How Should Diuretic-Refractory, Volume-Overloaded Heart Failure Patients Be Managed?

Clinical problem. Heart failure patients are frequently hospitalized with decompensated heart failure,1 usually with volume overload. Treatment guidelines recommend diuretics to optimize volume status,2 and are most effective administered intravenously. However, the management of patients refractory to diuretic therapy is not addressed in the guidelines of the American Heart Association/American College of Cardiology,3 the European Society of Cardiology4 or the Heart Failure Society of America.5 One problem with defining a treatment strategy in these patients is the lack of a consistent definition of diuretic resistance. Several alternative definitions could be used based on the lack of response to specific thresholds for pharmacotherapies or the lack of effectiveness of diuretics combined with adjunctive vasodilator or inotropic therapy. Alternatively, a definition could embrace the importance of metabolic derangements or azotemia as a result of diuretic therapies. Any such definition could be considered arbitrary, but for the purpose of this review, we defined diuretic resistance as the state of having an insufficient clinical response to maximally tolerated medical therapy. Diuretic resistance is more than merely a clinical inconvenience.6 Patients requiring more intense therapeutic regimens generally seem more sick, and a recent report demonstrated that such patients are at increased risk of death, independent of the usual prognostic factors.7 Unfortunately, no controlled clinical trials have defined the optimal treatment strategy for volume overloaded heart failure patients. Therefore, in this era of evidence-based medicine, secondary sources of information serve as the guide to our decision-making. Although the literature support several strategies for volume management, the focus is primarily pharmacologic. This review will demonstrate the need for more widespread consideration of mechanical therapies for volume management, particularly focused on the use of veno-venous hemofiltration. Standard medical management. Various critical pathways have been advocated for the hospitalized heart failure patient,2 each of which start with the assessment of volume status. This is a key first step, and one familiar to most invasive cardiologists but not to many other physicians. In this scenario, the cause of acute heart failure needs to be determined as the first step toward establishing the treatment plan, based on three different paths. In one scenario, a patient with acute myocardial ischemia presents with dyspnea and pulmonary congestion. While diuretics are useful, the key to treatment is reversing the underlying ischemia, and in fact, overly aggressive diuresis can lead to hypotension and impair perfusion, worsening ischemia. A second scenario, also familiar to invasive cardiologists, is the case of heart failure manifested as shock, wherein support devices including intra-aortic balloon pumps are needed. In either case, the invasive/interventional cardiologist is intimately involved in the management plan. There is a more common scenario that does not generally involve the invasive cardiologist, but perhaps should. This setting is that of patients admitted to the hospital for decompensated heart failure with marked volume overload. Such patients are managed with sodium restriction and diuretic therapy. In most cases, this is a sufficient first step toward long-term management with ACE inhibitor and beta-blocker. However, a subset of patients prove refractory to diuretic therapy, and are treated with adjunctive inotropic or vasodilatory medications, or in extreme cases, a decision may be made not to fully treat volume overload, commonly due to the azotemia that develops in the sicker patients. The purpose of this review is to focus the invasive/interventional cardiologist on the rationale for greater involvement in the care of patients admitted to the hospital with decompensated, volume overload, in particular when such patients are diuretic refractory. Before considering medical therapies, standard medical regimens can be simply and effectively implemented. In today’s cost-conscious environment, it is advantageous to do so in a time efficient manner. In addition, for the sake of the patients, who are suffering from severe dyspnea, prompt relief of symptoms has further advantages. To accomplish these goals, several strategies have been proposed for the treatment of volume overloaded heart failure patients. The first step is to rapidly find the effective dose of diuretics. Although most people use increments of 20 or 40 mg when dosing, based on familiarity with oral formulations, our experience is that too many dose choices may slow down the process of dose-finding (Figure 1). Due to the rapid effect of intravenous loop diuretics, assessment of the adequacy of a dose can be determined within 2–3 hours. While many may advocate that there should be a certain minimum urine output in order to consider the dose adequate, a simpler rule of thumb may prove as useful, and not depend upon whether there is adequate recording of such information. If the dose is correct, the patients will notice the production of significantly more urine than usual, and that the urine is very dilute, appearing clear like water. If both criteria are met, the dose is adequate, and should be administered 2 or 3 times a day until the patient is free of congestion, at which time the diuretic should be changed to an oral regimen. However, if after 2–3 hours a patient is not responding in the fashion outlined, the dose should be doubled, and administered at that point in time (not the next day). Reassessment follows that dose by 2–3 hours. By some standards, a lack of response to 200 mg of furosemide, or the equivalent, could define a patient as diuretic resistant. This becomes the crucial decision point where mechanical therapy could first be considered (Figure 1), but typically pharmacologic approaches would be used, including the use of additional diuretics, inotropes or vasodilators. The diuretic metolazone is commonly advocated, which can produce marked kaluresis, and therefore one must follow the serum potassium.8 However, an overlooked diuretic in the resistant patient is acetazolamide.9 Frequently, lack of effect of loop diuretics is due to the hypochloremic metabolic alkalosis; by using acetazolamide, this metabolic abnormality is reversed and the loop diuretics may work more effectively. No study has specifically evaluated the effect of inotropes on diuretic-resistant, volume-overloaded patients, but Optime is the closest study to focus of this population in that it focused on hospitalized patients with volume overload who were hemodynamically stable. There was no reduction in length of stay by adding milrinone, suggesting that inotropes did not resolve volume overload significantly better than diuretics alone.10 The effects of long-term vasodilator therapies are mixed at best, with minimal benefits with some11 and increased risk of death with others,12,13 despite the fact that vasodilator therapies are known to acutely lower cardiac filling pressures and reduce symptoms. Recent studies have highlighted the potential utility of nesiritide, a naturetic peptide.14 Although shown to reduce symptoms within 3 hours compared with placebo and to lower filling pressures faster than nitroglycerin,14 there is some evidence that suggests there may be an increased long-term risk associated with its use.15 Importantly, despite the expectation that a naturetic peptide would promote naturesis — a desirable effect in volume-overloaded patients — nesiritide does not have naturetic effects at the doses approved for clinical use.16 Similarly, renal-dose dopamine appears to have physiological effects suggesting that it should improve diuresis, yet the only comprehensive assessment of the utility of renal dopamine excludes patients with heart failure17 due to the paucity of literature. One study evaluated the effects on renal function in heart failure patients admitted with volume excess.18 Although the addition of dopamine to diuretics was associated with marked improvement in renal function after 5 days, this assessment was made in patients who were not refractory to diuretics. Diuretic-treated patients had the same urine production as patients in whom dopamine was added to their 1 mg bid of bumetamide (equivalent to furosemide 40 mg bid).18 Furthermore, dopamine can impair ventilatory responsiveness in heart failure patients via effects on the chemoreflex sensitivity.19 Therefore, even though 1 study suggests its utility, the relatively widespread use of renal dopamine should not be standardly advocated until definitive data can support its safety and efficacy. Combination therapy can overcome the resistance, in essence by improving renal blood flow. Options include high-dose nitroprusside or the combination of nitroprusside with a positive inotropic agent.20–23 Investigational options include the development of vasopressin antagonists, potentially useful for their diuretic effects, and positive inotropic agents including the calcium sensitizing drug levosimendan.24 Despite some of these approaches appearing advantageous to others, no regimen that includes a positive inotropic agent has been shown to be safe, even though able to improve status acutely,25,26 and similar concerns exist for direct-acting vasodilators.12,13,15 Management of refractory patients. One reason that heart failure has received so much attention is the cost and frequency of hospitalization. Perhaps the insufficient effect on reducing length of stay and readmission rates has to do with the difficulties involved in managing these patients who are refractory to the use of loop diuretics alone. For the past 3 decades, the literature has described a treatment modality for the volume-overloaded heart failure patient that has not become part of the mainstream.27,28 This approach rests on the principles of hemofiltration, using dialytic techniques, including hemodialysis, peritoneal dialysis and extracorporeal ultrafiltration, either via an arterio-venous or veno-venous configuration. In hemodialysis and peritoneal dialysis, toxic substances are removed from blood across a semipermeable membrane. This is achieved with the presence of a solute separated from the blood by the membrane. This membrane allows molecules of sufficiently small size to cross; the amount removed from the blood is controlled by the concentration gradient across the membrane. Varying the constitution and concentration of the solute therefore determines the amount of water and toxic substances removed. The membrane is synthetic for hemodialysis, while the peritoneum serves as a natural membrane for peritoneal dialysis. Because hemodialysis but not peritoneal dialysis can be implemented immediately, hemodialysis seems preferable. However, the metabolic changes and electrolyte shifts occurring during hemodialysis may be poorly tolerated by critically ill patients, and the hemodynamic stress may be a greater concern in patients with heart failure.29 In contrast to dialysis, ultrafiltration (or hemofiltration) is an extracorporeal technique by which an ultrafiltrate of plasma is produced by hydrostatic pressure exerted across a semipermeable membrane, essentially consisting of water and minerals, particularly sodium and potassium. Ultrafiltration is based on the principle of convective solute transport and differs from dialysis, wherein solutes diffuse across a semipermeable membrane into dialysate bath. Initial use of the technique used an arterial to venous connection configuration, and therefore, the rate of fluid removal was tied to the arterial pressure. This system worked well in patients with higher blood pressures, but was less useful when blood pressure was lower. An adaptation allowed connections from vein to vein, with the rate of fluid removal determined by a blood pump within the extracorporeal apparatus.28 When used in this veno-venous configuration, ultrafiltration does not produce marked changes in blood pressure, minimizing the risk of hemodynamic instability. Greater hemodynamic stability and control of blood flow: thus, fluid filtration rates make continuous veno-venous hemofiltration the optimal configuration for heart failure patients with resistant volume overload. The principle is simple. Blood is pumped from the patient, anticoagulated, and passed through a porous filter where fluid is removed according to the desired goal. The blood is then returned to the patient without large fluctuations in electrolytes or acid-base balance. In fact, because the ultrafiltrate has a potassium concentration similar to plasma, there is not the same concern about replacing potassium.30 In 1974, ultrafiltration was first reported as a modality for the treatment of volume overload, with several investigators reporting its utility for treatment of patients with cardiac disease,27,28,30–42 including those with contrast nephropathy after coronary intervention.43 Heart failure patients with refractory volume overload are an ideal target for this therapy, one which works independent of blood pressure (since it has a pump built in for veno-venous flow) and does not produce marked swings in blood pressure or volume.29,31 Ultrafiltration has been shown to be effective and well tolerated with up to 500 cc of ultrafiltrate removed per hour,27,30–33,36–40 although initial rates are usually 100–200 cc/hour. Initially, patients were instrumented and hemofiltration was continued until the right atrial pressure dropped by 50% or the hematocrit rose above 50.38–40,44 Currently, hemofiltration can be implemented to treat to clinical goals, such as reduction in symptoms or congestion, and not require invasive assessment of right atrial pressure.30,31 Table 1 lists several of the studies using ultrafiltration in patients with heart failure, which in general indicate that the technique is well tolerated even during large volume removal.33 In most cases, the studies focused on the technical aspects of performing hemofiltration, while in several, the clinical impact was evaluated as well. In 2 of 3 reports by Agostoni et al.,38–40 ambulatory, apparently optimized patients were randomized to a single session of CVVH or additional intravenous bolus diuretic therapy. In each group, patients averaged nearly 2 liters net fluid removal. Over the following 3–6 months, maximum oxygen volume improved significantly in the hemofiltrated group compared to the furosemide bolus group.38,39 Another interesting clinical observation is the restoration of responsiveness to diuretics after treatment in these diuretic-resistant patients.28,32,35,45 Select patients appear to respond with greater sensitivity to diuretic therapy after hemofiltration,28,32,34 although the frequency and predictors remain undefined. In fact, the response can be quite dramatic, with 1 series reporting that the average urine output increased from 605 ml in the 24 hours prior to hemofiltration to 1,965 ml in the 24 hours after completion of treatment. This increase occurred despite marked reduction in the furosemide doses during those time periods, from 289 mg to 40 mg.32 Although the cardiac effects of hemofiltration have not been studied specifically in patients with heart failure, the long-term safety relative to inotropic support was reported based upon a comparison of the experiences of 2 hospitals. In one hospital, eleven patients were treated with intermittent dobutamine, while another other 20 used intermittent hemofiltration. Despite the caveats warranted by such a comparison, the improved 1-year survival with hemofiltration42 suggests a potential benefit that needs to be proven in a prospective trial. A recent advance is the development of an apparatus that permits CVVH to be performed without central venous access. Twenty-one patients were treated with this device, leading to approval by the Food and Drug Administration for the treatment of severe volume overload.30,31 This system uses catheters placed in the antecubital veins, one similar to a PICC line (for withdrawal) and the other a short, large-bore intravenous catheter placed typically in the opposite arm. Sensors control the blood flow rates to prevent vein collapse, and can yield up to 500 ml/hour of ultrafiltrate removal. Treatment was up to 8 hours in duration and fluid removal averaged 3,725 ml. Patients felt better and experienced little change in serum electrolytes.30,31 Summary. Despite these studies demonstrating the feasibility, safety and effectiveness of volume management using hemofiltration, its use has not been widespread for 3 primary reasons. First, central access requirements have made Intensive Care Unit admission and logistical considerations become a barrier. Second, the techniques have traditionally been viewed as dialytic/nephrologic ones, and cardiologists have been hesitant to embrace them as their own. Third, heart failure specialists as well as clinical cardiologists and primary care providers treating heart failure do not generally consider mechanical treatments as a primary option, in contrast to invasive cardiologists. With the development of peripheral access systems for CVVH, the logistical barriers are markedly reduced. Although a randomized controlled trial would be ideal to demonstrate the clinical and pharmacoeconomic impact on heart failure, current data support the use of hemofiltration in a more widespread fashion, in particular in the volume-overloaded, diuretic-refractory patient.

1. Heart Disease and Stroke Statistics — 2003 Update. Volume 2003: American Heart Association, 2002. 2. Clearinghouse NG. Congestive heart failure guidelines. Volume 2003: National Guideline Clearinghouse, 2003. 3. 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). Developed in collaboration with the International Society for Heart and Lung Transplantation and endorsed by the Heart Failure Society of America. Circulation 2001;104:2996–3007. 4. Remme W, Swedberg K, Cleland J, et al. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560. 5. Heart Failure Society of America (HFSA) practice guidelines. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction — Pharmacological approaches. J Card Fail 1999;5:357–382. 6. Lucas C, Johnson W, Hamilton M, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J 2000;140:840–847. 7. Neuberg G, Miller A, O’Connor C, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 2002;144:31–38. 8. Cody R, Pickworth K. Approaches to diuretic therapy and electrolyte imbalance in congestive heart failure. Cardiol Clin 1994;12:37–50. 9. Knauf H, Mutschler E. Sequential nephron blockade breaks resistance to diuretics in edematous states. J Cardiovasc Pharmacol 1997;29:367–372. 10. Cuffe M, Califf R, Adams KJ, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA 2002;287:1541–1547. 11. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration cooperative study. N Engl J Med 1986;314:1547–1552. 12. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:44–54. 13. Moe G, Rouleau J, Charbonneau L, et al. Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan. Am Heart J 2000;139:587–595. 14. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002;287:1531–1540. 15. Sackner-Bernstein J, Kowalski M, Fox M. Is there risk associated with the use of nesiritide for acute heart failure? (Abstr). J Am Coll Cardiol 2003;41. 16. Katz S. Nesiritide (hBNP): A new class of therapeutic peptide for the treatment of decompensated congestive heart failure. Congest Heart Fail 2001;7:78–87. 17. Marik P. Low-dose dopamine: A systemic review. Intens Care Med 2002;28:877–883. 18. Varriai P, Mossavi M. The benefit of low-dose dopamine during vigorous diuresis for congestive heart failure associated with renal insufficiency: Does it protect renal function? Clin Cardiol 1997;20:627–630. 19. Van de Borne P, Oren R, Somers V. Dopamine depresses minute ventilation in patients with heart failure. Circulation 1998;98:126–131. 20. Monrad E, Baim D, Smith H, Lanoue A. Milrinone, dobutamine and nitroprusside: Comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure. Circulation 1986;73:III168–III174. 21. Kieback A, Iven H, Stolzenburg K, Baumann G. Saterinone, dobutamine and sodium nitroprusside: Comparison of cardiovascular profile in patients with congestive heart failure. J Cardiovasc Pharmacol 1998;32:629–636. 22. Capomolla S, Febo O, Opasich C, et al. Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: Safety and clinical outcome. Eur J Heart Fail 2001;3:601–610. 23. Yamani M, Haji S, Starling R, et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome and economic impact. Am Heart J 2001;142:998–1002. 24. Follath F, Cleland J, 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;360:196–202. 25. O’Connor C, Gattis W, Uretsky B, 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;138:78–86. 26. Silver M, Horton D, Ghali J, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol 2002;39:798–803. 27. Silverstein M, Ford C, Lysaght M, Henderson L. Treatment of severe fluid overload by ultrafiltration. N Engl J Med 1974;291:747–751. 28. Asaba H, Bergstrom J, Furst P, et al. Treatment of diuretic-resistant fluid retention with ultrafiltration. Acta Med Scand 1978;204:145–149. 29. Dormans T, Huige R, Gerlag P. Chronic intermittent hemofiltration and hemodialysis in end-stage chronic heart failure with edema refractory to high-dose frusemide. Heart 1996;75:349–351. 30. Clinical summary: CHF Solutions System 100. Volume 2002: CHF Solutions, 2002. 31. Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003;9:727–731. 32. Rimondini A, Cipolla C, DellaBella P, et al. Hemofiltration as short-term treatment for refractory congestive heart failure. Am J Med 1987;83:43–48. 33. DiLeo M, Paciti A, Bergerone S, et al. Ultrafiltration in the treatment of refractory congestive heart failure. Clin Cardiol 1988;11:449–452. 34. Akiba T, Taniguchi K, Marumo F, Matsuda O. Clinical significance of renal hemodynamics in severe congestive heart failure: Responsiveness to ultrafiltration therapies. Jpn Circ J 1989;53:191. 35. Canaud B, Cristol J, Klouche K, et al. Slow continuous ultrafiltration: A means of unmasking myocardial functional reserve in end-stage cardiac disease. Contrib Nephrol 1991;93:79–85. 36. Biasoli S, Barbaresi F, Barbiero M, et al. Intermittent venovenous hemofiltration as a chronic treatment for refractory and intractable heart failure. ASAIO J 1992;38:M663–M685. 37. Pepi M, Marenzi G, Agostoni P, et al. Sustained cardiac diastole changes elicited by ultrafiltration in patients with moderate congestive heart failure: Pathophysiological correlates. Br Heart J 1993;70:135–140. 38. Agostoni P, Marenzi G, Pepi M, et al. Isolated ultrafiltration in moderate congestive heart failure. J Am Coll Cardiol 1993;21:424–431. 39. Agostoni P, Marenzi G, Lauri G, et al. Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency. Am J Med 1994;96:191–199. 40. Agostoni P, Marenzi G, Sganzerla P, et al. Lung-heart interaction as a substrate for the improvement in exercise capacity after body fluid depletion in moderate congestive heart failure. Am J Cardiol 1995;76:793–798. 41. Ramos R, Salem B, DePawlikowsky M, et al. Outcome predictors of ultrafiltration in patients with refractory congestive heart failure and renal failure. Angiology 1996;47:447–454. 42. Sacco A, Agliata S, Schweiger K, et al. Peritoneal dialysis and chronic dobutamine, two experiences contrasted. Possible role and indications in refractory cardiac decompensation. Minerva Urol Nefrol 1998;50:91–95. 43. Marenzi G, Bartorelli A, Lauri G, et al. Continuous veno-venous hemofiltration for the treatment of contrast-induced acute renal failure after percutaneous coronary intervention. Cathet Cardiovasc Intervent 2003;58:59–64. 44. Marenzi G, Lauri G, Guazzi M, et al. Ultrafiltration in moderate heart failure. Exercise oxygen uptake as a predictor of the clinical benefits. Chest 1995;108:94–98. 45. Inoue T, Morooka S, Hayashi T, et al. Effectiveness of continuous arteriovenous hemofiltration for patients with refractory heart failure. Jpn Heart J 1988;29:595–602. 46. Inoue T, Sakai Y, Morooka S, et al. Hemofiltration as treatment for patients with refractory heart failure. Clin Cardiol 1992;15:514–518.