Kirubel Minsamo, BPharm, MSc.

[Clinical Pharmacist]
 Chapter Outline
1. Hypertension
2. Heart failure
3. Coronary heart disease
4. Acute coronary syndromes
5. VTE
6. Hyperlipidemia
7. Stroke
8. Shock

9. Peripheral Arterial Disease Assignment and

10. Cardiovascular testing Seminar topics
11. Cardiopulmonary Resuscitation 2
LEARNING OBJECTIVES
Upon Completion of the Unit, the students Will be
able to:
 Classify blood pressure levels and treatment goals.
 Recognize the underlying causes and contributing
factors in the development of hypertension.
 Recommend appropriate lifestyle modifications and
pharmacotherapy for patients with hypertension.
 Construct an appropriate monitoring plan to assess
hypertension treatment.

4
 Introductory Case

• Mr FH, a 48-year-old van driver, was identified by his

general practitioner (GP) as having a resting BP of 162/92
mmHg.
• He was in reasonably good health and purchased OTC
ibuprofen 400 mg, which he took up to three times daily for
arthritis-type pain when necessary.
• He weighed 95 kg, was 5’7” tall, and had a resting pulse
rate of 82 beats per minute (bpm).
• He smoked 15 cigarettes per day and drank at least 6 units
on 4 nights each week.
• His total cholesterol (TC) had been measured as 5.9mmol/L
and his high-density lipoprotein (HDL) as 1.5 mmol/L
(TC:HDL ratio 4.5).
5
Introductory Case
Q1. Why is it important to control blood pressure?
Q2. How would you assess Mr FH’s cardiovascular
disease (CVD) risk?
Q3. According to current guidelines, should Mr FH be
treated for hypertension?
Q4. What non-drug approaches can Mr FH adopt to
reduce his blood pressure and/or his cardiovascular
(CV) risks, and why are these important?
Q5. What first-line treatments would be suitable for
Mr FH’s hypertension?

6
 Hypertension(HTN)

 Hypertension (HTN) is the most common CVD

 Sustained arterial HTN damages blood vessels in
kidney, heart, & brain & leads to an ↑ed incidence of
renal failure, coronary disease, HF, stroke, &
dementia
• Cardiovascular morbidity & mortality risk directly
correlated with BP; antihypertensive drug therapy
reduces cardiovascular & mortality risk

7
 Blood Pressure (BP)
 BP: SBP/DBP
 Systolic BP (SBP):
 represents the peak value, which is achieved during cardiac
contraction.
 Diastolic BP (DBP):
 achieved after contraction when the cardiac chambers are
filling, and represents the nadir value.
 Mean arterial pressure (MAP):
 reflects both SBP and DBP
 MAP = 1/3(SBP) + 2/3(DBP)
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 Blood Pressure (BP)
 HTN is defined as an elevated SBP, DBP, or both.
 A clinical diagnosis of HTN is based on the mean of two
or more properly measured seated BP measurements
taken on two or more occasions(SBP ≥140 mm Hg or
DBP ≥90 mmHg, or both)
 This mean BP is also used initially to classify and stage
HTN
 The JNC7 classification includes
 Normal BP, PreHTN, stage 1 HTN, and stage 2 HTN

9
10
 Epidemiology
 The overall incidence is similar between men and women,
but varies depending on age.
 BP values increase with age, and HTN is very common in the
elderly.
 The lifetime risk of developing HTN among those 55 years of age
and older who are normotensive is 90%.
 Prevalence differs by ethnic group(African Americans Vs
Asia Americans)

11
 Pathophysiology of BP Regulation
 Various neural and humoral factors are known to
influence and regulate BP. These include
 Adrenergic nervous system (controls α- and β-receptors)
 RAAS (regulates systemic and renal blood flow)
 Renal function and renal blood flow (influences fluid and
electrolyte balance)
 Several hormonal factors (adrenal cortical hormones,
vasopressin, thyroid hormone, insulin), and
 Vascular endothelium (regulates release of nitric oxide,
bradykinin, prostacyclin, endothelin)

BP= CO X TPR 12
 TABLE Potential Mechanisms of Pathogenesis

Elevated BP can result from increased CO and/or increased TPR.

Increased Increased cardiac preload:
cardiac Increased fluid volume from excess sodium intake or renal sodium retention
output (from reduced number of nephrons or decreased glomerular filtration)

Venous constriction:
Excess stimulation of the renin-angiotensin aldosterone system (RAAS)
Sympathetic nervous system overactivity
Increased Functional vascular constriction:
peripheral Excess stimulation of the RAAS
resistance Sympathetic nervous system overactivity
Genetic alterations of cell membranes
Endothelial-derived factors
Structural vascular hypertrophy:
Excess stimulation of the RAAS
Sympathetic nervous system overactivity
Genetic alterations of cell membranes
Endothelial-derived factors
Hyperinsulinemia resulting from the metabolic syndrome 13
Types of Hypertension
 Essential or primary HTN
 90% of pts with high BP have essential HTN
 No identifiable cause for elevated BP
 Cannot be cured, but it can be controlled
 Secondary Hypertension
 <10% of patients have secondary HTN
 Identifiable cause for elevated BP
 Secondary causes are potentially correctable
 Isolated systolic HTN
 Pts with DBP<90 mm Hg & SBP >140 mm Hg
14
Secondary Causes of Hypertension

15
Types of Hypertension
 Hypertensive crisis [BP>180/120 mm Hg]
 Hypertensive emergency :
• with acute or progressing target organ damage
• require hospitalization for immediate BP lowering using IV
medications and intraarterial BP monitoring.
 Hypertensive urgency:
• without acute or progressing target organ injury
• do not require immediate BP lowering; instead, BP should be
slowly reduced within 24 hours
 Resistant HTN
 Patients failing to achieve goal BP despite maximum doses
of three antihypertensives including a diuretic 16
 Clinical Presentation
 Symptoms:
 Usually none related to elevated BP.
 Signs:
 Previous BP values in either the preHTN or the HTN category
 Laboratory Tests:
 BUN/serum creatinine, fasting lipid panel, fasting blood
glucose, serum electrolytes (sodium, potassium), spot urine
albumin-to-creatinine ratio.
 Other Diagnostic Tests:
 12-lead ECG, estimated glomerular filtration rate [using
modification of diet in renal disease (MDRD) equation].
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Clinical Presentation
 Hypertension-Related Target-Organ Damage:
 Brain (stroke, transient ischemic attack, dementia)
 Eyes (retinopathy)
 Heart (left ventricular hypertrophy, angina, prior MI, prior
coronary revascularization, heart failure)
 Kidney (chronic kidney disease)
 Peripheral vasculature (peripheral arterial disease)

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HTN Management
 HTN is treated with both lifestyle modifications and
pharmacotherapy
 Lifestyle modification alone is appropriate therapy for
most patients with prehypertension.
 Lifestyle modifications alone are not considered
adequate for patients with HTN and additional CV risk
factors or HTN-associated target organ damage
 The choice of initial drug therapy depends on the
degree of BP elevation and presence of compelling
indications(
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HTN Management….Goal
 Overall Goal of Treatment
 To reduce HTN-associated morbidity and mortality
• HTN -associated complications are the primary causes of
death in patients with HTN.
 To reducing major CV risk factors
• major CV risk factors that increase the likelihood of
developing HTN-associated complications, not HTN

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21
22
 HTN Management….Goal BP Values

JNC 7 AHA
Most Patients for General Prevention <140/90 mm Hg <140/90 mm Hg
Patients with <130/80 mm Hg <130/80 mm Hg
Diabetes
Significant chronic kidney disease
Microsoft
PowerPoint Presentation

Patients with No specific <130/80 mm Hg

Known coronary artery disease (MI, stable recommendation
angina, unstable angina)
Noncoronary atherosclerotic vascular
disease (ischemic stroke, transient ischemic
attack, peripheral arterial disease,
abdominal aortic aneurysm)
Framingham risk score of 10% or greater
Patients with left ventricular dysfunction (heart No specific 120/80 mm Hg
failure) recommendation

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 Microsoft
PowerPoint Presentation

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25
 Lifestyle Modifications to Prevent and Manage HTN

Modification Recommendation Approximate SBP

Reduction (mm Hg)
Weight loss Maintain normal body weight (body mass index, 5–20 per 10-kg
18.5–24.9 kg/m2) weight loss
DASH-type Consume a diet rich in fruits, vegetables, and 8–14
dietary low-fat dairy products with a reduced content
patterns of saturated and total fat
Reduced salt Reduce daily dietary sodium intake as much as 2–8
intake possible, ideally to 65 mmol/day (1.5 g/day
sodium, or 3.8 g/day sodium chloride)
Physical Regular aerobic physical activity (at least 30 4–9
activity minutes/day, most days of the week)
Moderation of Limit consumption to less than or equal to 2 2–4
alcohol intake drink equivalents per day in men and less than
or equal to 1 drink equivalent per day in
Microsoft
PowerPoint Presentation

women and lighter weight personsb

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DASH, Dietary Approaches to Stop Hypertension.
Pharmacotherapy
 First-line Agents
 Angiotensin Converting Enzyme Inhibitors (ACEIs)
 Angiotensin Receptor Blockers (ARBs)
 Calcium Channel Blockers (CCBs)
 Thiazide Diuretics
 Second-line Agents
 β-Blockers
 Aldosterone Antagonists
 Alternative Antihypertensive Agents
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29
Stepped approach

 A stepped-care approach to the treatment of HTN

involves the sequential addition of medications until BP
is normalized
 Substitution therapy involves the replacement of one
antihypertensive drug class with another and is most
appropriate if the drug class first chosen either does
not lower BP or is associated with serious or
bothersome adverse effects
 Best applied to stage 1 HTN because a single drug may
often be sufficient for BP control

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 Step down therapy
 Primary prevention patients with a goal BP <140/90
mmHg who have very well controlled BP for at least 1
year might be eligible for a trial of step-down therapy.
This option should not be considered for pts who have
 a Framingham risk score≥10%,
 Compelling indications, or HTN-associated complications.
 Consists of attempting to gradually decrease the
dosage, number of antihypertensive drugs, or
both without compromising BP control.

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 Individual Antihypertensive Agents
Diuretics
 Diuretics, preferably a thiazide, are first-line agents for HTN
 when combination therapy is needed , a diuretic is
recommended to be one of the agents used.
 Potassium-sparing diuretics are weak antihypertensive
agents but provide an additive effect when used in
combination with a thiazide or loop diuretic.
 Aldosterone antagonists (spironolactone and eplerenone)
may be technically considered potassium-sparing agents, but
are more potent antihypertensives.
 They are viewed by the JNC7 as an independent class
because of evidence supporting compelling indications.
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 Hypotensive mechanisms of diuretics
• Initial diuresis
 reductions in plasma and stroke volume
 decreases cardiac output and BP.
compensatory increase in PVR
• With chronic diuretic therapy
 ECF and plasma volume return to near pretreatment values.
 PVR decreases to values that are lower than the pretreatment
baseline.
responsible for chronic antihypertensive effects.

 Parameters to monitor
 BP, Weight, electrolyte, BUN, Scr, Cholesterol levels 33
34
ACE Inhibitors

 Are first-line agents for hypertension.

 Have compelling indications in: diabetes, HF, post-MI,
CKD, or recurrent stroke prevention
 Believed to provide unique CV benefits by:
 Improving endothelial function, Promoting LVH regression,
Improving insulin sensitivity
 Evaluating BP response 2 to 4 weeks after starting or
changing the dose of an ACEI is appropriate

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ACEIs: Adverse Effects
 Cough
 5-20% of pts, Non-productive, Caused by bradykinin
 Continue if possible ???, Consider change to ARB
 Acute Renal Failure
 Rare complication
 Risk factors: Bilateral renal artery stenosis or stenosis of
solitary kidney
 Start with low dose & Go slow!
• Decrease in GFR
• Expect slight  SCr
• If SCr.  > 30%, stop or ↓ dose
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ACEIs: Adverse Effects…
 Hypotension
 Higher risk in hypovolemia, CHF, elderly, diuretics,
vasodilators
 Start with low dose if already on diuretic
 decreasing the dose of the diuretic, or
 Stopping the diuretic before initiating the ACEI
 Avoid if SBP < 80 mmHg
 Hyperkalemia
 Due to decreased aldosterone
 Risk factors: CKD, K+ sparing diuretics, DM, NSAIDs
 Monitor K+ within 2-4 wks of initiation or dose changes
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ACEIs: Adverse Effects…

 Cough

ACEIs induced cough

5-20% of pts  The cough has the following clinical features:

 It usually begins within 1-2 wks of instituting therapy,
but can be delayed up to 6 months
 Women are affected more frequently than men


 Chinese, at least in Hong Kong, have a high

Non-productive prevalence that approaches 50 %

 It typically resolves within 1-4 days of discontinuing
therapy, but can take up to 4 wks
 It generally recurs with rechallenge, either with the
same or a different ACEI
 It does not occur more frequently in asthmatics than in
nonasthmatics but it may be accompanied by


bronchospasm

Caused by bradykinin
 Continue if possible ???
 Consider change to ARB
 Angioedema
 Rare event 0.1-0.5% of pts
 Typically involves the mouth, lips, tongue, larynx, pharynx, &
subglottic tissues
 Increase risk in African Americans Angioedema

 Angioedema can be distinguished clinically from

other forms of edema by the following
characteristics:

 Do not start ACE if hx of angioedema

 Relatively rapid onset of presentation (min to
hrs)
 Asymmetric distribution
 Distribution not in dependent areas
 Involvement of lips, larynx, and bowel
 Association of some forms of angioedema with
anaphylaxis

 Discontinue ACE
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ACEIs: Contraindications

 Angioedemia
 Pregnancy
 B/c of the risk of fetal hypotension, anuria, and renal
failure, sometimes associated with fetal malformations or
death
 Bilateral renal artery stenosis
Avoid:
 SBP < 80 mmHg
 SCr > 3.0
 Suspected bilateral renal artery stenosis
 K+ > 5.5

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Calcium Channel Blockers (CCBs)

 Both dihydropyridine CCBs and nondihydropyridine

CCBs, are first-line agents for hypertension.
 Have compelling indications in CHD and in diabetes
 Dihydropyridine CCBs:
 Potent vasodilators
 Little or no negative effect upon cardiac contractility or
conduction, rate
 very effective in older patients with ISH
 In pts with HTN and DM appear to be less cardio-protective
than ACEIs
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Calcium Channel Blockers (CCBs)

 Non-Dihydropyridines CCBs:
 Less potent vasodilators: Verapamil &, to a lesser extent,
diltiazem
 Have a greater depressive effect on cardiac conduction &
contractility compared to DHP (verapamil > diltiazem)
 Can be used to treat tachyarrhythmias (AF)
 Contraindications
• Wolff-Parkinson-White (WPW) syndrome
• Hypotension, Acute CHF, AV blocks

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44
 β-Blockers
 First-line agents to treat specific compelling indications
(post-MI, coronary disease).
 Additional therapy for other compelling indications (heart
failure and diabetes)
 Produce HF if used in high initial doses in pts with
preexisting LVD & started during acute HF exacerbation
 Abrupt cessation can produce: unstable angina, MI,
rebound HTN
 Should always be tapered gradually over 1 to 2 weeks
before eventually discontinuing the drug.
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 Beta blockers

Type of β - Comment
blockers
Cardio- Abrupt discontinuation may cause rebound HTN
selective inhibit β1 receptors at low to moderate dose, higher doses also block β2
receptors; may exacerbate asthma when selectivity is lost
have additional benefits in pts with atrial tachyarrhythmia or preoperative
HTN
Non-selective Abrupt discontinuation may cause rebound HTN
inhibit β1 & β 2 receptors at all doses; can exacerbate asthma
have additional benefits in pts with essential tremor, migraine headache,
thyrotoxicosis
ISA Abrupt discontinuation may cause rebound HTN
partially stimulate β-receptors while blocking against additional
stimulation; C/I in pts MI
Mixed α-& β - Abrupt discontinuation may cause rebound HTN
blockers Additional blockade produces vasodilation & more orthostatic
hypotension
Cardio- Abrupt discontinuation may cause rebound HTN
selective & Additional vasodilation does not result in more orthostatic hypotension
vasodilatory 46
47
β-Blockers

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49
 Hypertensive Emergencies: Principles of
treatment
 As an initial goal, reduce mean arterial pressure (MAP) by no
more than 25% within minutes to hours.
 Reach BP of 160/100 mm Hg within 2-6 hours.
 Measure BP every 5-10 minutes until goal MAP is reached and
life-threatening target organ damage resolves.
 Maintain goal BP for 1-2 days, and further reduce BP toward
normal over several weeks.
 Excessive falls in BP may precipitate renal, cerebral, or coronary
ischemia.
 Intravenous agents are preferred because of the ability to titrate
dosages on the basis of BP response; however, specific agents
should be chosen on the basis of patient findings.
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52
Hypertensive Urgencies: Principles of
treatment
• There is no agent of choice; medications should be
selected on the basis of patient characteristics.
• Oral therapy is preferred.
• Onset of action should be in 15-30 minutes, and peak
effects should be seen in 2-3 hours.
• Check BP every 15-30 minutes to ensure response.
• Use of immediate-release nifedipine is inappropriate
to lower BP in patients with hypertensive urgencies.

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Agents Used to Treat Hypertensive Urgencies

54
 Evaluation of Therapeutic Outcome
 BP response should be evaluated 2 to 4 weeks after
initiating or making changes in therapy, then every 3 to 6
months once goals BP values are obtained
 Other clinical parameters that should be monitored
periodically include funduscopic changes on eye
examination, LV hypertrophy on ECG, proteinuria, and
changes in kidney function.
 Monitoring for adverse drug effects should typically occur 2
to 4 weeks after starting a new agent or dose increases,
and then every 6 to 12 months in stable patients.
 Patient adherence with the therapeutic regimen should be
assessed regularly. 55
Pharmacotherapy: A Pathophysiologic Approach
 LEARNING OBJECTIVES
 Upon Completion of the unit, the students Will be able to:
 Differentiate between the common underlying etiologies of HF
 Describe the pathophysiology of HF
 Identify signs and symptoms of heart failure and classify a given
patient by NYHA-FC/ACC/AHA Heart Failure Staging
 Describe the goals of therapy for a patient with acute or chronic HF
 Develop a nonpharmacologic treatment plan which includes patient
education for managing HF
 Develop a specific evidence-based pharmacologic treatment plan for a
patient with acute or chronic heart failure based on disease severity
and symptoms
 Formulate a monitoring plan for the nonpharmacologic and
pharmacologic treatment of a patient with heart failure.

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 Introductory Case
 BE is a 62-year-old female with a history of known CAD and type 2
DM who presents for a belated follow-up clinic visit (her last visit
was 2 years ago). She states that she used to be able to walk over
one-half mile (0.8 km) and two flights of stairs before
experiencing chest pain and becoming short of breath. Since her
last visit, she has had increasing symptoms and has now
progressed to shortness of breath (SOB) with walking only half a
block and doing chores around the house. She also notes her
ankles are always swollen and her shoes no longer fit, therefore she
only wears slippers. Additionally, her appetite is decreased, and she
often feels bloated. She also feels full after eating only a few bites of
each meal.
 What information is suggestive of a diagnosis of heart failure?
 What additional information do you need to know before creating a
treatment plan for BE?

58
 Heart failure[HF]…Definition
 Heart failure (HF): is a clinical syndrome caused by the
inability of the heart to pump sufficient blood to meet the
metabolic needs of the body.
 Congestive Heart Failure(CHF): is a clinical syndrome
characterized by a history of specific signs and symptoms
related to congestion and hypoperfusion.
 Acute Heart Failure (AHF) is used to signify either an acute
decompensation of a patient with a history of chronic HF or to
refer to a patient presenting with new-onset HF symptoms.
 Cardiomyopathy & LV dysfunction terms are not equivalent to
HF but describe possible structural or functional reasons for
the development of HF
 HF can result from any disorder that reduces ventricular filling
(diastolic dysfunction) and/or myocardial contractility
(systolic dysfunction).

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 HF: Etiology
 HF can result from any disorder that affects the ability of the
heart to contract (systolic function) and/or relax (diastolic
dysfunction)_ It may be either systolic HF or diastolic HF
 The most common causes of HF are CAD, HTN, and dilated
cardiomyopathy
 HF can be classified by the primary underlying etiology as
 Ischemic Versus Nonischemic
 With 70% of HF related to ischemia
 CAD resulting in an acute MI and reduced ventricular function
is a common presenting history
 Nonischemic etiologies : HTN, thyroid disease, excessive alcohol
use, illicit drug use, pregnancy-related heart disease…

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 HF: Etiology
 Systolic Versus Diastolic Dysfunction
 Systolic dysfunction/Abnormal ventricular contraction
LVEF is <40%, dropping to <20% in advanced HF
 Most HF is associated with evidence of LV systolic
dysfunction (evidenced by a reduced EF)
 Diastolic dysfunction/Abnormal ventricular filling
 LVEF may or may not be abnormal, most importantly,
the EF remains ≥45%
 Diastolic HF is a clinical syndrome of HF characterized
by a normal ejection fraction and abnormal diastolic
function

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 HF: Etiology
 Low-Output Versus High-Output Failure
 Low-output failure
 >90% of cases
 The hallmark of classic low-output HF is a diminished volume
of blood being pumped by a weakened heart in patients who
have otherwise normal metabolic needs.
 High-output failure
 the heart itself is healthy and pumps a normal or even higher
than normal volume of blood.
 Because of high metabolic demands (e.g., hyperthyroidism,
anemia), the heart becomes exhausted from the increased
workload and eventually cannot keep up with demand.
 Treatment: amelioration of the underlying disease

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 HF: Etiology
 Left Versus Right Ventricular Dysfunction
 Left-sided VD
 Most common form
 major target for pharmacologic intervention
 results in pulmonary symptoms/congestion
 Right-sided VD
 relatively uncommon
 Caused by primary or secondary PAH
 manifests as systemic congestion

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Causes of Heart Failure

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 Pathophysiology:
Normal Cardiac Function
 CO is defined as the volume of blood ejected per unit time
(L/min) and is the product of heart rate (HR) and stroke
volume (SV):
 CO = HR × SV
 The r/ship between CO and MAP is: MAP = CO × systemic
vascular resistance (SVR)
 Stroke volume, CO, or both are low in both systolic and
diastolic left ventricular dysfunction, resulting in decreased
tissue perfusion.

65
 In an individual with normal left ventricular (LV) function, increasing
systemic vascular resistance has little effect on stroke volume.
 As the extent of LV dysfunction increases, the negative, inverse
relationship between stroke volume and systemic vascular resistance
66 becomes more important
 Pathophysiology
Compensatory Mechanisms in Heart Failure
 When the heart begins to fail, the body activates several
complex compensatory mechanisms in an attempt to
maintain CO and oxygenation of vital organs. These include
 increased sympathetic tone

 activation of the RAAS

 sodium and water retention,

 Other neurohormonal adaptations, and

 Cardiac “remodeling” (ventricular dilation, cardiac

hypertrophy, and changes in left ventricular lumen
shape).
 The long-term consequences of these adaptive mechanisms
can create more harm than good, however
67
 Compensatory Responses in HF
Compensatory Beneficial Effects of Detrimental Effects of
Response Compensation Compensation
Increased preload Optimize stroke-volume via Frank- Pulmonary and systemic congestion
(through Na+ & Starling mechanism Microsoft
and edema formation
water retention) PowerPoint Presentation
Increased MVO2
Vasoconstriction Maintain BP in face of reduced CO Increased MVO2
Shunt blood from nonessential Increased afterload decreases stroke
organs to brain and heart volume and further activates the
compensatory responses
Tachycardia and Helps maintain CO Increased MVO2
increased Shortened diastolic filling time
contractility β1-receptor downregulation, decreased
(because of SNS receptor sensitivity
activation) Precipitation of ventricular arrhythmias
Increased risk of myocardial cell death
Ventricular Helps maintain CO Diastolic dysfunction
hypertrophy and Reduces myocardial wall stress Systolic dysfunction
remodeling Decreases MVO2 Increased risk of myocardial cell death
Increased risk of myocardial ischemia
Increased arrhythmia risk
Fibrosis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: 68
http://www.accesspharmacy.com
Precipitating and Exacerbating Factors in HF
 HF patients exist in one of two clinical states.
 When a patient’s volume status and symptoms are
stable, their HF condition is said to be “compensated.”
 In situations of volume overload or other worsening
symptoms, the patient is considered “decompensated.”
 Acute decompensation can be precipitated by numerous
etiologies that can be grouped into cardiac, metabolic,
or patient-related causes

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Drugs that may precipitate or exacerbate HF

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 Clinical Presentation of Chronic HF
 Symptoms___ Dyspnea, particularly on exertion,
orthopnea, PND, exercise intolerance, tachypnea, cough,
fatigue, nocturia, hemoptysis, abdominal pain, anorexia,
nausea, bloating, Poor appetite, early satiety, ascites,
mental status changes, weight gain or loss.
 Signs__ Pulmonary rales, Pulmonary edema, S3 gallop,
cool extremities, Pleural effusion, cheyne-Stokes
respiration, tachycardia, narrow pulse pressure,
cardiomegaly, peripheral edema, jugular venous
distention, hepatojugular reflux, hepatomegaly, venous
stasis changes, lateral displacement of apical impulse

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 Laboratory Tests
 BNP(B-type natriuretic peptide) >100 pg/mL (>29 pmol/L)
 Electrocardiogram may be normal or it could show
numerous abnormalities including acute ST- wave changes
from myocardial ischemia, atrial fibrillation, bradycardia,
left ventricular hypertrophy
 Serum creatinine: it may be increased due to hypoperfusion.
 Complete blood count useful to determine if heart failure
due to reduced oxygen-carrying capacity.
 Chest x-ray: useful for detection of cardiac enlargement,
pulmonary edema, and pleural effusions
 Hyponatremia: serum sodium <130 mEq/L (<130 mmol/L)

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 DX: Framingham criteria
 Major criteria  Minor criteria
 PND  Extremity edema
 Neck vein distension  Night cough
 +ve HJR  Exertional dyspnea
 Bibasal rales  Hepatomegaly
 Cardiomegally  Pleural effusion
 S3 gallop  Tachycardia(≥100)
 Raised JVP

 2 major or 1 major + 2 minor criteria establish clinical DX of

HF

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 Heart Failure Classification
 There are two common systems for categorizing
patients with HF.
1. The New York Heart Association (NYHA)
Functional Classification (FC) system is based on the
patient’s activity level and exercise tolerance.
 It divides patients into one of four classes
 reflects a subjective assessment by a health care
provider and can change frequently over short periods
of time.
 Functional class correlates poorly with EF; however, EF
is one of the strongest predictors of prognosis.
 In general, anticipated survival declines in conjunction
with a decline in functional ability.
75
NYHA Functional Classification
Functional Class
I Pts with cardiac disease but without limitation of physical activity. Ordinary
physical activity does not cause undue fatigue, dyspnea, or palpitation

II Patients with cardiac disease that results in slight limitations of physical

activity. Ordinary physical activity results in fatigue, palpitation, dyspnea, or
angina.

III Patients with cardiac disease that results in marked limitation of physical
activity. Although patients are comfortable at rest, less-than-ordinary
activity will lead to symptoms.

IV Patients with cardiac disease that results in an inability to carry or physical

activity without discomfort. Symptoms of congestive heart failure are
present even at rest. With any physical activity, increased discomfort is
experienced.

76
Heart failure classification
2. The American College of Cardiology/American Heart
Association (ACC/AHA)
 based on the development and progression of the disease.
 placed patient into stages A through D

 Draw back: patients can move between NYHA functional

classes as symptoms improve with treatment, whereas
HF staging does not allow for patients to move to a lower
stage (e.g., patients cannot be categorized as stage C and
move to stage B after treatment

77
The American College of Cardiology/American Heart
Association (ACC/AHA)

78
TREATMENT OF CHRONIC HEART FAILURE
Desired Therapeutic Outcomes

 There is no cure for HF.

 The general management goals for chronic HF include

 preventing the onset of clinical symptoms or

 reducing symptoms, preventing or reducing hospitalizations,

 slowing progression of the disease

 Improving quality of life, and prolonging survival.

79
Treatment algorithm for chronic heart failure.

80
Nonpharmacologic Interventions
 Nonpharmacologic treatment involves

 dietary modifications such as sodium and fluid

restriction

 risk factor reduction including smoking cessation,

 timely immunizations, and

 Supervised regular physical activity.

 Mechanical, Surgical, and Device Therapies

81
 Pharmacologic Therapy: Diuretics
 The primary rationale for the use of diuretic therapy is to maintain
euvolemia in symptomatic or stages C and D heart failure
 However, do not prolong survival and alter disease progression,
and therefore not considered as mandatory therapy.
 In milder HF, diuretics may be used on an as-needed basis.
 However, once the development of edema is persistent, regularly
scheduled doses will be required.
 Diuretic therapy is usually initiated in low doses in the outpatient
setting, with dosage adjustments based on symptom
assessment and daily body weight.
 diuretics are relatively contraindicated in persons who are volume
depleted or have compromised renal blood flow.
 The concept of ceiling doses for loop diuretics should be
understood.
82
Loop diuretics

The maximal response to diuretics is reduced in HF, creating a “ceiling dose” above
which there is limited added benefit.
83
 ACEIs
 Cornerstone of pharmacotherapy for patients with SHF
 Deleterious effects of angiotensin II and aldosterone blocked
 Improve survival by 20% to 30% compared with placebo.
 Prevent the development of HF and reduce cardiovascular risk
 ACE inhibitors improve symptoms, slow disease progression,
and decrease mortality in patients with HF and reduced LVEF
(Stage C) is unequivocal
 The benefits of ACE inhibitor therapy are independent of the
etiology of HF (ischemic vs. non-ischemic) and are observed in
patients with mild, moderate, or severe symptoms.
 ACE inhibitors administered after MI improve overall survival,
decrease development of severe HF, and reduce reinfarction and
HF hospitalization rates.
84
 ACEIs
 ACE inhibitors should be prescribed to all patients with HF due
to left ventricular systolic dysfunction (LVEF) unless they have a
contradiction to their use or have been shown to be unable to
tolerate treatment with these drugs
 ACE inhibitors should be initiated using low doses and titrated
up to target doses over several weeks depending on tolerability
(adverse effects and blood pressure)
 Higher doses of ACEI may reduce the risk of hospitalization,
but not mortality, compared with lower doses.
 However, clinicians should attempt to use ACE inhibitor doses
proven beneficial in clinical trials.

85
Dosing and Monitoring for Neurohormonal Blocking Agents

86
 Hydralazine and Isosorbide Dinitrate
 Complementary hemodynamic actions originally led to the
combination of nitrates with hydralazine.
 Nitrates reduce preload by causing primarily venous vasodilation
through activating guanylate cyclase and a subsequent increase in
cyclic guanosine monophosphate (cGMP) in vascular smooth
muscle.
 Hydralazine reduces afterload through direct arterial smooth
muscle relaxation via an unknown mechanism.
 The beneficial effect of an external nitric oxide source may be
more apparent in the African-American population, which
appears to be predisposed to having an imbalance in nitric oxide
production
 In addition, hydralazine may reduce the development of nitrate
tolerance when nitrates are given chronically
87
 Beta-Adrenergic Antagonists
 They reduce morbidity and mortality in patients with SHF__
carvedilol, metoprolol succinate (CR/XL), and bisoprolol.
 should be used in all stable patients with HF and a reduced left
ventricular EF in the absence of contraindications or a clear
history of β-blocker intolerance
 Patients should receive a β-blocker even if their symptoms are
mild or well controlled with diuretic and ACE inhibitor therapy.
 Importantly, it is not essential that ACE inhibitor doses be
optimized before a β-blocker is started because the addition of
a β-blocker is likely to be of greater benefit than an increase in
ACE inhibitor dose.
 β-blocker therapy is expected to positively influence disease
progression and survival even if there is little to no symptomatic
improvement.
88
 Beta-Adrenergic Antagonists
 In addition to improving survival, β-blockers have been shown to
improve:
 all-cause hospitalization
 reductions in hospitalizations for worsening HF
 increases in LVEF of 5 to 10 units
 β-Blockers have also been shown to decrease ventricular mass,
improve the sphericity of the ventricle, and reduce systolic and
diastolic volumes (left ventricular end-systolic volume and
LVEDV)___ Reverse remodelling.
 In the absence of more compelling evidence, ACE inhibitors
should be started first in most patients.

89
 Beta-Adrenergic Antagonists
 Initiating a β-blocker first may be advantageous for patients with:
 evidence of excessive SNS activity (e.g., tachycardia) and
 renal function or potassium concentrations preclude starting
an ACE inhibitor (or ARB) at that time.
 Anti-arrhythmic effects, attenuating or reversing ventricular
remodeling.
 β-Blockers should be initiated in stable patients who have no or
minimal evidence of fluid overload.
 To minimize the likelihood for acute decompensation, β-blockers
should be started in very low doses with slow upward dose
titration.
 β-Blocker doses should be doubled no more often than every 2
weeks
90
 Beta-Adrenergic Antagonists
 In patients with HFpEF, β-blockers may help to lower and maintain
low pulmonary venous pressures by decreasing HR and increasing
the duration of diastole
 Tachycardia is poorly tolerated in patients with HFpEF for several
reasons.
 rapid HRs cause an increase in myocardial oxygen demand and
a decrease in coronary perfusion time.
 incomplete relaxation between cardiac cycles may result in an
increase in diastolic pressure relative to volume.
 rapid rate reduces diastolic filling time and ventricular filling

91
92
 Aldosterone Antagonists
 Currently, the aldosterone antagonists available are
spironolactone and eplerenone.
 Both agents are inhibitors of aldosterone that produce weak
diuretic effects while sparing potassium concentrations.
 Eplerenone is selective for the mineralocorticoid receptor and
hence does not exhibit the endocrine adverse-effect profile
commonly seen with spironolactone.
 The initial rationale for specifically targeting aldosterone for
treatment of HF was based on the knowledge that ACE inhibitors
do not suppress the chronic production and release of
aldosterone.
93
 Aldosterone Antagonists
 The major risk related to aldosterone antagonists is

 hyperkalemia

 Renal failure

 Gynecomastia ( spironolactone)

 Eplerenone is a CYP3A4 substrate and should not be used

concomitantly with strong inhibitors of 3A4

94
 Digoxin
 Digoxin exerts positive inotropic effects through binding to
sodium- and potassium activated adenosine triphosphatase (ATP)
pumps, leading to increased intracellular sodium concentrations
and subsequently more available intracellular calcium during
systole.
 Neurohormonal effects( restore baroreceptor sensitivity)
 Digoxin was shown to decrease HF-related hospitalizations but
did not decrease HF progression or improve survival

95
Clinical Pharmacokinetics of Digoxin

96
 Acute and Advanced Heart Failure
 The phrase “acute heart failure” (AHF) is used to signify either an
acute decompensation of a patient with a history of chronic heart
failure or to refer to a patient presenting with new-onset HF
symptoms
 Clinical presentation
 Patients with AHF present with symptoms of worsening fluid
retention or decreasing exercise tolerance and fatigue (typically
worsening of symptoms presented in the chronic heart failure
clinical presentation

97
PRINCIPLES OF THERAPY BASED ON
HEMODYNAMIC SUBSETS

98
PRINCIPLES OF THERAPY BASED ON
HEMODYNAMIC SUBSETS

99
PRINCIPLES OF THERAPY BASED ON
HEMODYNAMIC SUBSETS

100
Diagnosis : Exacerbating or Precipitating Factors
in Heart Failure

101
 Treatment of Acute Heart Failure
 The goals of therapy for AHF are to:
 correct the underlying precipitating factor(s);
 relieve the patient’s symptoms;
 improve hemodynamics;
 optimize a chronic oral medication regimen; and
 educate the patient, reinforcing adherence to
lifestyle modifications and the drug regimen.

102
 PHARMACOTHERAPY

 Diuretics: IV loop diuretics

 Positive Inotropic Agents: Dobutamine, Milrinone,
Dopamine
 Vasodilators:
 Nitroprusside, Sodium nitroprusside
 Nitroglycerin

103
Usual Hemodynamic Effects of Commonly Used
Intravenous Agents for Treatment of Acute or
Severe Heart Failure

104
Usual Doses and Monitoring of Commonly Used
Hemodynamic Medications

105
3. Ischemic Heart Disease(IHD)
Learning Objectives
 Upon completion of the chapter, you will be able
to:
 Identify risk factors for the development of IHD
 Recognize the symptoms and diagnostic criteria of IHD
 Pathophysiology of IHD
 Identify the treatment goals of IHD and appropriate
 Design an appropriate therapeutic regimen for the
management of IHD
 Formulate a monitoring plan to assess effectiveness and
adverse effects of an IHD drug regimen.

107
Ischemic Heart Disease (IHD)
 Also called Coronary Heart disease (CHD) or Coronary Artery
Disease(CAD)
 Ischemia
 lack of oxygen and decreased or no blood flow in the myocardium
 Common clinical manifestations of IHD
 Chronic stable angina
 Acute coronary syndromes (ACS)
 Angina pectoris is discomfort in the chest that occurs when
the blood supply to the myocardium is compromised.
 Chronic stable angina
 chronic and predictable occurrence of chest discomfort due to
transient myocardial ischemia with physical exertion or other
conditions that increase oxygen demand.

108
109
 IHD: Etiology
Type Comments
Atherosclerosis Most common cause.
Risk factors: HTN, hypercholesterolemia, DM, smoking, family
history of atherosclerosis
Spasm Coronary artery vasospasm can occur in any population but is most
prevalent in Japanese.
Vasoconstriction appears to be mediated by histamine, serotonin,
catecholamines, and endothelium-derived factors. Because spasm can
occur at any time, the chest pain is often not exertion-related.
Emboli Rare cause of coronary artery disease. Can occur from vegetations in
patients with endocarditis.
Congenital Congenital coronary artery abnormalities are present in 1 to 2% of the
population. However, only a small fraction of these abnormalities
cause symptomatic ischemia.

110
IHD: Risk Factors

111
 IHD: Pathophysiology
 Results from an imbalance between myocardial oxygen supply
and oxygen demand
 Usually caused by atherosclerosis in one or more of the epicardial
coronary arteries
 If the size of the atherosclerotic plaque obscures
 <50% of the diameter of the vessel, the patient is pain free
 ≥70% of the artery, the patient may begin to experience angina during
activities that increase myocardial oxygen demand
 i.e., chronic stable angina

 The hallmark feature in the pathophysiology of chronic stable

angina is an established atherosclerotic plaque that impedes
coronary blood flow
 Atherosclerotic plaque rupture with subsequent thrombus
formation is the hallmark feature in the pathophysiology of
unstable angina and MI 112
Clinical Presentation And Diagnosis
 General
 Patients with chronic stable angina will generally be in no acute distress.

 Symptoms of Angina Pectoris

 Patients typically describe pain as a sensation of pressure, heaviness, or
squeezing in the anterior chest area.
 Pain may radiate to the neck, jaw, shoulder, back, or arm.
 Pain usually lasts from 0.5 to 30 minutes often with a visceral quality
(deep location)
 Precipitating factors include exercise, cold environment, walking after a
meal, emotional upset, fright, anger, and coitus.
 Relief occurs with rest and nitroglycerin

113
114
 Diagnostic Tests
 Electrocardiogram(ECG)
 ST-segment depression >2 mm
 T-wave inversion
 Precipitating Factors
 Mild, moderate, or heavy exercise, depending on patient
 Effort that involves use of arms above the head
 Cold environment
 Walking against the wind
 Walking after a large meal
 Emotions: fright, anger, or anxiety
 Coitus

115
116
 IHD: Treatment
Desired Outcome
 Short-term goals
 To reduce or prevent the symptoms of angina that limit
exercise capability
 To impair quality of life

 Long-term goals
 To prevent CHD events such as MI, arrhythmias, HF

 To extend the patient’s life

 Primary prevention of IHD through the identification and

modification of risk factors prior to the initial morbid event
would be the optimal management approach

117
 Treatment: Stable IHD(Exertional AP)
 The current guidelines recommend that all patients be given the
following unless contraindications exist:
1. Aspirin
2. β-blockers with prior MI
3. ACEI to patients with CAD and diabetes or LV systolic dysfunction
4. LDL-lowering therapy with CAD and an LDL >130 mg/dL
5. Sublingual nitroglycerin for immediate relief of angina
6. Calcium antagonists or long-acting nitrates for reduction of
symptoms when β-blockers are contraindicated
7. Calcium antagonists or long-acting nitrates in combination with β-
blockers when initial treatment with β-blockers is not successful
8. Calcium antagonists or long-acting nitrates as a substitute for β-
blockers if initial treatment with β-blockers leads to unacceptable
side effects

118
Recommendations for Medical Therapy to Prevent
MI and Death[1]
 Antiplatelet therapy with Aspirin 75 to 162 mg daily
 Should be continued indefinitely in the absence of contraindications
 Clopidogrel is a reasonable alterative when aspirin is contraindicated.
 Aspirin 75 to 162 mg daily and clopidogrel 75 mg daily might be
reasonable in certain high-risk patients with SIHD.
 Dipyridamole is not recommended as antiplatelet therapy for patients
with SIHD
 β-Blocker therapy
 Should be started for all pts with
 Normal LV function after MI or an ACS for 3 years,
 LVEF ≤40% with HF or prior MI unless contraindicated
 Considered as chronic therapy for all other patients with CAD or
other vascular disease
 Only carvedilol, metoprolol succinate, and Bisoprolol
119
Recommendations for Medical Therapy to Prevent
MI and Death[2]
 Angiotensin Converting Enzyme Inhibitors (ACEIs)
 Should be used in all patients with SIHD who also have HTN,
DM, LVEF ≤40%, or CKD unless contraindicated
 Angiotensin Receptor Blockers (ARBs)
 Can be substituted for ACEI intolerance
 Annual influenza vaccine is recommended for pts with SIHD

120
121
 Recommendations for Medical Therapy for the
Relief of Symptoms for SIHD
 All of the following are Class I recommendations:
 β-Blockers should be prescribed as initial therapy
 CCB or long-acting nitrates should be prescribed for the
relief of symptoms when β-blockers are contraindicated or
cause unacceptable adverse effects.
 CCB or long-acting nitrates, in combination with β-blockers,
should be prescribed for relief of symptoms when initial
treatment with β-blockers is unsuccessful
 Sublingual (SL) nitroglycerin or Nitroglycerin spray is
recommended for immediate relief of angina in patients
with SIHD

122
Nonpharmacologic Therapy
1. Revascularization[PCI, CABG)
 The decision to undertake PCI(Primary Coronary Intervention)
or CABG(Coronary artery bypass grafting) for revascularization
is based on the extent of coronary disease (number of vessels
and location/amount of stenosis) and ventricular function

123
 Pharmacologic Therapy
 β-Adrenergic blocking agents
 First-line drug in chronic angina requiring daily maintenance
therapy
 ↓ HR, ↓ contractility, and a slight to moderate ↓ in BP →↓ in
oxygen demand for effort induced angina
 But do not improve oxygen supply
 Blunt reflex tachycardia from nitrate therapy
 making this a common and useful combination therapy

 Ideal candidates for β-blockers include:

 Pts in which physical activity precipitates their anginal attacks
(exertional angina)
 Pts with coexistent HTN, history of supraventricular
arrhythmias or post-MI angina.
 Pts with severe angina, rest angina, or variant angina may be
better treated with CCBs or long-acting nitrates 124
125
Nitrates
 For alleviation of acute anginal attacks (oral and IV
routes).

126
 Potential mechanisms of action of nitrates
 reduction of MVO2 secondary to venodilation and arterial–
arteriolar dilation, leading to a reduction in wall stress from
reduced ventricular volume and pressure
 Systemic venodilation also promotes increased flow to deep
myocardial muscle.
 Pharmacokinetic common to the organic nitrates
 Large first-pass hepatic metabolism_ short to very short half-lives
(except for ISMN),
 Large volumes of distribution and high clearance rates
 Nitrate therapy may be used:
 To terminate an acute anginal attack
 To prevent effort or stress induced attacks or
 for long-term prophylaxis, usually in combination with β-blockers
or CCB

127
 SL nitroglycerin 0.3 to 0.4 mg will relieve pain in about 75% of
patients within 3 minutes, with another 15% becoming pain-
free in 5 to 15 minutes.
 NOTE: Pain persisting beyond about 20 to 30 minutes following
the use of two or three nitroglycerin tablets is suggestive of ACS
and the patient should be instructed to seek emergency aid
 Keep nitroglycerin in original tightly closed container
 Nitrates may be combined with other drugs(like BB, CCB)
 Chronic prophylactic therapy
 pts with more frequent or Sxs not responding to β-blockers alone
(nitrates plus β-blockers or calcium blockers)
 in pts intolerant of β-blockers or CCBs
 pts having an element of vasospasm leading to decreased supply
(nitrates plus calcium blockers)

128
 Good candidates for CCB in angina include patients with:
 contraindications or intolerance of β-blockers,coexisting
 conduction system disease (except for verapamil and diltiazem)
 Prinzmetal’s angina (vasospastic or variable threshold angina)
 PVD
 Severe ventricular dysfunction (amlodipine is probably CCB of choice)
 Concurrent HTN
 Tolerance with nitrate therapy
 To minimize tolerance is to provide a daily nitrate-free interval of 6 to 8
hours.
 Example: ISDN should not be used more often than three times per
day if tolerance is to be avoided
• Adverse effects of nitrates:
 Postural hypotension with associated CNS symptoms
 Headaches and flushing secondary to vasodilation
 Occasional nausea from smooth muscle relaxation 129
 Coronary Artery Spasm and Variant Angina
Pectoris (Prinzmetal’s Angina).
 Patients are usually younger and have fewer coronary risk factors
 commonly smoke than patients with chronic stable angina.
 The onset of chest discomfort is usually in the early morning hrs.
 Hyperventilation, exercise, and exposure to cold may precipitate
variant angina attacks.
 The exact cause of is not well understood, but it may be:
 imbalance between vasodilator factors (prostacyclin, nitric
oxide) and vasoconstrictor factors (e.g., endothelin,
angiotensin II)
 genetic mutation

130
 The diagnosis of variant angina is based on ST-segment
elevation during transient chest discomfort (usually at rest) that
resolves when the chest discomfort diminishes.
Variant angina therapy:
1. Nitrates __SL nitroglycerin or ISDN
 They have been the mainstay of therapy for the acute
attacks of variant angina and coronary artery spasm
 IV and intracoronary nitroglycerin may be very useful for
patients not responding to SL preparations.
 high doses are often required
2. Calcium antagonists-Nifedipine, verapamil, and diltiazem
 may be more effective, have few serious adverse effects in
effective doses, and can be given less frequently than nitrates

131
 Evaluation of therapeutic outcomes
 Improved symptoms of angina, improved cardiac performance,
and improvement in risk factors may all be used to assess the
outcome of treatment of IHD and angina.
 Symptomatic improvement in exercise capacity (longer
duration) or fewer symptoms at the same level of exercise is
subjective evidence that therapy is working.
 Once patients have been optimized on medical therapy,
symptoms should improve over 2 to 4 weeks and remain stable
until their disease progresses

132
Learning Objectives
 Upon Completion of The Unit, You Will Be Able To:
 Define the role of an atherosclerotic plaque, platelets, and
coagulation system in an ACS
 List key ECG and clinical features identifying a patient with
NSTE- ACS who is at high risk of MI or death.
 Devise a pharmacotherapy treatment & monitoring plan
for a patient with ACS
 Devise a pharmacotherapy and risk-factor modification
treatment plan for secondary prevention of ACS

134
Introductory Case
 SD is a 55-year-old, 85 kg (187 lb) male who developed chest tightness while in a
store in Sun Valley, Idaho, after 4 hours of skiing. SD developed substernal
chest tightness at 20:30 hours that radiated into his left arm following an
altercation with another patron in the men’s room.
 He became short of breath and diaphoretic. Local paramedics were summoned
and he was given three 0.4 mg sublingual nitroglycerin tablets by mouth, 325
mg aspirin by mouth, and 5 mg metoprolol IV push without relief of chest
discomfort. SD presented to St. Matthew’s Hospital in Sun Valley at 21:15 hours.
St. Matthew’s does not have a cardiac catheterization laboratory and transport
time to St. Matthew’s in Boise is 1.5 hours door to door via air transport.
 PMH
 Hypertension (HTN) × 10 years, Dyslipidemia × 6 months
 Two-vessel coronary artery disease (60% right coronary artery [RCA] and
80% left anterior descending artery [LAD] occlusion) after intracoronary
CYPHERTM stent placement to the mid-LAD artery lesion 10 months ago.

135
Introductory Case
 SH: Smoked 1 pack per day × 30 years, quit 10 weeks ago
 Meds: Metoprolol 25 mg by mouth twice daily, ASA 325 mg by mouth once
daily, Lovastatin 20 mg by mouth once daily at bedtime and Enalapril 5 mg by
mouth once daily
 PE: Lungs: rales bilaterally
 ECG: 3 mm ST-segment elevation anterior leads
 CXR: congestive heart failure, borderline upper normal heart size
 Echocardiogram:
 hypocontractile left ventricle, akinesis of anterior apical wall, ejection
fraction 20%
 Then:
 What information is suggestive of acute MI?
 What complications of MI are present?

136
Introduction
 ACS, including unstable angina (UA) and myocardial
infarction (MI), are a form of coronary heart disease (CHD)
that comprises the most common cause of CVD death
 The cause of an ACS is the rupture of an atherosclerotic plaque
with subsequent platelet adherence, activation, and
aggregation and the activation of the clotting cascade.
 Ultimately, a clot forms composed of fibrin and platelets
 Each year, more than 1.1 million Americans will experience an
ACS, and 150,000 die of an MI
 Etiology
 The predominant cause of ACS in more than 90% of patients is
atheromatous plaque rupture, fissuring, or erosion of an unstable
atherosclerotic plaque that occludes less than 50% of the
coronary lumen prior to the event.
 Stable stenoses are characteristic of stable angina (>70%
occlusion)
137
Pathophysiology
 ACS results primarily from diminished myocardial blood flow
secondary to an occlusive or partially occlusive coronary artery
thrombus
 ACS are classified according to electrocardiogram (ECG)
changes into
 STE ACS (STE MI) or
 NSTE ACS (NSTE MI and Unstable angina)

Unstable Angina NSTEMI STEMI

Symptoms present + + +
ECG changes None ST segment depression, T ST segment
wave inversion, or no elevation
changes
Biochemical marker No changes Increased troponins & CK ↑ed troponins
MB & CK MB

138
Pathophysiology
 Plaque Rupture & Clot Formation
 > 90% of ACSs caused by rupture/erosion of an atherosclerotic
plaque
 Exposure of collagen & tissue factor from the plaque induces
platelet adhesion & activation
 which promote the release of platelet-derived vasoactive substances
including adenosine diphosphate (ADP) and thromboxane A2 (TXA2).
 These produce vasoconstriction and potentiate platelet activation
 Platelet activation: changes on platelet glycoprotein (GP
IIb/IIIa )receptors lead to formation of fibrin bridges
 inclusion of many platelets creates “white” clots
 more common in NTSE ACS
 incomplete artery occlusion

139
Pathophysiology
 Coagulation cascade activated: fibrin traps RBCs
 clots have red appearance
 more common in STE ACS
 more likely to completely occlude vessels
 Myocardial ischemia can result from microthrombi embolization
& lead to necrosis
 Ventricular Remodeling
 Changes in size, shape & function of the left ventricle→ HF
 ACE inhibitors, ARBs, β-blockers, aldosterone antagonists
 slow down or reverse remodeling
 improve chance of survival

140
Complications
 Cardiogenic shock:
 5 to 6% of STEMI pts and 2% of NSTE ACS and
 mortality rate: 60%
 Others:
 Heart failure, valve dysfunction, arrhythmias, heart block,
pericardititis, stroke, VTE, LV free-wall rupture

141
Clinical Presentation and Diagnosis[1]
 Symptoms
 The patient is typically in acute distress and may present with
cardiogenic shock
 The classic symptom of ACS is midline anterior chest discomfort.
 Accompanying symptoms may include arm, back, or jaw pain,
nausea, vomiting, or shortness of breath.
 Severe new-onset or ↑ing angina > 20 minutes
 Patients less likely to present with classic symptoms include
elderly patients, diabetic patients, and women.
 Signs
 No signs are classic for ACS
 However, patients with ACS may present with signs of
 Acute HF: JVD and S3 sound on auscultation
 Arrhythmias: tachycardia, bradycardia, or heart block
142
Clinical Presentation and Diagnosis[2]
 Laboratory Tests
 Biochemical Markers
 Evaluate troponin & CK MB to confirm MI
 3 measurements taken over the 1st 12 to 24 hrs
 MI diagnosis:
 > 1 one troponin value greater than MI decision limit set by lab or
 2 CK MB values greater than MI decision limit set by lab
 Other Lab tests
 Blood chemistry tests mainly potassium and magnesium, which may
affect heart rhythm.
 SCr and CrCl measurement to identify patients who may need dosing
adjustments for some medications
 Baseline CBC and coagulation tests (aPTT and INR), as most patients will
receive antithrombotic therapy
 Fasting lipid panel

143
144
Clinical Presentation and Diagnosis[3]
 Other Diagnostic Tests
 ECG: Key findings indicating myocardial damage
 ST-segment elevation
 ST-segment depression
 T-wave inversion
 Risk Stratification
 Treat STEMI patients as fast as possible
 NST ACS patients stratified based on clinical
presentation, lab findings
 Risk categories: high, medium, low
 TIMI: Thrombolysis In Myocardial Infarction
 Treatment based on TIMI score
145
 TIMI Risk Score for Non–ST-Segment Elevation Acute Coronary Syndromes

Past Medical History Clinical Presentation

Age >65 years ST-segment depression (>0.5 mm)
>3 Risk factors for CAD >2 episodes of chest discomfort in the past 24 hrs
Hypercholesterolemia Positive biochemical marker for infarctiona
HTN
DM
Smoking
Family Hx of premature CHD
50% stenosis of coronary artery)
Use of aspirin within the past 7 days
Using the TIMI Risk Score
One point is assigned for each of the seven medical history and clinical presentation findings. The score (point)
total is calculated, and the patient is assigned a risk for experiencing the composite end point of death, myocardial
infarction or urgent need for revascularization as follows:
High Risk Medium Risk Low Risk
TIMI risk score 5–7 points TIMI risk score 3–4 points TIMI risk score 0–2 points

aTroponin I, troponin T, or creatinine kinase MB greater than the MI detection limit. 146
Treatment: Desired Outcome
 Short-term desired outcomes in a patient with ACS are:
 Early restoration of blood flow to the infarct-related artery to
prevent infarct expansion (in the case of MI) or prevent complete
occlusion and MI (in unstable angina)
 prevention of death and other complications
 prevention of coronary artery reocclusion; and
 relief of ischemic chest discomfort
 Long-term desired outcomes
 control of risk factors
 prevention of additional cardiovascular events, and
 improvement in quality of life

147
General Approach to Treatment
 All STE MI and high- and intermediate-risk NSTE ACS
1. Admission to hospital and oxygen administration (if
oxygen saturation is low, less than 90%),
2. Continuous multilead ST-segment monitoring for
arrhythmias and ischemia,
3. Frequent measurement of vital signs
4. Bed rest for 12 hours in hemodynamically stable patients,
5. Avoidance of the Valsalva maneuver (prescribe stool
softeners routinely)
6. pain relief

148
Non-pharmacologic Therapy
 Primary Percutaneous Coronary Intervention(PCI) for STE
MI
 Early reperfusion therapy with primary PCI of the infarct
artery within 90 minutes of first medical contact is the
reperfusion treatment of choice for patients presenting with
STE MI who present within 12 hours of symptom onset.
 PCI in High risk NST ACS patients
 Coronary angiography with either PCI or coronary artery
bypass graft (CABG) surgery revascularization as an early
treatment (early invasive strategy) for patients with NSTE
ACS at an elevated risk for death or MI, including those with
a high risk score or patients with refractory angina, acute HF,
other symptoms of cardiogenic shock, or arrhythmias

149
Early Pharmacotherapy for STE MI
 The first day of hospitalization, and preferably in the emergency
department.
 Intranasal oxygen (if oxygen saturation is low, <90%))
 sublingual (SL) nitroglycerin (NTG),
 ASA,
 Anticoagulant, and Fibrinolysis in eligible candidates
 Morphine is administered to patients with refractory angina as an
analgesic and a venodilator that lowers preload, but it does not
reduce mortality
 Oral β-blockers should be initiated within the first day in patients
without contraindications like cardiogenic shock
 ACE inhibitor should be started within 24 hours of presentation,
particularly in patients who have either an anterior wall MI or with
LVEF ≤40% and no contraindications.

150
Fibrinolytic Therapy
 Indicated in patients with STE MI:

 Eligible patients should be treated as soon as possible, but preferably within

30 minutes from the time they present to the emergency department, with
one of the following regimens:
 Alteplase: 15-mg IV bolus followed by 0.75-mg/kg infusion (maximum 50
mg) over 30 minutes, followed by 0.5-mg/kg infusion (maximum 35 mg) over 60
minutes (maximum dose 100 mg).
151
 The mortality benefit of fibrinolysis is highest with early
administration and diminishes after 12 hours.
 The use of fibrinolytics between 12 and 24 hours after symptom
onset should be limited to patients with ongoing ischemia.
152
Aspirin
 Preferred anti-platelet agent in the treatment of all ACSs
 ASA administration within 24 hours before or after hospital
arrival is a quality performance measure for MI.
 In patients receiving fibrinolytics, ASA reduces mortality, and
its effects are additive to fibrinolysis alone.
 For STE MI recommend an initial ASA dose of 162 to 325 mg
 The first dose can be chewed in order to achieve high blood
concentrations and platelet inhibition rapidly
 Although the risk of major bleeding, particularly GI-bleeding,
appears to be reduced by using lower doses of aspirin, low-
dose aspirin, taken chronically, is not free of adverse effects.
 Patients should be counseled on the potential risk of bleeding.
 Aspirin therapy should be continued indefinitely

153
Anticoagulants
 For patients undergoing primary PCI, either UFH or
bivalirudin is preferred,
 Whereas for fibrinolysis, UFH, enoxaparin, or fondaparinux
may be administered.
 For patients undergoing PCI, anticoagulation is discontinued
immediately following the PCI procedures.
 In patients receiving an anticoagulant plus a fibrinolytic, UFH
is continued for a minimum of 48 hours and if either
enoxaparin or fondaparinux is selected, those agents are
continued for the duration of hospitalization, up to 8 days.
 Anticoagulant therapy should be initiated in the emergency
department and continued for at least 48 hours in selected
patients who will be bridged over to receive chronic warfarin
anticoagulation following acute MI
154
Anticoagulants

155
β-Blockers
 A β-blocker should be administered early in the care of patients
with STE MI and continued indefinitely
 reduce the risk for recurrent ischemia, infarct size, risk of re-
infarction, and occurrence of ventricular arrhythmias in the
hours and days following MI
Statins
 A high-intensity statin (either atorvastatin 80 mg or
rosuvastatin 40 mg) should be administered to all patients
prior to PCI (regardless of prior lipid-lowering therapy) to
reduce the frequency of periprocedural MI following PCI.

156
Nitrates
 One SL NTG tablet should be administered every 5 minutes for
up to three doses in order to relieve myocardial ischemia.
 IV NTG should then be initiated in all patients with an ACS
who have persistent ischemia, HF, or uncontrolled high BP in
the absence of contraindications.
 IV NTG should be continued for approximately 24 hours after
ischemia is relieved
Calcium Channel Blockers
 used for relief of ischemic symptoms in patients who have
certain contraindications to β-blockers.
 No clinical outcomes beyond symptom relief
 should be avoided in the acute management of all ACSs unless
there is a clear symptomatic need or a contraindication to β-
blockers
157
 Early Pharmacotherapy for NSTE ACSs
 Similar to that of STE MI, in the absence of contraindications,
all patients with NSTE ACS should be treated in the emergency
department with:
 Intranasal oxygen (if oxygen saturation is low),
 SL NTG, ASA, and an anticoagulant
 Oral β-blockers should be initiated within the first 24 hours in
patients without cardiogenic shock.
 Morphine is administered to patients with refractory angina
 Fibrinolytic therapy is never administered because increased
mortality has been reported with fibrinolytics compared with
controls

158
Aspirin
 ASA reduces the risk of death or developing MI by about 50% in
patients with NSTE ACS__ ASA remains the cornerstone of early
treatment for all ACS.
 Low-dose ASA is continued indefinitely.
Anticoagulants
 For patients treated by an early invasive strategy, UFH,
enoxaparin, or bivalirudin should be administered.
Nitrates
 SL NTG followed by IV NTG should be administered to patients
with NSTE ACS and ongoing ischemia, HF, or uncontrolled high
BP.

159
β-Blockers
 oral β-blockers should be initiated within 24 hours of hospital
admission to all patients in the absence of contraindications.
 Similar benefit as STE MI.
 β-Blockers are continued indefinitely in patients with LVEF less
than or equal to 40% (0.40) and for at least 3 years in patients
with normal LV function.
Calcium Channel Blockers
 Second-line treatment for pts with certain contraindications
to β-blockers and those with continued ischemia despite β-
blocker and nitrate therapy.
 either diltiazem or verapamil preferred unless the patient has
LV systolic dysfunction, bradycardia, or heart block,
 amlodipine or felodipine is preferred.
 Nifedipine is contraindicated.
160
 Secondary Prevention Following MI
 The long-term goals following MI are to
o control modifiable CHD risk factors;
o prevent the development of systolic HF;
o prevent recurrent MI and stroke;
o prevent death, including sudden cardiac death; and
o prevent stent thrombosis following PCI
o Pharmacotherapy that has been proven to decrease mortality,
heart failure, reinfarction, or stroke should be initiated prior to
hospital discharge for secondary prevention
 Following MI from either STE or NSTE ACS, patients should
receive indefinite treatment with
 Aspirin, β-blocker, ACEIs and “high-intensity” statin
 Warfarin in selected patients
161
A β- blocker should be continued for:
 at least 3 years in patients without HF or EF < 40%
 indefinitely in pts with LVS dysfunction or HF symptoms
 β-blockers should be avoided in patients with decompensated HF
 Initiation of β-blockers prior to hospital discharge is safe in these
patients once heart failure symptoms have resolved
Calcium Channel Blockers
 In Contraindication to a β- blocker, a calcium channel blocker
can be used to prevent angin symptoms but should not be used
routinely in the absence of such symptoms
ACE Inhibitors
 The largest reduction in mortality is observed for patients with
LV dysfunction (low LVEF) or heart failure symptoms.
 In patients with LV dysfunction, administration should
continue indefinitely
162
Anticoagulants
 Anticoagulation with Warfarin should be considered in selected
patients following an ACS
 Pts with an LV thrombus, pts demonstrating extensive ventricular
wall-motion abnormalities on cardiac echocardiogram, and pts
with a Hx of thromboembolic disease or chronic atrial fibrillation
 warfarin therapy targeted to INR <2 cannot be recommended
for secondary prevention of CHD events following MI.
Aspirin
 ↓es the risk of death, recurrent MI, and stroke following MI
 An aspirin prescription at hospital discharge is a quality care
indicator in MI patients
 Should be given indefinitely to all patients, or clopidogrel to
patients with a contraindication to aspirin
 After an initial dose of 325 mg, chronic therapy with aspirin
should be 75 to 81 mg once daily.
163
Lipid-Lowering Agents
 Following MI, statins reduce total mortality, CV mortality, and
stroke
 All pts with CAD should receive dietary counselling and a statin
in order to reach a LDL < 100 mg/dL

 Evaluation of Therapeutic Outcomes

Monitoring parameters for efficacy of therapy include:
 relief of ischemic discomfort
 return of ECG changes to baseline
 absence or resolution of heart failure signs

164
 Learning Objectives
 Upon completion of the chapter, u will be able to:
 Identify risk factors and signs and symptoms of deep vein
thrombosis and pulmonary embolism.
 Determine a patient’s relative risk (low, moderate, high, or
very high) of developing venous thrombosis.
 Formulate an appropriate prevention strategy for a patient at
risk for deep vein thrombosis.
 Formulate an appropriate treatment plan for a patient who
develops a deep vein thrombosis or pulmonary embolism

166
 Venous Thromboemblism(VTE)
 Results from clot formation in the venous circulation
 Manifested as deep vein thrombosis (DVT) and pulmonary
embolism (PE)
 DVT is a thrombus composed of cellular material (red and white
blood cells, platelets) bound together with fibrin strands.
 PE is a thrombus that arises from the systemic circulation and lodges
in the pulmonary artery causing complete or partial obstruction of
pulmonary blood flow.
 ETIOLOGY
 A number of factors increase the risk of developing VTE (Table 1).
 These risk factors are additive and can be identified easily in clinical
practice.
167
168
 Pathophysiology
 Originates as a platelet nidus in the region of venous valves located
in the veins of the lower extremities.
 Further growth occurs by accretion of platelets and fibrin and
progression to red fibrin thrombus, which may either break off and
embolize or result in total occlusion of the vein
 Three primary components—venous stasis, vascular injury, and
hypercoagulability (Virchow’s triad)
 play a role in the development of a pathogenic thrombus

169
Virchows Triad

170
 Clinical Finding
1. DVT
 Leg pain and Swelling
 Unequal Leg Measurements
 Red or Warm Leg
 Dilated Veins
2. PE
 Unexplained dyspnea,
Tachypnea, or Tachycardia
 Cough and hemoptysis,pleurisy
and friction rub – Small emboli
 S3 and/or S4 gallop, Cyanosis-
massive PE
171
 Diagnosis
Non imaging Modalities
 Blood Test – D-dimer, ABG, cardiac biomarkers
 ECG
Diagnostic tests of DVT :
 duplex ultrasonography (most common)
 venography or phlebography (gold standard)
Diagnostic tests of PE :
 ventilation-perfusion (V/Q) & computerized tomography (CT)
scans are most common
 pulmonary angiography (gold standard)

172
 Complications of VTE
 Postthrombotic syndrome (a long-term complication of DVT caused
by damage to venous valves) may produce chronic lower extremity
swelling, pain, tenderness, skin discoloration, and ulceration.
 Recurrent VTE
 Chronic thromboembolic pulmonary hypertension
 Right Ventricular Failure
 Sudden Death

173
 Treatment of VTE
Desired Therapeutic Outcomes
 Short-term Goals (i.e., the first few days to 6 months)
 Prevent propagation of the clot, embolization, and death
 Long-term Goals(i.e., more than 6 months after the first event)
 Prevent complications of VTE
General Approach to the Treatment of VTE
 Anticoagulation therapy remains the mainstay of treatment for VTE
 The standard approach is to initiate therapy with UFH by
continuous intravenous infusion or a LMWH by subcutaneous
injection and to make the transition to warfarin for maintenance
therapy
 In rare circumstances the use of venous thrombectomy or
thrombolysis can be considered
174
175
176
177
178
 Unfractionated Heparin (UFH)
 Heterogeneous mixture of sulfated glycosaminoglycans
 Molecular weight of UFH molecules: 3,000 to 30,000 daltons(mean
weight: 15,000 daltons)
 Anticoagulant profile & clearance of UFH molecules varies based on
length
 UFH–antithrombin complex is 100 to 1,000 times more potent
than antithrombin alone
 through its action on thrombin, the UFH–antithrombin complex
inhibits thrombin-induced activation of factors V & VIII
 Prevents growth & propagation of a formed thrombus and allows
patient's own thrombolytic system to degrade the clot
 Factors IIa (thrombin) & Xa most sensitive to inhibition by UFH–
179
antithrombin complex
 Unfractionated Heparin (UFH)
 Heterogeneous mixture of sulfated glycosaminoglycans
 Molecular weight of UFH molecules: 3,000 to 30,000 daltons(mean
weight: 15,000 daltons)
 Anticoagulant profile & clearance of UFH molecules varies based on
length
 UFH–antithrombin complex is 100 to 1,000 times more potent
than antithrombin alone
 through its action on thrombin, the UFH–antithrombin complex
inhibits thrombin-induced activation of factors V & VIII
 Prevents growth & propagation of a formed thrombus and allows
patient's own thrombolytic system to degrade the clot
 Factors IIa (thrombin) & Xa most sensitive to inhibition by UFH–
180
antithrombin complex
 Unfractionated Heparin (UFH)
 Contraindications:
 Hypersensitivity to the drug, active bleeding, hemophilia, severe liver
disease with elevated prothrombin time (PT), severe
thrombocytopenia, malignant hypertension, and inability to
meticulously supervise and monitor treatment
 UFH must be given parenterally, preferably by the IV or SC route.
 IM administration is discouraged because absorption is erratic and it
may cause large hematomas
 IV administration is needed when rapid anticoagulation is required.
A weight-based IV bolus dose followed by a continuous IV infusion
is preferred

181
Weight-Baseda UFH Dosing for Continuous
IV Infusion
Indication Initial Loading Dose Initial Infusion Rate

DVT/PE 80-100 units/kg 17-20 units/kg/hr

Max = 10,000 units Max = 2,300 units/hr

Maintenance Infusion Rate

AntiXa(U/mL)/aPTT (sec)b Dose adjustment
< 0.15/< 37 80 units/kg bolus, then  infusion by 4 units/kg/hr
0.15-0.29/37-47 40 units/kg bolus, then  infusion by 2 units/kg/hr
0.3-0.7/48-71 No change
0.71-1/72-93  Infusion by 2 units/kg/hr
> 1/> 93 Hold infusion for 1 hr, then  by 3 units/kg/hr
aUse actualbody weight for all calculations. Adjusted body weight may be used for
obese patients. baPTT may vary based on individual assays.
182
 Unfractionated Heparin (UFH)
 Therapeutic Monitoring
 Activated partial thromboplastin time (aPTT) is still used at some
institutions
 Antifactor Xa level has replaced aPPT at some facilities
 target concentration: 0.3 to 0.7 U/ml
 Measure prior to initiation to determine baseline
 IV infusion: evaluate response 6 hr after initiation or dose change
 Some acute VTE & MI patients have diminished response to UFH
(“heparin resistance”)
 suspected in pts who require > 40,000 units of UFH per 24-hour
period
 adjust dose based on antifactor Xa concentrations
183
 Unfractionated Heparin (UFH)
 Primary adverse effect: bleeding
 more closely related to underlying risk factors than high aPTT
 Presence of concomitant bleeding risks increase risk of UFH-
induced hemorrhage
 Thrombocytopenia, use of other antithrombotic therapy, preexisting
source of bleeding
 Thrombocytopenia common (platelet count < 150,000)
 Heparin-AssociatedThrombocytopenia (HAT)
 benign, transient, mild
 generally within the 1st few days of treatment in heparin-naive patients
 Heparin-InducedThrombocytopenia (HIT)
 serious and requires immediate intervention
184
 Unfractionated Heparin (UFH)
 Long-term UFH
 Alopecia, priapism, suppressed aldosterone synthesis with subsequent
hyperkalemia, osteoporosis
Management of Adverse Effects
 monitoring closely for bleeding signs & symptoms
 regular monitoring: hemoglobin, hematocrit, BP
 When major bleeding occurs
 discontinue UFH immediately
 identify and treat underlying source of bleeding
 administer IV protamine sulfate 1 mg per 100 units of UFH (maximum
50 mg) slow IV infusion over 10 min
 neutralizes UFH in 5 min and activity persists for 2 hr

185
 Low Molecular Weight Heparin
 Fragments of UFH produced by chemical or enzymatic
depolymerization ~1/3 the molecular weight of UFH
 3 LMWHs: enoxaparin, dalteparin, tinzaparin
 Advantages over UFH:
 predictable anticoagulation dose response
 improved subcutaneous bioavailability
 dose-independent clearance
 longer biologic t½
 lower incidence of thrombocytopenia
 reduced need for laboratory monitoring
 Prevent growth, propagation of formed thrombi
 Enhance/accelerate antithrombin activity: bind specific
186 pentasaccharide sequence
 Low Molecular Weight Heparin
 Elimination t½ with severe renal impairment
 CrCl < 30 mL/min
 reduce enoxaparin dose
 extend dosing interval to once daily
 pharmacokinetics of dalteparin & tinzaparin less characterized in renal
insufficiency
 studies suggest lower degree of accumulation

 Monitoring not necessary due to predictable anticoagulant response

with SQ administration
 Obtain baseline labs: PT/INR, aPTT, CBC with platelets, SrCr.
 Monitor CBC every 5 to 10 days during the first 2 weeks
 every 2 to 4 weeks thereafter

187
 Low Molecular Weight Heparin
 Adverse effects
 most common: bleeding
 thrombocytopenia, avoid with HIT history/diagnosis
 No proven reversal method of toxicity
 May give IV protamine sulfate
 not recommended if LMWH administered > 12 hr earlier
 Safe in pregnancy, does not cross placenta
 Preferred agents in pediatrics: monitor antifactor Xa

188
LMWH Doses
Indications Enoxaparin Dalteparin Tinzaparin

Hip-replacement 30 mg SC q 12 h initiated 2,500 units SC given 2 h prior to 75 units/kg SC q

surgery 12–24 h after surgery surgery, followed by 2,500 24 h initiated the
(prophylaxis) or international units the evening evening prior to
40 mg SC q 24 h initiated 12 after surgery and at least 6 h after surgery or 12 h
a
h prior to surgery first dose, then 5,000 after surgery
a
Extended prophylaxis may international units SC q 24 h or
a
be given for up to 3 weeks or 4,500 unit SC q 24
5,000 international units SC q 24 h initiated 12 h
h initiated the evening prior to prior to surgery
a
surgery

Knee-replacement 30 mg SC q 12 h initiated 75 units/kg SC q

a
surgery 12–24 h prior to surgery 24 h initiated the
(prophylaxis) evening prior to
surgery or 12 h
after surgery

Trauma 30 mg SC q 12 h starting 12–

(prophylaxis) 36 h after injury

aFDA approved dose for indication. 189

LMWH Doses
Indications Enoxaparin Dalteparin Tinzaparin

Abdominal surgery 40 mg SC q 24 h 2,500 units SC q 24 h initiated 1–2 h prior 3,500 unit SC q

a
(prophylaxis) initiated 2 h prior to surgery 24 h initiated
a
to surgery Patients with malignancy: 5,000 units SC 1–2 h prior to
the evening prior surgery then 5,000 units surgery
a
SC q 24 h
or
2,500 units SC 1–2 h prior to surgery then
2,500 units 12 h after surgery followed by
a
5,000 units SC q 24 h

a
Acute medical illness 40 mg SC q 24 h 2,500 units SC q 24 h
(prophylaxis)
a
Deep vein thrombosis 1 mg/kg SC q 12 h 100 units/kg SC q 12 h 175 units/kg SC
a
treatment (with or or or q 24 h
without pulmonary 1.5 mg/kg SC q 24 200 units/kg SC q 24 h
a
embolism) h
a a
Unstable angina or 1 mg/kg SC q 12 h 100 units/kg SC q 12 h (maximum dose
non–Q-wave 10,000 units)
myocardial infarction

aFDA approved dose for indication.

190
 Warfarin
 Anticoagulant of choice for long-term/extended anticoagulation
 FDA-approved indications
 VTE prevention & treatment
 prevention of thromboembolic complications associated with atrial
fibrillation, heart valve replacement, MI
 Requires continuous monitoring & patient education
 narrow therapeutic index
 many food & drug interactions
 Inhibits enzymes responsible for cyclic interconversion of vitamin K
in the liver
 No direct effect on previously circulating clotting factors or
previously formed thrombi
191
 Warfarin
 Time to pharmacologic effect dependant on the elimination t½’s of
coagulation proteins
 full antithrombotic effect achieved 8 to 15 days after initiation of therapy
 Prevents formation & propagation of thrombi by suppressing clotting
factor production
 Racemic mixture of R & S isomers
 S isomer: 2 to 5 times more potent than R isomer
 Rapidly & extensively GI absorption
 peak plasma concentration ~90 minutes
 PO bioavailability > 90%
 Both isomers 97 to 99% albumin bound
 Metabolized via hepatic cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2C8,
2C18, 3A4
 Large interpatient differences in dose requirements
 Dose changes should not be made more than every 3 days
192
193
 Warfarin
Adverse Effects
 Bleeding/hemorrhagic complications,Warfarin-induced skin necrosis,
Purple-toe syndrome
 Pregnancy category X
Management of Adverse effects
 Mildly elevated INR (3.5 to 5.0): reduce dose or hold 1 or 2 doses
 PO or IV vitamin K for swift reductions
 INR 5 to 9: hold warfarin ± low dose vitamin K
 Serious/life-threatening bleeding
 IV vitamin K
 fresh frozen plasma
 clotting factor concentrates
194  recombinant factor VII
 Warfarin
Interactions
 Vitamin K-containing foods
 stress dietary consistency, moderation
 Drugs that inhibit or induce CYP2C9, 1A2, 3A4
 Protein-binding displacement interactions
 transient changes
 Drugs that alter hemostasis, platelet function, or clotting factor
clearance
 Special Populations
 Pregnancy category X
 Safe to use while breast-feeding
 Patients undergoing procedures:
 generally not discontinued for minimally invasive procedures (dental work)
 higher-risk procedures: stop 4 to 5 days prior
195
General Approach to Periprocedural Anticoagulation Therapy Management
Days Relative Anticoagulation Management
to Procedure
–7 to –10 Assess thrombosis and bleeding risk
aWarfarin stopped on day –5 if
Determine appropriate bridging plan
Obtain INR INR drawn on day –7 to –10 is
–7 Stop aspirin or other antiplatelet therapy 2.0 to 3.0 or day –6 if INR
–6 or –5 Stop Warfarina drawn on day –7 to –10 is 2.5 to
–4 or –3 Start LMWHb
3.5.
–2 LMWH bLMWH is initiated 2 days (36
–1 Give last dose of LMWH 12–24 hours before procedure to 48 hours) after warfarin is
Obtain INR discontinued.
0 = Surgery Resume warfarinc at usual maintenance dose on
cProphylactic dose LMWH may
evening after procedure
+1 Resume be used in low bleeding-risk
LMWHd procedures.
Warfarin
dFull (treatment) doses of
+2 to + 3 LMWHd
Warfarin LMWH can be resumed on days
Obtain INR and CBC 1, 2, and 3 once hemostasis is
+4 to +5 LMWH adequate.
Warfarin
Obtain INR and CBC
> +6 Stop LMWH once INR is therapeutic

196
 VTE: Special Populations
 Pregnancy
 UFH and LMWH preferred during pregnancy
 avoid warfarin during first trimeste
 Pediatrics
 UFH & warfarin used most frequently in pediatrics
 LMWH can also be used
 Cancer patients
 VTE frequent complication of malignancy
 warfarin: often complicated by drug interactions & interruptions due to
procedures
 LMWH: lower incidence of bleeding
 continue anticoagulation as long as the cancer is “active” & patient is
receiving antitumor therapy
197
 Prevention of VTE
 The goal of an effective VTE prophylaxis program is to
 identify all patients at risk
 determine each patient’s level of risk, and
 select and implement regimens that provide sufficient protection for the
level of risk
 At the time of hospital admission, all patients should be evaluated for
their risk of VTE, and strategies to prevent VTE appropriate for each
patient’s level of risk should be routinely employed
 Prophylaxis should be continued throughout the period of risk

198
Risk Classification and Consensus Guidelines for VTE Prevention
Level of Risk Calf Vein Symptomatic Fatal PE Prevention Strategies
Thrombosi PE (%) (%)
s (%)

Low
• Minor surgery, age <40 2 0.2 0.002 Ambulation
years, and no clinical risk
factors
Moderate 10–20 1–2 0.1–0.4 UFH 5,000 units SC q 12 h
• Major or minor surgery, Dalteparin 2,500 units SC q 24 h
age 40–60 years, and no Enoxaparin 40 mg SC q 24 h
clinical risk factors Tinzaparin 3,500 units SC q 24 h
• Major surgery, age <40 IPC
years, and no clinic risk Graduated compression stockings
factors
• Minor surgery, with clinical
risk factor(s)
• Acutely ill (e.g., MI,
ischemic stroke, CHF
exacerbation), and no clinical
risk factors
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Risk Classification and Consensus Guidelines for VTE Prevention
Level of Risk Calf Vein Symptomatic Fatal PE Prevention Strategies
Thrombosis PE (%) (%)
(%)
High
• Major surgery, age >60 years, and no 20–40 2–4 0.4–1.0 UFH 5,000 units SC q 8 h
clinical risk factors Dalteparin 5,000 units SC q 24 h
• Major surgery, age 40–60 years, with Enoxaparin 40 mg SC q 24 h
clinical risk factor(s) Fondaparinux 2.5 mg SC q 24 h
• Acutely ill (e.g., MI, ischemic stroke, Tinzaparin 75 units/kg SC q 24 h
CHF exacerbation), with risk factor(s) IPC

Highest
• Major lower-extremity orthopedic 40–80 4–10 0.2–5 Adjusted dose UFH SC q 8 h (aPTT >36 s)
surgery Dalteparin 5,000 units SC q 24 h
• Hip fracture Desirudin 15 mg SC q 12 h
• Multiple trauma Enoxaparin 30 mg SC q 12 h
• Major surgery, age >40 years, and Fondaparinux 2.5 mg SC q 24 h
prior history of VTE Tinzaparin 75 units/kg SC q 24 h
• Major surgery, age >40 years, and Warfarin (INR = 2.0–3.0)
malignancy IPC with UFH 5,000 units SC
• Major surgery, age >40 years, and
hypercoagulable state
• Spinal cord injury or stroke with limb
paralysis

aPTT, activated partial thromboplastin time; INR, International Normalized Ratio; IPC, intermittent pneumatic compression; PE,
200
pulmonary embolism; SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism.
 Evaluation of Therapeutic Outcomes
 Patients should be monitored for resolution of symptoms, the
development of complications
 Hemoglobin, hematocrit, and blood pressure should be monitored
carefully to detect bleeding from anticoagulant therapy.
 Coagulation tests (aPTT, PT, INR) should be performed prior to
initiating therapy to establish the patient’s baseline values and guide
later anticoagulation.
 Outpatients taking warfarin should be questioned about medication
adherence and symptoms related to bleeding and thromboembolic
complications.
 Any changes in concurrent medications should be carefully explored.

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 Learning Objectives
 Upon Completion of the Chapter, The Trainee Will Be Able To:
 Identify the common types of lipid disorders.
 Determine a patient’s coronary heart disease risk and
corresponding treatment goals
 Recommend appropriate therapeutic lifestyle changes (TLC)
and pharmacotherapy interventions for patients with
dyslipidemia.
 Describe the components of a monitoring plan to assess
effectiveness and adverse effects of pharmacotherapy for
dyslipidemias.

203
 Introduction
 Major Lipids in the body
 Cholesterol, triglycerides, and phospholipids
 Transported as complexes of lipid & proteins known as lipoproteins (LP)
 Plasma LP are spherical particles with surfaces that consist largely of
phospholipid, free cholesterol, and protein
 Major classes of LP found in serum are:
 Chylomicrons
 low-density lipoproteins (LDL)
 high-density lipoproteins (HDL)
 very-low-density lipoproteins (VLDL)
 Intermediate-density lipoprotein (IDL)

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 Introduction
 Abnormalities of plasma LP can result in a predisposition to:
 Coronary, cerebrovascular, and PVD and constitute one of the major risk
factors for CHD.
 Elevated total and LDL cholesterol and reduced HDL linked
with development of CHD.
 VLDL, the major lipoprotein associated with triglycerides
 Enriched with cholesterol esters, and is smaller, denser, and more
atherogenic than less dense VLDL.
 Lipid lowering drug therapy reduces
 risk of cardiovascular/ cerebrovascular events, death
 Dyslipidemia: refers to any abnormality in circulating lipid levels: Elevated
TC, elevated LDL, elevated triglycerides (TG), reduced HDL, or some
combination of these abnormalities.
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 Lipoprotein metabolism and transport
 LDL
 carries 60% to 70% of the total serum cholesterol
 make the greatest contribution to the development of
atherosclerosis
 The primary target of cholesterol-lowering therapy.
 Approximately half removed from the systemic circulation by the
liver;
 the other half may be taken up by peripheral cells or deposited in
the intimal space of coronary, carotid, and other peripheral
arteries, where atherosclerosis can develop
 HDL
 20% to 30% of the total cholesterol
 Transport cholesterol from peripheral cells back to the liver, a
process called reverse cholesterol transport.
 Less availability contribute to atherogenesis
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 Lipoprotein metabolism and transport
 VLDL
 Formed in the liver
 Carries about 10% to 15% of serum cholesterol
 Precursor for LDL
 The concentration of cholesterol in these particles is approximately
one fifth of the total TG.
 are large and appear to play only a small role in the pathogenesis of
atherosclerosis.
 Chylomicrons
 Transport fatty acids and cholesterol derived from the diet or
synthesized in the intestines from the gut to the liver (exogenous
system).

207
 Lipoprotein metabolism and transport
 Apolipoproteins
 Each lipoprotein particle contains proteins on its outer surface
called apolipoproteins.
 A-I, A-II, B-100, C, and E are the five most clinically relevant
apolipoproteins
 Apolipoproteins serve four main purposes, they:
 are required for assembly and secretion of lipoproteins (such as
apolipoproteins B-100);
 serve as major structural components of lipoproteins;
 act as ligands (apolipoprotein B-100 and apolipoprotein E) for
binding to receptors on cell surfaces (LDL receptors); and
 can be co-factors (such as apolipoprotein C-II) for activation of
enzymes (such as lipoprotein lipase [LPL]) involved in the
breakdown of TGs from chylomicrons and VLDL
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 Lipoprotein metabolism and transport
 LDL Receptor
 The uptake of cholesterol into peripheral and hepatic cells is
accomplished by the binding of apolipoproteins B-100 and E on
circulating lipoproteins to cell-surface LDL receptors.
 The synthesis of LDL receptors is stimulated by a low intracellular
cholesterol concentration.

Microsoft Office
PowerPoint Presentation

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210
 Abnormalities in Lipid Metabolism
1. Polygenic Hypercholesterolemia
 The most prevalent form of dyslipidemia
 caused by a combination of environmental (e.g., poor
nutrition, sedentary lifestyle) and genetic factors (thus, the
term “polygenic”).
 Saturated fatty acids in the diet of these patients can reduce
LDL receptor activity.
 have mild to moderate LDL-C elevations (usually in the
range of 130 to 250 mg/dL), but no unique physical
findings are seen.
 Family history of premature CHD (20% of cases)
 Patients are effectively managed with dietary restriction and
211
by drugs that lower LDL-C levels.
2. Atherogenic Dyslipidemia
 found in about 25% of patients who have a lipid disorder.
 It is characterized by a
• Moderate TG elevation (150 to 500 mg/Dl)
• a low HDL-C level (<40 mg/dL); and a
• moderately high LDL-C level
 commonly, these patients are either overweight or obese
with increased waist circumference, hypertensive, and insulin
resistant
 Can often be effectively managed with weight reduction
and increased physical activity.
 If needed, drugs that enhance the removal of remnant VLDL
and small dense LDL particles (i.e., statins) and that lower TG
levels (i.e., niacin or fibrates) are effective in the management
212
of these cases.
3. Familial Hypercholesterolemia
 Classic lipid disorder of defective clearance.
 The disorder is strongly associated with premature CHD.
 Heterozygotes of this disorder inherit one defective LDL
receptor gene__double the LDL-C level of unaffected
patients (i.e., LDL-C of 250 to 450 mg/dL)
 Clinically, FH patients may deposit cholesterol in the:
Iris, leading to arcus senilis.
Tendons _ leading to tendon xanthomas
 Clinical diagnosis will be:
 very high LDL-C level
 a strong family history of premature CHD events, and
213  the presence of tendon xanthomas.
 Classification of Hyperlipoproteinemia
(Fredrickson-Levy-Lees )

Type Lipoprotein Elevation

I Chylomicrons

IIa LDL

IIb LDL + VLDL

III IDL (LDL1)

IV VLDL

V VLDL + Chylomicrons

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 Clinical Presentation
Symptoms: Signs
none
  none
severe chest pain, palpitations
  severe abdominal pain
sweating
  pancreatitis
anxiety
  eruptive xanthomas
SOB
  peripheral polyneuropathy
loss of consciousness
  HTN
speech or movement difficulty
  BMI > 30 kg/m2
abdominal pain
  waist size > 40 in (men), > 35
sudden death
 in (women)
Lab Tests:
•↑ TC, ↑ LDL , ↑ TG, ↑ apolipoprotein B, ↑ C-reactive protein, ↓ HDL

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 Patient Evaluation
 Fasting lipid panel every 5 yrs adults > 20 years
 if patient not fasting only TC & HDL are reliable
 TC > 200 or HDL < 40: obtain follow-up fasting lipid panel
 Once lipoprotein abnormality confirmed; assess health & CV risk
factors
 Initiate individualized LDL goals & treatment

216
 Classification

217
218
 Risk Factorsa
Age
 Men: 45 years
Women: 55 years or premature menopause without estrogen replacement
therapy
Family history of premature CHD
definite myocardial infarction or sudden death before age 55 years in father or
other male first-degree relative, or before age 65 years in mother or other
female first-degree relative
Cigarette smoking : Within the past month
Hypertension (140/90 mm Hg or taking antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)b

aDiabetesregarded as coronary heart disease (CHD) risk equivalent.

bHDL cholesterol >60 mg/dL counts as "negative" risk factor; its presence removes

one risk factor from the total count.

219
 Treatment Goals & Cutpoints
Risk Category LDL Goal LDL Level atW/c to LDL Level atW/c to Consider
(mg/dL) Initiate TLC (mg/dL) Drug Therapy (mg/dL)
High risk: CHD or CHD risk <100 (optional 100 100(<100 mg/dL;)
equivalents (10-year risk >20%) goal: <70) consider drug options)a
Moderately high risk: 2+ risk <130 130 130(100–129)
factors (10-year risk >10%– consider drug options
20%)
Moderate risk: 2+ risk factors <130 130 160
(10-year risk <10%)
Lower risk: 0–1 risk factorb <160 160 190(160–189)
LDL-lowering drug optional)

aSome authorities recommend use of LDL-lowering drugs in this category if LDL-C <100 mg/dL cannot
be achieved by therapeutic lifestyle changes (TLC). Others prefer to use drugs that primarily modify TG
and HDL, e.g., nicotinic acid or fibrates. Clinical judgment also may call for deferring drug therapy in this
subcategory.
bAlmost all people with 0–1 risk factor have a 10-year risk <10%; thus,10-year risk assessment in people

with 0–1 risk factor is not necessary.

220
 General Treatment Approach
 Initial treatment for any lipoprotein disorder is TLC (Therapeutic
Lifestyle Changes)
 restricted total fats, saturated fats, cholesterol intake
 modest increase in polyunsaturated fat, increased soluble fiber intake
 exercise: moderate intensity 30 min/day most days
 weight reduction (initial goal of 10%) if needed, smoking cessation, treat
HTN
 Most patients should receive 3 month TLC trial before initiating
pharmacologic therapy unless very high risk
 If patient unable to reach goals with TLC alone choose lipid-lowering
drugs based on lipoprotein disorder
 Combination therapy may be necessary
 monitor closely: increased risk of drug interactions, adverse effects

221
Pharmacologic Therapy
 Reduction of LDL reduces CHD event rates
 Although many efficacious lipid-lowering drugs exist,
none is effective in all lipoprotein disorders, and all such
agents are associated with some adverse effects.
 Lipid-lowering drugs can be broadly divided into agents that:
Decrease the synthesis of VLDL and LDL
Enhance VLDL clearance
enhance LDL catabolism
decrease cholesterol absorption
elevate HDL, or some combination of these characteristics

222
 Drug Mechanism of Effects on Effects on Comment
Action Lipids Lipoproteins
BA ↑ LDL ↓Cholesterol ↓ LDL Problem with compliance; binds
catabolism ↓ VLDL many coadministered acidic drugs
↓ Cholesterol
absorption
Niacin ↓ LDL and ↓ ↓ VLDL , ↓ LDL Problems with patient acceptance;
VLDL synthesis Triglyceride ↑ HDL good in combination with bile acid
↓Cholesterol resins; ER niacin causes less flushing
and is less hepatotoxic than SR form

Fibric Acids ↑ VLDL ↓ ↓ VLDL Clofibrate causes cholesterol

clearance Triglyceride ↓ LDL gallstones; modest LDL lowering;
↓ VLDL ↓Cholesterol ↑ HDL raises HDL; gemfibrozil inhibits
synthesis glucuronidation of simvastatin,
lovastatin, atorvastatin
STATINS ↑ LDL catabolism; ↓Cholesterol ↓ LDL Highly effective in heterozygous familial
inhibit LDL hypercholesterolemia and in combination
synthesis with other agents

Absorption Blocks cholesterol ↓Cholesterol ↓ LDL Few adverse effects; effects additive to
Inhibitor absorption across other drugs; ENHANCE trial – no change
the intestinal border in carotid intima media thickness (CIMT)
compared to simvastatin monotherapy in
223 patients with familial hypercholesterolemia
 Recommended Drug Treatment
Lipoprotein Type Drug of Choice Combination Therapy
I Not indicated —
IIa Statins Niacin, BAR
Cholestyramine or colestipol Statins, niacin
Niacin Statins, BAR
IIb Statins, BAR, fibrates,b niacin
Fibrates Statins, niacin, BARa
Niacin Statins, fibrates
Ezetimibe
III Fibrates Statins niacin
Niacin Statins fibrates
Ezetimibe
IV Fibrates, Niacin Niacin, Fibrates

V Fibrates, Niacin Niacin, Fish oils

aBile
acid resins (BARs) not 1st line if TGs are elevated at baseline; hypertriglyceridemia may
224
worsen with BAR monotherapy. bFibrates: gemfibrozil, fenofibrate
STATINS
 most potent cholesterol-lowering potential.
 Rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin,
and fluvastatin in descending order of potency
 They lower LDL-C by approximately 20% to 40% with initial
doses and 35% to 60% with maximal doses.
 Reduce TG levels by 15% to 45% and increase HDL-C
modestly (5% to 8%)
 The LDL-C lowering is dose dependent and log linear
 statins can significantly reduce CHD death and nonfatal MI,
revascularization procedures, strokes, and total mortality

225
STATINS
 Dosed once daily in evening
 hepatic cholesterol production peaks at night
 exceptions: atorvastatin, rosuvastatin
 Adverse effects:
 elevated serum transaminases, myalgia, myopathy,
rhabdomyolysis, flu-like symptoms, mild GI disturbance

226
227
Bile Acid Resins
 Colestipol, cholestyramine, colesevelam
 Bind intestinal bile acid
 Normally 2nd-line agents when statins not sufficient or not tolerated
 May aggravate hypertriglyceridemia
 caution if TG > 200 mg/dL
 contraindicated if TG > 400 mg/dL
 Adverse effects:
 GI distress, constipation: titrate slowly, increase fluid intake, increase
dietary bulk, add stool softeners
 impair fat soluble vitamin absorption: A, D, E, K
 reduce bioavailability of other medications: warfarin, digoxin
 dose 6 hrs from other medications to avoid interactions

228
Nicotinic Acid/Niacin
 IR, SR, & ER formulations
 May exacerbate gout & DM
 monitor closely, slow dose titration
 Contraindications: active liver disease, severe gout
 Combination with statin or gemfibrozil therapy increases myopathy
risk
 Adverse effects:
 cutaneous flushing, itching
 ASA 325mg 30 min prior
 titrate dose slowly, avoid spicy foods/hot beverages
 GI intolerance
 elevated LFTs, hyperuricemia, hyperglycemia
 niacin associated hepatitis
 more common with SR

229
Fibric Acids
 Gemfibrozil, fenofibrate, clofibrate
 May increase HDL > 10 to 15%
 20 to 25% LDL reduction in patients with heterozygous familial
hypercholesterolemia
 Efficacy depends on lipoprotein type, baseline TG
 Gemfibrozil dosed BID 30 min before meals
 Fenofibrate can be taken without regards to food
 Contraindicated in renal failure
 Combination therapy with niacin or statins increases risk of muscle
toxicity

230
Fibric Acids
 Adverse effects:
 GI complaints, rash, myalgia, headache, fatigue
 transient increase in transaminase & alkaline phosphatase
 gallstones (clofibrate)
 enhanced hypoglycemic effects in patients on sulfonylureas
 may potentiate effects of oral anticoagulants
 monitor PT/INR closely in patients on anticoagulants

 Absorption Inhibitor: Ezetimibe

 Inhibits cholesterol absorption across the gut by 23 to 50%; hepatic LDL
synthesis upregulation partially offsets impaired absorption
 Often used in combination with statins, other drugs
 Dosed once daily without regard to meals
 ~18% LDL reduction
 Effect of ezetimibe on CV morbidity & mortality unknown
231
Fish Oils
 Omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic
acid), the predominant fatty acids in the oil of coldwater fish
 lower triglycerides by as much as 35% when taken in large amounts.
 < 3 g/day generally recognized as safe
 Until further research is done on nutraceuticals it is recommended
that patients get dietary EPA & DHA
 2 to 4 g of EPA & DHA may be used for very high TG
 Adverse effects:
 GI disturbance
 fishy aftertaste
 increased bleeding risk
 worsening glycemic control
 increased LDL
 abnormal LFTs
232
 Treatment of elevated triglycerides (> 150 mg/dL)
 Primary aim of therapy is to reach LDL goal
 Intensify weight management
 Increase physical activity
 If triglycerides are >200 mg/dL after LDL goal is reached,
set secondary goal for non-HDL cholesterol (total – HDL)
30 mg/dL higher than LDL goal.

233
 If triglycerides 200-499 mg/dL after LDL goal is reached,
consider adding drug if needed to reach non-HDL goal:
 intensify therapy with LDL-lowering drug, or add nicotinic acid or
fibrate to further lower VLDL.
 Very high TGs (> 500 mg/dL) associated with pancreatitis
 dietary fat restriction (10% to 20% of calories)
 weight loss, alcohol restriction, treat coexisting disorders
 Medications for TG > 500 mg/dL
 gemfibrozil: preferred in diabetics
 Niacin, higher-potency statins: atorvastatin, rosuvastatin, simvastatin
 fenofibrate may be preferred in combination with statins
 does not impair glucuronidation
 minimizes potential drug interactions

 Successful treatment: TG < 500 mg/dL

234
Treatment of low HDL cholesterol (<40 mg/dL)
 First reach LDL goal, then:
 Intensify weight management and increase physical activity
 If triglycerides 200-499 mg/dL, achieve non-HDL goal
 If triglycerides <200 mg/dL (isolated low HDL) in CHD or
CHD equivalent consider nicotinic acid or fibrate.
 Diabetic Dyslipidemia
 Characterized by hypertriglyceridemia, low HDL, &
minimally elevated LDL
 1˚target: LDL
 Goal of treatment: LDL-C < 100 mg/dL
 LDL > 130 mg/dL: TLC + drug therapy often required
 Statins often considered initial drugs of choice
235
 Hyperlipidemia in Pregnancy
 TC & TG levels increase throughout pregnancy
 average cholesterol increase: 30 to 40 mg/dL around weeks 36 to 39
 TGs may increase as much as 150 mg/dL
 Drug therapy typically not initiated/continued during pregnancy
 TLC is the mainstay but BARs & absorption inhibitors may be
considered in high risk patients
 ezetimibe: category C , Statins: category X

Elderly Patients
 More susceptible to adverse effects of lipid-lowering drug
therapy
 Start with lower doses, titrate slowly to minimize adverse effects
236
 Concurrent Disease States
 Nephrotic syndrome, ESRD, HTN compound dyslipidemia risks
 Statins reduce TC & LDL-C in nephrotic syndrome
 TLC may slow pregression of renal disease & CV complications
 Bile acid sequestrants not effective
 Niacin may be useful in nondiabetic patients with renal insufficiency
 Treat CKD patients to LDL goal < 100 mg/dL
 HTN management
 avoid drugs that elevate cholesterol
 diuretics
 α-blockers
 niacin may magnify vasodilator hypotensive effects

237
 Hyperlipidemia in Children
 AHA considers TG > 150 & HDL< 35 abnormal for
children/adolescents
 Children should receive fasting lipid profile after age 2 but no later
than 10 years if:
 family history of dyslipidemia or premature CVD
 unknown family history
 overweight, DM, HTN, smoker
 Lipid Level Classification: Children & adolescents (age < 20 yrs)
 Acceptable: TC < 170 mg/dl, LDL < 110 mg/dL
 Borderline: TC 170-199 mg/dL, LDL 110-129 mg/dL
 Elevated: TC > 200 mg/dL, LDL > 130 mg/dL

238
 Hyperlipidemia in Children
 Implement healthy lifestyle/diet in all children > 2 yrs
 low-fat dairy products in children > 1 year who are overweight or
family history of obesity, dyslipidemia, CVD
 Drug therapy not recommended age < 8 years
 exception: LDL > 500 mg/dL such as seen in homozygous familial
hypercholesterolemia
 Statins safe & effective in children
 BARs, absorption inhibitors may also be used
 Pharmacologic intervention considered in patients age > 8 years
after failure of dietary therapy when:
 LDL > 190 mg/dL if no additional risk factors
 LDL > 160 mg/dL if family history or > 2 additional risk factors
 LDL > 130 mg/dL if patient has diabetes mellitus
239
 Monitoring
Statins Baseline FLP, LFTs, CK
Repeat LFTs at 6 weeks, 3 months, periodically

Bile Acid Resins Baseline FLP

Repeat FLP at 6 weeks, periodically

Nicotinic Acid Baseline FLP, glucose, LFTs, uric acid

Repeat all tests 4-6 weeks after dose change

Fibric Acid Baseline FLP

Repeat FLP at 12 months, periodically
Cholesterol Baseline FLP
Inhibitors Repeat FLP at 6 weeks, periodically

240
 7. Stroke

241
 Learning Objectives
 Upon Completion of the Unit, the students Will be able to:
 Discuss the types and pathophysiology of cerebrovascular
disease(ischemic stroke and hemorrhagic stroke)
 Identify risk factors associated with ischemic and hemorrhagic stroke
 Discuss the various treatment options for acute ischemic stroke and
hemorrhagic stroke.
 Develop an appropriate therapeutic plan for patient with ischemic
stroke, including an appropriate agent to prevent stroke recurrence.

242
 Stroke: Introduction
 Cerebro-vascular disease:
 disorders of the arterial or venous circulatory systems of the CNS
 generally refers to Stroke or Transient Ischemic Attack (TIA)
 Stroke
 an abrupt onset of focal neurologic deficit due to focal
vascular cause lasting more than 24hrs
 The definition of stroke is clinical, and laboratory studies
including brain imaging are used to support the diagnosis.
 Transient ischemic attack (TIA)
 Transient focal neurologic deficit that last less than 24 hours
 TIA typically last for 5 to 15 minutes, but the 24 hours is used
for the definition.
243
 Epidemiology
 An individual's risk of having a stroke increases substantially as
he or she ages, with a doubling of risk for each decade older
than 55 years of age
 African Americans have stroke rates that are twice those of
whites
 Men are at a higher risk of stroke than women when matched
for age, but women who suffer from a stroke are more likely to
die from it.
 The annual cost of stroke in the United States is estimated to be
$69 billion.

244
 Etiology and Classification
Stroke can be either:
 Ischemic (87%)
 Hemorrhagic (13%)
Hemorrhagic strokes include
 Subarachnoid hemorrhage
 Intracerebral hemorrhage
 Subdural hematomas
Subarachnoid hemorrhage(SAH) occurs when
 blood enters the subarachnoid space (where CSF is housed) owing
to
 trauma
 rupture of an intracranial aneurysm, or
 rupture of an arteriovenous malformation (AVM).
245
 Etiology and Classification
Intracerebral Hemorrhage(ICH) occurs when
 a blood vessel ruptures within the brain parenchyma itself,
resulting in the formation of a hematoma
 very often associated with uncontrolled high BP and sometimes
antithrombotic or thrombolytic therapy.
Subdural Hematomas refer to
 collections of blood below the dura (covering of the brain), and
they are caused most often by trauma.
Hemorrhagic stroke
 although less common, is significantly more lethal than ischemic
stroke, with 30-day case-fatality rates that are two to six times
higher
246
 Etiology and Classification
Ischemic strokes are caused either by
 local thrombus formation or embolic phenomena, resulting in
occlusion of a cerebral artery.
 Atherosclerosis, particularly of the cerebral vasculature, is a causative
factor in most cases, although 30% are cryptogenic
 Emboli can arise from either intra- or extracranial arteries (including
the aortic arch) or, as is the case in 20% of all ischemic strokes, the
heart.
 Cardiogenic embolism is presumed to have occurred if the patient has
concomitant atrial fibrillation, valvular heart disease, or any
other condition of the heart that can lead to clot formation.
 Distinguishing between cardiogenic embolism and other causes
of ischemic stroke is important in determining long-term
247 pharmacotherapy in a given pt
 Risk Factors
 Non-modifiable risk  Modifiable risk factors
factors
• Hypertension
• Age
o single most important risk
• Gender factor for ischemic stroke
• Race
• Atrial fibrillation
• Family history of
o most important and treatable
stroke cardiac cause of stroke
• Low birth weight
• Diabetes—independent risk factor
• Sickle cell disease
• Lifestyle factors—Obesity, Physical
inactivity, Alcohol, Cigarette smoking
• dyslipidemia
248
 Pathophysiology: Ischemic Stroke
 Final result of both thrombus formation and embolism is an arterial
occlusion, decreasing cerebral blood flow(CBF) and causing ischemia
 Normal CBF averages 50 mL/100 g/minute, and this is maintained
over a wide range of BP(MAP of 50 to 150 mm Hg) by a process
called cerebral autoregulation
 When local CBF decreases below 20 mL/100 g/minute, ischemia
ensues, and when further reductions below 12 mL/100 g/minute
persist, irreversible damage to the brain occurs, which is called
infarction
 Tissue that is ischemic but maintains membrane integrity is referred
to as the ischemic penumbra because it usually surrounds the infarct
core
 This penumbra is potentially salvageable through therapeutic intervention
249
 Pathophysiology: Hemorrhagic Stroke
 Presence of blood in the brain parenchyma causes damage to the
surrounding tissue through the mechanical effect it produces
(mass effect) and the neurotoxicity of the blood components and
their degradation products
 ≈ 30% of ICH continue to enlarge over the first 24 hours, most
within 4 hours
 Hemorrhage volumes >60 mL are associated with 71% to 93%
mortality at 30 days
 Much of the early mortality(up to 50% at 30 days) is caused by
the abrupt ↑ in ICP that can lead to herniation and death
 Both early and late edema contributes to worsened outcome
250 after intracerebral hemorrhage
 Clinical Presentation
 Symptoms
 Pt may complain of weakness on one side of the body, inability to
speak, loss of vision, vertigo, or falling.
 Stroke pts may complain of headache; however, with hemorrhagic
stroke, the headache can be severe and accompanied with vomiting
 Signs
 Specific deficits are determined by the area of the brain involved.
 Hemiparesis or monoparesis…….hemisensory deficit
 Vertigo and double vision…..posterior circulation involvement
 Aphasia……………anterior circulation strokes
 dysarthria, visual field defects, and altered levels of
consciousness
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 Diagnostic Tests
 CT scan of the head will reveal an area of hyperintensity (white)
identifying that a hemorrhage has occurred.
 CT scan will either be normal or hypointense (dark) in an area
where an infarction has occurred
 CT scan may take 24 hrs (rarely longer) to reveal area of infarction
 MRI of the head will reveal areas of ischemia earlier and with better
resolution than a CT scan.
 ECG will determine whether the pt has Atrial fibrillation, which
is a major risk factor for stroke

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 Treatment of Stroke
 Goals of treatment:
 reduce the ongoing neurologic injury and decrease mortality
and long-term disability
 decrease mortality and long-term disability
 prevent complications secondary to immobility and
neurologic dysfunction
 prevent stroke recurrence

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 General Approach to Treatment
 Ensure that the patient is supported from a respiratory and cardiac
standpoint
 Quickly determine whether the lesion is ischemic or hemorrhagic,
based on a CT scan
 Ischemic stroke patients presenting within hours of the onset of
their symptoms should be evaluated for reperfusion therapy
 TIAs also require urgent intervention to reduce the risk of stroke,
which is known to be highest in the first few days after TIA
 Pts with elevated BP should remain untreated unless their BP
>220/120 mm Hg, or have evidence of aortic dissection, AMI,
pulmonary edema, or hypertensive encephalopathy
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 If BP is treated, short-acting parenteral agents, such as
labetalol and nicardipine, or nitroprusside, are favored

Table- BP Treatment Guidelines in Acute Ischemic Stroke Patients

Treatment Received t-PA Did Not Receive t-PA
None <180/105 < 220/120

Labetalol IVa or Nicardipine IVb 180–230/105–120 >220/121–140

Nitroprusside c Diastolic >140 Diastolic >140

t-PA, tissue plasminogen activator.

a Labetalol IV = 10–20 mg, doubled every 10–20 minutes, to a maximum of 300

mg. Also can use an infusion of 2–8 mg/min.

b Nicardipine IV = infusion starting at 5 mg/h up to 15 mg/h.
c Nitroprusside IV = infusion starting at 0.5 mcg/kg/min, with continuous arterial

blood pressure monitoring.

Acute phase of the stroke…first week after the event
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 Nonpharmacologic Therapy
Ischemic Stroke
 Surgical interventions in the acute ischemic stroke patient are
limited.
 But in certain cases of ischemic cerebral edema owing to a large
infarction, craniectomy to release some of the rising pressure
has been tried.
Hemorrhagic Stroke
 As in patients with SAH owing to a ruptured intracranial
aneurysm, in arteriovenous malformations (AVMs)
 surgical intervention to either clip or ablate the offending vascular
abnormality substantially reduces mortality owing to rebleeding.
.
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 Pharmacologic Therapy: Ischemic Stroke
 Acute treatment
a) IV tissue plasminogen activator (tPA)_ 0.9mg/kg/hr
with 10% given as initial bolus over 1 minute
• Within 4.5 hours of onset
• avoidance of antithrombotic (anticoagulant or antiplatelet)
therapy for 24 hours, and
• close pt monitoring for elevated BP, response, and hemorrhage
• shown to reduce the ultimate disability
b) Aspirin 160–325 mg daily within 48 hours of onset.
 never be given within 24 hours of the administration of tPA
 shown to reduce long-term death and disability
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Antiplatelet Agents
 All patients who have had an acute ischemic stroke or TIA
should receive long term antithrombotic therapy for
secondary prevention.
 Acetylsalicylic acid (ASA), clopidogrel, and extended-release
dipyridamole plus aspirin (ERDP-ASA) are considered first-
line antiplatelet agents.
Oral Anticoagulants
 The treatment of choice for the prevention of stroke in
patients with atrial fibrillation within 14 days.
 target INR of 2.5 is recommended in the secondary
prevention of stroke
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Blood Pressure Lowering
 Elevated blood pressure is very common in ischemic stroke
patients, and treatment of hypertension in these patients is
associated with a decreased risk of stroke recurrence.
 AHA/ASA guidelines recommend an ACE inhibitor and a
diuretic for the reduction of BP in pts with stroke or TIA.
 Early blood pressure lowering can worsen symptoms,
however; therefore, recommendations are limited to pts
outside of the acute stroke period (first 7 days).
 Despite this, there is support for carefully restarting
antihypertensive therapy after 24 hrs in the acute stroke pt

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Statins
 The statins have been shown to reduce the risk of stroke by
approximately 30% in patients with coronary artery
disease and elevated plasma lipids.
 It is now recommended that ischemic stroke patients,
regardless of baseline cholesterol, be treated with high-
intensity statin therapy(e.g. atorvastatin 80 mg daily) to achieve
a reduction of LDL of at least 50% for secondary stroke
prevention
Heparin for Prophylaxis of DVT
 recommended for the prevention of DVT in hospitalized
patients with decreased mobility.
 For acute stroke period has never been proven to positively
261 affect stroke outcome.
 Pharmacologic Therapy: Hemorrhagic Stroke
 Management of ICH involves a combination of medical and
surgical interventions.
 Use of antipyretic medications to lower body temperature to
normothermia in febrile pts with stroke
 Hyperglycemia in the first 24 hours after stroke is associated
with adverse outcomes insulin treatment for elevated serum
glucose >140 to 185 mg/dL
 Subarachnoid hemorrhage (SAH) owing to aneurysm rupture is
associated with a high incidence of delayed cerebral ischemia
(DCI) in the 2 weeks following the bleeding episode.
 CCB, nimodipine (60 mg every 4 hours for 21 days) to reduce
the incidence and severity of neurologic deficits owing to DCI
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 Reversal of anticoagulation
 When ICH occurs in a pt on warfarin (INR >1.3), rapid
reversal of anticoagulation to prevent expansion and allow
surgical intervention is recommended.
 The methods recommended to achieve reversal include
 all anticoagulant and antiplatelet drugs should be discontinued acutely
for at least one to two weeks after the onset of hemorrhage, and
 IV vitamin K, fresh frozen plasma (FFP), and hemostatic agents (factor
VIIa and prothrombin-complex concentrate (PCC).
 High doses (ie, 10 to 20 mg) of IV vitamin K can fully
reverse warfarin-induced anticoagulation.
 However, this effect takes approximately 12 to 24 hours, during which
time the ICH may continue to enlarge.
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 Intracranial pressure control
 Increased ICP due to ICH can result from the hematoma itself
and from surrounding edema, and may contribute to brain
injury and neurologic deterioration.
 Approach to the management of elevated ICP
 Elevate the head of the bed to 30 degrees, once hypovolemia is
excluded.
 Analgesia and sedation, particularly in unstable, intubated pts
 Glucocorticoids should not generally be used to lower the ICP
in patients with ICH.
 A randomized trial found that dexamethasone did not improve outcome
but did increase complication rates, primarily infection.

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 Intracranial pressure control
 Aggressive measures — Monitoring and treatment of ICP
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should be considered for pts with GCS <8

 IV mannitol is the treatment of choice to lower increased ICP
 Administered as an initial bolus of 1 g/kg, followed by infusions
of 0.25 to 0.5 g/kg every six hours.
 Goal of therapy is to achieve plasma hyperosmolality (300 to
310 mosmol/kg) while maintaining an adequate plasma volume
 Barbiturate anesthesia can be used if mannitol fails to lower ICP
to an acceptable range. Barbiturate coma acts by reducing
cerebral metabolism, which results in a lowering of cerebral
blood flow and thus decreases ICP
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 Blood pressure control
 Severe elevations in BP may worsen ICH by representing a
266

continued force for bleeding

 If SBP is >200 mm Hg or MAP is >150 mm Hg, then consider
aggressive reduction of BP with continuous IV meds monitor BP
q 5 minutes
 If SBP is >180 mm Hg or MAP is >130 mm Hg and there is
suspicion of increased ICP, reducing BP using intermittent or
continuous IV meds to keep CPP >60 to 80 mm Hg
 If SBP is >180 mm Hg or MAP is >130 mm Hg and no
suspicion of elevated ICP, then consider a modest reduction of
BP(eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg)
using intermittent or continuous IV medications to control BP,
and clinically reexamine the patient every 15 minutes.
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 Resumption of Antiplatelet therapy
 The timing of antiplatelet use after ICH is largely empiric.
267

 There is risk of rebleeding and hematoma expansion in the first

several hours. At 10 days, rebleeding is unlikely.
 Guidelines state that antiplatelets should be discontinued for at
least one to two weeks.
 Some experts have argued that aspirin can be used safely as soon
as 48 hours after ICH in those who require prophylaxis for
venous thromboembolism.
 If aspirin is used after ICH, a lower dose (30 to 160 mg daily) is
both effective and safer than higher doses

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 Evaluation Of Therapeutic Outcomes
 Patients with acute stroke should be monitored intensely for the
268

development of neurologic worsening, complications, and adverse

effects from treatments.
 The most common reasons for clinical deterioration in stroke pts are:
a) extension of the original lesion in the brain;
b) development of cerebral edema and raised intracranial pressure; (3)
hypertensive emergency;
c) infection (e.g., urinary and respiratory tract);
d) venous thromboembolism;
e) electrolyte abnormalities and rhythm disturbances; and
f) recurrent stroke

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 Learning Objectives
 Upon Completion of the Unit, the students Will be able to:
 List the most common etiologies of decreased intravascular volume in
hypovolemic shock patients
 Describe the major hemodynamic and metabolic abnormalities that
occur in patients with hypovolemic shock
 Describe the clinical presentation for the typical hypovolemic shock pt
 Prepare a treatment plan with clearly defined outcome criteria for a
hypovolemic shock patient
 Compare and contrast advantages and disadvantages of crystalloids,
colloids, and blood products in the treatment of hypovolemic shock
 Formulate a stepwise monitoring strategy for a hypovolemic shock pt.

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 Overview
 Shock refers to conditions manifested by hemodynamic
alterations (e.g., hypotension, tachycardia, low CO, and
oliguria) caused by
 Intravascular volume deficit (Hypovolemic shock)
 Myocardial pump failure (Cardiogenic shock), or
 Peripheral vasodilation (Distributive shock)
 The underlying problem in these situations is
inadequate tissue perfusion resulting from
circulatory failure.

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 Classifications and Etiology

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 Pathophysiology
 Hypovolemic shock symptoms begin to occur with decreases in
intravascular volume in excess of 750 mL or 15% of the circulating
blood volume (20 mL/kg in pediatric patients)
 Hypovolemic shock is considered to be essentially a profound deficit
in preload
 ↓Preload → ↓Stroke volume (SV) → ↓CO and eventually MAP
 This neurohumoral response to hypovolemia is mediated by the
sympathetic nervous system in an attempt to preserve perfusion to
vital organs such as the heart and brain (Fig. 1)
 Protracted tissue hypoxia sets in motion a downward spiral of events
secondary to organ dysfunction and eventual failure if untreated
 Relative failure of more than one organ, regardless of etiology, is
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referred to as the multiple organ dysfunction syndrome (MODS)
 FIGURE 1. Expected neurohumoral response to hypovolemia. ACTH,
adrenocorticotropic hormone; ADH, antidiuretic hormone
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 Clinical Presentation and Diagnosis
 Symptoms: Thirst, Weakness, Lightheadedness
 Signs
 Hypotension, SBP <90 mm Hg or fall in SBP >40 mm Hg
 Tachycardia,Tachypnea, Hypothermia
 Oliguria, Dark, yellow-colored urine
 Skin color: pale to ashen; may be cyanotic in severe cases
 Mental status: confusion to coma
 Laboratory Tests
 Hypernatremia, ↑Scr, ↑BUN,
 ↓Hgb/HCT(hemorrhagic hypovolemic shock)
 Hyperglycemia, Increased serum lactate, Decreased arterial pH
 Regardless of etiology, the most distinctive clinical manifestations of hypovolemic shock
are arterial hypotension and metabolic acidosis.
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 Monitoring Parameters

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Treatment : Desired Outcome
 The ultimate goals are to prevent further progression of the disease
with subsequent organ damage and, if possible, to reverse organ
dysfunction that has already occurred.
General Principles
 Supplemental O2 should be initiated at the earliest signs of shock,
beginning with 4 to 6 L/min via nasal cannula or 6 to 10 L/min by
face mask.
 Adequate fluid resuscitation to maintain circulating blood volume is
essential in managing all forms of shock.
 If fluid challenge does not achieve desired end points, pharmacologic
support is necessary with inotropic and vasoactive drugs.

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 Fluid Resuscitation for Hypovolemic Shock
 The use of fluids is the cornerstone of managing all forms of
shock
 Initial fluid resuscitation consists of
 Crystalloid (electrolyte-based solutions)
 Colloid (large molecular weight solutions)
 Blood Product
 Choice of solution is based on
 O2-carrying capacity (e.g., hemoglobin, hematocrit)
 Cause
 Accompanying disease states
 Degree of fluid loss
 Required speed of fluid delivery
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 Fluid Resuscitation for Hypovolemic Shoc
 Most clinicians agree that crystalloids should be the initial
therapy of circulatory insufficiency.
 Crystalloids are preferred over colloids as initial therapy for
burn patients because they are less likely to cause interstitial
fluid accumulation.
 If volume resuscitation is suboptimal following several liters of
crystalloid, colloids should be considered.
 Some patients may require blood products to assure
maintenance of O2-carrying capacity, as well as clotting factors
and platelets for blood hemostasis

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 Crystalloids
 Consist of electrolytes (e.g., Na+, Cl–, K+) in water solutions, with
or without dextrose.
 Lactated Ringer’s solution may be preferred because it is
unlikely to cause the hyperchloremic metabolic acidosis seen with
infusion of large amounts of Normal saline
 Crystalloids are administered at a rate of 500 to 2,000 mL/hour
 Usually 2 to 4 L of crystalloid normalizes intravascular volume
 Advantages: rapidity and ease of administration, compatibility with
most drugs and low cost
 Disadvantage: large volume necessary to replace or augment
intravascular volume.
 In addition, dilution of colloid oncotic pressure leading to pulmonary
285edema is more likely to follow crystalloid than colloid resuscitation.
 Colloids
 Larger molecular weight solutions (>30,000 daltons) that have been
recommended for use in conjunction with or as replacements for
crystalloid solutions
 Albumin is a monodisperse colloid because all of its molecules
are of the same molecular weight
 Albumin 5% and 25% concentrations are available
 The 5% albumin solution is relatively iso-oncotic, whereas 25%
albumin is hyperoncotic and tends to pull fluid into the compartment
containing the albumin molecules.
 In general, 5% albumin is used for hypovolemic states.
 Advantage : prolonged intravascular retention time compared to
crystalloid solutions. However, albumin is much more costly than
286crystalloid solutions.
 Blood Products
 Used only in instances involving hemorrhage (or severe preexisting
anemia)
General Indications for Blood Products in Acute Circulatory Insufficiency Due to
Hemorrhage
Packed red blood cells
Increase oxygen-carrying capacity of blood: Usually indicated in patients with continued
deterioration after volume replacement. must be warmed, particularly when used in
children
Fresh-frozen plasma
Replacement of clotting factors: Generally overused; indicated if ongoing hemorrhage in patients with
PT/PTT >1.5 times normal, severe hepatic disease, or other bleeding diathesis

Platelets
Used for bleeding due to severe thrombocytopenia (i.e., platelet count <10,000 mcL) or
rapidly dropping platelet counts as would occur with massive bleeding
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 Pharmacologic Therapy: Vasopressor Therapy
 Vasopressor is the term used to describe any pharmacologic agent that
can induce arterial vasoconstriction through stimulation of the α1-
adrenergic receptors.
 Use of vasopressors may be warranted as a temporary measure in
patients with profound hypotension or evidence of organ dysfunction
in the early stages of shock
 Dopamine or norepinephrine may be preferred over epinephrine
because epinephrine has an increased potential for causing cardiac
arrhythmias and impaired abdominal organ (splanchnic) circulation
 In cases involving concurrent heart failure, an inotropic agent such as
dobutamine may be needed, in addition to the use of a vasopressor.

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 Treatment of Lactic Acidosis
 Lactic acidosis, which typically accompanies hypovolemic
shock as a consequence of tissue hypoxia, is best treated by
reversal of the underlying cause
 Administration of alkalizing agents such as sodium bicarbonate
has not been demonstrated to have any beneficial effects and
may actually worsen intracellular acidosis.
 Nonetheless, administration of sodium bicarbonate, 100 to 150
mEq intravenously, can be considered when the PH< 7.1

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 Supportive Care Measures
 Prevention of stress-related mucosal disease
 histamine2-receptor antagonists and proton pump inhibitors
 Prevention of thromboembolic events
 Sequential compression devices and/or
 Antithrombotic therapy(LMWH or unfractionated heparin)
 Patients with adrenal insufficiency due to preexisting disease
 Glucocorticoid replacement therapy

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 Outcome Evaluation
 Restoration of BP to baseline values and reversal of associated organ
dysfunction
 Therapy goals include:
 SBP˃ 90 mm Hg (MAP >60 mm Hg) within 1 hour;
 Organ dysfunction reversal evident by increased urine output to >0.5
mL/kg per hour (1.0 mL/kg per hour in pediatrics), return of mental
status to baseline, and normalization of skin color and temperature over
the first 24 hours;
 HR should begin to decrease reciprocally to increases in the intravascular
volume within minutes to hours
 Normalization of base deficit and serum lactate is recommended within
24 hours to potentially decrease mortality
 Achievement of PAOP to a goal pressure of 14 to 18 mm Hg occurs
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(alternatively CVP 8 to 15 mm Hg).