artwork by aaron jameson cast of characters n importance n evaluate a case n explain the...
TRANSCRIPT
Artwork by
Aaron Jameson
Cast of Characters
Importance Evaluate a Case Explain the Pathophysiology Develop the Armamentarium
– Why they work– How to monitor
Cover the important evidence for each group
Plan of Attack
CHF and Super Heroes
The Role of Rx Man
Surgeon General’s Warning This lecture will require you to
write some things down You could develop carpal tunnel
syndrome You could develop an irreversible
hand cramp You could retain something longer
than 5 minutes
A Fatal Choice You can have a cancer that:
kills 40% of people in 5 years
OR You can have your first
episode of symptomatic CHF
Did You Choose CHF?
OOPS !!
Epidemiology
CHF Kills A LOT of People CHF Makes A LOT of People’s
lives miserable CHF costs a WHOLE LOT of $
New York Heart Association
Class I Class II Class III Class IV
New Approach to the Classification of Heart Failure
Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)
Refractory end-stage HFD
Known structural heart disease Shortness of breath and
fatigue Reduced exercise tolerance
Symptomatic HFC
Previous MI LV systolic dysfunction Asymptomatic valvular disease
Asymptomatic HFB
Hypertension CAD Diabetes mellitus Family history of
cardiomyopathy
High risk for developing heart failure (HF)
APatient Description
Stage
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease)
Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional ClassACC/AHA HF Stage NYHA Functional Class
NoneNone
B Structural heart disease but without symptoms of heart failure
I Asymptomatic
C Structural heart disease with prior or current symptoms of heart failure
II Symptomatic with moderate exertion
III Symptomatic with minimal exertion
D Refractory heart failure requiring specialized interventions
IV Symptomatic at rest
2113.
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
PenelopeA 74 year old white female 5 feet tall 160 pounds S/P CVA Hx mild CHF , HTN and DM 2
Penelope : Episode 1
Admitted to ER with Acute SOB.
Auscultation reveals crackles 1/2 way up on both sides
CXR shows mild interstitial infiltrates
BP: 150/80 2+ pitting edema
Penelope : Episode 1
Admitted to ER with Acute SOB. Auscultation reveals crackles
1/2 way up on both sides CXR shows mild interstitial
infiltrates BP: 150/80 2+ pitting edema NYHA class?
Penelope
Drugs: Insulin Dyazide daily Zestril 5 mg daily
Penelope is tied to the railroad tracks
You can save her from floods You can give her a pillow and
make her more comfortable You can even delay the train But you can’t take her off the
tracks.
Circulation Review
PreloadPreload AfterloadAfterload
Low Low pressurepressure
High High pressurepressure
Famous Last Words
Everything that can be invented has been invented.”
--Charles H. Duell, Commissioner, U. S. Office of Patents, 1899.
Systolic vs. Diastolic Dysfunction
120 ml
Normal Heart
70ml
EF 70/120
58 %EF 70/120
58 %
CO = 70ml /beatCO = 70ml /beat
Normal Heart
120 ml
* 72/min* 72/min=5040 ml/min=5040 ml/min
Systolic Dysfunction
160 ml
40ml
Systolic Dysfunction
160 ml
CO = 40ml /beatCO = 40ml /beat * 72/min* 72/min=2880 ml/min=2880 ml/min
EF 70/120
58 %EF 40/160
25 %
57 ml
Diastolic
Dysfunction
40ml
Diastolic Dysfunction
57 ml
EF 70/120
58 %EF 40/57
70%
CO 40ml / beatCO 40ml / beat * 72/min* 72/min =2880 ml/min=2880 ml/min
Diastolic Heart Failureand Intravascular Congestion
Describe Diastolic Dysfunction
Other Neuroendocrine mediators
Arginine Vasopressin (ADH)
Stimulated by extreme low kidney perfusion, just like Aldosterone. Causes free water retention and hyponatremia
Endothelin
One of the absolute most potent vasoconstrictors. Endothelin antagonists in the works
Atrial and B-type Natriuretic peptide
Stimulated by stretch of the atria and the ventricles and cause sodium and water excretion. Sort like a counter-regulatory hormone to aldosterone
CHF: CompensationCardiac Output
Kidney Perfusion
ReninAngiotensinAldosterone
Na+ & H2O
retention
Preload
SNS
Cardiac Output
((Compensated)
CHF: CompensationCardiac Output
CHF: Compensation
Kidney Kidney PerfusionPerfusion
Cardiac Output
CHF: Compensation
Kidney Perfusion
ReninReninAngiotensinAngiotensinAldosteroneAldosterone
Cardiac Output
CHF: Compensation
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
Na+Na+ andand H2OH2O
retentionretention
Cardiac Output
CHF: Compensation
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
CHF: Compensation
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload
CardiacCardiacOutputOutput
(CompensatedCompensated))
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
CHF: Compensation
Kidney Kidney PerfusionPerfusion
ReninAngiotensinAldosterone
Na+ and H2O
retention
Preload
Cardiac Output CardiacCardiacOutputOutput
(Compensated)Compensated)
CHF: Compensation
Kidney Perfusion
ReninAngiotensinAngiotensinAldosterone
Na+ and H2O
retention
SNSSNS
Cardiac Output CardiacCardiacOutputOutput
(CompensatedCompensated))
Preload
CHF: Warning: New Slide!
Cardiac Output
WHY?
CHF: Warning: New Slide!
Cardiac Output
WHY?
SystolicSystolic DilatedDilated CardiomyopathyCardiomyopathy CADCAD HTNHTN
CHF: Warning: New Slide!
Cardiac Output
WHY?
SystolicSystolic DilatedDilated CardiomyopathyCardiomyopathy CADCAD HTNHTN
Diastolic
Hypertension
CAD
Hypertrophic Cardiomyopathy
Another famous last quoteGod is Dead
Nieztsche 1885
Nieztsche is
DeadGoGod d
20072007
CHF: The Viscious CycleThe Viscious Cycle
Kidney Perfusion
ReninAngiotensinAldosterone
Cardiac Output
CHF: The Viscious Cycle
Kidney Perfusion
ReninAngiotensinAngiotensinAldosterone
VasoconstrictionVasoconstriction
SNS
Cardiac Output
CHF: The Viscious CycleCardiacCardiac OutputOutput
Kidney Perfusion
ReninAngiotensinAngiotensinAldosterone
VasoconstrictionVasoconstriction
SNS
AfterloadAfterload
High Pressure
Left VentricleLeft Ventricle ArteriesArteries
High Pressure: Vasoconstriction
Left VentricleLeft Ventricle ArteriesArteries
CHF: The Viscious Cycle
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
Cardiac Output
CHF: The Vicious Cycle
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
Na+Na+ andand H2OH2O
retentionretention
Cardiac Output
CHF: Vicious Cycle
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload and and Pulmonary EdemaPulmonary Edema
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
CHF: Vicious Cycle
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload and and Pulmonary EdemaPulmonary Edema
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
StrainStrain
CHF: Symptoms
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload and and Pulmonary EdemaPulmonary Edema
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
StrainStrainLow PerfusionLow PerfusionLow PerfusionLow Perfusion
Fluid OverloadFluid OverloadFluid OverloadFluid Overload
CHF Pharmacotherapy
New Drugs Mechanism(s)
Monitoring for Efficacy
Monitoring for Adverse Effects
Back to Penelope: Episode 1
Admitted to ER with Acute SOB.
Auscultation reveals crackles 1/2 way up on both sides
CXR shows mild interstitial infiltrates
BP: 150/80 2+ pitting edema
This is a Job for...
Water Boy
Diuretics: Mechanism
Sodium and Water Excretion
Preload
Necessary Poison
Low perfusion Loss of Renal Function
Fluid OverloadPulmonary Edema
Low perfusion Loss of Renal Function
Fluid OverloadPulmonary Edema
Low perfusion Loss of Renal Function
Fluid OverloadPulmonary Edema
Diuretics: Efficacy
~1 Kg / day (short term) ~1000 mls net loss / day 700 mls insensible loss
(output) Lung Sounds / CXR Decreased Edema
Diuretics: Efficacy
Example:
Input: IV at 100ml/hour
Output: 2700 ml in 24 hours
Net:
Don’t forget 700ml insensible + 300ml = 1000ml lost
Diuretic Dosing
Long Term:Be a Sissy.
Short Term:The Nike Rule
Diuretics: Thiazides vs LoopsLoopstorsemide vs furosemideAbsorption, duration and CostOther loops
Potency vs efficacy
Diuretics: Side Effects
BUN / Cr Ratio Potassium Do Orthostatics !! Clinical Hydration Status Glucose Uric Acid Ca++
Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles
1/2 way up on both sides CXR shows mild interstitial
infiltrates BP: 150/80 2+ pitting edema
BP 150/80
Which rule should we use? Nike or Sissy?
Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles
1/2 way up on both sides CXR shows mild interstitial
infiltrates BP: 150/80 2+ pitting edema
BP 150/80
What about the Zestril dose?
ACE of Hearts
Angiotensin IAngiotensinogen
Renin
COW HERE
Angiotensin IAngiotensinogen
Renin
Angiotensin I
Angiotensin II
Angiotensinogen
ACE
Renin
Angiotensin I
Angiotensin II
Aldosterone
Vasoconstriction
Angiotensinogen
ACE
Renin
Na+
K+K+ Lost
Na+ Retained
Aldosterone
Angiotensin I
Angiotensin II
Vasoconstriction
ACE I
Angiotensinogen
ACE
Renin
K+K+ Retained
Aldosterone
Angiotensin I
Angiotensin II
Aldosterone
Vasoconstriction
Kinins
Breakdown
ACE I
Angiotensinogen
Renin
ACE
Kinins
OK,
So how does this benefit the fluid overloaded, under-perfused CHF patient
insert preload diagram hereinsert preload diagram here
LowLowPressurPressuree
Whew !!!
I Can Breathe !!
High Pressure: AfterloadHigh Pressure: Afterload
Left VentricleLeft Ventricle ArteriesArteries
High Pressure: Post DilationHigh Pressure: Post Dilation
Left VentricleLeft Ventricle ArteriesArteries
OK,
So how does this benefit the fluid overloaded, under-perfused CHF patient
Breathing and fluid
improved
Exercise capacity improved
Mental Status Improved
B. P.
Ace Inhibitors: Efficacy
BUN / Creatinine
Ace I: Adverse Effects
Potassium
Hypotension (dizziness)
Cough
AngioedemaACE & Kidneys
Ace Inhibitors:Warning Signs
Impaired Renal Perfusion Diuretic CHF
– Especially w/ Hyponatremia Ascites
Ace Inhibitors : Dosing
CHF vs HTN Caution: Hyponatremia
Ace Inhibitors : Drug Intx
Potassium Sparing Diuretics NSAIDS
What is the intx with ACE Inhibitors and NSAIDS?
V-HeFT I
Enalapril vs. Placebo Class II & III Mortality
– 34.3 vs 25.6 @ 2 years NNT 11.5– 53.6 vs 49.7 @ 4 years NNT 25.6
(benefit diminishes w/ time)
CONSENSUS I
Class IV Mortality at one year 52% vs 36% NNT 6 !!! Average dose 18.4 mg /day
SOLVD-Treatment
Class II & III Mortality at 4 years 39.7 % vs 35.2 % NNT 22 Mean daily dose of enalapril= 16.6
mg
Penelope :
Increase Zestril to 10 mg daily
Because :
Ace Inhibitors Save Lives
Penelope : Episode 2
One month later…
Develops an intractable cough
Your questions?
Your recommendation?
Vasoconstriction
Angiotensin I
Angiotensin II
Aldosterone
Angiotensinogen
Renin
Na+
K+
Kinins
Breakdown
Chymase
Aldosterone Vasoconstriction
K+ Retained
Aldosterone
Vasoconstriction
AT1 AT1
Angiotensin IIAngiotensin II
AT2
AT3
AT4
Feedback Fetal effects Many others
ARBs
Similar to ACE inhibitors but also many differences
Highly variable half lives Highly variable AT1 receptor
affinity
RESOLVD
Candesartan vs. candesartan +enalapril vs. enalapril alone
Class II – IV Terminated early due to
candesartan groups doing worse. Difficult to interpret due to
unusually low mortality and morbidity in enalapril group
RESOLVD
Because the study wasn’t powered to show mortality, the authors conclusion didn’t mention higher mortality in the candesartan groups!
“Candesartan was as effective, safe, and tolerable as enalapril”
“The Combination… was more beneficial for preventing left ventricular remodeling”
Elite II Losartan 50mg / d vs. placebo Class III & IV Mortality: No difference
ValHeft
Valsartan Class II-IV Some benefit added to ACE OR
to a Beta Blocker INCREASED MORTALITY When added to both !!
CHARM (as in snake?)
Alternative – In ACE intolerant
patients – Improved outcomes
moderately Added
– Improved outcomes minimally
– Beta blocker would be better (opinion)
Preserved– No statistical
improvement Overall
– Statistical improvement
Penelope
Cozaar 50mg daily Continue Lasix etc.
Penelope: Episode 3
Four months later…
There has been trouble getting weights in the nursing home
Another episode of SOB, 02 saturation 85% Weight 178 pounds BUN / Cr: 40 / 1.4
Penelope
Treatment now?
Right Again! Vitamin L
Treatment: Lasix 80 mg BID
What will that do to the BUN / Cr?
Penelope:
Two weeks later…
Wt. 175 pounds Breathing improved but not good No CXR or ausculation BUN / Cr 50 / 1.5 What do you recommend ?
My Momma Always Said:
Patience is a Virtue
Penelope
Weight decreases to 158 over the next 2 months.
Breathing greatly improved in the last month.
BP: 110 / 70 Guesses on the BUN and Creat?? 90 / 2.0
Penelope: Episode 5
What next??
Decline in mental status. Sleeping 18 to 20 hours per day. Confused, wild delusions.
What do you do now?
The Hemodynamic Duo!!
Nitrates / Hydralazine: Mechanisms
Hemodynamic effects similar to Ace
Inhibitors
Nitrates decrease Preload
Hydralazine decreases afterload
Nitrates / Hydralazine PERHAPS a little:
– less mortality benefit
– more symptom benefit
Less renal impairment risk
Nitrates / Hydralazine: Efficacy
Similar to Ace Inhibitors Better in African Americans?
Nitrates / Hydralazine: Adverse Effects
P.O.S. (Pill overload syndrome)
Headache
Nausea
Hypotension
Nitrates / Hydralazine:
BIDIL®
Could we use digoxin?
Digimon
Digoxin: Mechanisms
Increased force of contraction
Decreased hospitalizations
No mortality benefit or harm
Digoxin: Efficacy
Urine Output
Mental Status
Exercise capacity improved
Digoxin: Adverse Effects
Potassium
Mental Status
Pulse / EKG
Nausea / Vomiting
Digoxin: Evidence
The Dig Trial
No difference in mortality 67.1% vs 64.3%
hospitalization 1% vs 2 % hospitalized for
suspected dig toxicity
Digoxin Pharmacology? Clinical Effect?
Meanwhile, Penelope is still on the Railroad Tracks
Increase Cozaar BUN goes to 120 (oops) Decrease Cozaar Add Hydralazine and Nitrates Titrate up to 50 mg TID and
20 mg TID
Penelope
Result?
Somnolence improves Delusions resolve BUN / Cr 80 / 1.8 Weight 158 BP: 100/60 Add a beta blocker?
Sir Blocksalot
0
10
20
30
40
50
60
70
80
Mean + SD.Adapted from Bristow M. J Am Coll Cardiol. 1993;22(4 Suppl A):61A–71A.
Normal function (n=12) Cardiomyopathy (n=54)
1
2
1*P<.05 vs normal function
Rec
epto
r d
ensi
ty (
fmo
l/mg
p
rote
in)
1: 2 80%:20% 1: 2 65%:35%
Adrenergic Receptors in Normal vs Failing Left Ventricles
*
Beta Blockers
Improve Cardiac Function ??
Decreased Mortality
Don’t Use Unless CHF is stable
Beta Blockers Block
Death
Beta Blockers: MERIT-HF
Metoprolol XL Mostly Class II & III Mortality over one year
– 11% vs. 7.2% NNT 26 Dosing
Beta Blockers:Carvedilol Trial
Mostly Class II & III Mortality over 6 months
– 3.2% vs. 7.8% NNT 21 hospitalization 14% vs 19% NNT 20 2% died or deteriorated during run in
Which beta blockers are proven in CHF?
Penelope
She does well for 3 months
Penelope died July 9, 1998
Penelope
What do we know now that we didn’t know then?
Spiro the Super Mouse
CHF: Vicious Cycle
Kidney Perfusion
ReninAngiotensinAldosteroneAldosterone
PreloadPreload and and Pulmonary EdemaPulmonary Edema
Cardiac Output
Na+Na+ andand H2OH2O
retentionretention
StrainStrain
AldosteroneAldosterone
Sodium Retention Magnesium and Potassium Loss Sympathetic Activation Parasympathetic Inhibition Myocardial fibrosis Vascular Fibrosis Impairs arterial compliance
AldosteroAldosteronene
RALES
Spironolactone 25 mg / d vs. Placebo
Class III & IV Mortality at 11 months (stopped early) 46% vs 35 % NNT: 9
Newbies
Tezosentan endothelin receptor antagonist Who knows
Levosimendan Calcium sensitizer on troponin C may increase force of contraction without increasing myocardial oxygen consumption.
Nesiritide - Origin
Stretch receptors in the Atria (ANP) and the Ventricles (BNP)
Cause natriuresis and vasodilation Makes perfect sense Easy to Market Benefit??
Nesiritide This is also known as BNP and
causes diuresis and vasodilation. Studies show it superior to placebo
and equal to conventional therapy. If you don’t count mortality It costs about $1 million per dose,
may be useful in highly specific cases
Nesiritide – On the Other Hand
BNP is a good test in diagnosing CHF <100 mcg/ml NOT CHF 101 to 999 NOT normal, but
probably not CHF 1000 to 4000 CHF or related
condition >4000 almost certainly
CHF
Seven Roles for Rx Man
Sell them a scale Poke at their ankles Ensure labs (K+) Teach them to take their pulse NSAIDS Salt Police Cough Syrup patrol
Clinical Signs and Sx of CHF
Fluid Overload Shortness of Breath DOE Orthopnea / PND Pedal Edema CXR
Clinical Signs and Sx of CHF
Inadequate Perfusion Decreased Urine Output Increased BUN/Cr ratio Impaired Mental Status Cool, Clammy Skin Fatigue
Recap: AHA/ACC Heart Failure GuidelinesJ Heart Lung Transplant Feb, 2005
Class I Recommendations– Diuretics for patients with fluid retention (A)– ACEI for all patients unless contraindicated
(A)– Beta-blockers for all stable patients unless
contraindicated (A)– Digitalis for treatment of symptoms (A)– Withdrawal of drugs that may adverse the
status of heart failure patients (NSAIDs, most antiarrhythmics, most calcium channel blockers) (B)
Recap: AHA/ACC Heart Failure GuidelinesJ Heart Lung Transplant Feb, 2005
Class I Recommendations (cont’d)• Exercise training• Implantable defibrillator if history of
arrest, V Fib or bad V. Tach• Resynchronization therapy where
indicated
Recap: AHA/ACC Heart Failure GuidelinesJ Heart Lung Transplant Feb, 2005
Class IIa Recommendations (conflicting evidence/opinion but evidence favors)– Spironolactone for recent Class IV symptoms (B)– ARBs for patients not tolerating ACEI due to cough or
angioedema (A)– Combination of hydralazine + nitrate in patients not an
ACEI candidate due to hypotension/renal insufficiency (B)• Digitalis for treatment of symptoms (A)• Use of a CCB with negative inotropic effect may be harmful low
ejection fraction (A)
Class IIb Recommendations (conflicting evidence/opinion with less evidence to support)– Addition of an ARB to an ACEI (B)– Addition of nitrate +/- hydralazine to patients on ACEI (B)
Recap: AHA/ACC Heart Failure GuidelinesJ Heart Lung Transplant Feb, 2002
Class III Recommendations (no data or harmful)– Intermittent IV positive inotropes (C)– ARB instead of an ACEI in patients never tried
on or could tolerate an ACEI (B)– Use of an ARB before beta-blocker in a patient
on an ACEI– Use of a CCB to treat CHF (B)– Routine use of nutritional supplements
(CoQ10, etc.) or hormones (thyroid, growth) (C)
Case #1
KK is a 71 year old male with known history of CHF admitted for hypotension and shortness of breath
Case #1 Albuterol Ipratropium Phenytoin Neurontin Levothyroxine Protonix Lasix 20mg /day Amiodarone Verapamil 240mg/day
Labs BNP 995 Troponin <0.3 x 3 LDL <100 Na 137 K 4.1 Cl 101 TCO2 29 BUN 33 Creat 1.3
Weight on admission= 84 kg BP 102/63 Heart Rate 58 TSH 2.2
#1 Monitoring Parameter? 84 Kg on admission Day 1: 83.5 Day 2: 83.3 Day 3: 83.1
Case #1