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1. HYPERTENSION

2. Introduction
2
 Hypertension is a common disease that is simply defined as
persistently elevated arterial blood pressure (BP).
 Hypertensive crisis is categorized as hypertensive
emergency (extreme BP elevation with acute or progressing
end-organ damage) or hypertensive urgency (extreme BP
elevation without acute or progressing endorgan injury).
 Although elevated BP was perceived to be “essential” for
adequate perfusion of vital organs,
 It has been identified as one of the most significant risk
factors for cardiovascular (CV) disease for decades.

3. Classification of Blood Pressure in
Adults
3

4. Epidemiology
4
 Almost half (46%) of American adults age 20 years and
older have hypertension according to the ACC/AHA
definition.
 The overall incidence of hypertension is similar between
men and women but varies depending on age.
 The prevalence of high BP is higher in men than women
before the age of 65 and
 is similar between the ages 65 and 74.

5. 5
 BP values increase with age, and hypertension (persistently
elevated BP values) is very common in older patients.
 Most patients have elevated BP before they are diagnosed
with hypertension,
 with most diagnoses occurring between the third and fifth
decades of life.

6. Etiology
6
 In most patients, hypertension results from unknown
pathophysiologic etiology (essential or primary
hypertension).
 A smaller percentage of patients have a specific cause of
their hypertension (secondary hypertension).
 In most of these cases, renal dysfunction resulting from
severe CKD or renovascular disease is the most common
secondary cause.
 Certain agents (drugs or other products), either directly or
indirectly, can increase BP and cause or exacerbate
hypertension.

7. Secondary Causes of
Hypertension
7

8. Pathophysiology
8
 Multiple physiologic factors control BP and abnormalities
of these factors are potential contributing components in the
development of essential hypertension.
 Factors contributing to development of primary
hypertension include:
o Humoral abnormalities involving the renin–angiotensin–
aldosterone system (RAAS), natriuretic hormone, and
hyperinsulinemia;
o Disturbances in the CNS, autonomic nerve fibers,
adrenergic receptors, or baroreceptors;

9. 9
o Abnormalities in renal or tissue autoregulatory processes for
sodium excretion, plasma volume, and arteriolar
constriction;
o Deficiency in synthesis of vasodilating substances in
vascular endothelium (prostacyclin, bradykinin, nitric
oxide) or
o Excess vasoconstricting substances (angiotensin II,
endothelin I);
o High sodium intake or lack of dietary calcium.

10. 10
 Major causes of death include
 Cerebrovascular events,
 Cardiovascular (CV) events, and
 Renal failure.
 Probability of premature death correlates with the severity
of BP elevation.

11. Renin–angiotensin–aldosterone
system
11

12. Clinical presentation
12
 Patients with uncomplicated primary hypertension are usually
asymptomatic initially.
 Patients with secondary hypertension may have symptoms of
the underlying disorder:
 Pheochromocytoma —headaches, sweating, tachycardia,
palpitations, orthostatic hypotension;
 Primary aldosteronism —hypokalemic symptoms of muscle
cramps and weakness;
 Cushing syndrome —moon face, buffalo hump, hirsutism,
weight gain, polyuria, edema, menstrual irregularities, acne,
muscle weakness.

13. Diagnosis
13
 Elevated BP may be the only sign of primary hypertension
on physical examination.
 Diagnosis should be based on the average of two or more
readings taken at each of two or more clinical encounters.
 Signs of end-organ damage occur primarily in the eyes,
brain, heart, kidneys, and peripheral vasculature.
 Funduscopic examination may reveal
 Arteriolar narrowing, focal arteriolar constriction,
arteriovenous nicking,
 Retinal hemorrhages and exudates, and disk edema.

14. 14
 Presence of papilledema usually indicates a hypertensive
emergency requiring rapid treatment.
 Cardiopulmonary examination may reveal abnormal heart rate or
rhythm, LV hypertrophy, coronary artery disease, or HF.
 Peripheral vascular examination may reveal aortic or abdominal
bruits, distended veins, diminished or absent peripheral pulses, or
lower extremity edema.
 Patients with renal artery stenosis may have an abdominal
systolic-diastolic bruit.
 Baseline hypokalemia may suggest mineralocorticoid-induced
hypertension.

15. 15
Treatment

16. 16
Goals of Treatment:
 The overall goal is to reduce morbidity and mortality from CV events.
 The 2017 ACC/AHA guideline recommends a goal BP of <130/80 mm
Hg for most patients,
 including those with clinical arteriosclerotic cardiovascular disease
(ASCVD), diabetes, or CKD.
 For older ambulatory, community-dwelling patients, the goal is SBP
<130 mm Hg.
 For institutionalized older patients and those with a high disease burden
or limited life expectancy, consider a relaxed SBP goal of <150 mm Hg
(or <140 mm Hg if tolerated).

17. Nonpharmacologic therapy
17
 Implement lifestyle modifications in all patients with elevated
BP or stage 1 or 2 hypertension.
 These measures alone are appropriate initial treatment for
patients with elevated BP or stage 1 hypertension who are at
low risk of ASCVD.
 Start drug therapy for these patients when BP is ≥140/90 mm
Hg.
 For patients with stage 1 or 2 hypertension who already have
ASCVD (secondary prevention) or an elevated 10-year
ASCVD risk ≥10%,

18. 18
 The threshold for starting drug therapy is ≥130/80 mm Hg
with a goal BP of <130/80 mm Hg.
 Lifestyle modifications shown to lower BP include
 (1) weight loss if overweight or obese,
 (2) the Dietary Approaches to Stop Hypertension (DASH)
eating plan,
 (3) reduced salt intake, ideally to 1.5 g/day sodium (3.8 g/day
sodium chloride),
 (4) physical activity (90–150 min/week of aerobic or dynamic
resistance training), and

19. 19
 (5) moderation of alcohol intake (≤2 drinks/day in men and
≤1 drink/day in women).

20. Pharmacologic therapy
20
General Approach to Treatment
 Initial drug selection depends on the degree of BP
elevation and presence of compelling indications for
certain drugs.
 Use a single first-line drug as initial therapy in most
patients with newly diagnosed stage 1 hypertension.
 Start combination drug therapy (preferably with two first-
line drugs) as the initial regimen in patients with newly
diagnosed stage 2 hypertension.

21. 21
 The four first-line options are
 Angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARBs), calcium channel
blockers (CCBs), and thiazide diuretics.
 β-Blockers should be reserved to treat a specific compelling
indication or in combination with a first-line antihypertensive
agent for patients without a compelling indication.
 Other antihypertensive drug classes (α1-blockers, direct renin
inhibitors, central α2-agonists, and direct arterial vasodilators)
may be used for select patients after implementing first-line
agents.

22. 22
 They are generally reserved for resistant hypertension or as
add-on therapy with multiple other first-line agents.

23. Compelling indications
23
 Compelling indications are specific comorbid conditions
for which clinical trial data support using specific
antihypertensive drug classes to treat both hypertension
and the compelling indication.

24. 24
HFrEF
 GDMT consists of three to four drugs: ACE inhibitor or ARB
plus diuretic, followed by addition of an evidence-based β-
blocker and possibly a mineralocorticoid receptor antagonist.
 Start an ACE inhibitor or ARB in low doses to avoid orthostatic
hypotension because of the high renin state in HF.
 Diuretics reduce edema, and loop diuretics are often needed,
especially in patients with advanced HF and/or CKD.
 β-Blockers modify disease in HFrEF and are part of standard
treatment; adding a β-blocker to a diuretic with an ACE
inhibitor or ARB reduces CV morbidity and mortality.

25. 25
 After implementation of a standard three-drug regimen,
other agents may be added to further reduce CV morbidity
and mortality, and reduce BP if needed.
 A mineralocorticoid receptor antagonist (spironolactone or
eplerenone) may be considered at this point.
 Unlike interventions in HFrEF that decrease morbidity and
mortality,
 trials using the same medications in HFpEF have not
shown similar benefits.

26. 26
Stable Ischemic Heart Disease (SIHD)
 β-Blockers (without ISA) are first-line therapy in SIHD; they
reduce BP and improve angina symptoms by decreasing
myocardial oxygen consumption and demand.
 β-Blockers should be used for hypertension treatment in
patients with SIHD.
 An ACE inhibitor or ARB has been shown to reduce CV
events as an add-on to a β-blocker.
 A long-acting nondihydropyridine CCB is an alternative to a
β-blocker in SIHD, but β-blockers are the therapy of choice.

27. 27
 All four first-line antihypertensive classes reduce CV events
in patients with diabetes.
 Regardless of the initial agent selected, most patients require
combination therapy, which typically includes an ACE
inhibitor (or ARB) with a CCB or thiazide.
 After first-line agents, a β-blocker is a useful add-on therapy
for BP control in patients with diabetes.
 A thiazide diuretic, either alone or combined with an ACE
inhibitor, is recommended for patients with history of stroke
or transient ischemic attack.

28. Algorithm for treatment of elevated BP and hypertension based on
BP category at initial diagnosis
28

29. Compelling indications for individual drug
classes
29

30. 30
First-line antihypertensive agents

31. Angiotensin-Converting Enzyme
Inhibitors
31
 ACE inhibitors block conversion of angiotensin I to
angiotensin II, a potent vasoconstrictor and stimulator of
aldosterone secretion.
 ACE inhibitors also block degradation of bradykinin and
stimulate synthesis of other vasodilating substances.
 Starting doses should be low with slow dose titration.
 Acute hypotension may occur at the onset of therapy,
especially
 In patients who are sodium or volume depleted, in HF
exacerbation, very elderly, or on concurrent vasodilators or
diuretics.

32. 32
 ACE inhibitors decrease aldosterone and can increase
serum potassium concentrations.
 AKI is an uncommon but serious side effect;
 preexisting kidney disease increases risk.
 Bilateral renal artery stenosis or unilateral stenosis of a
solitary functioning kidney renders patients dependent on the
vasoconstrictive effect of angiotensin II on efferent arterioles,
 making them particularly susceptible to AKI.

33. 33
 GFR decreases somewhat when ACE inhibitors are started
 because of inhibition of angiotensin II vasoconstriction on
efferent arterioles.
 Angioedema occurs in <1% of patients.
 Drug withdrawal is necessary, and some patients may require drug
treatment and/or emergent intubation to support respiration.
 A persistent dry cough occurs in up to 20% of patients and is
thought to be due to inhibition of bradykinin breakdown.
 ACE inhibitors (as well as ARBs and direct renin inhibitors) are
contraindicated in pregnancy.

34. Angiotensin II Receptor Blockers
34
 Angiotensin II is generated by the renin–angiotensin pathway
(which involves ACE) and an alternative pathway that uses other
enzymes such as chymases.
 ACE inhibitors block only the renin–angiotensin pathway, whereas
ARBs inhibit angiotensin II generated by either pathway.
 The ARBs directly block the angiotensin II type 1 receptor that
mediates the effects of angiotensin II.
 All ARBs have similar antihypertensive efficacy and fairly flat
dose-response curves.
 Addition of a CCB or thiazide diuretic significantly increases
antihypertensive efficacy

35. Calcium Channel Blockers
35
 Dihydropyridine and nondihydropyridine CCBs are first-
line antihypertensive therapies and
 Are also used in addition to or instead of other first-line
agents for the compelling indication of ischemic heart
disease.
 CCBs cause relaxation of cardiac and smooth muscle by
blocking voltage-sensitive calcium channels,
 thereby reducing entry of extracellular calcium into cells.
 This leads to vasodilation and a corresponding reduction in
BP.

36. 36
 Verapamil decreases heart rate, slows atrioventricular (AV) nodal
conduction, and produces a negative inotropic effect that may
precipitate HF in patients with borderline cardiac reserve.
 Diltiazem decreases AV conduction and heart rate to a lesser
extent than verapamil.
 Both can cause peripheral edema and hypotension.
 Verapamil causes constipation in about 7% of patients.
 Dihydropyridines cause a baroreceptor-mediated reflex increase
in heart rate.
 Dihydropyridines do not decrease AV node conduction and are
not effective for treating supraventricular tachyarrhythmias.

37. Diuretics
37
 Thiazides are the preferred type of diuretic and are a first-line
option for most patients with hypertension.
 Chlorthalidone is preferred over hydrochlorothiazide, especially
in resistant hypertension.
 Loop diuretics are more potent for inducing diuresis but are not
ideal antihypertensives unless edema treatment is also needed.
 Potassium-sparing diuretics are weak antihypertensives when
used alone and provide minimal additive effect when combined
with a thiazide or loop diuretic.
 Their primary use is in combination with another diuretic to
counteract potassium-wasting properties.

38. 38
 Mineralocorticoid receptor antagonists (spironolactone and
eplerenone) are also potassium-sparing diuretics that are usually
used to treat resistant hypertension because elevated aldosterone
concentrations are prevalent in this setting.
 Acutely, diuretics lower BP by causing diuresis.
 The reduction in plasma volume and stroke volume associated
with diuresis decreases cardiac output and BP.
 The initial drop in cardiac output causes a compensatory
increase in peripheral vascular resistance.
 Reduced peripheral vascular resistance is responsible for
persistent hypotensive effects.

39. 39
 Combining diuretics with other antihypertensive agents
usually results in an additive hypotensive effect because of
independent mechanisms of action.
 Furthermore many nondiuretic antihypertensive agents
induce sodium and water retention,
 which is counteracted by concurrent diuretic use.
 Side effects of thiazides include
• Hypokalemia, hypomagnesemia, hypercalcemia,
hyperuricemia, hyperglycemia, dyslipidemia, and sexual
dysfunction.

40. 40
 Hypokalemia and hypomagnesemia may cause muscle
fatigue or cramps, and severe electrolyte abnormalities may
result in serious cardiac arrhythmias.
 Potassium-sparing diuretics may cause hyperkalemia.
 Spironolactone may cause gynecomastia in up to 10% of
patients; this effect occurs rarely with eplerenone.

41. Most Common First-Line and Other Antihypertensive
Agents
41

42. Most Common First-Line and Other Antihypertensive
Agents ……………..
42

43. Most Common First-Line and Other Antihypertensive
Agents ……………..
43

44. Most Common First-Line and Other Antihypertensive
Agents ……………..
44

45. 45
Alternative antihypertensive
agents

46. β-Blockers
46
 Evidence suggests that β-blockers may not reduce CV events as
well as ACE inhibitors, ARBs, CCBs, or thiazides when used as
the initial drug in patients who do not have a compelling
indication for a β-blocker.
 β-Blockers are appropriate first-line agents
 when used to treat specific compelling indications or
 when an ACE inhibitor, ARB, CCB, or thiazide cannot be used.
 Their hypotensive mechanism may involve
 Decreased cardiac output through negative chronotropic and
inotropic cardiac effects and inhibition of renin release from the
kidney.

47. 47
 Cardiac side effects include bradycardia, AV conduction
abnormalities, and acute HF.
 Blocking β2-receptors in arteriolar smooth muscle may
cause cold extremities and aggravate intermittent
claudication or Raynaud phenomenon.
 Increases in serum lipids and glucose appear to be transient
and of little clinical significance.
 Abrupt cessation of β-blocker therapy can produce
 Cardiac ischemia (angina, chest pain), a CV event, or even
death in patients with coronary artery disease.

48. α1 -Receptor Blockers
48
 Prazosin, terazosin, and doxazosin are selective α1 -receptor
blockers that inhibit catecholamine uptake in smooth muscle
cells of peripheral vasculature,
 resulting in vasodilation and BP lowering.
 A first-dose phenomenon characterized by orthostatic
hypotension accompanied by
 Transient dizziness or faintness, palpitations, and even syncope
may occur within 1–3 hours of the first dose or after later
dosage increases.
 Occasionally, orthostatic hypotension and dizziness persist with
chronic administration.

49. 49
 Sodium and water retention can occur; these agents are most
effective when given with a thiazide to maintain
antihypertensive efficacy and minimize edema.
 Although they can provide symptomatic benefit in men with
benign prostatic hyperplasia,
 They should be used to lower BP only in combination
with first-line antihypertensive agents.

50. Central α2 -Agonists
50
 Clonidine, guanfacine, and methyldopa lower BP primarily
by stimulating α2-adrenergic receptors in the brain,
 which reduces sympathetic outflow from the vasomotor
center and increases vagal tone.
 Stimulation of presynaptic α2-receptors peripherally may
contribute to reduced sympathetic tone.
 Consequently, there may be decreases in heart rate, cardiac
output, total peripheral resistance, plasma renin activity, and
baroreceptor reflexes.

51. 51
 Chronic use results in sodium and fluid retention.
 Other side effects include
 Depression, orthostatic hypotension, dizziness, and
anticholinergic effects (eg, dry mouth, sedation).
 Abrupt cessation may lead to rebound hypertension.
 Methyldopa rarely causes hepatitis or hemolytic
anemia.

52. Direct Arterial Vasodilators
52
 Hydralazine and minoxidil directly relax arteriolar smooth
muscle, resulting in vasodilation and BP lowering.
 Compensatory activation of baroreceptor reflexes increases
sympathetic outflow,
 Thereby increasing heart rate, cardiac output, and renin
release.
 Direct vasodilators can precipitate angina in patients with
underlying SIHD unless the baroreceptor reflex mechanism
is blocked with a β-blocker.

53. 53
 Hydralazine may cause a dose-related, reversible
lupus-like syndrome.
 Minoxidil is a more potent vasodilator than
hydralazine, and compensatory increases in heart
rate, cardiac output, renin release, and sodium
retention are more dramatic.

54. Hypertensive urgencies and
emergencies
54
 Hypertensive urgencies are ideally managed by
 Adjusting maintenance therapy,
 Adding a new antihypertensive, increasing the dose of a
current medication, or
 Treating anxiety as applicable.
 Acute administration of a short-acting oral drug (captopril,
clonidine, or labetalol) followed by careful observation for
several hours to ensure a gradual BP reduction is an option.

55. 55
 Hypertensive emergencies require immediate BP reduction
with a parenteral agent to limit new or progressing end-
organ damage.
 The rate of BP reduction depends on whether the patient
has aortic dissection, severe preeclampsia or eclampsia, or
pheochromocytoma with hypertensive crisis.
 For patients with a hypertensive emergency without aortic
dissection, severe preeclampsia or eclampsia, or
pheochromocytoma with hypertensive crisis,
 The initial target is reduction in mean arterial pressure of up to
25% over the first hour.

56. 56
 Precipitous drops in BP may cause end-organ ischemia or
infarction.
 If BP reduction is well tolerated, additional gradual decreases
toward the goal BP can be attempted after 24–48 hours.
 Nitroprusside is the agent of choice for minute-to-minute control
in most cases.
 When the nitroprusside infusion must be continued longer than
72 hours, measure serum thiocyanate levels, and discontinue the
infusion if the level exceeds 12 mg/dL (~2.0 mmol/L.
 Other adverse effects are nausea, vomiting, muscle twitching,
and sweating.

57. Parenteral Antihypertensive Agents for
Hypertensive Emergency
57

58. Evaluation of therapeutic outcomes
58
 Both clinic-based and self-measurement home BP monitoring
are important for monitoring and managing hypertension.
 Evaluate BP response in the clinic 4 weeks after initiating or
making changes in therapy and compare the results to home
BP readings.
 Once goal BP is obtained, monitor BP every 3–6 months,
assuming no signs or symptoms of acute end-organ damage.
 Evaluate more frequently in patients with a history of poor
control, nonadherence, progressive end-organ damage, or
symptoms of adverse drug effects.

59. 59
 Monitor patients routinely for adverse drug events, which may
require dosage reduction or substitution with an alternative
antihypertensive agent.
 Perform laboratory monitoring 4 weeks after starting a new
agent or dose increase, and then every 6–12 months in stable
patients.
 For patients treated with a mineralocorticoid receptor antagonist
 Monitor potassium concentrations and kidney function within 3
days of initiation and again at 1 week to detect potential
hyperkalemia.
 Monitor patients for signs and symptoms of hypertension-
associated complications.

60. 60
 Take a careful history for ischemic chest pain (or pressure),
palpitations, dizziness, dyspnea, orthopnea, headache, sudden
change in vision, one-sided weakness, slurred speech, and
loss of balance.
 Monitor funduscopic changes on eye examination, LV
hypertrophy on ECG, albuminuria, and changes in kidney
function periodically.
 Assess patient adherence with the regimen regularly.
 Ask patients about changes in their general health perception,
physical functioning, and overall satisfaction with treatment.

61. 61
Heart Failure

62. Introduction
62
 Heart failure (HF) is a progressive syndrome that can result
from any changes in cardiac structure or function that impair the
ability of the ventricle to fill with or eject blood.
 HF may be caused by an abnormality in systolic function,
diastolic function, or both.
 HF with reduced systolic function (ie, reduced left ventricular
ejection fraction, LVEF) is referred to as HF with reduced
ejection fraction (HFrEF).
 Preserved LV systolic function (ie, normal LVEF) with
presumed diastolic dysfunction is termed HF with preserved
ejection fraction (HFpEF).

63. 63
 HF is the final common pathway for numerous cardiac
disorders including
 Those affecting
 the pericardium,
 heart valves, and
 myocardium.

64. Epidemiology
64
 HF is an epidemic public health problem in the United States.
 Approximately 6.5 million Americans have HF with 1,000,000
new cases diagnosed each year.
 A large majority of patients with HF are elderly, with multiple
comorbid conditions that influence morbidity and mortality.
 Although the mortality rates have declined over the last 50
years, the overall 5-year survival remains approximately 42%
for all patients with a diagnosis of HF,
 with mortality increasing with symptom severity.

65. Etiology
65
 HF can result from any disorder that affects
 The ability of the heart to contract (systolic function)
and/or relax (diastolic dysfunction).
 The leading causes of HF are coronary artery disease and
hypertension.

66. Causes of Chronic Heart Failure
66

67. Pathophysiology
67
 HFrEF is a progressive disorder initiated by any event that
impairs the ability of the heart to contract and sometimes
relax resulting in a decrease in CO.
 The index event may have
 An acute onset, as with MI, or
 The onset may be slow, as with long-standing HTN.
 Regardless of the index event, a decrease in CO results in
activation of compensatory responses to maintain the
circulation:

68. 68
 (1) Tachycardia and increased contractility through
sympathetic nervous system activation,
 (2) The Frank–Starling mechanism, whereby increased
preload (through sodium and water retention) increases
stroke volume,
 (3) Vasoconstriction, and
 (4) Ventricular hypertrophy and remodeling.
 Although these compensatory mechanisms initially maintain
cardiac function, they are responsible for the symptoms of
HF and contribute to disease progression.

69. Relationship between cardiac output and preload
69

70. Relationship between stroke volume and
systemic vascular resistance
70

71. Beneficial and Detrimental Effects of the
Compensatory Responses in Heart
71

72. Key components of the pathophysiology of cardiac
remodeling
72

73. 73
 In the neurohormonal model of HF, an initiating event (eg,
acute MI) leads to decreased CO;
 The HF state then becomes a systemic disease whose
progression is mediated largely by neurohormones and
autocrine/paracrine factors that drive
 Myocyte injury, oxidative stress, inflammation, and
extracellular matrix remodeling.
 These substances include angiotensin II, norepinephrine,
aldosterone, natriuretic peptides, and arginine vasopressin
(AVP).

74. 74
 Chronic activation of the neurohormonal systems results in a
cascade of events that affect the myocardium at the molecular
and cellular levels.
 These events lead to changes in
 Ventricular size (left ventricular hypertrophy), shape,
structure, and function known as ventricular remodeling.
 The alterations in ventricular function result in further
deterioration in cardiac systolic and diastolic functions that
further promotes the remodeling process.

75. 75
 Common precipitating factors that may cause a previously
compensated HF patient to decompensate include
o Myocardial ischemia and MI, pulmonary infections,
o Nonadherence with diet or drug therapy, and
o Inappropriate medication use.
 Drugs may precipitate or exacerbate HF through negative
inotropic effects, direct cardiotoxicity, or increased sodium
and water retention.

76. Clinical presentation
76
 Patient presentation may range from asymptomatic to
cardiogenic shock.
 Primary symptoms are dyspnea (especially on exertion) and
fatigue, which lead to exercise intolerance.
 Other pulmonary symptoms include orthopnea, paroxysmal
nocturnal dyspnea (PND), tachypnea, and cough.
 Fluid overload can result in pulmonary congestion and
peripheral edema.
 Nonspecific symptoms may include fatigue, nocturia,
hemoptysis, abdominal pain, anorexia, nausea, bloating, ascites,
poor appetite or early satiety, and weight gain or loss.

77. 77
 Physical examination may reveal
o Pulmonary crackles, S3 gallop, cool extremities, Cheyne–
Stokes respiration,
o Tachycardia, narrow pulse pressure, cardiomegaly,
o Symptoms of pulmonary edema (extreme breathlessness and
anxiety, sometimes with coughing and pink, frothy sputum),
o peripheral edema, jugular venous distention (JVD),
o Hepatojugular reflux (HJR), hepatomegaly, and
o Mental status changes.

78. Diagnosis
78
 Consider the diagnosis of HF in patients with characteristic
signs and symptoms.
 A complete history and physical examination with
appropriate laboratory testing are essential in evaluating
patients with suspected HF.
 Laboratory tests for identifying disorders that may cause or
worsen HF include
 CBC; serum electrolytes (including calcium and
magnesium); renal, hepatic, thyroid function tests, and iron
studies; urinalysis; lipid profile; and A1C.

79. 79
 Hyponatremia
 Serum creatinine may be increased due to hypoperfusion;
preexisting renal dysfunction can contribute to volume
overload.
 B-type natriuretic peptide (BNP) is usually >100 pg/mL (29
pmol/L) and NT-proBNP >300 pg/mL (35 pmol/L).
 Ventricular hypertrophy can be demonstrated on chest
radiograph or electrocardiogram (ECG).
 Chest radiograph may also show pleural effusions or
pulmonary edema.

80. 80
 Echocardiogram can identify abnormalities of the pericardium,
myocardium, or heart valves and quantify LVEF to determine if
systolic or diastolic dysfunction is present.
 The New York Heart Association Functional Classification
System is intended primarily to classify symptoms according to
the physician’s subjective evaluation.
 Functional class (FC)-I patients have no limitation of physical
activity, FC-II patients have slight limitation, FC-III patients
have marked limitation, and FC-IV patients are unable to carry
on physical activity without discomfort.
 The ACC/AHA staging system provides a more comprehensive
framework for evaluating, preventing, and treating HF.

81. Treatment of chronic heart failure
81
Goals of Treatment:
 Improve quality of life, relieve or reduce symptoms, prevent
or minimize hospitalizations, slow disease progression, and
prolong survival.
General approach
 The first step is to determine the etiology or precipitating
factors. Treatment of underlying disorders (eg,
hyperthyroidism) may obviate the need for treating HF.
 ACC/AHA Stage A: These are patients at high risk for
developing HF.

82. 82
 Identify and modify risk factors to prevent development of
structural heart disease and subsequent HF.
 Strategies include smoking cessation and control of
hypertension, diabetes mellitus, and dyslipidemia.
 Although treatment must be individualized, ACE inhibitors
or ARBs are recommended for HF prevention in patients
with multiple vascular risk factors.
 ACC/AHA Stage B: These patients have structural heart
disease but no HF signs or symptoms.

83. 83
 Treatment is targeted at minimizing additional injury and
preventing or slowing the remodeling process.
 In addition to treatment measures outlined for stage A,
patients with reduced LVEF (<40%) should receive ACE
inhibitors (or ARB) and an evidence-based β-blocker to
prevent development of HF, regardless of whether they have
had an MI.
 Patients with a previous MI and reduced LVEF should also
receive an ACE inhibitor or ARB, evidence-based β-
blockers, and a statin.

84. 84
 ACC/AHA Stage C: These patients have structural heart
disease and previous or current HF symptoms and include both
HFrEF and HFpEF.
 In addition to treatments for stages A and B, patients with
HFrEF in stage C should receive GDMT that includes
o An ACE inhibitor, ARB, or angiotensin receptor–neprilysin
inhibitor together with an evidence-based β-blocker, and an
aldosterone antagonist in eligible patients to reduce morbidity
and mortality.
 Loop diuretics, hydralazine–isosorbide dinitrate (ISDN),
digoxin, and ivabradine are also used in select patients.

85. 85
 ACC/AHA Stage D HFrEF: These patients have persistent
HF symptoms despite maximally tolerated GDMT.
 They should be considered for specialized interventions,
including
 Mechanical circulatory support, continuous IV positive
inotropic therapy, cardiac transplantation, or hospice care
(when no additional treatments are appropriate).

86. GDMT algorithm for patients with ACC/AHA stage C
HFrEF
86

87. NONPHARMACOLOGIC THERAPY OF CHF
87
 Interventions include cardiac rehabilitation and restriction of
fluid intake and dietary sodium intake (<2–3 g of sodium/day)
with daily weight measurements.
 In patients with hyponatremia (serum sodium <130 mEq/L
[mmol/L]) or persistent volume retention despite high diuretic
doses and sodium restriction, limit daily fluid intake to 2 L/day
from all sources.
 Revascularization or anti-ischemic therapy in patients with
coronary disease may reduce HF symptoms.
 Drugs that can aggravate HF should be discontinued if possible.

88. Pharmacologic therapy for stage C HFrEF
88
 In general, patients with stage C HFrEF should receive an
ACE inhibitor, ARB, or ARNI along with an evidence-based
β-blocker, plus an aldosterone antagonist in select patients.
 Administer a diuretic if there is evidence of fluid retention.
 A hydralazine–nitrate combination, ivabradine, or digoxin
may be considered in select patients.

89. Diuretics
89
 Compensatory mechanisms in HF stimulate excessive sodium
and water retention, often leading to systemic and pulmonary
congestion.
 Consequently, diuretic therapy (in addition to sodium
restriction) is recommended for all patients with clinical
evidence of fluid retention.
 However, because they do not alter disease progression or
prolong survival,
 Diuretics are not required for patients without fluid
retention.

90. 90
 Thiazide diuretics (eg, hydrochlorothiazide) are relatively
weak and are infrequently used alone in HF.
 However, thiazides or the thiazide-like diuretic metolazone
can be used in combination with a loop diuretic to promote
very effective diuresis.
 Loop diuretics are usually necessary to restore and maintain
euvolemia in HF.
 Unlike thiazides, loop diuretics maintain their effectiveness
in the presence of impaired renal function, although higher
doses may be necessary.

91. 91
 Adverse effects of diuretics include
Hypovolemia, hypotension, hyponatremia,
hypokalemia, hypomagnesemia, hyperuricemia,
and renal dysfunction.

92. Angiotensin-Converting Enzyme
Inhibitors
92
 ACE inhibitors decrease angiotensin II and aldosterone,
attenuating many of their deleterious effects that drive HF
initiation and progression.
 ACE inhibitors also inhibit the breakdown of bradykinin, which
increases vasodilation and also leads to cough.
 ACE inhibitors improve symptoms, slow disease progression,
and decrease mortality in patients with HFrEF.
 Current guidelines recommend that all patients with HFrEF,
regardless of whether or not symptoms are present, should
receive an ACE inhibitor to reduce morbidity and mortality,
unless there are contraindications.

93. 93
 Clinical trials have documented favorable effects of ACE
inhibitors on symptoms, HF progression, hospitalizations, and
quality of life.
 ACE inhibitors improve survivalby 20%–30% compared with
placebo.
 The benefits are independent of HF etiology (ischemic vs
nonischemic) and are greatest in patients with the most severe
symptoms.
 Start therapy with low doses followed by gradual titration as
tolerated to the target or maximally tolerated doses.
 Dose titration is usually accomplished by doubling the dose
every 2 weeks.

94. 94
 Evaluate blood pressure (BP), renal function, and serum
potassium at baseline and within 1–2 weeks after the start of
therapy and after each dose increase.
 Although symptoms may improve within a few days of
starting therapy, it may take weeks to months before the full
benefits are apparent.
 Even if symptoms do not improve, continue long-term
therapy to reduce mortality and hospitalizations.
 The most common adverse effects include hypotension,
renal dysfunction, and hyperkalemia.

95. 95
 A dry, nonproductive cough (occurring in 15%–20% of patients)
is the most common reason for discontinuation.
 Because cough is a bradykinin mediated effect, replacement with
an ARB is reasonable; however, caution is required because
crossreactivity has been reported.
 Angioedema occurs in approximately 1% of patients and is
potentially life threatening;
 ACE inhibitors are contraindicated in patients with a history of
angioedema.
 ACE inhibitors are contraindicated in pregnancy due to various
congenital defects.

96. Angiotensin Receptor Blockers
96
 The ARBs block the angiotensin II receptor subtype AT1 ,
preventing the deleterious effects of angiotensin II on
ventricular remodeling.
 Because they do not affect the ACE enzyme, ARBs do not affect
bradykinin, which is linked to ACE inhibitor cough and
angioedema.
 ARBs are now a guideline-recommended alternative in patients
who are unable to tolerate an ACE inhibitor due to cough or
angioedema.
 Although numerous ARBs are available, only candesartan,
valsartan, and losartan are recommended in the guidelines
because efficacy has been demonstrated in clinical trials.

97. 97
 As with ACE inhibitors, initiate therapy with low doses and
then titrate to target doses.
 Evaluate BP, renal function, and serum potassium within 1–2
weeks after starting therapy and after dosage increases,
 with these parameters used to guide subsequent dose
changes.
 ARBs are not suitable alternatives in patients with
hypotension, hyperkalemia, or renal insufficiency due to ACE
inhibitors because they are just as likely to cause these
adverse effects.

98. 98
 Careful monitoring is required when an ARB is used with
another inhibitor of the renin-angiotensin-aldosterone (RAAS)
system
 Because this combination increases the risk of these adverse
effects.
 Because ARBs do not affect bradykinin, they are not
associated with cough and have a lower risk of angioedema
than ACE inhibitors.
 Similar to ACE inhibitors, ARBs are contraindicated in
pregnancy.

99. Angiotensin Receptor–Neprilysin
Inhibitor
99
 Valsartan/Sacubitril is an ARNI approved to reduce the risk
of cardiovascular death and hospitalization for HF in
patients with NYHA class II–IV HF and reduced LVEF.
 In patients with HFrEF and NYHA class II–III symptoms
tolerating an ACE inhibitor or ARB, current guidelines
recommend replacing those drugs with the ARNI to further
reduce morbidity and mortality.
 Discontinue ACE inhibitors 36 hours prior to initiating the
ARNI; no waiting period is needed in patients receiving an
ARB.

100. 100
 Titrate the initial starting dose to the target dose after 2–4 weeks.
 Closely monitor BP, serum potassium, and renal function after
the start of therapy and after each titration step.
 The most common adverse effects include hypotension,
dizziness, hyperkalemia, worsening renal function, and cough.
 Sacubitril/valsartan is contraindicated in patients with a history
of angioedema associated with an ACE inhibitor or ARB.
 It is also contraindicated in pregnancy and should not be used
concurrently with ACE inhibitors or other ARBs.

101. β-Blockers
101
 β-Blockers antagonize the detrimental effects of the sympathetic
nervous systems in HF and slow disease progression.
 Clinical trial evidence demonstrated that certain β-blockers
reduce HF mortality, all-cause hospitalizations, and
hospitalizations for worsening HF, among other endpoints.
 The ACC/AHA guidelines recommend use of β-blockers in all
stable patients with HFrEF in the absence of contraindications or
a clear history of β-blocker intolerance.
 Patients should receive a β-blocker even if symptoms are mild or
well controlled with ACE inhibitor and diuretic therapy.

102. 102
 It is not essential that ACE inhibitor doses be optimized
before a β-blocker is started.
 β-Blockers are also recommended for asymptomatic persons with
a reduced LVEF (stage B) to decrease the risk of progression to
HF.
 Carvedilol, metoprolol succinate (CR/XL), and bisoprolol are the
only β-blockers shown to reduce mortality in large HF trials.
 Because bisoprolol is not available in the necessary starting dose
of 1.25 mg, the choice is typically limited to either carvedilol or
metoprolol succinate.

103. 103
 Initiate β-blockers in stable patients who have no or minimal
evidence of fluid overload.
 Because of their negative inotropic effects, start β-blockers in
very low doses with slow upward dose titration to avoid
symptomatic worsening or acute decompensation.
 Doses should be doubled no more often than every 2 weeks, as
tolerated, until the target or maximally tolerated dose is reached.
 In addition, dose titration is a long, gradual process; response to
therapy may be delayed; and HF symptoms may actually
worsen during the initiation period.

104. 104
 Adverse effects include
 Bradycardia or heart block, hypotension, fatigue, impaired
glycemic control in diabetic patients, bronchospasm in patients
with asthma, and worsening HF.
 Absolute contraindications include uncontrolled bronchospastic
disease, symptomatic bradycardia, advanced heart block
without a pacemaker, and acute decompensated HF.
 However, β-blockers may be tried with caution in patients with
asymptomatic bradycardia, COPD, or well-controlled asthma.

105. Aldosterone Antagonists
105
 Spironolactone and eplerenone block mineralocorticoid
receptors, the target for aldosterone.
 In the heart, aldosterone antagonists inhibit cardiac
extracellular matrix and collagen deposition, thereby
attenuating cardiac fibrosis and ventricular remodeling.
 Aldosterone antagonists also attenuate the systemic
proinflammatory state, atherogenesis, and oxidative stress
caused by aldosterone.

106. 106
 Current guidelines recommend adding a low-dose
aldosterone antagonist to standard therapy
 To improve symptoms, reduce the risk of HF
hospitalization, and
 Increase survival in select patients provided that serum
potassium and renal function can be carefully monitored.
 Start with low doses (spironolactone 12.5 mg/day or
eplerenone 25 mg/day) especially in older persons and
those with diabetes or a creatinine clearance.

107. Ivabradine
107
 Ivabradine inhibits the If current in the sinoatrial node that is
responsible for controlling HR, thereby slowing spontaneous
depolarization of the sinus node and resulting in a dose-
dependent slowing of the HR.
 Ivabradine is indicated to reduce the risk of hospitalization for
worsening HF in patients with LVEF ≤35% who are in sinus
rhythm with resting HR ≥70 bpm and are either on a maximally
tolerated dose of a β-blocker or have a contraindication to β-
blocker use.
 The usual starting dose is 5 mg twice daily with meal. After 2
weeks of treatment, if the resting HR is between 50 and 60
bpm, the dose should be continued.

108. Digoxin
108
 It attenuates the excessive sympathetic nervous system activation in HF
and increases parasympathetic activity, thereby decreasing HR and
enhancing diastolic filling.
 Based on available data, digoxin is not considered a first-line agent in
HF, but a trial may be considered in conjunction with GDMT including
ACE inhibitors (or ARBs), β-blockers, and diuretics in patients with
symptomatic HFrEF to improve symptoms and reduce hospitalizations.
 In the absence of digoxin toxicity or serious adverse effects, digoxin
should be continued in most patients.
 Digoxin withdrawal may be considered for asymptomatic patients who
have significant improvement in systolic function with optimal ACE
inhibitor and β-blocker treatment.

109. Drug Dosing Recommendations for Stage C
HFrEF
109

110. Drug Dosing Recommendations for Stage C
HFrEF….
110

111. PHARMACOLOGIC THERAPY FOR
HFpEF
111
 Treatment includes controlling HR and BP, alleviating causes
of myocardial ischemia, reducing volume, and restoring and
maintaining sinus rhythm in patients with atrial fibrillation.
 A loop or a thiazide diuretic should be considered for
patients with volume overload.
 Avoid lowering preload excessively, which may reduce stroke
volume and CO.
 ACE inhibitors may be considered in all patients, especially
patients with symptomatic atherosclerotic cardiovascular
disease or diabetes and one additional risk factor.

112. 112
 Aldosterone antagonists can reduce the risk of hospitalization
in patients who do not have contraindications and are not at
risk for hyperkalemia.
 Nondihydropyridine calcium channel blockers should be
considered for patients with atrial fibrillation warranting
ventricular rate control who either are intolerant to or have
not responded to a β-blocker.
 A nondihydropyridine or dihydropyridine (eg, amlodipine)
CCB can be considered for symptom-limiting angina or
hypertension.

113. 113
Treatment of acute
decompensated heart failure
(ADHF)

114. General approach
114
 Acute decompensated heart failure involves patients with new
or worsening signs or symptoms (often resulting from volume
overload and/or low CO) requiring medical intervention, such
as emergency department visit or hospitalization.
 The overall goals are to relieve symptoms, improve
hemodynamic stability, and reduce short-term mortality so the
patient can be discharged in a stable compensated state on oral
drug therapy.
 Consider hospitalization based on clinical findings.
 Focus the history and physical exam on potential etiologies of
ADHF; presence of precipitating factors; onset, duration, and
severity of symptoms; and a careful medication history.

115. 115
 Symptoms of volume overload include dyspnea,
orthopnea, PND, ascites, GI symptoms (poor appetite,
nausea, early satiety), peripheral edema, and weight gain.
 Low output symptoms include altered mental status,
fatigue, GI symptoms (similar to volume overload), and
decreased urine output.
 Signs of volume overload include pulmonary crackles,
elevated jugular venous pressure, HJR, S3 gallop, and
peripheral edema.

116. 116
 Low output signs include tachycardia, hypotension (more
commonly) or hypertension, narrow pulse pressure, cool
extremities, pallor, and cachexia.
 Laboratory testing may include BNP or NT-proBNP, thyroid
function tests, complete blood count, cardiac enzymes, and
routine serum chemistries (eg, serum creatinine, liver function
tests).
 Ascertain hemodynamic status to guide initial therapy.
 Patients may be categorized into one of four hemodynamic
subsets based on volume status (euvolemic or “dry” vs volume
overloaded or “wet”) and CO (adequate CO or “warm” vs
hypoperfusion or “cold”.

117. 117
 Reserve invasive hemodynamic monitoring for patients refractory to
initial therapy, whose volume status is unclear, or who have significant
hypotension or worsening renal function despite appropriate initial
therapy.
 If fluid retention is evident on physical exam, pursue aggressive
diuresis, preferably with IV diuretics.
 In the absence of cardiogenic shock or symptomatic hypotension, strive
to continue all GDMT for HF.
 β-blockers may be temporarily held or dose-reduced if recent changes
are responsible for acute decompensation.
 Other GDMT may also need to be temporarily withheld in the presence
of renal dysfunction, with close monitoring of serum potassium.
 Most patients may continue to receive digoxin at doses targeting a
trough serum concentration of 0.5–0.9 ng/Ml.

118. Nonpharmacologic therapy for ADHF
118
 Place all patients with congestive symptoms on sodium restriction
(<2 g daily) and consider fluid restriction for refractory symptoms.
 Consider noninvasive ventilation for patients in respiratory distress
due to acute pulmonary edema, particularly those at risk for
intubation.
 Provide pharmacologic thromboprophylaxis with UFH or LMWH
for most patients with limited mobility.
 Most nonpharmacologic therapies for ADHF are reserved for
patients failing pharmacologic therapy
 Temporary mechanical circulatory support (MCS) with an intra-
aortic balloon pump (IABP), ventricular assist device (VAD), or
extracorporeal membrane oxygenation (ECMO) may be considered
for;

119. 119
 Hemodynamic stabilization until the underlying etiology of
cardiac dysfunction resolves or has been corrected (“bridge to
recovery”) or
 Until evaluation for definitive therapy (eg, durable MCS or
cardiac transplantation) can be completed (“bridge to decision”).
 Durable MCS with temporary device implantation is used for
patients awaiting heart transplantation who are unlikely to survive
until a suitable donor is identified (“bridge to transplantation”).
 Cardiac transplantation is the best option for patients with
irreversible advanced HF.

120. General management algorithm for ADHF based
on clinical presentation.
120

121. 121
PHARMACOLOGIC THERAPY FOR
ADHF

122. Loop Diuretics
122
 Current guidelines recommend IV loop diuretics (furosemide,
bumetanide) as firstline therapy for ADHF patients with volume
overload.
 Bolus administration reduces preload by functional venodilation within
5–15 minutes and later (>20 minutes) via sodium and water excretion,
thereby improving pulmonary congestion.
 Although patients with HFrEF can tolerate significant reductions in
preload without compromising stroke volume, excessive diuresis can
decrease CO.
 Excessive reductions in venous return may also compromise CO in
diastolic dysfunction, intravascular volume depletion, or patients in
whom CO is significantly dependent on adequate filling pressure.

123. 123
 Reflex increases in neurohormonal activation may result in
arteriolar and coronary vasoconstriction, tachycardia, and
increased myocardial oxygen consumption.
 Use low doses (equivalent to IV furosemide 20–40 mg) initially
in ADHF patients who are naïve to loop diuretics.
 Higher doses are associated with more rapid relief of congestive
symptoms but may also increase the risk of transient worsening
of renal function.
 Diuretic resistance may be improved by administering larger IV
bolus doses, transitioning from IV bolus to continuous IV
infusions, or adding a second diuretic with a different mechanism
of action.

124. Vasopressin Antagonists
124
 Vasopressin receptor antagonists affect one or two AVP (antidiuretic
hormone) receptors, V1A or V2 .
 Tolvaptan selectively binds to and inhibits the V2 receptor.
 It is an oral agent indicated for hypervolemic and euvolemic
hyponatremia
 in patients with SIADH, cirrhosis, or HF.
 Conivaptan nonselectively inhibits both the V1A and V2 receptors.
 It is an IV agent indicated for hypervolemic and euvolemic hyponatremia
due to a variety of causes but is not indicated for patients with HF.
 The role of vasopressin receptor antagonists in the long-term
management of HF is unclear.

125. Vasodilators
125
 Venodilators reduce preload by increasing venous
capacitance, improving symptoms of pulmonary congestion
in patients with high ventricular filling pressures.
 Arterial vasodilators counteract the peripheral
vasoconstriction and impaired CO that can result from
 Activation of the sympathetic nervous system, RAAS, and
other neurohormonal mediators in HF.
 Mixed vasodilators act on both arterial resistance and venous
capacitance vessels, reducing congestive symptoms while
increasing CO.

126. 126
 IV vasodilators should be considered before positive
inotropic therapy in patients with low CO and elevated SVR
(or elevated BP in those without a pulmonary artery
catheter).
 However, hypotension may preclude their use in patients
with preexisting low BP or SVR.
 IV nitroglycerin is often preferred for preload reduction in
ADHF, especially in patients with pulmonary congestion.
 It reduces preload and PCWP via functional venodilation
and mild arterial vasodilation.

127. 127
 In higher doses, nitroglycerin displays potent coronary
vasodilating properties and beneficial effects on myocardial
oxygen demand and supply, making it the vasodilator of choice
for patients with severe HF and ischemic heart disease.
 Initiate nitroglycerin at 5–10 mcg/min (0.1 mcg/kg/min) and
increase every 5–10 minutes as necessary and tolerated.
Maintenance doses usually range from 35 to 200 mcg/min (0.5–
3 mcg/kg/min).
 Hypotension and excessive decrease in PCWP are important
dose-limiting side effects.
 Tolerance to the hemodynamic effects may develop over 12–72
hours of continuous administration.

128. 128
 Sodium nitroprusside is a mixed arteriovenous vasodilator
that increases cardiac index (CI) to a similar degree as
dobutamine and milrinone despite having no direct inotropic
activity.
 However, nitroprusside generally produces greater
decreases in PCWP, SVR, and BP.
 Hypotension is an important dose-limiting adverse effect of
nitroprusside, and its use should be primarily reserved for
patients with elevated SVR.

129. 129
 Nitroprusside has a rapid onset and a duration of action
<10 minutes, necessitating continuous IV infusions.
 Initiate therapy with a low dose (0.1–0.2 mcg/kg/min) to
avoid excessive hypotension, and increase by small
increments (0.1–0.2 mcg/kg/min) every 5–10 minutes as
tolerated.
 Usual effective doses range from 0.5 to 3 mcg/kg/min.

130. Inotropes
130
 Prompt correction of low CO in patients with “cold” subsets (III
and IV) is required to restore peripheral tissue perfusion and
preserve end-organ function.
 Although IV inotropes can improve hypoperfusion by
enhancing cardiac contractility, potential adverse outcomes limit
their use to select patients with refractory ADHF.
 Inotropes should be considered only as
 A temporizing measure to maintain end-organ perfusion in
patients with cardiogenic shock or severely depressed CO and
low systolic BP (ie, ineligible for IV vasodilators) until
definitive therapy can be initiated,

131. 131
 as a “bridge” for patients with advanced HF who are eligible
for MCS or cardiac transplantation, or
 for palliation of symptoms in patients with advanced HF who
are ineligible for MCS or cardiac transplantation.
 Dobutamine and milrinone produce similar hemodynamic
effects, but
o Dobutamine usually causes more pronounced increases in
HR, and
o milrinone is associated with greater relaxation in arterial
smooth muscle.

132. 132
 Dobutamine is a β1 - and β2 -receptor agonist with some α1 -
agonist effects; its positive inotropic effects are due to effects on β1
-receptors.
 The net vascular effect is usually vasodilation.
 Milrinone inhibits phosphodiesterase III and produces positive
inotropic and arterial and venous vasodilating effects.
 During IV administration, milrinone increases stroke volume and
CO with minimal change in HR.
 However, the vasodilating effects may predominate, leading to
decreased BP and a reflex tachycardia.

133. 133
 Norepinephrine and dopamine have combined inotropic and
vasopressor activity.
 Although therapies that increase SVR are generally avoided in
ADHF,
 They may be required in select patients where marked
hypotension precludes use of traditional inotropes (eg,
septic shock, refractory cardiogenic shock).

134. 134