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(Circulation. 2003;108:492.)
© 2003 American Heart Association, Inc.
Cardiovascular Drugs |
From the Division of Cardiology, Brigham and Womens Hospital, Boston, Mass.
Correspondence to Lynne Warner Stevenson, MD, Division of Cardiology, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115.
Key Words: heart failure cardiomyopathy hemodynamics
| Introduction |
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| Chronic Inotropic Infusions as Bridging Therapy |
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Although its magnitude can be debated, there is clearly a population of patients who are considered by experienced heart failure teams to be dependent on intravenous inotropic infusions despite multiple weaning attempts.4 It is assumed that such patients would not survive hospital discharge without ongoing inotropic support, although consensus has not been reached on exactly who they are. Dependence is most often manifested as symptomatic hypotension, recurrent congestive symptoms, or worsening renal function early after discontinuation of inotropic therapy. It should be emphasized that dependence for clinical purposes should be defined by limited clinical function, not by measured hemodynamic parameters, although these numbers have been required for Medicare coverage of home infusions in some states. For patients considered dependent, continuous inotropic therapy is then used to serve as a "bridge" to arrival at a destination such as transplantation or the end of life.
Prolonged use requires insertion of an indwelling intravenous line, usually linked to a wearable drug-infusion pump. Before the catheter is inserted, it is critical to ascertain the adequacy of community home health agencies to help maintain the access site and pump and the understanding of the patient and family as to its function and ultimate purpose. Maintenance of chronic intravenous infusions is associated with numerous infectious and mechanical complications from the infusion catheter in addition to those related to the drug.5,6
Bridge to Transplant
The most common indication for bridging therapy is to provide hemodynamic support until a suitable donor heart becomes available for cardiac transplantation.6,7 Candidates in whom an inotropic infusion has become necessary frequently progress to higher doses, then combinations of dobutamine with milrinone. As the number of waiting candidates increases, some patients who appear to be stable on intravenous inotropic infusions have been sent home to wait, usually with implantable defibrillators in place. Such patients frequently require rehospitalization because of progressive hemodynamic instability but can occasionally improve to be weaned from inotropic support while still at home before transplantation.6,7 As waiting times on intravenous inotropic therapy lengthen, often to many months, it is increasingly recognized that organ function and nutritional status frequently continue to decline on this therapy. In some cases, an accelerated decline may result if eosinophilic myocarditis develops as an allergic response to the dobutamine.8 This is most often identified on examination of the explanted heart, but surveillance of peripheral eosinophil counts may identify most such patients. For transplant candidates dependent on inotropic infusions, ventricular assist devices are being considered earlier, particularly as indices of nutrition decline.
Survival With Outpatient Inotropic Therapy
When heart failure has progressed to the stage at which outpatient inotropic infusions are considered, survival is severely limited if heart transplantation is not an option. It cannot easily be resolved whether the use of inotropic therapy itself alters survival in this stage for patients considered dependent. If we accept that some patients are truly dependent, in that clinical status worsens progressively after discontinuation, it is a tautology that continuation is associated with better clinical status, at least initially. In the small, placebo-controlled trials, those patients considered dependent on inotropic therapy would not have been enrolled, so outcomes with and without inotropic therapy cannot be compared.
From collected experiences, the anticipated mortality rate at 6 months is more than 50%, and few survivors will remain at 1 year (Figure 1). Survival is the worst in a recent series of patients in whom inotropic dependence was defined prospectively after specific weaning attempts. In this experience from the University of Oregon, mortality was 94% at 1 year for 36 patients who failed multiple weaning attempts during a mean hospitalization of 3 weeks.3 In the Randomized Evaluation of Mechanical Assistance in Congestive Heart Failure (REMATCH) trial,9 50% of the trial population had been deemed inotrope dependent at the time of randomization by having failed 2 weaning attempts under the supervision of cardiologists specifically certified for heart failure clinical practice and clinical trial experience. Because these patients received intense supervision without other therapeutic option, they provide a benchmark of the characteristics and outcome of inotropic infusions in end-stage heart failure (Figure 1), with 61% mortality at 6 months and 79% mortality by 1 year.
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Bridging to the End of Life
With the high mortality on chronic inotropic infusions when transplantation is not an option, it should be considered a terminal therapy. The use of continuous outpatient inotropic infusions at the end of life is increasing, even at heart failure centers previously opposed to the practice. This reflects an evolving population who survive long enough to develop refractory symptoms. Chronic therapy with neurohormonal antagonists has reduced the incidence of sudden death, whereas progression of heart failure is delayed but not halted. The prevalence of implantable defibrillators further decreases the chance that death will occur before or during unremitting symptoms of circulatory decompensation. Our forward progress has driven us to desperation, where we reach back for the inotropic therapies that we learned to fear in the past. As our connections with patients span more years, we have had the opportunity to become more personally involved with them and their families through their journey and to respond personally to their desperation as the end approaches. It is difficult to withhold a therapy that recently restored comfort. In a recent survey of 71 US heart failure programs, more than 95% of the responding physicians indicated willingness to use outpatient inotropic infusions, although 80% had seen worsening heart failure, 69% had seen infectious complications, and 50% had seen sudden death during such infusions (J.B. Young, MD, Cleveland Clinic, and L.W. Miller, University of Minnesota, written communication, 1994). This consensus is reflected in the latest version of the American College of Cardiology/American Heart Association guidelines for heart failure.10
What do these inotropic therapies achieve? Prolonged survival is certainly not the goal (Figure 1). Are patients dying comfortably at home? The majority of patients are rehospitalized at least once, with a small number undergoing multiple rehospitalizations, to die eventually in the hospital.3 Many patients are able to die out of the hospital, which is desired by them and families. Some, however, are not able to endure the final vigil at home. This may be eased when the current hospice criteria more uniformly accept the use of intravenous inotropic agents for comfort and can provide other end-of-life support in the home. Alternatively, the judicious use of narcotics and anxiolytics may provide similar comfort for some patients without the need for intravenous catheters.
Intermittent Infusions for Outpatients
On the basis of the inpatient experiences, inotropic infusions have also been administered intermittently at home or at outpatient infusion clinics on a regular schedule.5,1113 Improvement in symptoms and reduction in rehospitalization have been demonstrated for some patients after enrollment in these programs. Other experiences in patients with more severe compromise have shown high early mortality (80% at 6 months in one study), without obvious clinical benefit.14 In the broader context of heart failure disease management, patients enrolled in such programs also receive extensive patient education, frequent phone contact, and regular clinical assessment, which have been shown to improve heart failure outcomes. The reimbursement for outpatient infusion clinics may have helped to support more staff to provide this vital education and ongoing personal connection that is otherwise not supported outside of research. It is unclear whether there is an additional benefit of the intermittent inotropic infusions that would outweigh the risks of increased ventricular tachycardia15 and ischemia during and after administration. Of 4 small randomized studies, 2 showed higher mortality with the use of intermittent infusions.16,17 A randomized study of hemodynamics after 1 month of dobutamine or placebo infusion showed the only significant difference to be a 2-kg weight loss compared with 1 kg in the placebo group, attributed to enhanced diuresis.18 A more recent randomized trial, which included 38 New York Heart Association functional class III or IV patients receiving 2.5 µg · kg-1 · min-1 of dobutamine for 48 hours weekly over 6 months, showed no improvement in clinical class or 6-minute walk distance.19 Much of the outpatient infusion experience has been with dobutamine, although there has been some experience with amrinone and milrinone.11,13 A randomized trial of intermittent outpatient infusions of milrinone, referred to as the ROME trial, was apparently terminated after
100 patients were enrolled, but no information has yet become available regarding the results. Unless these data indicated benefit, the negative results of the inpatient OPTIME trial (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) of 48-hour infusions might also be extrapolated to indicate a low likelihood of benefit from shorter milrinone infusions for routine management of outpatients with heart failure.20
| Future of Inotropic Therapy |
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The currently available inotropic therapies stimulate cAMP and increase intracellular calcium levels either through ß-adrenergic receptor stimulation or through phosphodiesterase inhibition as part of their primary mode of action. Increased cytosolic calcium contributes to altered gene expression and apoptosis and increases the chance of ventricular arrhythmias (Figure 2).
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The calcium sensitizers, exemplified by levosimendan,26 increase the sensitivity of troponin C to calcium in relation to calcium concentration. This allows improved contractility without increased intracellular calcium or compromise of diastolic relaxation. Short-term administration improves cardiac output and lowers filling pressures acutely,27 with small increases in heart rate. The oral formulation, which required adjustment for a long-acting metabolite, allowed frequent weaning of intravenous inotropic infusions in a pilot trial that has not yet been expanded.28 The intravenous form led to greater hemodynamic improvement than dobutamine at the end of 24-hour infusion, with a trend toward lower mortality at 6 months.29
Targeted Gene Expression
Elucidation of the molecular mechanisms involved in calcium regulation within the myocyte is revealing new targets for therapy to improve contractility, as reviewed recently.30 Impaired calcium uptake and release through the sarcoplasmic reticulum diminish systolic calcium release and the force of contraction and elevate diastolic calcium levels and filling pressures (Figure 2). The increasing efficiency of gene-transfer techniques has allowed demonstration of improved contractility and survival after viral transfection of the sarcoplasmic reticulum calcium ATPase (SERCA-2) into small animal models, and more recently in the swine model.30 Similar findings have been obtained with use of a phospholamban mutant that does not constrain SERCA-2 activity and an adenovirus that encodes antisense of phospholamban.31,32 In each approach, improvement was seen in both inotropic and lusitropic performance. Furthermore, the acute hemodynamic benefits were associated with prolonged survival of the animal models. Therapy directed to improve calcium cycling addresses both the systolic and diastolic components of dysfunction (Figure 2).
Beyond calcium regulation, other major targets may be identified for intervention, such as increasing the proportion of the more powerful
-myosin heavy chains that are diminished in heart failure.33 It is not yet known with what feasibility targeted gene approaches can be translated to human heart failure with catheter-based and surgical techniques. They may also represent one of the strategies through which functional myocardial improvement may be achieved as the heart rests during mechanical unloading with assist devices.
Looking Backward and Forward
Therapy with inotropic agents evolved through the enthusiasm of increased contractility and disappointment of increased mortality for chronic heart failure. Paradoxically, the success of current neurohormonal therapies and implantable defibrillators has created a population of survivors with less chance of sudden death who now require increasing hospitalizations as the disease approaches its end. Right ventricular failure and cardiorenal interactions further limit the efficacy of currently recommended therapy. For most patients with comorbidities and advancing age, transplantation and current ventricular assist devices are mirages that intensify the desire for something better. Although the heaviest symptom burden is that of congestion, the backward failure, improvement of contractility and forward perfusion is sometimes the only direct route to relief. After the abandonment of previous oral inotropic agents with modest decrement in survival, chronic inotropic therapy is now offered in a more morbid form, as catheter infusion "until" something else happens, usually death. Looking forward, it remains to be revealed how far we will advance beyond draining congestive symptoms and squeezing forward flow to restore myocyte function and circulatory integration.
| Footnotes |
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This is Part II of a 2-part article. Part I appeared in the July 22, 2003, issue of Circulation (Circulation. 2003;108:367372).
| References |
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2. Stevenson LW, Dracup KA, Tillisch JH. Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation. Am J Cardiol. 1989; 63: 461464.[CrossRef][Medline] [Order article via Infotrieve]
3. Hershberger R, Nauman D, Walker T, et al. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure. J Card Fail. 2003; 9: 180187.[CrossRef][Medline] [Order article via Infotrieve]
4. Young JB, Moen EK. Outpatient parenteral inotropic therapy for advanced heart failure. J Heart Lung Transplant. 2000; 19: S49S57.[CrossRef][Medline] [Order article via Infotrieve]
5. Applefeld MM, Newman KA, Sutton FJ, et al. Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients. Am Heart J. 1987; 114: 589595.[CrossRef][Medline] [Order article via Infotrieve]
6. Miller LW. Outpatient dobutamine for refractory congestive heart failure: advantages, techniques, and results. J Heart Lung Transplant. 1991; 10: 482487.[Medline] [Order article via Infotrieve]
7. Sindone AP, Keogh AM, Macdonald PS, et al. Continuous home ambulatory intravenous inotropic drug therapy in severe heart failure: safety and cost efficacy. Am Heart J. 1997; 134: 889900.[CrossRef][Medline] [Order article via Infotrieve]
8. Fernandez-Gonzalez AL, Panizo-Santos A. Eosinophilic myocarditis in heart transplant candidates. J Heart Lung Transplant. 1996; 15: 852853.[Medline] [Order article via Infotrieve]
9. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345: 14351443.
10. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001; 38: 21012113.
11. Marius-Nunez AL, Heaney L, Fernandez RN, et al. Intermittent inotropic therapy in an outpatient setting: a cost-effective therapeutic modality in patients with refractory heart failure. Am Heart J. 1996; 132: 805808.[CrossRef][Medline] [Order article via Infotrieve]
12. Cesario D, Clark J, Maisel A. Beneficial effects of intermittent home administration of the inotrope/vasodilator milrinone in patients with end-stage congestive heart failure: a preliminary study. Am Heart J. 1998; 135: 121129.[CrossRef][Medline] [Order article via Infotrieve]
13. Harjai KJ, Mehra MR, Ventura HO, et al. Home inotropic therapy in advanced heart failure: cost analysis and clinical outcomes. Chest. 1997; 112: 12981303.
14. Krell MJ, Kline EM, Bates ER, et al. Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J. 1986; 112: 787791.[CrossRef][Medline] [Order article via Infotrieve]
15. David S, Zaks JM. Arrhythmias associated with intermittent outpatient dobutamine infusion. Angiology. 1986; 37: 8691.
16. Dies F. Intermittent dobutamine in ambulatory patients with chronic heart failure. Br J Clin Pract. 1986; 45: 3740.
17. Ellis A, Bental T, Kimchi O, et al. Intermittent dobutamine treatment in patients with chronic refractory congestive heart failure: a randomized, double-blind, placebo-controlled study. Clin Pharmacol Ther. 1998; 63: 682685.[CrossRef][Medline] [Order article via Infotrieve]
18. Erlemeier HH, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failure: long-term effects and lack of tolerance. Cardiovasc Drugs Ther. 1992; 6: 391398.[CrossRef][Medline] [Order article via Infotrieve]
19. Oliva F, Latini R, Politi A, et al. Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. Am Heart J. 1999; 138: 247253.[CrossRef][Medline] [Order article via Infotrieve]
20. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287: 15411547.
21. Willman V. Expert panel review of NHLBI Total Artificial Heart Program. Available at: http://www.nhlbi.nih.gov/resources/docs/tah-rpt.htm. Accessed 1999.
22. Krumholz HM, Phillips RS, Hamel MB, et al. Resuscitation preferences among patients with severe congestive heart failure: results from the SUPPORT project: Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. Circulation. 1998; 98: 648655.
23. Lewis EF, Johnson PA, Johnson W, et al. Preferences for quality of life or survival expressed by patients with heart failure. J Heart Lung Transplant. 2001; 20: 10161024.[CrossRef][Medline] [Order article via Infotrieve]
24. Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure: Vesnarinone Trial Investigators. N Engl J Med. 1998; 339: 18101816.
25. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group. N Engl J Med. 1991; 325: 14681475.[Abstract]
26. Hasenfuss G, Pieske B, Castell M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998; 98: 21412147.
27. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000; 102: 22222227.
28. Hosenpud J. Oral levosimendan, a novel myofilament calcium sensitizer, is an effective substitute for intravenous inotropic therapy in class IV inotrope-dependent heart failure patients. J Am Coll Cardiol. 1998; 31 (suppl C): 63C.Abstract.
29. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002; 360: 196202.[CrossRef][Medline] [Order article via Infotrieve]
30. del Monte F, Hajjar R. Targeting calcium cycling proteins in heart failure through gene transfer. J Physiol. 2003; 546: 4961.
31. Hoshijima M, Ikeda Y, Iwanaga Y, et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med. 2002; 8: 864871.[Medline] [Order article via Infotrieve]
32. del Monte F, Harding SE, Dec GW, et al. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002; 105: 904907.
33. Miyata S, Minobe W, Bristow MR, et al. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res. 2000; 86: 386390.
34. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994; 330: 17171722.
35. Roffman DS, Applefeld MM, Grove WR, et al. Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure. Clin Pharm. 1985; 4: 195199.[Medline] [Order article via Infotrieve]
36. OConnor CM, Gattis WA, Uretsky BF, et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999; 138: 7886.[CrossRef][Medline] [Order article via Infotrieve]
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