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Ann Thorac Surg 1996;61:380-387
© 1996 The Society of Thoracic Surgeons
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
Abstract
Background. Patients with advanced heart failure often cannot undergo cardiac transplantation soon enough to prevent fatal hemodynamic deterioration or sudden death. The approach to these patients includes tailoring of medical therapy with vasodilators and diuretics, which allows stabilization of 60% to 80% of potential candidates. Current criteria for mechanical support before transplantation currently focus on the identification of hospitalized patients with at least 30% chance of death before transplantation. The much larger question relates to the potential use of mechanical support to bridge ambulatory patients, who represent 90% to 95% of the transplant waiting list, with waiting times frequently exceeding 2 years.
Methods. From 1988 to 1993, 265 potential candidates were discharged after evaluation for transplantation with New York Heart Association class IV status and left ventricular ejection fraction of 0.25 or less. Patients were analyzed for clinical hemodynamic and echocardiographic profiles that would identify ambulatory patients unlikely to survive without urgent transplantation.
Results. After tailored medical therapy, presenting hemodynamic parameters are not useful for predicting 2-year survival without urgent transplantation, which was 45% at 2 years. Left ventricular diastolic dimension of 80 mm or greater was associated with only 29% two-year survival without urgent transplantation. Serum sodium level less than 132 mEq/L predicted 35% two-year survival without urgent transplantation. Peak oxygen consumption less than 10 mL•kg-1•min-1 identified poor outcome but was often not measured in patients with resting symptoms.
Conclusions. Although definition of indications for urgent bridging requires complex clinical assessment based on immediate risk, it should be possible to identify a larger ambulatory population for whom improved devices will offer extended survival without transplantation.
Heart failure is not one disease but a broad spectrum of hemodynamic and neuroendocrine abnormalities. Clinical profile ranges from the active patient with few or no symptoms and an annualized mortality rate of 5% to 10% to the patient with critically compromised organ perfusion and life expectancy measured in hours. Of the estimated 3 million patients in the United States with heart failure, approximately 20% may have major limitations of daily activity, while an additional 5% also have severe symptoms of heart failure at rest. Elderly patients have the highest prevalence of heart failure, but also a high incidence of other medical conditions that limit life expectancy and the options for heart failure therapy. Current estimates of the number of heart failure patients who could realistically benefit from cardiac replacement or support range from 50,000 to 200,000 each year.
How should these patients be identified? The experience with this dilemma derives largely from the approach to the patient referred for cardiac transplantation:
As this population is almost exclusively less than 65 years of age, the approach will require modification when older patients are evaluated instead for other therapies. This discussion will focus on the presentation with chronic heart failure, which is the indication for transplantation in 90% to 95% of candidates, rather than the more acute heart failure occurring after myocardial infarction or cardiac operation.
Approach to Patients With Advanced Heart Failure
All patients should be evaluated for potentially reversible factors causing heart failure:
Major areas of reversible ischemia should be carefully sought and addressed. In general, appropriate viable areas and targets are found in about 5% of patients referred to major transplant centers [1]. Recent-onset nonischemic cardiomyopathy should be closely followed up, as spontaneous improvement may occur, regardless of histologic findings. Such improvement occurs in 20% to 30% of patients with sufficient compromise to be referred to cardiac transplantation, and is most likely in patients with short duration of symptoms and ejection fraction greater than 0.20 without significant mitral regurgitation [2]. Rare cases of fulminant acute myocarditis, presenting with cardiogenic shock and organ compromise within days of a viral syndrome, may require high-dose inotropic support or mechanical support for 5 to 10 days before spontaneous recovery of near-normal ventricular function.
Other common factors exacerbating heart failure of any cause are heavy alcohol consumption and atrial fibrillation. Patients with heart failure should be advised to abstain completely from alcohol. All attempts, including amiodarone loading and subsequent cardioversion, should be tried to restore sinus rhythm [3]. When that is not possible, rate control both at rest and during exercise should be achieved, with a consideration of atrioventricular node ablation if pharmacologic therapy is inadequate. Restoration of normal sinus rhythm has frequently been associated with significant improvements in ejection fraction and clinical status, eliminating the need for transplantation.
Role of Tailored Medical Therapy
All patients with chronic symptomatic heart failure should undergo careful dissection and reconstruction of their medical regimen. The potential for cardiac transplantation has concentrated patients with severe heart failure at transplant centers, where multiple lessons have been learned:
The routine performance of right heart catheterization in potential transplant candidates has provided extensive information regarding hemodynamic status and the potential for hemodynamic improvement.
In defining populations with advanced heart failure, it is important to recognize that hemodynamic status frequently reflects the vigor of previous therapy rather than refractory decompensation. Expert use of vasodilator and inotropic agents and manipulation of volume status can create multiple hemodynamic profiles within a given patient. The use of absolute hemodynamic criteria to determine need or eligibility for surgical intervention is thus unlikely to select similarly compromised patients at different institutions, where the available hemodynamic expertise varies.
The insertion and maintenance of a right heart catheter for optimization of loading conditions and cardiac output over a 2- to 4-day period is a minor intervention compared with a cardiac operation. Any patient with refractory or recurrent symptoms of heart failure should undergo hemodynamically guided therapy before any decisions are made regarding major surgical interventions [4]. (The exception may be cases of acute cardiogenic shock in which circulation cannot be maintained without emergency mechanical support.) Even when an operation will be required, previous establishment of optimal hemodynamic status will reduce perioperative complications. Advantages of the monitored approach include (1) ability to optimize volume status and vascular tone simultaneously to a more precise degree than allowed by clinical assessment, (2) safe titration of rapid-acting intravenous agents, and (3) identification of oral regimens with similar efficacy to allow stabilization and discharge of many patients.
The major hemodynamic abnormality causing refractory symptoms in most chronic heart failure patients is severe elevation of ventricular filling pressures, which directly causes orthopnea and shortness of breath on minimal exertion, and indirectly leads to the elevations of right-sided venous pressure that cause anorexia, abdominal symptoms, and edema. These cardinal characteristics of class IV heart failure are due solely to pulmonary and systemic venous congestion and not to reductions in forward cardiac output and systemic perfusion. The degree of filling pressure elevation is commonly underestimated both before and after referral, due in part to (1) the pulmonary lymphatic adaptation, which often keeps the lungs clear in chronic heart failure despite left ventricular filling pressures of more than 30 mm Hg, and (2) the marked variation in tendency to peripheral edema, which is apparent in only about 25% of patients with severe heart failure. The average patient referred to a transplant center from a community cardiologist is 4 to 5 L of fluid above optimal status.
Therapy to relieve symptoms of congestion has often been limited by concern that reduction of filling pressures will further compromise cardiac output in the failing ventricle. Major progress in therapy of these patients has resulted from demonstration that reduction of filling pressures to near-normal levels in dilated heart failure not only allows maintenance of cardiac output, but actually leads to the best cardiac output [5]. Although this may appear counterintuitive, the improvement in cardiac output with lower filling pressures results from reduction in mitral regurgitation, which otherwise often consumes up to 80% of the total left ventricular stroke volume [6]. In addition, reduction of filling pressures and left ventricular size decreases myocardial oxygen consumption and improves subendocardial blood flow. The general goal is a pulmonary capillary wedge pressure of 15 mm Hg, although further reduction may be possible and beneficial in some patients.
Successful reduction of filling pressures to these levels usually requires a combination of intravenous diuretics to reduce total circulating volume and vasodilators to reduce the venous and arterial vasoconstriction. Filling pressures can rarely be effectively reduced until systemic vascular resistance is brought into the range of 1,000 to 1,200 dynes•s•cm-5. Cardiac output improves with effective therapy of loading conditions, but is not itself the best target for further adjustment during the design of a regimen for eventual hospital discharge. (The minority of patients who require more specific inotropic support are discussed below.) The specific approach to tailored therapy is as follows:
15 mm Hg 12 dynes • s • cm-5 8 mm Hg 
80 mm Hg
Representative hemodynamic responses are shown for 265 patients with class IV symptoms and left ventricular ejection fraction of 0.25 or less in Table 1
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Cardiac transplantation, with limited availability, has thus led paradoxically to many benefits for the medical therapy of heart failure, often offered as a ``consolation prize'' to ineligible patients as well as to the candidates who expect long waiting periods at home. Some of the efficacy of medical therapy for potential transplant candidates can be explained by application of the same commitment of dedicated physician/nursing teams as has been available for posttransplantation care. In addition, referring physicians who once preserved their control of heart failure patients first yielded to greater expertise in posttransplantation care and now are beginning to recognize the parallel expertise in care of advanced heart failure that is available at dedicated transplant centers. Far from increasing costs, referral to transplant cardiologists has been shown in at least two studies to decrease the cost of medical care for heart failure patients, in terms of total dollar costs and in terms of an 85% decrease in the rate of rehospitalization [8, 9].
Outcome of Tailored Therapy
Patients Requiring Continued Hospitalization
Although medical therapy tailored to hemodynamic goals as described above has resulted in successful discharge of 80% of patients transferred from other hospitals as ``refractory'' to nonsurgical intervention, approximately 10% of these patients will require continued hospitalization for hemodynamic stability. The majority of these will be ambulatory on intermediate doses of intravenous dobutamine and at relatively low risk for poor outcome, although amassing large hospital bills while awaiting transplantation.
A smaller number of patients will remain decompensated despite moderate inotropic support. These patients often have a recent history of a major event such as pulmonary infection, myocardial infarction, or cardiac operation, but occasionally represent the end of a slow decline of chronic heart failure, usually in relation to secondary compromise of renal or hepatic function. The classic stepped approach to therapy in these patients after optimization of loading conditions includes therapy with dobutamine, sometimes with dopamine as well, with subsequent addition of an intravenous phosphodiesterase inhibitor such as milrinone. The addition of full agonists such as epinephrine or isoproterenol usually provides an additional boost to cardiac output.
The indications for mechanical assistance have been difficult to establish. As discussed above, hemodynamic criteria represent a moving target and can frequently be coaxed above or below threshold values according to the bias of the clinician deciding on the need for further support. The criteria originally proposed for insertion of intraaortic balloon counterpulsation for heart failure (not in the setting of myocardial infarction) include cardiac index less than 2 L•min-1•m-2, pulmonary capillary wedge pressure greater than 20 mm Hg, and systemic vascular resistance greater than 2,100 dynes•s•cm-5, which actually represent a hemodynamic profile typical of patients who will often respond to revision of medical therapy (see Table 1
). The adaptation of an individual to low cardiac output depends on chronicity, intrinsic organ function, and age, but is very difficult to predict. Few heart failure experts would debate the necessity for further intervention when cardiac index cannot be maintained greater than 1.5 L•min-1•m-2, systemic venous saturation greater than 50%, and systolic blood pressure greater than 75 mm Hg or when hypoperfusion leads to mental obtundation or lactic acidosis. The minority of patients receiving mechanical support for heart failure actually meet these criteria, but in most patients the decision to intervene reflects a multifaceted clinical assessment that irrevocable deterioration is imminent without other intervention.
Pulmonary capillary wedge pressure elevation itself is rarely an adequate indication for mechanical support, usually indicating a good target for more aggressive therapy with drugs or ultrafiltration. Anuria may be another indication for escalated support, but may reflect many factors other than immediate cardiac output. Other concurrent conditions making medical management untenable may include recurrent ischemia causing pulmonary edema despite low baseline filling pressures or recurrent ventricular arrhythmias causing hemodynamic compromise.
Options for mechanical support include intraaortic balloon counterpulsation, centrifugal pumps, extracorporeal pulsatile devices, and implantable left ventricular assist devices. The intraaortic balloon is increasingly coming to be regarded as a short-term option to allow further decisions, essentially a bridge to a bridge. Controversy remains as to whether major benefit is derived from this support, particularly in the patient without epicardial coronary artery disease. The centrifugal and extracorporeal pulsatile devices are also short-term options that require a less extensive operation than implantable ventricular support devices but do not allow major patient mobility for an extended waiting period.
With current experience, justification for implantation of a left ventricular assist device in a potential transplant candidate requires that the assessment of risk without such support approach or exceed the 30% mortality seen with the current left ventricular assist devices before transplantation [11, 12]. Although this risk is difficult to assess, consideration from this standpoint is a useful counterbalance to specific hemodynamic criteria, which have not been validated either. As the results of left ventricular assist device bridging improve, however, a major additional consideration will be the potential for good outcome after transplantation, which may be better for critical patients after device support than more ``conservative'' management. A patient who will probably survive until transplantation but presents major risk for progressive multiorgan failure in the perioperative period may eventually be considered to be at lower total risk after left ventricular assist device insertion and recovery of secondary organ function before transplantation. A future could be envisioned where any patient who cannot be rendered ambulatory before transplantation should first undergo left ventricular assist device insertion and rehabilitation.
Patients Able to Be Discharged
INDICATIONS FOR CARDIAC TRANSPLANTATION.
The majority of patients considered for cardiac transplantation can be discharged, even when the clinical presentation and hemodynamic profile at the time of referral indicate severe compromise, as shown in Table 1 for 265 patients with initial class IV symptoms and ejection fraction of 0.25 or less. How should triage for further intervention be provided for these ambulatory patients? The threshold at which heart failure is considered ``end-stage'' or ``refractory'' continues to be challenged and extended. Initial class IV symptoms are no longer sufficient indication for cardiac transplantation (Fig 1).In general, it is anticipated that candidates for transplantation will have a 2-year survival of less than 50%. Rather than considering a longer horizon for survival as the basis for initial decision, patients once evaluated should continue to undergo frequent reevaluation. This approach is further supported by the decreasing rates of sudden death in the stable heart failure population [15].
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It is emphasized in that report that ``therapy should be adjusted until clinical congestion has been resolved or until further therapy has been repeatedly limited by severe hypotension (generally systolic blood pressure <80 mm Hg) or marked azotemia. Patients should not be considered to have refractory hemodynamic decompensation until therapy with intravenous followed by oral vasodilators and diuretic agents has been pursued using continuous hemodynamic monitoring to approach hemodynamic goals.''
THE WAITING LIST FOR AMBULATORY PATIENTS.
Unfortunately, receiving a beeper on the waiting list is only marginally related to receiving a donor heart. The median waiting time for ambulatory patients, listed as United Network for Organ Sharing status 2, has increased to almost 2 years. As the incremental risk of death decreases rapidly after the first 6 months on the list, those ambulatory patients surviving to undergo transplantation may often be those with the least need of the procedure [17].
The lengthening waiting lists have spurred earlier and earlier listing of patients who ``may soon need transplantation,'' who then further confound the dilemma of donor heart distribution. Concerns regarding the appropriate priorities for outpatients will soon become irrelevant, however, if these current listing practices continue. Approximately 70% of donor hearts are now being used for patients waiting in the hospital. Within the next few years all the hearts will be distributed to patients waiting in the hospital, and ambulatory candidates will serve as the control group [18]. The patients deteriorating to require urgent transplantation will paradoxically have the better outcome, a situation that distorts incentives for the physicians responsible. The long waiting times for outpatients have, however, frequently allowed time for progressive improvement in patients originally considered to need transplantation according to current criteria. By 3 to 6 months, up to 30% of strictly selected ambulatory candidates may demonstrate sufficient improvement in clinical and exercise status to be removed from the waiting list with subsequent 2-year survival equal to or better than that after transplantation [19].
A related financial issue during the struggle for affordable health care is the cost of maintaining patients in the hospital until transplantation. Even for inpatients, the wait often extends 2 to 3 months, with proportionately greater hospital costs. In addition to the inequities of current organ distribution, financial factors are thus forcing the development of new options for long-term care of patients with advanced heart failure.
All of the above considerations suggest that cardiac transplantation is not a sufficient solution for most patients with advanced heart failure, even when it appears to be an option. Other therapies need to be identified that can be more readily provided to patients with an otherwise poor outcome.
What Ambulatory Patients Are at Highest Risk?
The heart failure population is a moving target, as survival continues to improve with better medical management as described above. A high-risk population can be estimated from the criteria used as indications for cardiac transplantation, which is perhaps the best first step for identification of patients for other procedures as well. Cardiac transplantation is, however, associated with an operative mortality of only about 4% to 6% for ambulatory patients. The initiation of other procedures, such as placement of wearable assist devices, is currently associated with slightly higher operative mortality, although this would be expected to decline with use in less compromised patients. The selection of patients for these procedures should thus be slightly stricter than for cardiac transplantation in terms of indications, although the contraindications for long-term support should be less rigid due to the absence of accompanying immunosuppression. In examining current data for ``natural history'' of heart failure with tailored therapy and follow-up, the end points of sudden death at home, heart failure death, and urgent transplantation should all be considered [20] (Fig 2).
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. Left ventricular size is more predictive. In the group of 265 patients evaluated between 1988 and 1993 with initial class IV symptoms and ejection fraction of 0.25 or less, left ventricular diastolic dimension less than 70 mm was associated with survival without urgent transplantation of 66% at 1 year and 59% at 2 years. Left ventricular diastolic dimension of 80 mm Hg or more in this group was, in contrast, associated with only 49% survival without urgent transplantation at 1 year, and 25% at 2 years [20].
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). Similarly, those with initial pulmonary capillary wedge pressure above the median of 27 mm Hg did not have significantly worse survival, although these hemodynamics would predict higher mortality in a less uniformly compromised population that included milder heart failure. When filling pressures are aggressively reduced to minimum levels, the minimum levels reached are predictive of survival [20], but this approach is not standard and probably could not be used to compare populations between centers.
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Ambulatory patients rarely demonstrate continued class IV symptoms after tailored therapy as described above, as the congestive symptoms can usually be treated except where limited by intrinsic renal dysfunction. Those few such patients, however, do have poor survival as well as unacceptable quality of life without other support. In virtually all of these patients, peak oxygen consumption is usually 10 mL•kg-1•min-1 or less, which represents our best quantifiable measure of limitation, as long as the achievement of anaerobic metabolism confirms a good effort. Current practice often excludes patients with resting symptoms from undergoing full exercise testing; if these were all included, the apparent predictive value of peak oxygen consumption less than 10 mL•kg-1•min-1 for poor outcome would be even higher (Fig 5). Although the value of 14 mL•kg-1• min-1 is used as a threshold for cardiac transplantation [22], many patients, particularly older patients, can have reasonable quality of life at lower levels. The outlook for patients between 12 and 14 mL•kg-1•min-1 more resembles that for better patients than that for patients with peak oxygen consumption less than 10 mL • kg-1 • min-1.
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The current indications for bridging are widening. For patients who await transplantation while bedridden on intensive intravenous inotropic support or intraaortic balloon counterpulsation, the lengthening waiting times represent a major risk not only of pretransplantation death, but also of systemic deterioration to decrease the chance of effective rehabilitation after transplantation. The broader scope of potential candidates, however, includes those patients whose risk is less of immediate collapse than of death or deterioration during the next 1 to 2 years. Such patients may eventually be identified by intergrating information regarding clinical profile, left ventricular size, serum sodium level and other neuroendocrine indices, and peak oxygen consumption. As the supply of donor hearts will never be adequate for all of the people with advanced heart failure, the wearable assist devices currently under development and trial may provide ambulatory patients not only with bridges but with extended highways to better quality and length of life.
Footnotes
Presented at The Third International Conference on Circulatory Support Devices for Severe Cardiac Failure, Pittsburgh, PA, Oct 28-30, 1994.
Address reprint requests to Dr Stevenson, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
References
This article has been cited by other articles:
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  S. E. Sandner, D. Zimpfer, P. Zrunek, A. Rajek, H. Schima, D. Dunkler, M. Grimm, E. Wolner, and G. M. Wieselthaler Renal Function and Outcome After Continuous Flow Left Ventricular Assist Device Implantation Ann. Thorac. Surg., April 1, 2009; 87(4): 1072 - 1078. [Abstract] [Full Text] [PDF]
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 M. Williams, J. Casher, N. Joshi, T. Hankinson, M. Warren, M. Oz, Y. Naka, and D. Mancini Insertion of a left ventricular assist device in patients without thorough transplant evaluations: a worthwhile risk? J. Thorac. Cardiovasc. Surg., August 1, 2003; 126(2): 436 - 441. [Abstract] [Full Text] [PDF]
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L. W. Miller Patient selection for the use of ventricular assist devices as a bridge to transplantation Ann. Thorac. Surg., June 1, 2003; 75(90060): S66 - 71. [Abstract] [Full Text] [PDF]
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 H. Nagele, M. Bohlmann, U. Eck, B. Petersen, and W. Rodiger Combination therapy with carvedilol and amiodarone in patients with severe heart failure Eur J Heart Fail, March 1, 2000; 2(1): 71 - 79. [Abstract] [Full Text] [PDF]
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 S. A. Hunt and O.H. Frazier Mechanical Circulatory Support and Cardiac Transplantation Circulation, May 26, 1998; 97(20): 2079 - 2090. [Full Text] [PDF]
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H. R. Levin and M. L. Weisfeldt Deep Thoughts on Tin Men: Fact, Fallacy, and Future of Mechanical Circulatory Support Circulation, May 20, 1997; 95(10): 2340 - 2343. [Full Text]
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