CRS Final Presentation

7/29/2019 CRS Final Presentation

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The Cardio-Renal Syndrome

Stephen L. Rennyson MD


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68 y.o. man with iCMO

admitted with volumeoverload consistent withCHF exacerbation

Admitted 2 weeks prior --

similar presentation

Discharged with appropriateCHF regimen, furosemidediuretic

Laboratory StudiesSodium 132Creatinine 1.8Hemoglobin 9.8Albumin 2.2

Clinical Presentation


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Placed on BiPap in the ED, given 120 mg of iv

Lasix, transferred to CICU . . . Started NTG gtt

Initial success of 500 cc urine output

Morning laboratory studies showcreatinine rising

Midnight dose of lasix produced little

urine output

Blood pressure falling . . .


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Background

Pathophysiology

Management Options

Case

Cardio-Renal Syndrome


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Congestive Heart

Failure Epidemiology changing from acute management

to managing the chronicity of cardiac dysfunction

An indicence of 5 million persons

Responsible for over 1 million yearly

hospitalizations

280,000 deaths annually


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Comorbid Conditions . . .Associated with a worse prognosis

Anemia (Hb < 10.0)

Cirrhosis

Peripheral Vascular Disease

Hyponatremia (


7/58Hillege, H. L. et al. Circulation 2006;113:671-678

Cumulative incidence

Cardiovascular death

Unplanned ADHF

admission

reduced LVEF (LVEF40%)

Cardiovascular Outcomes

with renal dysfunctionStratified by GFR

Stratified by GFR


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ADHERE RegistryRegistry of Acute Decompensated Heart Failure(ADHF)

105,000 patient registry

QOC study evaluating variations in CHFtreatment

Best predictors of outcome:

BUNCreatinine


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Most Simplistic Description:

Associated loss of renal function in thesetting of advanced CHF

CRS or RCS?



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Subtypes

Type I, acute CRS

Type II, chronic CRS

Type III, acute renocardiac syndrome

Type IV, chronic renocardiac syndrome

Type V, secondary CRS -- sepsis,amyloidosis


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CHF patients at increased risk for CRS:

Hypertension

Diabetes

Severe Vascular Disease

Elderly


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Background

Pathophysiology

Management

Conclusions



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Pathophysiology

Neurohormonal Factors:

SNS, RAAS, AVP System

Hemodynamics:

Loss of Cardiac Output

Transrenal perfusion pressure

Intrarenal hemodynamics


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Neurohormonal Axis

Adenosine


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CHF Hemodynamics

Systolic or Diastolic CHF

Exacerbations -- Symptomatology seen objectively

Elevated PCWP

Elevations of INR, Alkaline Phosphatase

Elevations of Creatinine

Shift in paradigm


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CVP and Renal Failure

2,557 patients underwent RHC

Age 59 15 years

57% were men

Renal Function using estimated

Glomerular Filtration Rate (eGFR)

Damman, K. et al. J Am Coll Cardiol 2009;53:582-588


17/58Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values

Central Venous Pressure

Solid line = cardiac index 3.2

p = 0.0217


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CVP and Renal Failure

Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Kaplan-Meier Analysis of Event-Free Survival According to Tertiles of CVP


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Renal Hemodynamics Transrenal perfusion pressure TRPP = MAP - CVP

CVP influenced:

PAP -- Oxygenation,Valve Dysfunction, CO

Volume Status

MAP -- Perfusion Pressure

Cardiac Output


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Ultimately lack of adequate transrenalperfusion pressure:

Renal Hypoxia

Inflammation / CytokineRelease

Progressive loss of nephronfunction and structural

Activation of the

Neurohormonal cascade

Renal Hemodynamics


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Background

Pathophysiology

Management Options

Case



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The Cardio-Renal

Syndrome Treatment Goals

Same goals as ADHF

Removal of Volume

Optimizing Hemodynamics

Complicated by chronic renal failure andacutely worsening renal function


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Removal of Volume

Loop Diuretics

Brain Naturetic Peptide

Arginine Vasopressin Antatonism

Adenosine Antagonism

Ultrafiltration


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Loop Diuretics

Goal --> Deplete extracellular fluid volume

Balanced refilling interstitium tointravascular compartment

Reality --> Contraction of circulating volume--> Activation of neurohormonal response


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Loop Diuretics

Furosemide

Blockage of the thick ascendingloop Na/ K/ 2 Cl pump

Acts intraluminally

Travels Bound to albumin

High Na delivered to distal tubules

Chronic use -> cellular hypertrophy -> increased Na

reabsorption -> Failure of diuresis


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Diuretic Resistance

Inadequate dosing

Cellular Hypertrophy

Bolus vs ContinuousInfusion

Double Diuretic Therapy

Nutritionally DeficientPatients


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Loop Diuretic Dosing Dose response curve is not smooth

Thus, no diruresis until threshold dose reached

If 20 mg IV once a day is insufficient; BID will bejust as ineffective

Torsemide and Bumetanide vs Furosemide

Similar iv bioavailabiltiy

Improved Oral Bioavailablity


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Braking PhenomenonShort term tolerance after the first dose

Continuous Infusion

Limited DataCochrane Review

Improved safetyImproved diuresisShorter Hospital StayLower Cardiac Mortality in asingle study

Cochrane Database Syst Rev. 2004. p. CD003178.


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The DOSE TrialDiuretic Optimization Strategies Evaluation

DOSE Trial

308 patients with ADHFLow vs High Dose FurosemideContinuous vs a12 hour dosing

Overall no significant differenceamong all groups

Patients symptomsCreatinineHigh Dose group had a greaterdiuresis with transient increases in

creatinineN Engl J Med. 2011 Mar 3;364(9):797-805.


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Diuretic Resistance

Loop + Thiazide

Chlorothiazide 250 mg vs 500 mg IV /Metolazone 5-10 mg PO

Very Effective -- Weight loss and edemaresolution

Double Sodium Excretion

CAUTION: Hyponatremia, Hypotension,Worsening renal function

Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis

Double Diuretic Therapy or Sequential Nephron Blockade

J Am Coll Cardiol, 2010; 56:1527-1534, doi:10.1016/j.jacc.2010.06.034


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Diuretic Resistance

Advanced CHF / Chronically ill

Elevated catecholamines (Catabolic)

Low serum albumin

Decreased delivery of diuretic to renal tubules

Travels bound to albumin --> Delivered to Glomerulus --> Filtered --> Actsluminal side of thick ascending loop

Clin Pharmacokinet. 1990 May;18(5):381-408

**Addition of salt poor albumin**Furosemide-Albumin dimer allows better

drug delivery


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Brain Natriuretic Peptide

LV volume overload --> Cardiac Myocytes secrete BNPprecursor --> Converted to proBNP --> ProBNP cleavedinto:

C-terminal BNP (biologically active)

Decrease in SVR and CVP

Increase natriuresis

N-terminal BNP or NT-proBNP (biologically inactive)


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Nesiritide (Natrecor)New to market in 2001

Actions in ADHF

PCWP reduced within 15 minutes of administration

Resultant decreases in PA and RA pressure

Reduced SVRI

Resultant increase in CO

Enhances loop diuretic effects

Modest intrinsic natriuretic and diuretic effects

No tachyphylaxis

-

3):252-6. Review-6


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ASCEND-HF

Over 7000 patients with ADHF -- standardtherapy

Nesiritide infusion 24 hrs - 7 days vs placebo

Primary End points:

CHF mortality and readmission (30 days)

Self reported Dyspnea at 6 and 24 hours


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ASCEND-HF

End points Placebo (%), n=3511 Nesiritide (%), n=3496 p

30-d death/HF hospitalization* 10.1 9.4 0.31

30-d death 4.0 3.6

30-d HF rehospitalization 6.1 6.0

Dyspnea at 6 h* 42.1 44.5 0.030

Moderately better 28.7 29.5

Markedly better 13.4 15.0

Dyspnea at 24 h* 66.1 68.2 0.007

Moderately better 38.6 37.8

Markedly better 27.5 30.4

>25% decrease eGFR 29.5 31.4 0.11


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ASCEND-HF

Role of Natrecor:

Resolved Concerns:

Worsening mortality

Worsening renal function

No significant benefit compared to standard therapy

Improved Dyspnea Score ($500.00/day)


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Arginine Vasopressin

Arginine vasopressin (AVP),secreted by posterior pituitary

V1 Vascular receptor

V2 Renal receptorProportional to the severity of HF

Contributes to fluid retention and hyponatremia


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Hyponatremia


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ACTIV Trial Initial trial for Tolvaptan -- AVP antagonist

319 patients with systolic dysfunction (


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EVEREST Trial Efficacy of Vasopressin Antagonism in HF Outcome

Study With Tolvaptan

Over 4000 patients in two separate study groups

EF < 40%

Tolvaptan (30mg) vs Placebo in combination with

standard HF thearpy

Treatment time up to 7 days

JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25


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Tolvaptan(n=2072)

% of patients

Placebo(n=2061)

% of patients

Baseline Meds

Diuretics 97.1 96.6

ACEi / ARB 84.3 84.1

-blocker 70.8 69.6

Aldo blocker 53.6 54.7

IV inotrope 4.0 4.3

Nesiritide 4.2 5.1

Baseline HF Characteristics

Dyspnea 90.9 91.1Edema 79.3 79.3

JVD 10 cm H2O 27.0 26.9

Serum Na+


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EVEREST Trial

JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25


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EVEREST Trial

JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25


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EVEREST Trial

JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25


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EVEREST Trial

No change over 24 month follow up:

All Cause Mortality

Cardiovascular Mortality

Heart Failure Hospitalization

JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25


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Elevated levels seen in ADHF

Released locally in response to stress (Macula Densa) and sodiumdelivery to the DCT

Actions:

Afferent Arteriole Vasoconstriction

Decreased GFR

Sodium reabsorption

Tubuloglomerular feedback mechanism for regulation of GFR

Adenosine??


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Adenosine

Tubuloglomerular Feedback

Acute delivery of sodium to the distaltubules (Lasix)

Adenosine further released from the

macula densa

Further renal dysfunction

Br J Pharmacol. 2003 August 2; 139(8): 13831388.


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Adenosine AntagonismBG9719

63 patients with ADHF

Compared Groups

Lasix Alone

Adenosine Antagonist Alone

Combination thearpy

Circulation. 2002;105:1348-1353


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Adenosine

Circulation. 2002;105:1348-1353


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Ultrafiltration

The removal of isotonic volume across asemipermeable membrane

Hemodialysis -- Removal of volume and solutesusing a concentration gradient

UF does not decreasesodium presentation to the macula

densa

Avoids neurohormonallymediated sodium and waterreabsorption


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Ultrafiltration

Advantages

Low Flow Catheters -- Simple PICC line

Veno-Venous filtration

No ICU monitoring needed


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UNLOAD Trial

200 Patients with ADHF

Randomized:

Conventional IV Diuresis

UF up to 500cc/hr

Am Coll Cardiol. 2007 Feb 13;49(6):675-83.


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UNLOAD Trial

Hypotension during 48 h after randomization:

Similar UF(4 of 100) 4% vs. Standard (3 of 100)

3%

Net fluid loss 48 h after randomization:

UF 4.6 2.6 L

Standard-care 3.3 2.6 L (p = 0.001)



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UNLOAD Trial



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UNLOAD Trial



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68 y.o. man with iCMOadmitted with volumeoverload consistentwith CHF exacerbation

Diuresis poor

Creatinine Rising

Laboratory StudiesSodium 132Creatinine 1.8Hemoglobin 9.8

Albumin 2.2

Clinical Presentation

G l


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Goals:

Improve symptoms

Limit further activation of theneurohormonal cascase

Little has been done to

improve mortality

TRPP = MAP - CVP


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The Cardio-Renal Syndrome is a worst case

scenario for the CHF patient

Mortality is clearly worsened

Management is difficult:

Many options; nothing improves mortality

Promising new therapies -- Adenosine . . .

Each readmission for ADHF increases mortality

Conclusions

CRS Final Presentation

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