Volume Control in Heart Failure Wafaa El Aroussy,MD Prof of Cardiology Kasr El Aini Faculty of Medicine September 29 th, 2011 What is Heart Failure Heart failure is a multisystem disorder which is characterised by:- Abnormalities of cardiac, skeletal muscle, and Heart H t failure occurs when the heart cannot pump enough renal blood function fast enough to meet the metabolic needs of the body Stimulation of the sympathetic ti nervous system Complex pattern of neurohormonal changes. 1
It is an Epidemic Epidemic allover despite tt due to ageing > 5 million Americans have heart failure 500,000 new cases/year ½ will be dead within 5 years > 1 million hospitalizations/year with HF as primary diagnosis Most common reason for hospitalization ti in those >65 years old 85% of HF cases are in adults 65 and older Define Heart failure Different t Ways to Define HF Acute & Chronic Systolic & Diastolic HFNEF Left & Right sided Low & high output Backward and Forward 2
Additional HF Definitions HF With Reduced LVEF Sometimes: HF With a Dilated Left Ventricle A clinical syndrome characterized by signs and symptoms of HF and reduced LVEF. Most commonly associated with LV chamber dilation HF With Preserved LVEF Sometimes: HF With Nondilated LV A clinical syndrome characterized by signs and symptoms of HF with preserved LVEF. Most commonly associated with a nondilated LV chamber. May be the result of valvular disease or other causes Pathophysiology of Heart Failure The changes comprise both cardiac and systemic response Initially adaptive (truly compensatory) then maladaptive(cause or result) 3
Favorable Fluid effect overload on symptoms and pulmonary and a positive congestion effect as on the length main of stay, reasons rate of for rehospitalization, hospitalization and in the long-term great survival, and should therefore be an important therapeutic majority of decompensated patients goal. Compensatory Mechanisms in HF Congestive Heart Failure pages S1-S6, 23 JUL 2010 DOI: 10.1111/j.1751-7133.2010.00167.x http://onlinelibrary.wiley.com/doi/10.1111/j.1751-7133.2010.00167.x/full#f2 4
Maladaptive mechanisms in HF Congestive Heart Failure pages S1-S6, 23 JUL 2010 DOI: 10.1111/j.1751-7133.2010.00167.x http://onlinelibrary.wiley.com/doi/10.1111/j.1751-7133.2010.00167.x/full#f1 Mechanisms of Sodium and Water Retention in Heart Failure Chronic Decrease in Cardiac Output Or Decrease in Peripheral Vascular Resistance Increased Cardiac Filling Pressures Decrease Fullness of The Arterial Circulation Water Retention V 2 Receptors Stimulation Baroreceptor Desensitization Decreased Renal Perfusion Pressure Renal Vasoconstriction Increased Sodium and Water Retention Nonosmotic AVP Release Increased SNS Activity Increased RAAS Activity Resistance to Natriuretic Peptides Failure to Escape From Aldosterone Increased Water and Sodium Reabsorption in the Proximal Tubule Decreased GFR Reduced Distal Delivery of Sodium Adapted from Schrier RW: J Am Coll Cardiol 2006; 47:1-8 5
Volume Overload in Heart Failure The Syndrome of Heart Failure Circulation. 1999;100:999-1008 6
ACC Heart Failure Guidelines Based on the 2009 Focused Update Incorporated Into the ACCF/AHA 2005 guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With: International Society for Heart and Lung Transplantation Staging of Heart Failure T 7
How to Control Volume?? Diuretics Vasoactive medications Intravenous vasodilators Nesiritide Hemofiltration or dialytic techniques (hemodialysis, peritoneal dialysis and extracorporeal ultrafiltration, either via an arterio-venous or veno-venous configuration (Extracorporeal ultrafiltration - UF) 8
Diuretics Diuretics included as background therapy. Although diuretics have not been specifically tested in clinical trials, they should still be used as needed for the treatment of volume overload. Diuretics have consistently been part of background therapy in all published placebocontrolled mortality trials of ACE inhibitors, beta blockers and spironolactone (Aldactone) in the treatment of symptomatic patients. Non potassium-sparing diuretics. Loop Diuretics Given IV have been the mainstay of therapy for fluid overload. The first-line therapy (Guidelines of the Heart Failure Society of America,2007 & 2010) Although these drugs can achieve effective diuresis in the majority, their use in patients with DHF may be limited because of adverse effects such as:- electrolyte abnormalities, neurohormonal stimulation, and worsening of renal function HFSA 2006 Comprehensive Heart Failure Practice guideline J Card Fail 2006;12:10-38 9
HFSA 2010 Comprehensive Heart Failure Practice Guideline Key Recommendations HFSA 2010 Practice Guideline (7.23) Pharmacologic Therapy: Diuretics Diuretic therapy is recommended to restore and maintain i normal volume status t in patients t with clinical evidence of fluid overload, generally manifested by: Congestive symptoms Signs of elevated filling pressures Strength of Evidence = A Loop diuretics rather than thiazide-type diuretics are typically necessary to restore normal volume status in patients with HF. Strength of Evidence = B Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. 10
HFSA 2010 Practice Guideline (7.24) Pharmacologic Therapy: Diuretics Restoration of normal volume status may require multiple adjustments. Once a diuretic effect is achieved with short-acting loop diuretics, increase frequency to 2-3 times a day if necessary, rather than increasing a single dose. Strength of Evidence = B Oral torsemide may be considered in patients exhibiting poor absorption of oral medication or erratic diuretic effect. Strength of Evidence = C IV administration of diuretics may be necessary. Strength of Evidence = A Diuretic refractoriness may represent patient nonadherence, a direct effect of diuretic use on the kidney, or progression of underlying dysfunction. Adapted from: Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. Causes of Diuretic Resistance Inadequate Dose Patient Non Compliance Not taking drug High NaCl Intake Poor Absorption Impaired Secretion Chronic Kidney Disease Old Age Kidney Transplant Chronic Heart Failure Drugs NSAIDs Probenecid Proteinuria Hypoproteinemia p Hypotension Drugs-Direct Direct Inhibitors NSAIDs ACE/ARB ** Diuretic Tolerance (Structural/Functional Adaptation) Neurohormonal Activation Cardiorenal Limit 11
Inadequate Dosing AM PM FENa + FENa =0 Log Diuretic Concentration Log Diuretic Concentration Ineffective Dose Effective Dose Ineffective Dose Effective Dose Ellison DH. Cardiology 2001; 96:132 143 Pharmacokinetics of Loop Diuretics Maximal Intravenous Moderate Renal Severe Renal Heart Dose (mg) Insufficiency Insufficiency Failure Furosemide 80-160 160-200 40-80 Bumetanide 4-8 8-10 1-2 Torsemide 20-50 50-100 10-20 Maximal Intravenous Doses of Loop Diuretics in Patients with Diminished Responses to Oral Therapy Diuretic IV Loading Dose (mg) Infusion Rate (mg/hr) CrCl < 25 ml/min CrCl 25-75 ml/min CrCl > 75 ml/min Furosemide 40 20 then 40 10 then 20 10 Bumetanide 1 1 then 2 0.5 then 1 0.5 Torsemide 20 10 then 20 5 then 10 5 Brater DC. New Engl J Med 1998; 339; 387-95 12
Excessive Dietary Sodium Intake 250 200 => =0 = ECF Reduction 150 100 Dietary Na Intake 50 0 LD LD LD LD LD Time, 6 hour periods LD Wilcox CS, Mitch WE, Kelly RA, Skorecki K, Meyer TW, Friedman PA, Souney PF. J Lab Clin Med. 1983 Sep;102(3):450-8. Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. IV Loop Diuretics: Bolus vs. Continuous Infusion Rudy DW et al. Ann Intern Med 1991; 115:360 Metanalysis: Continuous Infusion Superior to Bolus Injection: Total UO P = 0.003 Increase in Sr. Creatinine P < 0.00001 Length of Hospitaliization P < 0.00001 All Cause Mortality P = 0.00005 Salvador DRK et al. The Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD003178.pub3. DOI: 10.1002/14651858.CD003178.pub3. 13
Diuretic Secretion Is Impaired in CKD Diuretics Act from the tubule lumen Loop Diuretics Na + - K Cl K Na Uremic Anions D D Uremic anions block diuretic secretion into the proximal tubule D D Diuretic Albumin Ellison DH. Cardiology 2001; 96:132 143 Dose-Response Curves for Loop Diuretics Ellison DH. Cardiology 2001; 96:132 143 14
Loop Diuretics Stimulate Renin + - Na K Cl K MD Renin Na LOOP DIURETIC + - Na K Cl K Na TAL Ellison DH. Cardiology 2001; 96:132 143 Adaptation to Loop Diuretics Chronic Furosemide Increases Thiazide-sensitive transporter mrna Chronic Furosemide Increases Thiazide-sensitive transporter Activity 350 Control Furosemide Obermüller et al. Am J Physiol 269: F900 Chronic Furosemide Increases Thiazide-sensitive transporter protein NaCl Cot transport 300 250 200 150 100 50 0 Control Furosemide Furo + Spiro Abdallah et al. J Am Soc C F +S Nephrol 12: 1335, 2001 Ellison et al. JCI 83: 113, 1989 15
Therapeutic Approaches Block Adaptive Processes Post Diuretic Na Retention Chronic infusion Long-acting diuretics (thiazides, spironolactone) Structural Adaptations DCT diuretics (thiazides, spironolactone, ACEI/ARBs) CD diuretics (spironolactone, ACEI/ARBs) Neurohormonal Activation ACE Inhibitors Spironolactone Beta blockers Nesiritide Ultrafiltration Loop Diuretics Agent Initial Daily Dose Max Total Daily Dose Elimination: Renal Met. Duration of Action Furosemide 20-40mg gqd 600 mg 65%R-35%M 4-6 hrs or bid Bumetanide 0.5-1.0 mg qd or bid 10 mg 62%R/38%M 6-8 hrs Torsemide 10-20 mg qd 200 mg 20%R-80%M 12-16 hrs Ethacrynic acid 25-50 mg qd or bid 200 mg 67%R-33%M 6 hrs Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. 16
Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. 17
Evidence-Based Treatment Across the Continuum of Systolic LVD and HF Control Volume Diuretics Renal Replacement Therapy* Improve Clinical Outcomes ACEI Aldosterone -Blocker or ARB Antagonist or ARB CRT an ICD* *In selected patients HDZN/ISDN* Treat Residual Symptoms Digoxin Potassium-Sparing Diuretics Agent Spironolactone Eplerenone Initial Daily Dose 12.5-25 mg qd 25-50 mg qd Max Total Daily Dose Elimination Duration of Action 50 mg Metabolic 48-72 hrs 100 mg Renal, Metabolic Unknown Amiloride 5 mg qd 20 mg Renal 24 hrs Triamterene 50-75 mg bid 200 mg Metabolic 7-9 hrs Lindenfeld J, et al. HFSA 2010 Comprehensive Heart Failure Guideline. J Card Fail 2010;16:e1-e194. 18
Non potassium-sparing diuretics. Loop Diuretics Refractoriness to diuretics is common in DHF and requires aggressive strategies, including the use of loop diuretics either in high doses or in combination with thiazide diuretics These practices, are associated with worsening renal function, prolongation of length of stay, and increased long-term morbidity and mortality Continuous IV infusion of loop diuretics has been shown to have a superior natriuretic and diuretic effect compared to intermittent bolus injections This treatment has not been commonly used; it should be used more often by clinicians for correction of fluid overload in patients with DHF Gupta & Neyses. Eur Heart J 2005;26:644-649 ACC/AHA Treatment Recommendations 19
Comparison of Guidelines for the Management of Systolic Dysfunction* Drug Class University of Michigan CONSENSUS HF Heart Failure Society of America Diuretics All symptomatic patients, dosed as necessary to control symptoms All symptomatic patients, dosed as necessary to control symptoms All symptomatic patients, dosed as necessary to control symptoms control symptoms control symptoms control symptoms *Consensus HF : Am J Cardiol. 1999;832A:1A 38A. *Heart Failure Society of America (HFSA) practice guidelines. J Card Fail. 1999;5:357 82. Diuretics, ACE Inhibitors Reduce the number of sacks on the wagon 20
Figure 1. Relationship between maximum in-hospital diuretic dose and mortality in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness study. Felker G M et al. Circ Heart Fail 2009;2:56-62 Copyright American Heart Association Vasoactive Medications Used to facilitate diuresis in DHF pts resistant to diuretics. Dobutamine and Milrinone have a potent hemodynamic effect and can significantly augment cardiac output Their effect on renal hemodynamics, as well as on urine output, in patients with DHF has not been sufficiently investigated and is therefore not clear. Associated with increased risk of long-term morbidity and mortality. Recommended only in selected patients Renal dose dopamine cardiac output, renal blood flow, and urine output May be associated with tachycardia and arrhythmias Their use in patients with DHF have not been extensively investigated. (ADHERE) J Am Coll Cardiol 2005;46:57-64 21
Intravenous Vasodilators Their use in addition to diuretics for rapid improvement of hemodynamic parameters and congestive symptoms in the absence of symptomatic hypotension Effectively and rapidly reduce LV filling pressure by virtue of their systemic vasodilatory effect, but their effect on the kidney has not been sufficiently studied Nitroglycerin infusion into the renal artery resulted in no significant effect on renal blood flow An early study using hemodynamically effective doses of Na Nitroprussideid also showed a significant ifi diuretic and natriuretic ti effect These potential effects of the drug, however, have not been further explored Nesiritide (B-type natriuretic peptide) The effect of Nesiritide has been studied more extensively than that of nitroglycerin and nitroprusside. Enhancement of diuretic effect may suggest a relation between the degree of volume overload and the effect of the drug on urine output More information is needed to explore the effect of Nesiritide on urine output in patients with DHF Wang et al., Circulation 2004;110:1620-1625 22
Extracorporeal ultrafiltration (UF) UF has also been used to correct hypervolemia in patients with DHF Early application of newly designed veno-venous UF was feasible and well tolerated in patients and allowed a significant removal of fluid This treatment t t resulted in symptomatic ti and hemodynamic improvement, as well as improvement in neurohormonal profile (RAPID-CHF) trial J Am Coll Cardiol 2005;46:2043-2046. Fluid Removal by Ultrafiltration Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue The transient removal of blood elicits a compensatory mechanism, called plasma or intravascular refill (PR), aimed at minimizing this reduction 1,2 1. Lauer et al. Arch Intern Med. 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol. 2001;38:4. UF K P Na P H 2 O Na Vascular Space Vascular Space PR Interstitial Space (Edema) Na Na K 23
Simplified Veno-Venous Venous Ultrafiltration 0.12 m2 polysulphone filter Blood flow adjustable (10-40 ml/minute) Access Return Total extracorporeal blood volume 33 ml Peripheral, midline, or central venous access Anticoagulation with heparin recommended Effluent Electrolytes Please remember that t many of these medications have severe impacts on patient s electrolyte panels Ch k l t l t l b i i Check electrolytes on a regular basis in patients with heart failure 24
URINE ELECTROLYTES AFTER INTRAVENOUS DIURETICS OR ULTRAFILTRATION Ali SS et al. Congest Heart Fail. 2009; 15:1-4 140 IVD UF 120 P= 0.000025 100 mg/dl 80 60 P= 0.000017 40 20 P= 0.017 0 Sodium Potassium Magnesium Should UF replace IV diuretics as a first-line therapy for patients with hypervolemia admitted for DHF? 25
UNLOAD [Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure] Costanzo et al.,j Am Coll Cardiol 2007;49:675-683 Guidelines Issued before the Publication of the UNLOAD Trial for the Use of UF in the Management of HF Expert Group ACC/AHA 1 CCVS 2 ESC 3 Comment If the degree of renal dysfunction is severe or if edema becomes resistant to treatment, ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention. This can produce clinical benefits and may restore responsiveness to conventional doses of loop diuretics. In highly selected patients, intermittent slow continuous venovenous ultrafiltration may be considered. This should be performed in comsultation with a nephrologist or a specialist physician* who has experience using ultrafiltration in a setting of close inpatient observation. In chronic heart failure, ultrafiltration can resolve pulmonary edema and overhydration in case of refractoriness to pharmacological therapies. In most patients with severe disease the relief is temporary. In acute heart failure, ultrafitration or dialysis can be considered if other strategies are ineffective. 1. Hunt SA et al. Circulation 2005;112:e154-e235 2. Arnold JM et al. Can J Cardiol 2007; 23: 21-45 3. Swedberg K et al. Eur Heart J 2005; 26: 115-40 * Heart Failure Specialist? 26
UNLOAD Objective : -To assess the efficacy and safety of UF for the treatment of patients with DHF Population :- 200 patients hospitalized for DHF secondary to left ventricular systolic dysfunction Randomized to either early UF (within 24 h of hospitalization) or to intravenous diuretics. UNLOAD Results :- The efficacy and safety of UF in correcting fluid overload in a patient population with a mean net fluid loss of 4.6 l at 48 h without a significant change in serum creatinine or blood pressure The clinical benefit of aggressive fluid removal in this patient population: A superior fluid loss achieved with UF compared to intravenous diuretics at the dose used in the study (4.6 vs. 3.3 l, p = 0.001) had a lasting effect and reduced the rate of rehospitalizations and unscheduled visits for 3 months after discharge Conclusions :- Rapid correction of volume overload with a careful and frequent monitoring of volume status and renal function is both safe and effective in patients with DHF. 27
UNLOAD The validity of such a concept needs to be proven in larger studies designed to compare efficacy, safety, and cost-effectiveness of a comparable net fluid loss with these 2 therapeutic modalities in patients with DHF due to both systolic and diastolic LV dysfunction. The results of the UNLOAD trial, however, clearly demonstrate a great potential for the use of UF in patients with DHF who are either resistant to diuretics or demonstrate unfavorable side effects. An early application of this technology in such patients should allow effective therapy, prevention of adverse events, and improvement of after-discharge outcome. Blood Volume Measurement A recently available US Food and Drug Administration (FDA)-approved semi-automated instrument enables noninvasive radioisotopic blood volume measurement to be performed within one and a half hours or less with a 98% accuracy. Assessment improves diagnostic precision and streamline strategies for optimization of medical therapy. 28
Blood Volume Measurement Technique IV injection of a small amount of radiolabeled albumin and collection of six serial venous blood specimens over a 40-minute period. Analyzed by semi-logarithmic plot to calculate the volume of distribution of albumin (plasma volume) and corrected hematocrit measurements are used to calculate red blood cell volume and total blood volume (red blood cell volume plus plasma volume). The results are adjusted for factors known to affect blood volume (body habitus, age, and gender) and displayed in both absolute and normalized values. This non-invasive method of blood volume measurement provides accurate and clinically accessible blood volume measurements for application in research and clinical settings. Note : Heterogeneity of Blood Volume in Heart Failure The classic blood volume abnormality in HF is expansion of the plasma volume. Plasma expansion occurs in conjunction with increased vasoconstriction when RAAS and other neurohormonal mechanisms are activated in response to decreased renal perfusion. Ttt of HF and/or comorbid conditions may further alter blood volume Diuretics reduce plasma volume, while long-term vasodilation with organic nitrates and other vasodilators can lead to an increase in blood volume. Nesiritide produces both vasodilation and mild diuresis and thus may have mixed effects on blood volume. 29
In conclusion Conclusions A structured therapeutic approach to correction of fluid overload in DHF, including:- diuretics vasoactive medications UF Rapid correction of LV filling pressure and cardiopulmonary congestion, lead to early improvement of symptoms, shortening of length of stay, and reduction in the need for rehospitalizations in HFpatient population. 30
Thank You. 31