Congestive Heart Congestive Heart FailureFailure

Eric J. Milie, D.O.Eric J. Milie, D.O.

Objectives:Objectives:

Recognize the different causes of right Recognize the different causes of right and left sided heart failureand left sided heart failure

Understand the different diagnostic Understand the different diagnostic modalities used to evaluate patients with modalities used to evaluate patients with heart failureheart failure

Explain the various therapeutic options Explain the various therapeutic options available for patients with heart failureavailable for patients with heart failure

Definition:Definition:

A pathopysiologic state characterized by A pathopysiologic state characterized by congestion in the pulmonary or systemic congestion in the pulmonary or systemic circulation. It is caused by the heart’s circulation. It is caused by the heart’s inability to pump sufficient oxygenated inability to pump sufficient oxygenated blood to meet the metabolic needs of the blood to meet the metabolic needs of the tissuestissues

Preload:Preload:

Degree of end-diastolic fiber stretchDegree of end-diastolic fiber stretch For clinical purposes, the end-diastolic For clinical purposes, the end-diastolic

pressure, especially if above normal, is a pressure, especially if above normal, is a reasonable indicator of preloadreasonable indicator of preload

Conditions that may effect preload Conditions that may effect preload include: LV dilatation, hypertrophy, and include: LV dilatation, hypertrophy, and changes in distensibility or compliancechanges in distensibility or compliance

AfterloadAfterload

Force resisting myocardial relaxation Force resisting myocardial relaxation after stimulation from the relaxed stateafter stimulation from the relaxed state

Determined by chamber pressure, Determined by chamber pressure, volume, and wall thickness at the time of volume, and wall thickness at the time of aortic valve openingaortic valve opening

Clinically, approximates systolic BP at or Clinically, approximates systolic BP at or neat the time of aortic valve opening and neat the time of aortic valve opening and represents peak systolic wall stressrepresents peak systolic wall stress

Frank-Starling PrincipleFrank-Starling Principle

Degree of end-diastolic fiber stretch Degree of end-diastolic fiber stretch (preload) within a physiologic range is (preload) within a physiologic range is proportional to the systolic performance proportional to the systolic performance of the ensuing ventricular contractionof the ensuing ventricular contraction

In effect in CHF, but suboptimal response In effect in CHF, but suboptimal response because the ventricle function is because the ventricle function is abnormalabnormal

Frank-Starling Frank-Starling cont.cont.

                                                                                      

The effects of myocardial compliance and contractility on the Frank-Starling mechanism. Figure reproduced from Internal Medicine, 4th edition, 1994, W.B. Saunders

Frank-Starling Frank-Starling cont.cont.

If Frank-Starling curve is depressed, fluid If Frank-Starling curve is depressed, fluid retention, vasoconstriction, and a retention, vasoconstriction, and a cascade of neurohormonal responses cascade of neurohormonal responses lead to CHFlead to CHF

Over time, LV remodeling, with Over time, LV remodeling, with hypertrophy and dilatation further hypertrophy and dilatation further compromises the heart’s functioncompromises the heart’s function

Left Ventricular FailureLeft Ventricular Failure

Characteristically develops in association Characteristically develops in association with CAD, HTN, and most forms of with CAD, HTN, and most forms of cardiomyopathy and congenital defects cardiomyopathy and congenital defects (i.e. VSD, PDA)(i.e. VSD, PDA)

Right Ventricular FailureRight Ventricular Failure

Most commonly caused by prior LV Most commonly caused by prior LV failure (failure ( pulmonary venous pressure and pulmonary venous pressure and leads to pulmonary artery HTN) and leads to pulmonary artery HTN) and tricuspid regurgitationtricuspid regurgitation

May be seen in the face of polycythemia, May be seen in the face of polycythemia, overtransfusion, acute renal failure, or overtransfusion, acute renal failure, or vena caval obstructionvena caval obstruction

Systolic DysfunctionSystolic Dysfunction

Failure to provide the tissues with Failure to provide the tissues with adequate circulatory outputadequate circulatory output

Most commonly caused by HTN, CAD, Most commonly caused by HTN, CAD, and dilated cardiomyopathyand dilated cardiomyopathy

More than 20 viruses shown to be causalMore than 20 viruses shown to be causal

Diastolic DysfunctionDiastolic Dysfunction

Resistance to ventricular filling (20-40% Resistance to ventricular filling (20-40% of cases)of cases)

Seen in hypertrophic cardiomyopathy, Seen in hypertrophic cardiomyopathy, marked ventricular hypertrophy, and marked ventricular hypertrophy, and amyloid infiltration of the myocardiumamyloid infiltration of the myocardium

High Output FailureHigh Output Failure

Persistently elevated cardiac output, Persistently elevated cardiac output, resulting in ventricular dysfunctionresulting in ventricular dysfunction

Conditions include anemia, beriberi, Conditions include anemia, beriberi, thyrotoxicosis, pregnancy, Paget’s thyrotoxicosis, pregnancy, Paget’s disease, and AV fistuladisease, and AV fistula

Treatment is aimed at the underlying Treatment is aimed at the underlying causecause

Etiology:Etiology:

Left Ventricular FailureLeft Ventricular Failure Systemic HypertensionSystemic Hypertension Valvular Hear Disease (AS, Valvular Hear Disease (AS,

AR, MR)AR, MR) CardiomyopathyCardiomyopathy MyocarditisMyocarditis Bacterial EndocarditisBacterial Endocarditis Myocardial InfarctionMyocardial Infarction IHSSIHSS

Right Ventricular FailureRight Ventricular Failure Valvular Heart Disease (MS)Valvular Heart Disease (MS) Pulmonary HypertensionPulmonary Hypertension Bacterial Endocarditis (right Bacterial Endocarditis (right

sided)sided) Right Ventricular InfarctionRight Ventricular Infarction

Clinical ManifestationsClinical Manifestations

Dyspnea: First on exertion, then with progressively less Dyspnea: First on exertion, then with progressively less strenuous activitystrenuous activity

Orthopnea: Orthopnea: Increased venous return in the recumbent Increased venous return in the recumbent positionposition

PND: multiple factorsPND: multiple factors Nocturnal Angina: Increased cardiac workload, 2º to Nocturnal Angina: Increased cardiac workload, 2º to

increased venous returnincreased venous return Cheyne Stokes Respiration: Alternating phases of Cheyne Stokes Respiration: Alternating phases of

apnea and hyperventilationapnea and hyperventilation Fatigue: low cardiac outputFatigue: low cardiac output Peripheral EdemaPeripheral Edema

Physical ExamPhysical Exam

Left Sided FailureLeft Sided Failure• Pulmonary RalesPulmonary Rales• TachypneaTachypnea• S3 GallopS3 Gallop• Cardiac Murmurs (AS, Cardiac Murmurs (AS,

AR, MR)AR, MR)• Paradoxical Splitting of Paradoxical Splitting of

S2S2

Right Sided FailureRight Sided Failure• Jugular Venous Jugular Venous

DistentionDistention• Peripheral EdemaPeripheral Edema• Peripheral/ Perioral Peripheral/ Perioral

cyanosiscyanosis• HepatomegalyHepatomegaly• AscitesAscites• Hepatojugular RefluxHepatojugular Reflux

Assessment of JVDAssessment of JVD

Shasham, Fadi, and Judith Mitchell, M.D. “Essentials of the Diagnosis of Heart Failure.” American Family Physician, March, 2001.

Kortakoff’s Sounds with ValsalvaKortakoff’s Sounds with Valsalva

Arterial blood pressure response and Korotkoff's sounds during Valsalva's maneuver. (A) Sinusoidal response in normal patient. (B) Absent overshoot in patient with heart failure. (C) Square wave response in patient with heart failure. The red lines indicate when Korotkoff's sounds are heard. (BP = blood pressure)

Framingham Criteria for Diagnosis of CHFFramingham Criteria for Diagnosis of CHF

Major CriteriaMajor Criteria• Paroxysmal Nocturnal Paroxysmal Nocturnal

DyspneaDyspnea• Neck Vein DistentionNeck Vein Distention• RalesRales• CardiomegalyCardiomegaly• Acute Pulmonary EdemaAcute Pulmonary Edema• S3 GallopS3 Gallop• Increased Venous PressureIncreased Venous Pressure• + Hepatojugular reflux+ Hepatojugular reflux

Minor CriteriaMinor Criteria• Extremity EdemaExtremity Edema• Night coughNight cough• Dyspnea on exertionDyspnea on exertion• HepatomegalyHepatomegaly• Pleural EffusionPleural Effusion• Vital Capacity Vital Capacity ↓ ⅓ from ↓ ⅓ from

normalnormal• Tachycardia (>120bpm)Tachycardia (>120bpm)

Major or Minor: Wt loss >4.5 kg over 5 days of treatment

To establish a clinical diagnosis of CHF by these criteria, at least 1 major and 2 minor criteria are required

Diagnosis: CXR FindingsDiagnosis: CXR Findings

• Cardiomegaly (Cardiothoracic ratio >0.5)Cardiomegaly (Cardiothoracic ratio >0.5)• Large Hila with indistinct marginsLarge Hila with indistinct margins• Prominence of superior pulmonary veinsProminence of superior pulmonary veins• Fluid in intralobar fissuresFluid in intralobar fissures• Kerley B linesKerley B lines• Alveolar edemaAlveolar edema

Classic CXRClassic CXR

EchocardiogramEchocardiogram

Two view and Doppler echocardiography Two view and Doppler echocardiography is useful to assess blood flow, global and is useful to assess blood flow, global and left ventricular function, and ejection left ventricular function, and ejection fractionfraction

Transesophageal echo offers higher Transesophageal echo offers higher quality images, but is invasive and is best quality images, but is invasive and is best reserved for when the quality of the 2D reserved for when the quality of the 2D images are unacceptableimages are unacceptable

Echocardiography:Echocardiography:

Two-dimensional echocardiogram showing a four-chambers view of the heart in a patient with systolic dysfunction. Note dilated LV.

Shasham, Fadi, and Judith Mitchell, M.D. “Essentials of the Diagnosis of Heart Failure.” American Family Physician, March, 2001.

EchocardiographyEchocardiography

Two-dimensional echocardiogram showing a four-chambers view of the heart in a patient with diastolic dysfunction. Note the normal LV size with hypertrophy.

EKGEKG

Should be performed on all patients with new diagnosis Should be performed on all patients with new diagnosis of CHF. No specific findings are indicitive of heart of CHF. No specific findings are indicitive of heart failure, but atrial and ventricular arrhythmias are failure, but atrial and ventricular arrhythmias are common fidings.common fidings.

Atrial Fibrillation is found in roughly 25% of individuals Atrial Fibrillation is found in roughly 25% of individuals with cardiomyopathy, especially elderly individuals with with cardiomyopathy, especially elderly individuals with advanced failureadvanced failure

Low voltage with conduction disturbances may be Low voltage with conduction disturbances may be associated with amyloidosisassociated with amyloidosis

AngiographyAngiography

Noninvasive method for assessing Noninvasive method for assessing systolic and diastolic functionsystolic and diastolic function

May be used when echo findings not May be used when echo findings not consistent with the clinical pictureconsistent with the clinical picture

Ectopic activity and Atrial Fibrillation may Ectopic activity and Atrial Fibrillation may adversely effect accuracyadversely effect accuracy

B-type Natriuretic B-type Natriuretic PeptidePeptide

New diagnostic test superior to diagnostic New diagnostic test superior to diagnostic decision making of the primary care physiciandecision making of the primary care physician

Has reduced clinical indecision from 43-11%Has reduced clinical indecision from 43-11% Median BNP levels in NYHA classes I, II, III, Median BNP levels in NYHA classes I, II, III,

and IV were 244, 389, 640, and 817 pg/ml, and IV were 244, 389, 640, and 817 pg/ml, respectively. respectively.

Values of 50 pg/ml or less had a negative Values of 50 pg/ml or less had a negative predictive value of 96% predictive value of 96%

Maisel, A et al. Rapid Measurement of B-Type Natriuretic Peptide in the Emergency Diagnosis of Heart Failure. New England Journal of Medicine. 2002 347(3):161-7.

Functional Classification:Functional Classification:New York Heart AssociationNew York Heart Association

Class IClass I: Symptomatic only with greater : Symptomatic only with greater than normal activitythan normal activity

Class IIClass II: Symptomatic with ordinary : Symptomatic with ordinary activityactivity

Class IIIClass III: Symptomatic with minimal : Symptomatic with minimal activity, asymptomatic at restactivity, asymptomatic at rest

Class IVClass IV: Symptomatic at rest: Symptomatic at rest

TreatmentTreatment

1.1. Removal of the precipitating causeRemoval of the precipitating cause

2.2. Correction of the underlying causeCorrection of the underlying cause

3.3. Prevention of deterioration of cardiac Prevention of deterioration of cardiac functionfunction

4.4. Control of the congestive heart failure Control of the congestive heart failure statestate

Drug Treatment of Drug Treatment of Systolic DysfunctionSystolic Dysfunction

DiureticsDiuretics ACE inhibitorsACE inhibitors ARBsARBs ΒΒ-blockers-blockers DigitalisDigitalis

Most patients treated with at least two of the above

DiureticsDiuretics

                                                                   

                                                                                                     

Diuretics Diuretics continuedcontinued

Loop diuretics are preferred, usually furosemide by mouthLoop diuretics are preferred, usually furosemide by mouth In resistant cases, Bumetanide 0.5 – 2.0mg or Metazolone PO In resistant cases, Bumetanide 0.5 – 2.0mg or Metazolone PO

may have additive effectsmay have additive effects Overuse may cause electrolyte imbalances (hyponatremia, Overuse may cause electrolyte imbalances (hyponatremia,

hypomagnesemia, and profound hypokalemia) or volume deficits, hypomagnesemia, and profound hypokalemia) or volume deficits, so routine monitoring of serum electrolytes is warrantedso routine monitoring of serum electrolytes is warranted

May induce renal failure in some patientsMay induce renal failure in some patients Adding K sparing diuretics may be used to offset the K-losing Adding K sparing diuretics may be used to offset the K-losing

effects of loop diureticseffects of loop diuretics Spironolactone may be beneficial in advanced (NYHA Class III or Spironolactone may be beneficial in advanced (NYHA Class III or

IV) cases of CHF, decreasing total morbidity and mortality.IV) cases of CHF, decreasing total morbidity and mortality.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

Diuretics Diuretics cont.cont.

Clinical efficacy of diuretics is heavily Clinical efficacy of diuretics is heavily dependant on dietary sodium restrictiondependant on dietary sodium restriction

Log of daily weights should be Log of daily weights should be maintained (maintained ( in greater than 2# needs to in greater than 2# needs to be evaluated)be evaluated)

No overall decrease in mortality, but relief No overall decrease in mortality, but relief of symptomsof symptoms

Konstam MA. Heart failure: evaluation and care of patients with left-ventricular systolic dysfunction. Rockville, Md.: U.S. Dept. of Health and Human Services, Agency for Health Care Policy and Research, 1994; Clinical Practice Guideline no. 11, AHCPR publication no. 94-0612.

ACE InhibitorsACE Inhibitors

Peripheral and arterial vasodilatationPeripheral and arterial vasodilatation ↓ ↓ left ventricular filling pressure at rest left ventricular filling pressure at rest

and during exerciseand during exercise Favorable effects on remodelingFavorable effects on remodeling Negative inotropic effect on the failing Negative inotropic effect on the failing

heartheart Decrease in overall mortality by 25-35%Decrease in overall mortality by 25-35%

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.

ACE Inhibitors ACE Inhibitors cont.cont.

Most common side effect is cough (5-Most common side effect is cough (5-20% of patients) probably 220% of patients) probably 2º to build-up º to build-up of bradykininof bradykinin

Caution in renal impairment, especially Caution in renal impairment, especially with concomitant use of diureticswith concomitant use of diuretics

ASA reduces the effects of ACE ASA reduces the effects of ACE Inhibitors in CHF patient (inhibits the Inhibitors in CHF patient (inhibits the effects of kinins)effects of kinins)

ARBsARBs

Theoretically as effective as ACE-Theoretically as effective as ACE-InhibitorsInhibitors

No associated cough (no effect on kinins)No associated cough (no effect on kinins) Losartan shown to decrease overall Losartan shown to decrease overall

mortality in patients with heart failuremortality in patients with heart failure No comparison trials (though No comparison trials (though

ONTARGET is ongoing)ONTARGET is ongoing)

Sharma D, Buyse M, Pitt B, Rucinska EJ. Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart

Failure Mortality Meta-analysis Study Group. Am J Cardiol 2000;85:187-92.

Hydralazine/ Oral NitrateHydralazine/ Oral Nitrate

Used in patients with increased serum Used in patients with increased serum creatinine levels, or those who cannot tolerate creatinine levels, or those who cannot tolerate ACEIACEI

Decrease overall mortality by 25-30%Decrease overall mortality by 25-30% Benefit in overall mortality not as pronounced Benefit in overall mortality not as pronounced

as in ACEIs, and not as easy to take or tolerateas in ACEIs, and not as easy to take or tolerate

Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, 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;314:1547-52.

DigitalisDigitalis

Weak inotropeWeak inotrope Blockade of AV NodeBlockade of AV Node Weak vasoconstrictorWeak vasoconstrictor Improves renal blood flowImproves renal blood flow Modestly improves LV functionModestly improves LV function Lowers dosage needed of diureticsLowers dosage needed of diuretics Reduces need for hospitilizationReduces need for hospitilization

Digitalis Digitalis cont.cont.

Digitalis Investigation Group (DIG) study Digitalis Investigation Group (DIG) study showed no decrease in mortality, but showed no decrease in mortality, but significant reduction in the number of significant reduction in the number of hospitalizations in patients treated with hospitalizations in patients treated with digitalisdigitalis

The Digitalis Investigation Group. The effect on digoxin in mortality and morbidity in patients with heart failure. N Eng J Med 1997;336:525-533

Digitalis ToxicityDigitalis Toxicity

11stst degree AV block, which may progress degree AV block, which may progress to Wenkebach. May also see life to Wenkebach. May also see life threatening arrhythmias (V. Fib., V. threatening arrhythmias (V. Fib., V. Tach.)Tach.)

Nausea, Vomiting, Anorexia, Diarrhea, Nausea, Vomiting, Anorexia, Diarrhea, Confusion, Amblyopia, and Confusion, Amblyopia, and Xerophthalmia (yellow vision)Xerophthalmia (yellow vision)

Digitalis Effect- EKGDigitalis Effect- EKG

American Society of Consultant Pharmacists, Inc.

ββ-Blockers-Blockers

Increase ejection fractionIncrease ejection fraction Reduce mortality by roughly 30%, if used Reduce mortality by roughly 30%, if used

properlyproperly Improved myocardial function achieved in 6-12 Improved myocardial function achieved in 6-12

months of therapymonths of therapy CIBIS II: Bisoprolol reduced cardiac deaths and CIBIS II: Bisoprolol reduced cardiac deaths and

hospitalizations compared to controlhospitalizations compared to control

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.

Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 1997;30:27-34

ββ-Blockers -Blockers cont.cont.

Carvedilol (Coreg) is the only Carvedilol (Coreg) is the only ββ-blocker -blocker specifically labeled for the treatment of specifically labeled for the treatment of heart failureheart failure

Found to be more effective than other Found to be more effective than other ββ--blockers in patients without ischemic blockers in patients without ischemic heart diseaseheart disease

Bonet S, Agusti A, Arnau JM, Vidal X, Diogene E, Galve E, et al. Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and non-vasodilating agents according to patients' characteristics: a meta-analysis of clinical trials. Arch Intern Med 2000;160:621-7.

Ca-Channel BlockersCa-Channel Blockers

Use in patients with decreased LV Use in patients with decreased LV function has been disappointingfunction has been disappointing

Some Ca-Channel blockers have Some Ca-Channel blockers have deleterious effect in systolic dysfunction deleterious effect in systolic dysfunction (Verapimil, Nifedipine, Diltiazem)(Verapimil, Nifedipine, Diltiazem)

Diastolic Dysfunction Diastolic Dysfunction TreatmentTreatment

May not tolerate reduced volume or blood May not tolerate reduced volume or blood pressure (vasodilators, diuretics relatively pressure (vasodilators, diuretics relatively contraindicated)contraindicated)

ACEIs and ARBs may decrease LV mass and ACEIs and ARBs may decrease LV mass and stiffnessstiffness

Valve replacement may improve LV functionValve replacement may improve LV function Treatment of underlying dominant systolic Treatment of underlying dominant systolic

dysfunctiondysfunction

Definitive TreatmentDefinitive Treatment

Heart transplant only treatment that potentially Heart transplant only treatment that potentially alters the long term course of the diseasealters the long term course of the disease

1- and 3-year survival rates 80% & 75%, 1- and 3-year survival rates 80% & 75%, respectivelyrespectively

Dynamic cardiomyoplasty: experimental; wrap Dynamic cardiomyoplasty: experimental; wrap the latissimus dorsi muscle around heart to the latissimus dorsi muscle around heart to stimulate contractility (reported functional stimulate contractility (reported functional status in 80% of pts, no long term data)status in 80% of pts, no long term data)

Implantable ventricular assist devices are Implantable ventricular assist devices are being studied, no long term data at this timebeing studied, no long term data at this time

Case StudyCase StudyMr. Balaban, a 63-year-old Filipino man, has recently been traveling in the Philippines. He has a long history of hypertension and usually takes one aspirin, Lisinopril, and hydrochlorothiazide (HCTZ). He admitted that he ran out of these when he was traveling. After he returns home, he tells his daughter that he is "very tired", gets short of breath while walking around the house, and can't put his shoes on. As he talks with his daughter, she notices that he is having trouble talking, as if it is hard for him to breathe. She becomes alarmed and takes him to the emergency room where the physician finds the following:

- 3+ pitting edema in both ankles- faint crackles in both lung fields- extreme fatigue- jugular vein distention when sitting- moderate shortness of breath- ten-pound weight gain in the last week- B/P 170/110; pulse 88 and irregular; EKG shows sinus tachycardia with nonspecific ST/T changes

Question One:Question One:Based on the patient’s presentation in the emergency department, what would you expect his BNP level to be?

A. 27

B. 250

C. 350

D. 500

E. 775

Answer: E. BNP value for Class III Heart Failure is above 640 pg/ml, Class IV above 817 pg/ml. Pt getting SOB with walking around the house, talking on the phone. No mention of dyspnea at rest. Most likely Class III-IV

Question Two:Question Two:

While under your care, a routine BMP shows the patient to have a serum Creatinine of 2.3. Which of the following pharmacological agents will have the greatest benefit towards decreasing this patient’s risk of mortality?

A. Lanoxin

B. Verapimil

C. Increasing dose of HCTZ

D. Hydralazine/ Isosorbide

E. Nifedipine

Answer: D. VACS trial showed a decrease in the overall mortality in patients receiving this medication roughly 20-25%.

Question Three:Question Three:You evaluate the patient two months after his hospital discharge. He is complaining of generalized malaise, with nausea and vomiting over the past two to three days, and has noted things have taken on a yellowish tint while looking at them over the past week. The family notes that he has been increasingly confused since his discharge. On physical exam, the patient has a pulse rate of 72. An EKG recorded in the office shows a sinus rhythm, with a PR interval of 0.22 and “scooped out” appearing ST segments. Which of the following medications was the patient most likely discharged from the hospital on?

A. Lasix

B. Losartan

C. Digoxin

D. Coreg

E. Norvasc

Answer: D. The patients clinical presentation is classical for digoxin toxicity/ In addition, the EKG findings of scooped out ST segments and 1st degree heart block are commonly seen on patients treated with digitalis.

Resources:Resources:

Beers, et al. Beers, et al. The Merck Manual of Diagnosis and TherapyThe Merck Manual of Diagnosis and Therapy. . Seventeenth edition. Ch 261. 2004.Seventeenth edition. Ch 261. 2004.

Braunwald, et al. Braunwald, et al. Harrison’s Principles of Internal MedicineHarrison’s Principles of Internal Medicine. . Fifteenth edition. Pp 1316-1332. 2001.Fifteenth edition. Pp 1316-1332. 2001.

Marino, Paul. Marino, Paul. The ICU BookThe ICU Book. Pp 242-246. Rose Tree, Maryland. . Pp 242-246. Rose Tree, Maryland. 1998.1998.