. Furthermore, intermittent intravenous dobutamine infusion in outpatients with congestive heart failure was reported to be associated with a temporary clinical improvement [8], however, long-term inotropic therapy has also been linked to an increased mortality [9]. No data are available about the use and efficacy of chronic intravenous vasodilator therapy in-patients with advanced heart failure.

Accordingly, in a group of patients with advanced heart failure undergoing chronic infusion with dobutamine or nitroprusside in addition to the oral therapy, we evaluated the effects of intravenous infusions of the two drugs on clinical response. Our aims were: (1) to evaluate the safety of chronic infusion; (2) to compare the efficacy of both drugs in managing unloading therapy; and (3) to evaluate the clinical outcome of the two therapeutic strategies in patients with advanced heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
2.1. Protocol
2.1.1. Patients
Between January 1994 and December 1998, 625 consecutive patients with severe chronic heart failure due to ischemic or idiopathic dilated cardiomyopathy, admitted to our Heart Failure Unit for evaluation and treatment of advanced heart failure, were considered.

The clinical diagnosis of congestive heart failure was confirmed by a documented history of cardiac decompensation requiring hospitalization, by the presence of symptoms (orthopnea, dyspnea, asthenia, palpitations) and by physical examination (S3, rales, raised jugular distention, hepato–jugular reflux, ascites, edema). Dilated cardiomyopathy was defined by two-dimensional echocardiographic demonstration of a dilated left ventricle (left ventricular end-diastolic volume index >78 ml/m2) with severe left ventricular systolic dysfunction (ejection fraction <35%).

One hundred and thirteen patients, receiving optimized oral therapy, were in functional class III/IV with symptoms and signs of refractory heart failure and required additional pharmacological support with either intravenous inotropic or vasodilator agents. There were no prefixed criteria for which treatment, either nitroprusside or dobutamine intravenous infusion, to administer as first choice therapy. The physician was free to choose either. Clinical, Doppler echocardiographic characteristics and therapeutic regimen of the two groups of patients are reported in Table 1


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  		Table 1 Baseline clinical, Doppler echocardiographic and hemodynamic characteristics of patients admitted to chronic intermittent intravenous nitroprusside or dobutamine infusion

 
2.2. Study protocol
The treatment was composed of the following four phases: (1) Stabilization of the patient with intravenous therapy. Diuretic and dobutamine or nitroprusside intravenous infusions were started and the dose optimized in response to clinical (diuresis, clinical status and symptoms) goals. To prevent the development of drug tolerance the two drugs were given as a 12-h/day continuous infusion. Later, without discontinuing their tailored oral medications, the patients were submitted to right heart catheterization. When arterial and pulmonary wedge pressures were steady, a hemodynamic evaluation was performed. Subsequently sodium nitroprusside was administered by intravenous infusion via a pump at incremental doses of 0.5 µg/kg/min every 5 min until a systolic arterial pressure <80 mmHg, pulmonary wedge pressure <15 mmHg (18) and/or patient's discomfort were observed. Dobutamine was administered by intravenous infusion at incremental doses of 5 µg/kg/min, when the steady state had been reached, at any given rate of infusion all measurements were repeated.

If the pulmonary wedge pressure fell below 15 mmHg or became higher than the baseline value, if the patient complained of serious discomfort or if non-sustained ventricular tachycardia and premature ventricular complexes >30/min occurred, incremental dosing of dobutamine was stopped. Between infusions of the two drugs a washout period (10 min) was observed, then the measurements were performed to verify that the hemodynamic values had returned to baseline values. (2) Optimization of heart failure therapy: nitroprusside or dobutamine and diuretic infusions were restarted and modified according to acute hemodynamic response; during this phase the patients received the maximum tolerated dose of ACE-inhibitors, digitalis and nitrates. (3) Attempted withdrawal of infusion therapy: once the patients were in a stable clinical condition on the oral therapy, withdrawal of nitroprusside or dobutamine infusion was attempted over a period of 1 week, if a patient's condition deteriorated, the dose of infusion therapy was restored to its previous level. (4) Long-term therapy: patients received either oral therapy alone or in combination with intravenous therapy when they could not be weaned from nitroprusside or dobutamine. This phase lasted indefinitely or until heart transplantation or death occurred. Patients receiving oral therapy were then discharged from the hospital (Fig. 1).


Figure 1
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  		Fig. 1 Protocol of the study. Management algorithm for patients with refractory heart failure and undergoing intravenous inotropic or vasodilator therapy.

 

   3. Follow-up
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
In the different phases of the study protocol, prospective evaluation of all patients included the following end-points: optimization of unloading therapy; other intravenous therapy integrations; weaning from intravenous therapy support; hospitalization for congestive heart failure; and overall mortality and heart transplantation in status one. The decision about whether a patient required hospitalization was not made by members of the study team. All patients underwent serial clinical and functional evaluations every 6 months in our center. In the period between two evaluations, the clinical status of patients was monitored by telephone contact with the patient and his physician and by questionnaires.


   4. Statistics
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
To compare the clinical and functional variables at baseline and after the drug infusions, paired and unpaired t-tests were performed. A probability value of <0.05 was considered as statistically significant. All values were expressed as mean±standard deviation. The association between hard cardiac events and drug infusions were investigated using logistic regression analysis. The significance of associations was assessed using analysis of maximum likelihood estimates (Wald chi-square). Survival function was evaluated by the product–limit Kaplan–Meier method. Comparisons between groups were made using the log-rank test. Patients who did not experience a given event were considered censored in the survival analysis for each main outcome measure. Statistical analyses were carried out using the SAS procedure [10].


   5. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
Of 113 patients treated, 101 were men and 12 women. Their mean age was 53±7 years (range 17–67) and their average duration of disease manifestation 2.9±1.6 years. The mean left ventricular ejection fraction was 19%. No significant clinical or hemodynamic differences were observed between patients treated with the two drugs (Table 2).


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  		Table 2 Laboratory findings of patients admitted to chronic intermittent intravenous nitroprusside or dobutamine infusion

 
5.1. Treatment choice
Dobutamine was the first line agent chosen for 43 patients; dobutamine was administered as a loading dose according to clinical responses (diuresis, symptoms, blood pressure, adverse events) and subsequently dosed to hemodynamic and clinical targets (Table 3). Maintenance therapy infusion for 12 h/day was continued for a mean of twenty days (range 4 to 86 days, median 33 days) at a dosage of 7±3 µg/kg/min. During the dobutamine treatment, 26 (74%) patients needed temporary nitroprusside integration to maintain clinical and hemodynamic targets; 22 (51%) patients were weaned off treatment after 17±5 days. The loading dose of nitroprusside was titered according to clinical effects and subsequent doses to hemodynamic profile (Table 3). The mean dosage was 0.76±0.99 µg/kg/min (range 0.25–4.5 µg/kg/min). The 12-h/day infusions were given for a mean of 22 days (range 6–189, median 37 days). Temporary integration of nitroprusside with dobutamine was needed in 7 (10%) patients; 51/70 (73%) of patients were weaned off nitroprusside after a mean of 14±7 days.


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  		Table 3 Hemodynamic response to Nitroprusside and Dobutamine titration

 
5.2. Clinical outcome
5.2.1. Management of unloading therapy
Nitroprusside infusion facilitated more unloading therapy by short-term ACE-inhibitors compared to the pre-infusion dose (55±30 mg/day vs. 127±30 mg/day P<0.0001) and that administered after dobutamine infusion (85±47 mg/day vs. 127±30 mg/day P<0.002). The long-term dose of ACE-inhibitors was also higher after nitroprusside infusion than after dobutamine infusion. During therapy infusion no differences were found between the two groups of patients in rate and dose of diuretics, nitrates and digitalis therapy. However, when we evaluated subgroups of weaned off patients, nitroprusside treated patients took a lower dose of high-loop diuretics (70±63 mg vs. 121±72 mg, P<0.003) and higher doses of short-term ACE-inhibitors (140±22 mg vs. 110±26 mg, P<0.004) and nitrates (115±30 mg vs. 65±24 mg, P<0.0001) than dobutamine-treated patients (Table 4).


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  		Table 4 Clinical management of patients receiving the different chronic intravenous therapies

 
5.2.2. Functional status
Thirty of the seventy patients treated with nitroprusside benefited from a significant improvement in NYHA functional class. Twenty-three patients moved from NYHA functional class IV at baseline to NYHA class III (22 patients) or II (1 patient) after nitroprusside infusion. Seven patients moved from NYHA functional class III at baseline to NYHA class II after nitroprusside infusion. All patients with improvement were weaned off nitroprusside. Only two patients worsened functional class, while still needing intermittent nitroprusside infusion. In the dobutamine subgroup of patients, no significant changes of NYHA functional class were observed. Three patients improved and moved from NYHA functional class IV at baseline to NYHA functional class III during and after stopping dobutamine infusion. Three patients improved and moved from NYHA functional class III at baseline to NYHA functional class II during and after stopping dobutamine infusion. Five patients worsened and reached NYHA functional class IV requiring prolonged dobutamine infusion (Fig. 2).


Figure 2
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  		Fig. 2 Changes of NYHA functional class in patients with refractory heart failure treated with different intravenous therapies. Top: nitroprusside group; bottom, dobutamine group. {circ} Baseline, {odot} unchanged, • improved, {blacktriangleup} worsened.

 
5.2.3. Cardiac events
As many as 109/113 (97%) patients entered into the study had a cardiac event during a mean follow-up of 337±264 days. Forty-four patients required hospitalization for worsening congestive heart failure, 45/113 (39%) patients died during follow-up and 27/113 (24%) patients received a heart transplant in status one. Twenty patients underwent elective cardiac transplantation and two patients died of non-cardiac causes. In the nitroprusside subgroup, hospitalization, because of worsening heart failure was less frequently required than in the dobutamine patients [29/51(58%) vs. 19/22 (86%) P<0.02]. The overall mortality was 28% (20/70) in the nitroprusside group and 58% (25/43) in the dobutamine group (odds ratio 0.33 CI 0.16–0.73, P<0.006). In the group treated with nitroprusside 16/33 (48%) patients had a heart transplant in status one, while in the dobutamine group 11/14 (78%) patients did (odds ratio 0.25 CI 0.06–1.02, P<0.06). The combined end-point of mortality/heart transplantation in status one was significantly lower in the patients treated with nitroprusside than in those treated with dobutamine [36/70 (51%) vs. 36/43, (84%)] — [odds ratio 0.34 CI 0.14–0.80 P<0.01].

5.2.4. Safety of treatment
The incidence of adverse events in the nitroprusside treated patients was similar to that in the dobutamine treated group (20% vs. 17% P=ns). There was a significantly higher incidence of asymptomatic hypotension in the nitroprusside group, close monitoring of blood pressure and change of the rate of the infusion pump prevented hypotension in these patients. In the dobutamine group three patients — with refractory heart failure — developed ventricular tachycardia requiring electrical cardioversion during infusion of the drug. No thiocyanate toxicity was found in the nitroprusside subgroup at a mean plasma concentration of 0.019±0.023 mg/ml (range 0.0025–0.045 mg/ml) (Table 5).


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  		Table 5 Serious adverse events in patients receiving the different chronic intravenous therapies

 

   6. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 
Despite oral medical therapy, patients with severe congestive heart failure have a poor prognosis with annual mortality rates that oscillate from 30 to 80% [11]. These patients often require additional therapeutic support with intravenous inotropic or vasodilator drugs in an attempt to obtain hemodynamic control and to prevent organ deterioration while waiting for heart transplantation. However, the increasing number of appropriate candidates for the heart transplantation program contrasts with the limited donor organ availability and the patient's wait can be long and painful. Hence there is a need to identify an algorithm of intensive and prolonged medical therapies to optimize tailored therapy, to improve the clinical status of the patient and identify the subgroup of patients refractory to medical therapy who need urgent heart transplantation [12].

This study compares the usefulness of long-term infusion of dobutamine or nitroprusside in producing clinical and hemodynamic improvement and optimizing unloading therapy in patients with worsening heart failure waiting for heart transplantation.

The results obtained show that long-term infusion of low doses of nitroprusside was better than dobutamine infusion in determining clinical improvement and aiding oral unloading therapy with weaning of intravenous infusion being more frequently possible. The subsequent stable clinical improvement was associated with a decreased rate of rehospitalization and ‘hard’ cardiac events. Furthermore, in the subgroup of patients with refractory end-stage heart failure, nitroprusside allowed safer management of the chronic state with fewer transplantations in status one than dobutamine. Short-term intravenous therapy with the two drugs has often been used during acute worsening of heart failure. However, the hemodynamic and acute clinical profile did not predict the subsequent clinical course [13]. Intermittent long-term dobutamine infusion gave controversial results and there was no evidence of sustained clinical benefit [14], indeed controlled data showed that chronic therapy with dobutamine increased mortality and did not reduce the rate of rehospitalization [9,15]. Several findings showed that inotropic therapy could contribute to an increase in the rate of left ventricular myocardial remodeling. At the molecular level, this action may be related to changes in myocardial structure including hypertrophy, direct toxicity to myocytes, apoptosis and an alteration of the extracellular matrix which act together to determine left ventricular function alterations [16–19]. Activation of cyclic AMP induced by dobutamine has been demonstrated to be arrhythmogenic, in addition the Ca2+ overload may lead to a delay after depolarization, these effects together with alteration of the extracellular matrix could predispose the genesis of ventricular arrhythmias [20–22]. In patients with severe chronic heart failure, dobutamine induced hemodynamic improvements but with discordant effects on left ventricular diastolic function and mitral regurgitation [23]. These structural and discordant functional effects could not restore the neurohormonal axis, which fed the vicious circle and worsening of chronic heart failure. Indeed, in our study only 45% of patients could be weaned from intravenous dobutamine therapy, furthermore, chronic intermittent dobutamine infusion was associated with an unloading strategy which had to rely more on diuretics than ACE-inhibitors and frequent temporary integration of nitroprusside in an attempt to provide symptom relief. This different management therapy plan could explain the poor actuarial event curves of these patients when compared to subgroups treated with chronic nitroprusside infusion (Fig. 3).


Figure 3
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  		Fig. 3 Survival and ‘free from hard cardiac events’ curves of patients classified according to inotropic or vasodilator intravenous therapy.

 
Nitroprusside improved cardiac output with a concomitant reduction of systemic and pulmonary resistances, right atrial and left ventricular filling pressures and mitral regurgitation [23]. Carrol showed how nitroprusside determines a global decrease in left chamber stiffness [5]. These short-term hemodynamic effects were the background of initial clinical benefits (increase of diuresis, symptom relief). Uptitration of ACE-inhibitors and nitrates diminished the clinical severity of heart failure and improved functional status, allowing more weaning from intravenous therapy. Previous studies demonstrated that acute unloading with nitroprusside allowed other pharmacological managements to be optimized and induced sustained chronic improvement in patients referred for urgent heart transplantation [24]. However, the ability to initiate or increase vasodilator therapy to a therapeutic dose can be limited due to hypotension and/or renal failure in patients whose cardiac function is severely compromised. In our study, patients referred for heart transplantation have typically experienced progressive differential declines in clinical and hemodynamic status, intermittent long-term unloading with nitroprusside was safe and not only improved hemodynamic imbalance and symptom relief, but also allowed an increase in oral vasodilator therapy with a 130% increase from pre-nitroprusside infusion and a 58% increase compared to the dose feasible after dobutamine infusion. Despite the apparent previous impossibility of receiving optimized therapy, after forced unloading patients may frequently enjoy prolonged stability of NYHA functional class and improved survival, with concomitant decrease in rehospitalization needs. These clinical goals were probably achieved by the arrest of neurohormonal axis activation and the reversal of detrimental remodeling of the left ventricle.

The safety of long-term intermittent infusion of nitroprusside is still under question. In our experience, this therapeutic strategy was sufficiently tolerated without causing important adverse events in patients. The most frequent adverse event was hypotension, that careful monitoring of blood pressure and infusion rate prevented, without relevant clinical effects in individual patients. Previous studies showed that transient hypotension secondary to nitroprusside infusion have no serious effects on the circulation in vital organs [25].


   7. Previous comparative studies
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
8. Study limitations
 9. Conclusions
 References
 
In patients with heart failure, clinical responses to the long-term administration of dobutamine have been evaluated by several studies in which an improvement of NYHA functional class status was observed [6,8,9]. Our dobutamine-treated patients, did not show an improvement in NYHA functional class. This apparent discrepancy could be explained by the time the studies were performed, it is important to remember that these comparative studies were carried out in the pre-ACE-inhibitor era, in our patient's functional improvement — obtained in comparative studies by dobutamine — could have been induced by ACE-inhibitors. In fact, recent data has shown that continuous or intermittent dobutamine infusion is associated with an increased risk of cardiac death and not clinical benefits [26,27]. However, it is equally essential to emphasize that our patients were treated for a shorter time than those in other studies, furthermore changes to the dosage of unloading therapy were made, although in the non-weaned subgroups no significant modification in functional class was found after 6 weeks. The only two controlled studies carried out on intermittent dobutamine infusions in patients with refractory congestive heart failure did not show an effect on the need for hospitalization and could not exclude adverse effects on mortality [9,15]. In our experience intermittent chronic infusion of dobutamine can allow transient relief of symptoms and acute hemodynamic improvement but does not help in the management of unloading therapy and in 7% of treated patients, dobutamine therapy was associated with serious cardiac arrhythmias requiring cardioversion and life support treatment.

Short-term infusion of nitroprusside with hemodynamic monitoring is routinely used when diuretic infusions do not cause clinical improvement or to facilitate subsequent titration of oral agents. However, to our knowledge, there are no reports in the literature on the long-term infusion of nitroprusside to patients with severe congestive heart failure. Several trials using vasodilators have produced conflicting results. Thus, the PROFILE trial, evaluating flosequinan, has underlined how in contrast to clinical and functional improvements, it induced an increase in mortality [28]. Still studies with the Ca2+ antagonist in the post-myocardial infarction has pointed out an unfavorable prognostic effect of that vasodilator [29,30]. These prognostic negative results are likely to be supported by consequent neurohormonal activation induced by the treatment [31]. Also, chronic infusion of vasodilators present dark points. The large-scale trial in patients with refractory heart failure (FIRST), that used chronic infusion of epoprostenol, has been interrupted due to an excess of mortality [32]. In examining our study data in comparison to the FIRST study, we have identified the following three important areas for consideration: pharmacological actions; hemodynamic effects; and neurohormonal activation. Epoprostenol induced a favorable effect on pulmonary and systemic rather than a venous tone [33]. In contrast nitroprusside in patients with chronic heart failure induced an active relaxation in smooth muscle tone of intestinal and pulmonary capacitance vessels with concomitant reduction of venous pressure [34]. The acute titration of epoprostenol showed a lesser effect on cardiac preload than that achieved by nitroprusside infusion [35]. This hemodynamic goal is mandatory because it induces a decrease in cardiac norepinephrine spillover in patients with chronic heart failure [36]. Furthermore, data exist indicating that the two drugs operate in different ways on neuroendocrine activity. So, while the epoprostenol action to neurohormone axis remains uncertain, nitroprusside induces concordant central and peripheral effects on restoration of neurohormone profile [37–40]. In our experience a short-term infusion (<72 h) of nitroprusside allowed optimized oral therapy to be achieved in only 9/70 (12.8%) of CHF patients reported to be refractory to oral therapy. Planning of chronic infusion care is safe and can allow careful adjustment of therapies (uptitration of ACE-inhibitors and decrease of diuretic regimen) with concomitant long-term decrease of hospitalization needs and survival improvements.


   8. Study limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
9. Conclusions
 References
 
Our study is not a randomized, controlled study. Furthermore, it is a retrospective analysis, not a prospective study. The extended periods in hospital occupying hospital beds at a high cost are the major limitation of the study strategy. However, in our Unit for CHF, patients awaiting heart transplantation and defined refractory to oral therapy were referred by peripheral centers. We showed that long-term planning of intravenous care could help to force unloading therapy and to identify patients with different prognosis and having different priorities in the cardiac transplantation program, the emerging data are that long-term therapy with nitroprusside is safe and effective. This result opens the prospective of a new possible long-term therapy in patients with refractory congestive heart failure.


   9. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
References
 
In patients awaiting heart transplantation chronic intermittent nitroprusside infusions are more effective and safer than dobutamine in relieving symptoms, facilitating unloading therapy management and improving survival in patients with end-stage heart failure. More patients could be weaned off intravenous nitroprusside than intravenous dobutamine treatment. Furthermore, the dobutamine subgroup more frequently needed the integration with nitroprusside than vice-versa. Whether nitroprusside can be given by a portable infusion pump or can be practical as outpatient therapy for refractory heart failure remains to be determined.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Follow-up
 4. Statistics
 5. Results
 6. Discussion
 7. Previous comparative studies
 8. Study limitations
 9. Conclusions
 References
 

  1. Garg R., Packer M., Pitt B., Yusuf S. Heart failure in the: evolution of a major public health problem in cardiovascular medicine. J Am Coll Cardiol (1993) 22:3A–5A. Suppl A.[Medline]
  2. Rich M.W. Heart failure disease management: a critical review. J Heart Failure (1998) 5:64–75.
  3. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Eng J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  4. Stevenson L.W., Massie B.M., Francis G.S. Optimizing therapy for complex or refractory heart failure: a management algorithm. Am Heart J (1998) 135:S293–S309.[CrossRef][Web of Science][Medline]
  5. Carrol J.D., Lang R.M., Neumann A.L., Borow K.M., Rajfer S.I. The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation (1986) 74:815–825.[Abstract/Free Full Text]
  6. Liang C.S., Sherman L.G., Doherty J.U., Wellington K., Lee V.W., Hood W. Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine. Circulation (1984) 69:113–119.[Abstract/Free Full Text]
  7. Berkowitz C., McKeever L., Croke R.P., Jacobs W.R., Loeb H.S., Gunnar R.M. Comparative responses to dobutamine and nitroprusside in patients with chronic low output cardiac failure. Circulation (1977) 56:918–924.[Abstract/Free Full Text]
  8. Applefeld M.M., Newman K.A., Sutton F.J., et al. Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients. Am Heart J (1987) 114:589–595.[CrossRef][Web of Science][Medline]
  9. Days F. Intermittent dobutamine in ambulatory patients with chronic heart failure. Br J Clin Pract (1986) 45:37–40. Suppl.
  10. SAS Institute. SAS Technical Report P-229 SAS/STAT Software Changes and Enhancement (release 6.07) (1992) Cary, NC: SAS Institute. 633–679.
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