crs final presentation
TRANSCRIPT
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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 (
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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?
Cardio-Renal Syndrome
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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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Cardio-Renal Syndrome
CHF patients at increased risk for CRS:
Hypertension
Diabetes
Severe Vascular Disease
Elderly
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Background
Pathophysiology
Management
Conclusions
Cardio-Renal Syndrome
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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
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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
Cardio-Renal Syndrome
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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
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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)
Am Coll Cardiol. 2007 Feb 13;49(6):675-83.
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UNLOAD Trial
Am Coll Cardiol. 2007 Feb 13;49(6):675-83.
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UNLOAD Trial
Am Coll Cardiol. 2007 Feb 13;49(6):675-83.
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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