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Acute Coronary Syndrome

Introduction

Background

The initial diagnosis of acute coronary syndrome (ACS) is based on history, risk factors, and,to a lesser extent, ECG findings. The symptoms are due to myocardial ischemia, the underlyingcause of which is an imbalance between supply and demand of myocardial oxygen.

Patients with ACS include those whose clinical presentations cover the following range ofdiagnoses: unstable angina, nonST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). This ACS spectrum concept is a useful frameworkfor developing therapeutic strategies.

A 50-year-old man with type 1 diabetes mellitus and hypertensionpresents after experiencing 1 hour of midsternal chest pain that

began after eating a large meal. Pain is now present but is

minimal. Aspirin is the single drug that will have the greatest

potential impact on subsequent morbidity. In the setting of

ongoing symptoms and ECG changes, nitrates titrated to 10%

reduction in blood pressure and symptoms, beta-blockers, and

heparin are all indicated. If the patient continues to have

persistent signs and/or symptoms of ischemia, addition of a

glycoprotein IIb/IIIa inhibitor should be considered.

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A 62-year-old woman with a history of chronic stable angina and a "valve

problem" presents with new chest pain. She is symptomatic on

arrival, complaining of shortness of breath and precordial chest

tightness. Her initial vital signs are blood pressure 140/90 mm Hg

and heart rate is 98. Her ECG is as shown. She is given

nitroglycerin sublingually, and her pressure decreases to80/palpation. Right ventricular ischemia should be considered in

this patient.

Pathophysiology

Myocardial ischemia is most often due to atherosclerotic plaques, which reduce the bloodsupply to a portion of myocardium. Initially, the plaques allow sufficient blood flow to matchmyocardial demand. When myocardial demand increases, the areas of narrowing may becomeclinically significant and precipitate angina. Angina that is reproduced by exercise, eating,and/or stress and is subsequently relieved with rest, and without recent change in frequency orseverity of activity that produce symptoms, is called chronic stable angina. Over time, the

plaques may thicken and rupture, exposing a thrombogenic surface upon which plateletsaggregate and thrombus forms. The patient may note a change in symptoms of cardiac ischemiawith a change in severity or of duration of symptoms. This condition is referred to as unstableangina.

Patients with STEMI have a high likelihood of a coronary thrombus occluding the infarctartery. Angiographic evidence of coronary thrombus formation may be seen in more than 90%of patients with STEMI but in only 1% of patients with stable angina and about 35-75% of

patients with unstable angina or NSTEMI. However, not every STEMI evolves into a Q-waveMI; likewise, a patient with NSTEMI may develop Q waves.

The excessive mortality rate of coronary heart disease is primarily due to rupture andthrombosis of the atherosclerotic plaque. Inflammation plays a critical role in plaque

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destabilization and is widespread in the coronary and remote vascular beds. Systemicinflammatory, thrombotic, and hemodynamic factors are relevant to the outcome. Evidenceindicates that platelets contribute to promoting plaque inflammation as well as thrombosis. Anew theory of unbalanced cytokine-mediated inflammation is emerging, providing anopportunity for intervention.

A less common cause of angina is dynamic obstruction, which may be caused by intense focalspasm of a segment of an epicardial artery (Prinzmetal angina). Coronary vasospasm is afrequent complication in patients with connective tissue disease. Other causes include arterialinflammation and secondary unstable angina. Arterial inflammation may be caused by orrelated to infection. Secondary unstable angina occurs when the precipitating cause is extrinsicto the coronary arterial bed, such as fever, tachycardia, thyrotoxicosis, hypotension, anemia, orhypoxemia. Most patients who experience secondary unstable angina have chronic stableangina as a baseline medical condition.

Spontaneous and cocaine-related coronary artery dissection remains an unusual cause of ACS

and should be included in the differential diagnosis, especially when a younger female orcocaine user is being evaluated. An early clinical suspicion of this disease is necessary for agood outcome. Cardiology consultation should be obtained for consideration for urgent

percutaneous coronary intervention.

Although rare, pediatric and adult ACS may result from the following (see MyocardialInfarction in Childhood):

ACS may occur with Marfan syndrome; Kawasaki disease; Takayasuarteritis; or cystic medial necrosis with aortic root dilatation, aneurysmformation, and dissection into the coronary artery.

Anomalous origin of the left coronary artery from the pulmonary artery mayoccur as unexplained sudden death in a neonate.

Coronary artery ostial stenosis may occur after repair of a transposition ofthe great arteries in the neonatal period.

An aberrant left main coronary artery with its origin at the right sinus ofValsalva may cause ACS, especially with exertion.

Traumatic myocardial infarction can occur in patients at any age. Accelerated atherosclerosis is known to occur in cardiac transplant

recipients on immunosuppressive therapy. ACS may occur with progeria.

Irrespective of the cause of unstable angina, the result of persistent ischemia is myocardialinfarction (MI).

Frequency

United States

Although the exact incidence of ACS is difficult to ascertain, hospital discharge data indicatethat 1,680,000 unique discharges for ACS occurred in 2001.
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International

In Britain, annual incidence rate of angina is estimated at 1.1 cases per 1000 males and 0.5cases per 1000 females aged 31-70 years. In Sweden, chest pain of ischemic origin is thoughtto affect 5% of all males aged 50-57 years. In industrialized countries, annual incidence rate of

unstable angina is approximately 6 cases per 10,000 people.

Mortality/Morbidity

When the only therapy for angina was nitroglycerin and limitation of activity, patients withnewly diagnosed angina had a 40% incidence of MI and a 17% mortality rate within 3 months.A recent study shows that the 30-day mortality rate from ACS has decreased as treatment hasimproved, a statistically significant 47% relative decrease in 30-day mortality rate amongnewly diagnosed ACS from 1987-2000. This decrease in mortality rate is attributed to aspirin,glycoprotein (GP) IIb/IIIa blockers, and coronary revascularization via medical intervention or

procedures.

Clinical characteristics associated with a poor prognosis include advanced age, male sex, priorMI, diabetes, hypertension, and multiple-vessel or left-mainstem disease.

Sex

Incidence is higher in males among all patients younger than 70 years. This is due to thecardioprotective effect of estrogen in females. At 15 years postmenopause, the incidence ofangina occurs with equal frequency in both sexes. Evidence exists that women more often havecoronary events without typical symptoms, which might explain the frequent failure to initially

diagnose ACS in women.

Age

ACS becomes progressively more common with increasing age. In persons aged 40-70 years,ACS is diagnosed more often in men than in women. In persons older than 70 years, men andwomen are affected about equally.

Clinical

History

Typically, angina is a symptom of myocardial ischemia that appears incircumstances of increased oxygen demand. It is usually described as asensation of chest pressure or heaviness, which is reproduced by activitiesor conditions that increase myocardial oxygen demand.

Not all patients experience chest pain. Some present with only neck, jaw,ear, arm, or epigastric discomfort.

Other symptoms, such as shortness of breath or severe weakness, mayrepresent anginal equivalents.

A patient may present to the ED because of a change in pattern or severityof symptoms. A new case of angina is more difficult to diagnose because

symptoms are often vague and similar to those caused by other conditions(eg, indigestion, anxiety).

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Patients may have no pain and may only complain of episodic shortness ofbreath, weakness, lightheadedness, diaphoresis, or nausea and vomiting.

Patients may complain of the following:o Palpitationso Pain, which is usually described as pressure, squeezing, or a burning

sensation across the precordium and may radiate to the neck,shoulder, jaw, back, upper abdomen, or either armo Exertional dyspnea that resolves with pain or resto Diaphoresis from sympathetic dischargeo Nausea from vagal stimulationo Decreased exercise toleranceo Patients with diabetes and elderly patients are more likely to have

atypical presentations and offer only vague complaints, such asweakness, dyspnea, lightheadedness, and nausea.

Stable anginao Involves episodic pain lasting 5-15 minuteso Provoked by exertiono Relieved by rest or nitroglycerin

Unstable angina: Patients have increased risk for adverse cardiac events,such as MI or death. Three clinically distinct forms exist, as follows:

o New-onset exertional anginao Angina of increasing frequency or duration or refractory to

nitroglycerino Angina at rest

Variant angina (Prinzmetal angina)o Occurs primarily at resto Triggered by smokingo Thought to be due to coronary vasospasm

Elderly persons and those with diabetes may have particularly subtlepresentations and may complain of fatigue, syncope, or weakness. Elderlypersons may also present with only altered mental status. Those withpreexisting altered mental status or dementia may have no recollection ofrecent symptoms and may have no complaints whatsoever.

As many as half of cases of ACS are clinically silent in that they do notcause the classic symptoms described above and consequently gounrecognized by the patient. Maintain a high index of suspicion for ACSespecially when evaluating women, patients with diabetes, older patients,patients with dementia, and those with a history of heart failure.

Physical

Physical examination results are frequently normal. If chest pain is ongoing,the patient will usually lie quietly in bed and may appear anxious,diaphoretic, and pale.

Hypertension may precipitate angina or reflect elevated catecholaminelevels due to either anxiety or exogenous sympathomimetic stimulation.

Hypotension indicates ventricular dysfunction due to myocardial ischemia,infarction, or acute valvular dysfunction.

Jugular venous distention Third heart sound (S3) may be present. A new murmur may reflect papillary muscle dysfunction.

Rales on pulmonary examination may suggest left ventricular (LV)dysfunction or mitral regurgitation.

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Presence of a fourth heart sound (S4) is a common finding in patients withpoor ventricular compliance due to preexisting ischemic heart disease orhypertension.

Causes

Atherosclerotic plaque is the predominant cause. Coronary arteryvasospasm is less common.

Alternative causes of angina include the following:o Ventricular hypertrophy due to hypertension, valvular disease, or

cardiomyopathyo Embolic occlusion of the coronary arterieso Hypoxia, as in carbon monoxide poisoning or acute pulmonary

disorderso Cocaine and amphetamines, which increase myocardial oxygen

demand and may cause coronary vasospasmo Underlying coronary artery disease, which may be unmasked by

severe anemiao Inflammation of epicardial arterieso Coronary artery dissection

Risk factors for ACS should be documented and include the following:o Male gendero Diabetes mellitus (DM)o Smoking historyo Hypertensiono Increased ageo Hypercholesterolemiao Hyperlipidemiao Prior cerebrovascular accident (CVA) - These patients constitute 7.5%

of patients with ACS and have high-risk features.o Inherited metabolic disorderso Methamphetamine useo Occupational stresso Connective tissue disease

Workup

Laboratory Studies

Troponin I is considered the preferred biomarker for diagnosing myocardialnecrosis. Troponins have the greatest sensitivity and specificity in detectingMI, and elevated serum levels are considered diagnostic of MI. They alsohave prognostic value.

o For early detection of myocardial necrosis, sensitivity of troponin issuperior to that of the creatine kinaseMB (CK-MB). Troponin I isdetectable in serum 3-6 hours after an MI, and its level remainselevated for 14 days.

o Troponin is a contractile protein that normally is not found in serum.It is released only when myocardial necrosis occurs.

o Troponin should be used as the optimum biomarkers for the

evaluation of patients with ACS who have coexistent skeletal muscleinjury.
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Troponin T has similar release kinetics to troponin I, and levels remainselevated for 14 days. False-positive results may occur in patients with renalfailure. Minor elevations in troponin T level also identify patients at risk forsubsequent cardiac events.

Elevated troponin levels may also point to minor myocardial injury due to

other causes. Zellweger et al described 4 patients with elevated troponinlevels after supraventricular tachycardia without evidence of coronaryartery disease and very low risk scores for ACS.1Similarly, Koller found thatendurance athletes may show elevated serum troponin levels in theabsence of ACS.2

CK-MB levels begin to rise within 4 hours after MI, peak at 18-24 hours, andsubside over 3-4 days. A level within the reference range does not excludemyocardial necrosis.

o The upper limit of normal for CK-MB is 3-6% of total CK. A normallevel in the ED does not exclude the possibility of MI. A single assayin the ED has a 34% sensitivity for MI. Serial sampling over periods of6-9 hours increases sensitivity to approximately 90%. Serial CK-MB

over 24 hours detects myocardial necrosis with a sensitivity near100% and a specificity of 98%.

o Occasionally, a very small infarct is missed by CK-MB; therefore,troponin levels should be measured for patients suspected to have MIwho have negative results from serial CK-MB tests.

o One study looked at using the 2-hour delta (increase or decrease) ofcardiac markers as 1 of 6 criteria in making the diagnosis of ACS andMI. According to one of the Erlanger criteria, an increase in the CK-MBlevel of 1.5 ng/mL or greater or an increase of the cardiac troponin Ilevel of 0.2 ng/mL or greater over 2 hours in itself would allow one tomake the provisional diagnosis of ACS with a high degree ofsensitivity and specificity, even if the total levels were within thenormal range. Patients with recent MI were also identified by adecreasing curve of CK-MB. Using this 2-hour delta of cardiacmarkers greatly reduces the number of cases of MI and ACS that areoverlooked in patients who are then inappropriately dischargedhome.

Myoglobin, a low-molecular-weight heme protein found in cardiac andskeletal muscle, is released more rapidly from infarcted myocardium thantroponin and CK-MB and may be detected as early as 2 hours after MI.Myoglobin levels, although highly sensitive, are not cardiac specific. Theymay be useful for early detection of MI when performed with other studies.

Cardiac markers should be used liberally to evaluate patients with

prolonged episodes of ischemic pain, with new changes on ECG, or withnondiagnostic or normal ECGs in whom the diagnosis of ACS or MI is beingconsidered.

Complete blood count is indicated to determine if anemia is a precipitant.Transfusion with packed red blood cells may be indicated.

A chemistry profile is indicated. Obtain a basic metabolic profile, including acheck of blood glucose level, renal function, and electrolytes levels, forpatients with new-onset angina. Potassium and magnesium levels should bemonitored and corrected. Creatinine levels must be considered before usingan angiotensin-converting enzyme (ACE) inhibitor.

Other biochemical markerso C-reactive protein (CRP) is a marker of acute inflammation. Patients

without biochemical evidence of myocardial necrosis but elevatedCRP level are at increased risk of an adverse event.

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o Interleukin 6 is the major determinant of acute-phase reactantproteins in the liver, and serum amyloid A is another acute-phasereactant. Elevations of either of these can be predictive indetermining increased risk of adverse outcomes in patients withunstable angina.

o

Several other biomarkers have been investigated with variablesensitivity and specificity that include sCD40 ligand,myeloperoxidase, pregnancy-associated plasma protein-A, choline,placental growth factor, cystatin C, fatty acid binding protein,ischemia modified albumin, chemokines ligand-5 and -18 (mediatorsof monocyte recruitment induced by ischemia), angiogenin, SCUBE1(a novel platelet protein), and others.3,4In a study that included 107patients presenting to an emergency department with chest pain,ischemia modified albumin was not found to have superior sensitivityand specificity over traditional biomarkers with a sensitivity of 0.86and specificity of 0.49.5

In one study, patients presenting to the ED with suspected myocardial

ischemia showing higher levels of inflammatory cytokines were associatedwith an increased risk of a serious cardiac event during the subsequent 3months. However, the cytokines have limited ability to predict a seriousadverse cardiac event.

Erythrocyte sedimentation rate rises above reference range values within 3days and may remain elevated for weeks.

Serum lactase dehydrogenase level rises above the reference range within24 hours of MI, reaches a peak within 3-6 days, and returns to the baselinewithin 8-12 days.

Imaging Studies

Chest radiograph may demonstrate complications of ischemia, such aspulmonary edema, or it may provide clues to alternative causes ofsymptoms, such as thoracic aneurysm or pneumonia.

Echocardiogram often demonstrates wall motion abnormalities due toischemia. It is of limited value in patients whose symptoms have resolved orin those with preexisting wall motion abnormalities. However,echocardiogram may be useful in identifying precipitants for ischemia, suchas ventricular hypertrophy and valvular disease.

Radionuclide myocardial perfusion imaging has been shown to havefavorable diagnostic and prognostic value in this setting, with an excellentearly sensitivity to detect acute myocardial infarction (MI) not achieved by

other testing modalities.o A normal resting perfusion imaging study has been shown to have a

negative predictive value of more than 99% in excluding MI.Observational and randomized trials of both rest and stress imagingin the ED evaluation of patients with chest pain have demonstratedreductions in unnecessary hospitalizations and cost savingscompared with routine care.

o Perfusion imaging has also been used in risk stratification after MIand for measurement of infarct size to evaluate reperfusiontherapies. Novel "hot spot" imaging radiopharmaceuticals thatvisualize infarction or ischemia are currently undergoing evaluation

and hold promise for future imaging of ACS. (See MyocardialIschemia - Nuclear Medicine and Risk Stratification.)

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Recent advances include CT coronary angiography and CT coronary arterycalcium scoring.

o The dual-source 64-slice CT scanners can do a full scan in 10 secondsand produce high-resolution images that allow fine details of thepatient's coronary arteries to be seen. This technology allows for

noninvasive and early diagnosis of coronary artery disease and thusearlier treatment before the coronary arteries become more orcompletely occluded. It allows direct visualization of not only thelumen of the coronary arteries but also plaque within the artery.Dual-source 64-slice CT scanning is being used with intravenouscontrast to determine if a stent or graft is open or closed.

o CT coronary artery scoring is emerging as an attractive riskstratification tool in patients who are low risk for acute coronarysyndrome. This imaging modality exposes the patient to very littleradiation (1-2 msV). No contrast is needed, and the study does nothave a requirement for heart rate.6

Technetium-99m (99mTc) tetrofosmin single-photon emission computed

tomography (SPECT) is a useful method to exclude high-risk patients amongpatients with chest pain in the emergency department.

Resting cardiac magnetic resonance imaging (MRI) has exhibited diagnosticoperating characteristics suitable for triage of patients with chest pain in theED. Performed urgently to evaluate chest pain, MRI accurately detected ahigh fraction of patients with ACS, including patients with enzyme-negativeunstable angina. MRI can identify wall thinning, scar, delayed enhancement(infarction), and wall motion abnormalities (ischemia). Coronary arteryassessment may be coupled with magnetic resonance (MR) angiography inthe future.

Other Tests

ECG is the most important ED diagnostic test for angina. It may showchanges during symptoms and in response to treatment, which wouldconfirm a cardiac basis for symptoms. It also may demonstrate preexistingstructural or ischemic heart disease (left ventricular hypertrophy, Q waves).A normal ECG or one that remains unchanged from the baseline does notexclude the possibility that chest pain is ischemic in origin. Changes thatmay be seen during anginal episodes include the following:

o Transient ST-segment elevations (fixed changes suggestacute MI) may be observed. In patients with elevated STsegments, consider LV aneurysm, pericarditis, Prinzmetal

angina, early repolarization, and Wolff-Parkinson-Whitesyndrome as possible diagnoses.

o Dynamic T-wave changes (inversions, normalizations, orhyperacute changes) may be observed. In patients withdeep T-wave inversions, consider CNS events or drugtherapy with tricyclic antidepressants or phenothiazines.

o ST depressions may be junctional, downsloping, orhorizontal.

o Diagnostic sensitivity may be increased by performingright-sided leads (V4 R), posterior leads (V8, V9), and serialrecordings.

ECGs from 2 patients are shown below.

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A 50-year-old man with type 1 diabetes mellitus and

hypertension presents after experiencing 1 hour of

midsternal chest pain that began after eating a large meal.

Pain is now present but is minimal. Aspirin is the single drug

that will have the greatest potential impact on subsequent

morbidity. In the setting of ongoing symptoms and ECG

changes, nitrates titrated to 10% reduction in blood pressure

and symptoms, beta-blockers, and heparin are all indicated.

If the patient continues to have persistent signs and/or

symptoms of ischemia, addition of a glycoprotein IIb/IIIa

inhibitor should be considered.

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A 62-year-old woman with a history of chronic stable angina and a "valve

problem" presents with new chest pain. She is symptomatic on

arrival, complaining of shortness of breath and precordial chest

tightness. Her initial vital signs are blood pressure 140/90 mm Hg

and heart rate is 98. Her ECG is as shown. She is given

nitroglycerin sublingually, and her pressure decreases to80/palpation. Right ventricular ischemia should be considered in

this patient.

Treatment

Prehospital Care

Generally, patients transported with chest pain should initially be managed under the

assumption that the pain is ischemic in origin. Prehospital interventions should be guided bythe nature of the presenting complaint, individual risk factors, and associated symptoms (eg,breathing difficulty, hemodynamic instability, appearance of ectopy). Airway, breathing, andcirculation should be rapidly assessed with institution of CPR, ACLS-guided interventions, orother measures as indicated for the unstable patient.

Obtain intravenous access. Administer supplemental oxygen. Aspirin (162-325 mg) should be given in the field, chewed and swallowed. Administer sublingual or aerosolized nitroglycerin if chest pain is ongoing

and is believed to be cardiac in origin. Additionally, recently, the AHA has published a statement on integrating

prehospital ECGs into care for ACS patients (see AHA Publishes Statementon Integrating Prehospital ECGs Into Care for ACS Patients). Prehospitalintegration of ECG interpretation, when AMI is present, has been shown todecrease "door to balloon time," to allow paramedics to bypass non-PCIhospitals in favor of better equipped facilities, and to expedite care byallowing an emergency physician to activate the catheterization laboratorybefore patient arrival.

Prehospital thrombolysis allows eligible patients to receive thrombolysis 30-60 minutes sooner than if treatment were given in the ED; however,prehospital thrombolysis is still under investigation and has not become atrend due to unproven benefit and due to the increase in availability of

percutaneous coronary intervention (PCI) in many medical centers as analternative to thrombolysis for STEMI.

Emergency Department Care

The ACS spectrum concept is a useful framework for developing therapeutic strategies.Antithrombin therapy and antiplatelet therapy should be administered to all patients with anACS regardless of the presence or the absence of ST-segment elevation. Patients presentingwith persistent ST-segment elevation are candidates for reperfusion therapy (either

pharmacological or catheter based) to restore flow promptly in the occluded epicardial infarct-related artery. Patients presenting without ST-segment elevation are not candidates for

immediate pharmacological reperfusion but should receive anti-ischemic therapy and PCI whenappropriate. "Time is myocardium" is a dictum to be remembered as survival has been shown
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to correlate with time to reperfusion in patients with acute MI. Many centers set goals for, androutinely record, door-to-ECG, door-to-needle (thrombolytic therapy), or door-to-vascularaccess (for patients receiving PCI) times as measures of quality of care provided.

Rathore et al found that any delay in primary percutaneous coronary intervention after a patient

with ST-elevation myocardial infarction (STEMI) arrives at hospital is associated with highermortality.7In a prospective cohort study of 43,801 patients enrolled in the American College ofCardiology National Cardiovascular Data Registry, 2005-2006, longer door-to-balloon timeswere associated with a higher adjusted risk of in-hospital mortality, in a continuous nonlinearfashion (30 min = 3%, 60 min = 3.5%, 90 min = 4.3%, 120 min = 5.6%, 150 min = 7%, 180min = 8.4%, P

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Treatment and evaluation guidelines are available from various sources including the AmericanCollege of Emergency Physicians, American College of Chest Physicians, and NationalAcademy of Clinical Biochemistry.9,10,11

Consultations

Cardiology or interventional cardiology consultation may be indicated for patients with any ofthe following:

STEMI - Depending on the center, the patient may be a candidate for PCI,and immediate interventional cardiology consultation is indicated.

o Ongoing symptoms highly suggestive of acute coronary ischemia andnondiagnostic ECG (eg, left bundle-branch block [LBBB])

o Ongoing symptoms refractory to aggressive medical therapyo Hemodynamic instabilityo Evidence of acute valvular dysfunction

o Shocko Known severe aortic stenosis and ongoing symptomso Uncertainty of the diagnosis

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial studied theimpact of age on outcomes in moderate- and high-risk non-ST-segment elevation acutecoronary syndrome (NSTE-ACS). Outcomes were analyzed at 30 days and 1 year in 4 agegroups, overall and among those undergoing percutaneous coronary intervention (PCI). Of13,819 patients in the ACUITY trial, 3,655 (26.4%) were younger than 55 years of age, 3,940(28.5%) were aged 55-64 years, 3,783 (27.4%) were aged 65-74 years, and 2,441 (17.7%) were75 years or older. Older patients had more cardiovascular risk factors and had a higher acuity at

presentation. Patients aged 75 years or older treated with bivalirudin alone had similar ischemicoutcomes but significantly lower rates of bleeding compared with those treated with heparinand glycoprotein IIb/IIIa inhibitors overall and in the PCI subset.12

Medication

The goals of treatment are to preserve patency of the coronary artery, augment blood flowthrough stenotic lesions, and reduce myocardial oxygen demand. All patients should receiveantiplatelet agents, and patients with evidence of ongoing ischemia should receive aggressivemedical intervention until signs of ischemia, as determined by symptoms and ECG, resolve.

The value of aspirin in primary prophylaxis for cardiovascular diseases was challenged in theAspirin for Asymptomatic Atherosclerosis trial. In this double-blind randomized controlledtrial, 28,980 men and women aged 50-75 years living in central Scotland, and recruited from acommunity health registry, who were free of clinical cardiovascular disease, but at higher riskof atherosclerosis and an increased risk of cardiovascular and cerebrovascular events based onlow ankle brachial index (ABI), were given 100 mg aspirin (enteric coated) or placebo.

The primary end point was a composite of initial fatal or nonfatal coronary event or stroke orrevascularization. Secondary end points included angina, intermittent claudication, or transientischemic attack; as well as all-cause mortality. After a mean (SD) follow-up of 8.2 (1.6) years,

none of the study end points showed statistically significant difference between groups. Therate of an initial event of major hemorrhage requiring admission to hospital was not also

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statistically different between the groups. Note though that this study was powered to detect a25% proportional risk reduction in events, which may not have been achieved.13,14

Antiplatelet agents

These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A2,which is a potent platelet activator. Antiplatelet therapy has been shown to reduce mortalityrates by reducing the risk of fatal strokes and fatal myocardial infarctions.

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Early administration of aspirin in patients with AMI may reduce cardiac mortality in firstmonth.

Dosing

Adult

160-324 mg PO or chewed; suppository if patient is unable to take PO medications

Pediatric

Not established

Nitrates

These agents oppose coronary artery spasm and reduce myocardial oxygen demand by reducingboth preload and afterload.

Nitroglycerin (Nitro-Bid)

Causes relaxation of the vascular smooth muscle via stimulation of intracellular cyclicguanosine monophosphate production, causing a decrease in blood pressure.

Dosing

Adult

400 mcg SL or spray q5min, repeated up to 3 timesIf symptoms persist, administer 5-10 mcg/min IV infusionDose should be titrated to reduce MAP by 10%, relieve symptoms, limit adverse effects ofhypotension (>30% reduction in MAP or

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Analgesics

These agents reduce pain, which decreases sympathetic stress, in addition to providing somepreload reduction.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

DOC for narcotic analgesia because of its reliable and predictable effects, safety profile, andease of reversibility with naloxone.Morphine sulfate administered IV may be dosed in a number of ways and commonly titrateduntil desired effect obtained.

Dosing

Adult

2-4 mg IV q5-15min; titrate to symptomatic relief or adverse effects (eg, lethargy, hypotension,respiratory depression)

Pediatric

Not established

Anticoagulants

These agents are used to prevent recurrence of clot after a spontaneous fibrinolysis.

Heparin

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does notactively lyse but is able to inhibit further thrombogenesis. Prevents recurrence of a clot afterspontaneous fibrinolysis.

Dosing

Adult

80 U/kg IV bolus, followed by an infusion of 18 U/kg/h

Pediatric

Not established

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Beta-adrenergic blockers

These agents have antiarrhythmic and antihypertensive properties as well as ability to reduceischemia. They minimize the imbalance between myocardial supply and demand by reducingafterload and wall stress. In patients with acute MI, they have been shown to decrease infarct

size as well as short- and long-term mortality, which is a function of their anti-ischemic andantiarrhythmic properties.

Metoprolol (Lopressor)

Selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions.During IV administration, carefully monitor blood pressure, heart rate, and ECG. Goal oftreatment is to reduce heart rate to 60-90 beats/min.

Adult

5 mg slow IV infusion q5min; to a maximum dose of 15 mg or desired heart rate

Pediatric

Not established

Glycoprotein IIB/IIA inhibitors

Glycoprotein (GP) IIb/IIIa antagonists prevent the binding of fibrinogen, thereby blockingplatelet aggregation. Studies to date suggest that as a class, the addition of intravenous GP

IIb/IIIa inhibitors to aspirin and heparin improves both early and late outcomes, includingmortality, Q-wave MI, need for revascularization procedures, and length of hospital stay.

Currently, IIb/IIIb antagonists in combination with aspirin are considered standard antiplatelettherapy for patients at high risk for unstable angina. Adenosine diphosphate (ADP) antagonistsare not considered standard therapy but may be used in patients unable to tolerate aspirin.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody. Binds to receptor with high affinity and reducesplatelet aggregation by 80%. Inhibition of platelet aggregation persists for up to 48 h after end

of infusion.Abciximab has been approved for use in elective/urgent/emergent percutaneous coronaryintervention.

Adult

0.25 mg/kg bolus IV followed by an infusion of 0.125 mcg/kg/min; maximum 10 mcg/min for12 h

Pediatric

Not established

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Adenosine diphosphate receptor antagonists

Two thienopyridines, clopidogrel and ticlopidine, are ADP antagonists that are approved for

antiplatelet activity. Both have irreversible antiplatelet activity but take several days tomanifest. A potential additive benefit exists when ADP antagonists are used in conjunctionwith aspirin.

These drugs may be considered alternatives to aspirin in patients intolerant or allergic toaspirin.

Clopidogrel (Plavix)

Generally preferred over ticlopidine because it more rapidly inhibits platelets and appears tohave a more favorable safety profile.

Adult

300 mg PO loading dose, followed by 75 mg PO qd

Pediatric

Not established

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Congestive Heart Failure and Pulmonary

EdemaIntroduction

Background

Congestive heart failure (CHF) is an imbalance in pump function in which the heart fails toadequately maintain the circulation of blood. The most severe manifestation of CHF,

pulmonary edema, develops when this imbalance causes an increase in lung fluid secondary toleakage from pulmonary capillaries into the interstitium and alveoli of the lung.

CHF can be categorized as forward or backward ventricular failure. Backward failure issecondary to elevated systemic venous pressure, whereas left ventricular failure is secondary toreduced forward flow into the aorta and systemic circulation. Furthermore, heart failure can besubdivided into systolic and diastolic dysfunction. Systolic dysfunction is characterized by adilated left ventricle with impaired contractility, whereas diastolic dysfunction occurs in anormal or intact left ventricle with impaired ability to relax and receive as well as eject blood.

Chest radiograph shows signs of congestive heart failure (CHF).

The New York Heart Association's functional classification of CHF is one of the most

useful. Class I describes a patient who is not limited with normal physical activity

by symptoms. Class II occurs when ordinary physical activity results in fatigue,dyspnea, or other symptoms. Class III is characterized by a marked limitation in

normal physical activity. Class IV is defined by symptoms at rest or with any

physical activity.

Pathophysiology

Congestive heart failure (CHF) is summarized best as an imbalance in Starling forces or animbalance in the degree of end-diastolic fiber stretch proportional to the systolic mechanicalwork expended in an ensuing contraction. This imbalance may be characterized as amalfunction between the mechanisms that keep the interstitium and alveoli dry and theopposing forces that are responsible for fluid transfer to the interstitium.

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Maintenance of plasma oncotic pressure (generally about 25 mm Hg) higher than pulmonarycapillary pressure (about 7-12 mm Hg), maintenance of connective tissue and cellular barriersrelatively impermeable to plasma proteins, and maintenance of an extensive lymphatic systemare the mechanisms that keep the interstitium and alveoli dry.

Opposing forces responsible for fluid transfer to the interstitium include pulmonary capillarypressure and plasma oncotic pressure. Under normal circumstances, when fluid is transferredinto the lung interstitium with increased lymphatic flow, no increase in interstitial volumeoccurs. However, when the capacity of lymphatic drainage is exceeded, liquid accumulates inthe interstitial spaces surrounding the bronchioles and lung vasculature, thus creating CHF.When increased fluid and pressure cause tracking into the interstitial space around the alveoliand disruption of alveolar membrane junctions, fluid floods the alveoli and leads to pulmonaryedema.

Etiologies of pulmonary edema may be placed in the following 6 categories:

1. Pulmonary edema secondary to altered capillary permeability: Acuterespiratory distress syndrome (ARDS), infectious causes, inhaled toxins,circulating exogenous toxins, vasoactive substances, disseminatedintravascular coagulopathy (DIC), immunologic processes reactions, uremia,near drowning, and other aspirations

2. Pulmonary edema secondary to increased pulmonary capillarypressure: Cardiac causes and noncardiac causes, including pulmonaryvenous thrombosis, stenosis or veno-occlusive disease, and volumeoverload

3. Pulmonary edema secondary to decreased oncotic pressure found withhypoalbuminemia

4. Pulmonary edema secondary to lymphatic insufficiency5. Pulmonary edema secondary to large negative pleural pressure withincreased end expiratory volume

6. Pulmonary edema secondary to mixed or unknown mechanisms includinghigh altitude pulmonary edema (HAPE), neurogenic pulmonary edema,heroin or other overdoses, pulmonary embolism, eclampsia,postcardioversion, postanesthetic, postextubation, and postcardiopulmonary bypass

This article is limited to cardiac causes of pulmonary edema and congestive heart failure (CHF)and its relevant emergency care.

Frequency

United States

More than 3 million people have congestive heart failure (CHF), and more than 400,000 newpatients present yearly. The prevalence rate of CHF is 1-2%.

Mortality/Morbidity

Approximately 30-40% of patients with congestive heart failure (CHF) arehospitalized every year. CHF is the leading diagnosis-related group (DRG)among hospitalized patients older than 65 years. The 5-year mortality rateafter diagnosis was reported in 1971 as 60% in men and 45% in women. In
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1991, data from the Framingham heart study showed the 5-year mortalityrate for CHF essentially remaining unchanged, with a median survival of 3.2years for males and 5.4 years for females. This may be secondary to anaging US population with declining mortality due to other diseases.

The most common cause of death is progressive heart failure, but suddendeath may account for up to 45% of all deaths. After auditing data on 4606patients hospitalized with CHF between 1992-1993, the total in-hospitalmortality rate was 19%, with 30% of deaths occurring from noncardiaccauses.

Patients with coexisting insulin-dependent diabetes mellitus have asignificantly increased mortality rate.

Race

Blacks are 1.5 times more likely to die of CHF than whites are.Nevertheless, black patients appear to have similar or lower in-hospitalmortality rates than white patients.

Sex

Prevalence is greater in males than in females in patients aged 40-75 years. No sex predilection is noted among patients older than 75 years.

Age

Prevalence of CHF increases with increasing age and affects about 10% ofthe population older than 75 years.

Clinical

History

Anxiety Dyspnea at rest Dyspnea upon exertion: This has been found to be the most sensitive

symptom reported, yet the specificity for dyspnea is less than 60%. Orthopnea and paroxysmal nocturnal dyspnea (PND): These symptoms are

observed; however, the sensitivity for orthopnea and PND is only 20-30%. Cough: Cough that produces pink, frothy sputum is highly suggestive of

congestive heart failure (CHF). Edema Nonspecific symptoms

o Weaknesso Lightheadednesso Abdominal paino Malaiseo Wheezingo Nausea

Past medical historyo Cardiomyopathy

o Valvular heart diseaseo Alcohol use

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o Hypertensiono Anginao Prior myocardial infarctiono Familial heart disease

Physical

Findings such as peripheral edema, jugular venous distention, andtachycardia are highly predictive of congestive heart failure (CHF). Overallspecificity of physical examination has been reported at 90%; however, thissame study reported a sensitivity of only 10-30%.

Tachypnea, using accessory muscles of respiration, has been observed. Hypertension may be present. Pulsus alternans (alternating weak and strong pulse indicative of depressed

left ventricle [LV] function) may be observed. The skin may be diaphoretic or cold, gray, and cyanotic. Jugular venous distention (JVD) is frequently present. Wheezing or rales may be heard on lung auscultation. Apical impulse is frequently laterally displaced. Cardiac auscultation may reveal aortic or mitral valvular abnormalities (S3

or S4). Lower extremity edema may also be noted, especially in the subacute

process.

Causes

Various cardiac diseases cause congestive heart failure (CHF) andpulmonary edema.

The most common cause of heart failure is coronary artery disease, which issecondary to loss of left ventricular muscle, ongoing ischemia, or decreaseddiastolic ventricular compliance.

Other disease processes include hypertension, valvular heart disease,congenital heart disease, other cardiomyopathies, myocarditis, andinfectious endocarditis.

CHF is often precipitated by cardiac ischemia or dysrhythmias, cardiac orextracardiac infection, pulmonary embolus, physical or environmentalstresses, changes or noncompliance with medical therapy, dietaryindiscretion, or iatrogenic volume overload.

One also must consider systemic processes such as pregnancy and

hyperthyroidism as precipitants of CHF.

Workup

Laboratory Studies

Until recently, differentiating asthma and other pulmonary disease has beendifficult in the acute setting, particularly because of the poor sensitivitiesand specificities of most elements of history and physical examination. Thestandard of care has been shotgun therapy, namely treating patients forboth congestive heart failure (CHF) and an acute pulmonary process such asasthma, with both diuretics and beta-agonists.

o The Breathing Not Properly Study has suggested that serum levels ofbeta-natriuretic peptide (BNP) and the BNP precursor, Pro-BNP, can
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help identify CHF as the origin of acute dyspnea.1This study foundsensitivities of 90% with specificities of 76%. Positive predictive valuewas 79%, with a negative predictive value of 89%. Mueller et al founda reduction in hospital length of stay of 3 days when BNP levels wereused.2This study assumed an average length of stay of 11 days;however, the average length of stay in the United States for CHFexacerbations is approximately 4 days. Also, although the time toinitiation of therapy was reduced in this study from 90 to 60 minutes,the general practice in the United States is immediate initiation ofshotgun therapy.

o In the primary care setting, Wright et al identified 305 patients withheart failure and then reevaluated them with or without the Pro-BNPresult.3Diagnostic accuracy improved from 52% to 60% without Pro-BNP and from 49% to 70% with Pro-BNP.

o Maisel et al identified in the Breathing Not Properly Study a 20%increase in patients with CHF who presented with dyspnea and ahistory of asthma or COPD but no prior history of CHF.4

o Mueller et al found that BNP reduced time to discharge from 12 to 3days and reduced costs of hospitalization by 15%.2

o BNP is available as a point-of-care test, with results available within15 minutes; however, only Pro-BNP can be concomitantly used withnesiritide.

o Serum levels of BNP lower than 100 pg/mL are unlikely to be fromCHF. In the Breathing Not Properly Study, a BNP level of 50 pg/mLincreased sensitivity from 90% to 97%, although specificity wasreduced.1levels of 100-500 pg/mL may be CHF. However, otherconditions that also elevate right filling pressures (eg, pulmonaryembolus, primary pulmonary hypertension, end-stage renal failure,cirrhosis, hormone replacement therapy) may also cause elevatedBNP levels in this range. BNP levels more than 500 pg/mL are mostconsistent with CHF.

o Steinhart et al derived and validated a diagnostic prediction modelfor acute heart failure that incorporates both clinical assessment andN-terminal pro-B-type natriuretic peptide (NT-proBNP).5Variablesused to predict acute heart failure were age, pretest probability, andlog NT-proBNP. Validation of the model in 1073 patients showed thatlikelihood ratios for acute heart failure with NT-proBNP were 0.11(95% confidence interval [CI], 0.06-0.19) for cut-point values lessthan 300 pg/mL, increasing to 3.43 (95% CI, 2.34-5.03) for values2700-8099 pg/mL, and 12.80 (95% CI, 5.21-31.45) for values 8100

pg/mL or higher. When the model was applied to external data, 44%of patients who had been clinically classified as having intermediateprobability of acute heart failure were appropriately reclassified toeither low or high probability categories, with negligible (

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Increased creatinine levels, hyperbilirubinemia, and dilutional hyponatremiaare observed in severe cases.

Imaging Studies

Chest radiographyo Although diagnostic tests are of limited benefit in acute congestive

heart failure (CHF), chest radiography is the most useful tool. Arecent study showed that 1 out 5 patients admitted to the hospitalwith CHF lacked signs of congestion on chest radiograph.6

o Cardiomegaly may be observed with a cardiothoracic ratio greaterthan 50%. Pleural effusions may be present bilaterally or if they areunilateral more commonly observed on the right.

o Early CHF may manifest as cephalization of pulmonary vessels,generally reflecting a pulmonary capillary wedge pressure (PCWP) of12-18 mm Hg. As the interstitial fluid accumulates, more advancedCHF may be demonstrated by Kerley B lines (PCWP is 18-25 mm Hg).

o Pulmonary edema is observed as perihilar infiltrates often in theclassic butterfly pattern, reflecting a PCWP of more than 25 mm Hg.

o Several limitations to chest radiography are observed whenattempting to diagnose CHF. Classic radiographic progression is oftennot found, and as much as a 12-hour radiographic lag from onset ofsymptoms may occur. In addition, radiographic findings frequentlypersist for several days despite clinical recovery.

Emergency transthoracic echocardiographyo Emergency transthoracic echocardiography (ECHO) may help identify

regional wall motion abnormalities as well as globally depressed ormyopathic left ventricular function.

o ECHO may help reveal cardiac tamponade, pericardial constriction,and pulmonary embolus.

o ECHO is also useful in revealing valvular heart disease, such as mitralor aortic stenosis or regurgitation.

Other Tests

ECG is a nonspecific tool but may be useful in diagnosing concomitantcardiac ischemia, prior myocardial infarction (MI), cardiac dysrhythmias,chronic hypertension, and other causes of left ventricular hypertrophy.

Procedures

No defined role is recognized for invasive monitoring devices such ascentral venous placement (CVP) lines. Time-consuming placement ofpulmonary artery catheters has not been shown to prolong survival, even inthe coronary care unit and, thus far, has not been well studied in theemergency department (ED) setting.

Cardiac catheterization may be necessary for a complete evaluation andassessment of prognosis.

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Treatment

Prehospital Care

Prehospital notification by emergency medical services (EMS) personnel

should alert ED staff of a patient presenting with signs and symptoms ofcongestive heart failure (CHF) and pulmonary edema. They should receiveonline medical advice for patients with high-risk presentations.

Begin treatment with the ABCs. Administer supplemental oxygen, initially100% nonrebreather facemask.

Use cardiac monitoring and continuous pulse oximetry. Obtain intravenous access, as well as a prehospital ECG, if available. Provide nitroglycerin sublingual or spray for active chest pain in the patient

without severe hypotension and intravenous furosemide.


Begin ED treatment of a patient presenting with signs and symptoms ofcongestive heart failure (CHF) and pulmonary edema with the ABCs.Administer supplemental oxygen, initially 100% nonrebreather facemask.Use cardiac monitoring and continuous pulse oximetry. Obtain intravenousaccess.

To reduce venous return, elevate the head of the bed. Patients may be mostcomfortable in a sitting position with their legs dangling over the side of thebed, which allows for reduced venous return and decreased preload.

Therapy generally starts with nitrates and diuretics if patients arehemodynamically stable. Many other treatment modalities may play somerole in acute management.

If possible, treat the underlying cause as well, if identified. This isparticularly necessary for patients with known diastolic dysfunction whorespond best to reductions in blood pressure, rather than to diuretics,nitrates, and inotropic agents. Serum BNP levels may be very useful in thesetting of undifferentiated dyspnea, or in the future may be useful to gaugetherapeutic success.

Eliminate contributing factors when possible. Restrict fluid and sodium. Consider other treatment modalities, including nesiritide. Nesiritide may be

useful in lieu of nitroglycerin in patients with moderate respiratory distress,particularly if the patient will not tolerate noninvasive ventilation or in thepatient who cannot have nitroglycerin by protocol (ie, in an observationunit).

o Data comparing nasal CPAP therapy and facemask ventilationtherapy have demonstrated decreased need for intubation rateswhen these modalities are used.7However, in patients with severeCHF treated with CPAP, no significant difference was found in short-term mortality rates and length of hospital stay. Although BiPAPtherapy may improve ventilation and vital signs more rapidly thanCPAP, a higher incidence of MI associated with BiPAP has beenreported. BiPAP and CPAP are contraindicated in the presence ofacute facial trauma, the absence of an intact airway, and in patientswith an altered mental status or who are uncooperative.

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o Alternating tourniquets, formerly a mainstay of therapy, have beenused to decrease preload. Their use has been supplanted by newertherapies such as intravenous nitroglycerin and nitroprusside.

o Phlebotomy with removal of 500 mL of blood or via plasmapheresis isanother former mainstay of therapy used to decrease preload. Its use

has been supplanted by newer therapies such as intravenousnitroglycerin and nitroprusside.

Consultations

Cardiologist Critical care specialist Cardiothoracic surgeon, for possible heart valve surgery or transplantation

Medication

The goal of pharmacotherapy is to achieve a PCWP of 15-18 mm Hg and a cardiac index ofmore than 2.2 L/min/m2 while maintaining adequate blood pressure and perfusion to essentialorgans. These goals may need to be modified for some patients.

Use of diuretics, nitrates, analgesics, and inotropic agents are indicated for the treatment ofcongestive heart failure (CHF) and pulmonary edema. Calcium channel blockers, such asnifedipine and nondihydropyridines, increase mortality and increase prevalence of recurrentCHF with chronic use. Conflicting evidence currently argues both in favor of and against theuse of calcium channel blockers in the acute setting; at this time, limit their acute use to

patients with diastolic dysfunction and heart failure, a condition not easily determined in theemergency department.

ACE inhibitors, such as sublingual (SL) captopril or intravenous enalapril, may rapidly reversehemodynamic instability and symptoms, possibly avoiding an otherwise imminent intubation.Haude et al compared 25 mg of SL captopril with 0.8 mg of sublingual nitroglycerin in 24

patients with class III and class IV CHF and found that captopril induces a more sustained andmore pronounced improvement in hemodynamics.8Annane et al gave 1 mg of intravenousenalapril to 20 patients presenting with acute class III and class IV CHF over 2 hours andreported rapid hemodynamic improvement with no significant adverse effects on cardiac outputor hepatosplanchnic measurements.9

Captopril may play a unique role in sustaining patients with renal failure and concomitant acuteCHF while awaiting definitive therapy with dialysis. Because the information on this subject isstill controversial and is limited to small studies, the routine use of ACE inhibitors cannot berecommended at this time. ACE inhibitors remain a promising area in need of further study.

Beta-blockers, possibly by restoring beta-1 receptor activity or via prevention of catecholamineactivity, appear to be cardioprotective in patients with depressed left ventricular function. TheUS Carvedilol Heart Failure study group demonstrated a two-thirds decrease in mortality in

patients taking carvedilol with left ventricular ejection fractions of 35% or less. Beta-blockers,particularly carvedilol, have been shown to improve symptoms in patients with moderate-to-severe heart failure. However, the role of beta-blockers in the acute setting is currently unclear;

limit use until hemodynamic studies indicate that further deterioration is not possible.

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Because differentiating CHF and asthma exacerbations is often difficult, treating both with theshotgun approach is often used, particularly as both may cause bronchospasm. Aerosolized

beta-2 agonists, which are the more selective of beta-agonists, decrease tachycardia,dysrhythmias, and cardiac work while transiently enhancing cardiac function. Terbutaline has

been shown to be successful in this setting, as well as albuterol, isoetharine, and bitolterol.

Limit roles of theophylline and aminophylline in the acute setting. They are positive inotropicagents mediated by an increase in catecholamines, and they dilate coronaries and exert milddiuretic effects. Nevertheless, they can exacerbate dysrhythmias (eg, multifocal atrialtachycardia [MAT], ischemia) by increasing cardiac work.

Steroids, intravenous or orally administered, have been shown to worsen preexisting heartfailure due to systemic sodium retention and volume expansion, hypokalemia, and occasionalhypertension. Inhaled steroids, because of their lack of systemic side effects, may be areasonable option in this confusing patient presentation; however, given their delayed onset ofaction, they remain an area in need of further study.

Please see the article on Asthma for dosing schedules.

Diuretics

First-line therapy generally includes a loop diuretic such as furosemide, which inhibits sodiumchloride reabsorption in the ascending loop of Henle.

Furosemide (Lasix)

Administer loop diuretics IV because this allows for both superior potency and higher peakconcentration despite increased incidence of side effects, particularly ototoxicity.

Adult

A reasonable approach for furosemide might be as follows:10-20 mg IV for patients symptomatic with CHF not already using diuretics40-80 mg IV for patients already using diuretics80-120 mg IV for patients whose symptoms are refractory to the initial dose after 1 h of its

administrationHigher doses and more rapid redosing may be appropriate for the patient in severe distress

Pediatric

Not established

Nitrates

These agents reduce myocardial oxygen demand by lowering preload and afterload.

In patients with severe hypertension, nitroprusside causes more arterial dilatation thannitroglycerin. Nevertheless, due to thiocyanate toxicity and the coronary steal phenomenon

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associated with nitroprusside, intravenous nitroglycerin is still the therapy of choice forafterload reduction.

Nitroglycerin (Nitro-Bid, Nitrol, Nitrostat)

SL nitroglycerin and nitrospray are particularly useful in patients who present with acutepulmonary edema with a systolic blood pressure of at least 100 mm Hg.Similar to SL, nitrospray's onset is 1-3 min with a half-life of 5 min. Applicability of nitrospraymay be easier, and storage is up to 4 y. One study reported significant and rapid hemodynamicimprovement in 20 patients given nitrospray with pulmonary edema in an ICU setting.Topical nitrate therapy is reasonable in a patient presenting with class I to II CHF. However, in

patients with more severe signs of heart failure or pulmonary edema, IV nitroglycerin ispreferred because it is easier to monitor hemodynamics and absorption, particularly in thepatients with diaphoresis.

Because of delayed absorption, PO nitrates have little role in the acute presentations of CHF.

Adult

Nitrospray: Single spray (0.4 mg) equivalent to a single 1/150 SL; may repeat q3-5min ashemodynamics permit, up to a maximum of 1.2 mgOintment: Apply 1-2 inches of nitropaste to chest wallInjection: Start at 20 mcg/min IV and rate to effect in 5-10 mcg increments q3-5min

Pediatric

Not established

Analgesics

Intravenous morphine is an excellent adjunct in acute therapy. In addition to being both ananxiolytic and an analgesic, its most important effect is venodilation, which reduces preload.This agent also causes arterial dilatation, which reduces systemic vascular resistance (SVR) andincreases cardiac output. Narcan can also reverse the effects of morphine. However, someevidence indicates that morphine use in acute pulmonary edema may increase the intubationrate.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

DOC for narcotic analgesia due to reliable and predictable effects, safety profile, and ease ofreversibility with naloxone.Morphine sulfate administered IV may be dosed in numerous ways and is commonly titrateduntil desired effect is obtained.

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Adult

2-5 mg IV and repeated q10-15min unless respiratory rate is

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Angina Pectoris

Introduction

Background

Angina pectoris (AP) represents the clinical syndrome occurring when myocardial oxygendemand exceeds supply. The term is derived from Latin; the literal meaning is "the choking ofthe chest;" angere, meaning "to choke" and pectus, meaning "chest." The first English-writtenaccount of recurrent angina pectoris was by English nobleman Edward Hyde, Earl ofClarendon. He described his father as having, with exertion, "a pain in the left armso muchthat the torment made him pale".1The first description of angina as a medical disorder camefrom William Heberden. Heberden, a prodigious physician, made many noteworthycontributions to medicine during his career. He presented his observations on "dolor pectoris"to the Royal College of Physicians in 1768. Much of his classic description retains its validitytoday.2

Angina pectoris has a wide range of clinical expressions. The symptoms most often associatedto angina pectoris are substernal chest pressure or tightening, frequently with radiating pain tothe arms, shoulders, or jaw. The symptoms may also be associated with shortness of breath,nausea, or diaphoresis. Symptoms stem from inadequate oxygen delivery to myocardial tissue.

No definitive diagnostic tools that capture all patients with angina pectoris exist. This,combined with its varied clinical expression, makes angina pectoris a distinct clinical challenge

to the emergency physician. The disease state can manifest itself in a variety of forms:

Stable angina pectoris is classified as a reproducible pattern of anginalsymptoms that occur during states of increased exertion.

Unstable angina pectoris (UA) manifests either as an increasing frequencyof symptoms or as symptoms occurring at rest.

Prinzmetal angina or variant angina occurs as a result of transient coronaryartery spasms. These spasms can occur either at rest or with exertion.Unlike stable or unstable angina, no pathological plaque or deposition ispresent within the coronary arteries that elicits the presentation. Onangiography, the coronary arteries are normal in appearance with spasm onangiography.

Cardiac syndrome X occurs when a patient has all of the symptoms ofangina pectoris without coronary artery disease or spasm.

Pathophysiology

The past 2 decades has greatly expanded our overall understanding of the

pathophysiology of myocardial ischemic syndromes. The primary dysfunction in

angina pectoris is decreased oxygen delivery to myocardial muscle cells. The 2

predominant mechanisms by which delivery is impaired appear to be coronary

artery narrowing and endothelial dysfunction. Any other mechanism that affects

oxygen delivery can also precipitate symptoms.

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Extracardiac causes of angina include, but are by no means limited to, anemia, hypoxia,hypotension, bradycardia, carbon monoxide exposure, and inflammatory disorders.3The endresult is a shift to anaerobic metabolism in the myocardial cells. This is followed by astimulation of pain receptors that innervate the heart. These pain receptors ultimately arereferred to afferent pathways, which are carried in multiple nerve roots from C7 through T4.

The referred/radiating pain of angina pectoris is believed to occur because these afferentpathways also carry pain fibers from other regions (eg, the arm, neck, and shoulders).

Coronary artery narrowing

Coronary artery narrowing appears to be the etiology of cardiac ischemia in the preponderanceof cases. This has clinical significance when atherosclerotic disease diminishes or halts bloodflow through the coronary arterial circulation, interfering with normal laminar blood flow. Thesignificance of even a small change in the diameter of a blood vessel can be profound. ThePoiseuille law predicts this outcomethe rate of flow is decreased exponentially by anychange in the radius of the lumen. As with a smaller pediatric airway, even relatively minute

changes in diameter have dramatic consequences in flow rates. Thus, when a lumen isnarrowed by one fifth, the flow rate is decreased by about one half. This predicts that even asmall change in a coronary artery plaque size can affect the oxygenation through that vessel'sterritory.

The epicardial vessel, where atherosclerosis often takes place, has the capacity to dilate viaautoregulatory mechanisms to respond to increased demand. Angina occurs as thiscompensatory mechanism is overwhelmed either by large plaques (typically considered 70% orgreater obstruction) or by significantly increased myocardial demand.4

Endothelial factors

Endothelial factors also play an important role in angina pectoris. During sympatheticstimulation, the endothelium is subjected to mediators of both vasoconstriction andvasodilatation. Alpha-agonists (catecholamines) directly cause vasoconstriction, whileendothelial nitrous oxide synthase creates nitrous oxide (NO), which counteracts thisconstricting force via vasodilatation.

In the diseased coronary artery, NO production is reduced or absent. In this setting, thecatecholamine drive can overwhelm the autoregulatory mechanisms. In addition, theendothelium of the plaque-laden artery may, in itself, be dysfunctional. This limits the ability of

the intra-arterial endothelium to produce mediators, which, in a healthy artery, would protectagainst further vasoconstriction, assist dilatation, and provide protection from plateletaggregation. Small lesions in these vessels may produce incompletely obstructing aggregates of

platelets. This would further impede flow through the affected vessel.4

In the diseased heart, these 2 factors, coronary artery narrowing and endothelial dysfunction,synergistically result in reduced oxygen delivery to the myocardium. The net result is angina

pectoris.

Extrinsic factors

Extrinsic factors can also play a role in specific circumstances. The oxygen-carrying capacityof blood is based on a number of factors. The most important of which is the amount of

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hemoglobin. Any alteration in the ability of blood to carry oxygen can precipitate angina.Anemia of any degree can result in anginal symptoms. Given a scenario where demand isincreased, such as climbing a flight of stairs, increased stress, or even sexual intercourse, theanginal symptoms may appear.5Abnormal hemoglobin, such as methemoglobin,carboxyhemoglobin, or any of a number of hemoglobinopathies, creates an environment at

greater risk for precipitating angina.

Other extrinsic factors that affect hemoglobin formation, such as lead poisoning or iron-deficiency states, also lead to a similar decrease in oxygen-carrying capacity. Any mechanismthat impedes oxygen delivery to the red blood cells has a similar effect. Therefore, any numberof pulmonary causes, such as pulmonary embolism, pulmonary fibrosis or scarring, pneumonia,or congestive heart failure, can exacerbate angina. A decreased oxygen environment, such astravel to a higher elevation, has similar consequences due to the decrease in concentration ofatmospheric oxygen.

Variant angina

The etiology of variant angina is currently not well understood. Research suggests thatinflammatory mediators may result in focal coronary artery vasospasm. Another possibility isthat perfusion is decreased through microvascular circulation. Spasm or intermittent narrowingof this microscopic lumen may result in transient areas of hypoperfusion and oxygendeprivation.6

Syndrome X

Syndrome X is the triad of angina pectoris, a positive ECG stress test result, and a normalcoronary angiogram. The pathophysiology of this disease is not well understood. Many theoriesexist as to the underlying pathology. Decreased oxygenation of the underlying myocardiummay be the result of impaired vasodilatation, dysfunctional smooth muscle cells, poor ordeficient microvascular circulation, or even structural problems on a cellular level (eg, aninappropriately functioning sodium ion channel).6

Frequency

United States

An estimated 6,500,000 people in the United States experience angina pectoris.

Each year, 400,000 new cases of angina pectoris develop.

Conservative 2006 data show 733,000 acute coronary syndrome (ACS) discharges fromhospitals.7

Mortality/Morbidity

In 2005, 1 in 5 deaths is from coronary heart disease (both angina and myocardial infarction).

Coronary heart disease is the single greatest killer of American men and women.7

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The estimated direct and indirect cost for Americans with coronary heart disease in 2006 was$142.5 billion.

Race

The Centers for Disease Control and Prevention (CDC) note that the prevalence of anginaand/or coronary heart disease is highest and increasing in Hispanics followed by whites and

black non-Hispanics (5%, 4.2%, 3.7%, respectively). This information includes the 50 USstates, the District of Columbia, Puerto Rico, and the US Virgin Islands .87

Sex

Among Americans aged 40-74 years, the age-adjusted prevalence of angina pectoris (AP) washigher among women than men.7 Although 2005 CDC data suggest that men (5.5%) have ahigher prevalence of angina and/or coronary heart disease than women (3.4%).8

Age

The incidence of new and recurrent angina increases with age but then declines at around 85years.

Statistics from American Heart Association (2008 Data) andCenters for Disease Control andPrevention.

Clinical

History

Classically, angina presents as substernal chest discomfort that occurs with exertion, but it alsomay occur at rest. The discomfort is frequently described as a pressure or heaviness. Othercommonly used adjectives for anginal pain include dull, aching, or squeezing. Pain may radiateto one or both arms, to one or both shoulders, or to the neck or jaw. Symptoms are highlyvariable. The entity cannot be expected to present with the classic triad of chest pressure withexertion radiating to the left arm. The diversity of disease expression is likely related to a

patient's age, sex, race, and culture.

The caveat is to have a high index of suspicion for the disease. Many factors influence the

expression of anginal symptoms. Familiar terms such as anginal equivalent and atypical chestpain are frequently used in these cases. In addition, systemic diseases, such as diabetes mellitusor chronic pain syndromes, may alter presenting anginal symptoms; while other diseases, suchas prior cerebral vascular accident or dementia, may limit the patient's reporting ofsymptoms. A pain-free variant of anginasometimes referred to as silent chest painalsoexists. These patients can present with complaints of shortness of breath, nausea, alteredmentation, or abdominal pain.9

Chest discomfort qualityo Paino Pressure

o Squeezingo Dullness
http://www.americanheart.org/downloadable/heart/1136308648540Statupdate2006.pdfhttp://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.108.191261http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5606a2.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5606a2.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5606a2.htmhttp://www.americanheart.org/downloadable/heart/1136308648540Statupdate2006.pdfhttp://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.108.191261http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5606a2.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5606a2.htm

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o Burningo Heavinesso Absent chest discomfort (eg, dyspnea, vomiting, altered sensorium)

Location (often diffuse to any location of C7-T4 dermatomes)o Retrosternal or substernalo

Inframammaryo Left sidedo Right sidedo Upper abdominalo Shoulder, neck, armo Teeth, jaw, lower face (above C7 unclear etiology)o Back, scapular region

Radiationo Unilateral or bilateral armso Unilateral or bilateral shoulderso Backo Necko Jaw, ear, or lower face

Temporalo Onset to maximum discomfort is progressive.

With exertion (with or without increasing frequency) At rest

o Alleviation to relief is progressive.o Alleviation mediators

Oxygen Nitroglycerin Reduction of stressful activity Pain medication

Placebo effect (eg, "GI cocktail") Severity

o Mild to severe (1/10 to >10/10)o "Like my heart pain" - Patients in the emergency department (ED)

may refer to the pain as being consistent with prior heart pains.

Physical

The physical examination may reveal signs of a hyperadrenergic state. One might observetachycardia, tachypnea, hypertension, and/or diaphoresis. In addition, ischemia may lead to the

presence of crackles due to the loss in contractility with subsequent pulmonary edema or a

reduction in the S1 intensity.10

That said, no definitive examination findings suggest angina. Much of the information obtainedfrom the physical examination may suggest other comorbidities that place the patient at higherrisk for anginal symptoms (eg, chronic obstructive pulmonary disease[COPD], tachycardia,

pale conjunctiva). Therefore, the physical examination is necessary to qualify the patient'scurrent physical state and comorbidities. In this manner, the emergency physician obtains a

baseline physical examination. Also, as mentioned, comorbid illnesses that affect the patient'slevel of cardiac, pulmonary, and circulatory function can be assessed.

As with many presentations to the emergency department, the physical examination in angina

pectoris also serves as a marker for response to therapy. Important comorbidities that can beidentified on physical examination includeaortic stenosis, gastrointestinal bleeding, and airway
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obstruction. Unfortunately, no examination findings are pathognomonic for angina pectoris. Inaddition, no physical examination findings rule out the disease state.

Of note, while the reproducibility of chest wall pain with palpation may lower the likelihood ofangina, this alone cannot rule out angina ormyocardial infarction.11,12

Workup

Laboratory Studies

CBC (anemia, leukocytosis may suggest an alternative diagnosis) BUN and creatinine level, if intravenous contrast is anticipated Electrolyte levels are of virtually no value unless the patient is on a diuretic

and concern for an abnormality exists. Cardiac enzyme levels, if positive may suggest nonST-segment elevation

myocardial infarction (NSTEMI); negative results do not rule out ischemia

Coagulation studies, if anticoagulation or antiplatelets are anticipated Type and screen, if surgery or transfusions are considered

Imaging Studies

Chest radiography is used to rule out an alternative diagnosis orcontributing factors (eg, pneumothorax [PTX], pneumonia [PNA], congestiveheart failure); it is also used to evaluate the aorta prior to anticoagulantadministration.

CT of the chest may be considered for evaluation of aortic or pulmonarydisease; if evaluating the aorta, include the abdominal aorta. Of note, the

forthcoming "triple rule out CT scan" exposes the patient to an exorbitantlyhigh dose of radiation and should only be used in certain circumstances. Limited CT coronary scans may help to reduce the posttest probability of

coronary artery disease while utilizing potentially less radiation exposurethan the "triple rule out scan." Coronary artery calcification suggests thepresence of an atherosclerotic plaque. Calcium scores are determined bythe density of calcium and the total area. Higher calcium scores maysuggest a higher risk of current or future adverse cardiac events. Multiplesites are currently conducting trials to see if this modality will benefitpatients in the emergency department.

Bamberg et al found that, in patients with acute chest pain and aninconclusive initial evaluation (nondiagnostic electrocardiographic findings,

negative cardiac biomarkers), age and gender can serve as simple criteriato select patients who would derive the greatest diagnostic benefit fromcoronary computed tomographic angiography (CTA).13In an observationalcohort study in 368 low-risk patients, positive findings on 64-slice coronaryCTA led to restratification to high risk, and negative findings led torestratification to very low risk, in men younger than 55 years and womenyounger than 65 years. In contrast, in women older than 65 years and menolder than 55 years, a negative result on CTA did not result inrestratification to a low-risk category.

Nuclear imagingo V/Q (PE evaluation)o Resting Sestamibi (In the appropriate clinical setting, a normal study

in a patient with ongoing chest pain may rule out myocardialischemia.14)

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ECGo Results may be normal or show signs of ischemia.o Main use is to establish a baseline and R/O acute ST-segment

elevation myocardial infarction (STEMI). Intraluminal coronary artery sonography (ICAS) is a highly invasive modality

that may provide additional information to a patient's coronary arteryanatomy and disease. Coronary atherosclerosis, which does not result incoronary artery narrowing, may be missed by conventional forms ofcoronary angiography. If clincially suspected, ICAS may be utilized to detectthe presence or absence of such lesions. ICAS is not readily available; assuch, it is highly unlikely that ICAS will be utilized from the emergencydepartment in the foreseeable future.

Treatment

Prehospital Care

Often, patients with angina pectoris rest or lie down to alleviate the pain. If the patient is notnaive to cardiac disease, he or she may have access to nitroglycerin. Often, the patient usesnitroglycerin at home to palliate his or her symptoms. A patient who has known stable anginaoften is able to report what exacerbates the condition and what (as well as how often) is a"normal" number of tablets for him or her to use prior to alleviation of anginal symptoms.Patients are often instructed by their physicians that the use of more than 3 tablets ofnitroglycerin necessitates a higher level of care (eg, calling for an ambulance). Some patientsare instructed to take aspirin as well. A knowledgeable patient who reports a change in the

pattern or presentation of his or her symptoms should be suspected as having worsening orunstable angina. However, any patient who presents to the ED with symptoms of angina should

be assessed promptly for signs of acute myocardial infarction (AMI).

Most prehospital care for angina pectoris consists of administering nitroglycerin, oxygen, andaspirin. The ability to obtain a prehospital ECG is becoming more prevalent.


In the ED, the patient who complains of chest discomfort needs to be immediately assessed forAMI as well as other high-risk diagnoses (eg, aortic dissection, pulmonary embolism). Vital inthis assessment is an early ECG and a rapid history and physical examination. Should thisinitial encounter not reveal a definitive diagnosis, then a more focused history and physical

examination needs to be performed. Serial ECGs, especially in the setting of changingsymptoms, is imperative. Labeling the ECGs with the patient's level of pain is often useful. Aconsecutive series of ECGs taken when a patient is having "10/10" pain, "3/10" pain, and"0/10" pain may yield valuable information that would not be readily apparent with an isolatedcardiogram. Continuous telemetry monitoring is recommended for higher-risk patients.15

The patient who presents with chest pain is presumed to have underlyingclinically significant cardiac pathology (ie, unstable angina or NSTEMI).

The initial treatment consists of administration of oxygen, aspirin,nitroglycerin, morphine, and a beta-blocker. Given an altered, yetnondiagnostic ECG and no contraindications, further treatment with

heparin (low-molecular weight or unfractionated), clopidogrel, orother antiplatelet agents may be initiated. Most often, an additional

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abnormal marker (eg, an elevated serum troponin, myoglobin, or CPKlevel) will be verified prior to antiplatelet therapy.

For persistent symptoms unresponsive to initial therapy, glycoproteininhibitors can be considered. These appear to demonstrate anadditional benefit in the patient population who will be undergoingcardiac catheterization (PCI).16Persistent pain, in spite of thistreatment, suggests either AMI or an alternative diagnosis. In thecase of AMI, angioplasty or thrombolytics should be administered ifavailable and not contraindicated. The American College ofCardiology offers an excellent evidenced-based online treatmentresource (see American College of Cardiology ClinicalStatements/Guidelines).

Atypical presentations of angina, unfortunately, are often diagnosedretrospectively. This subset of patients is identified either when theircondition progresses to STEMI or through elevated serum marker levels orcardiac dysrhythmia (often ventricular tachycardia or fibrillation). It cannotbe understated that the variance of expression of angina pectoris makes it

imperative that the clinician have a high level of suspicion for the disease.Little value exists in relying on a constancy of expression or on ECG, history,or physical examination alone for making the diagnosis. Angina pectorisshould be considered as well as an extensive differential diagnosis, in justabout any patient who presents to the ED with chest pain with or withoutother nonspecific complaints.

Syndrome X and Prinzmetal angina are not diagnosed in the ED, but thepatient's medical records or primary care physician may be helpful inrecognizing these disorders.

Admission is indicated for patients with unstable angina.

Consultations

In the setting of unstable angina or AMI, consultation with a cardiologist is warranted.

Medication

The goal of all of the following medications is either to improve myocardial oxygen andglucose supply or to reduce myocardial oxygen and glucose demand.

The use of thrombolytics in unstable angina and NSTEMI are not useful and potentiallyharmful. They should be reserved for use in STEMI when indicated.17(For more information,

see American College of Cardiology Clinical Statements/Guidelines.)

Anti-platelet agents

These agents inhibit platelet aggregation.

Aspirin (Anacin, Bayer Aspirin, Ascriptin)

Aspirin inhibits platelet cyclooxygenase-1, which blocks the formation of thromboxane A2,thus inhibiting platelet aggregation. Aspirin is arguably the most cost-effective medication in

medicine.
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Adult

81-325 mg PO qd

Pediatric

Not established

Clopidogrel (Plavix)

Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequentADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting plateletaggregation.May have a positive influence on several hemorrhagic parameters and may exert protectionagainst atherosclerosis not only through inhibition of platelet function but also through changesin the hemorrhagic profile.May have additive effect when used in combination with aspirin. Useful alternative therapy in

patients with a salicylate allergy.

Adult

75 mg PO qd

Pediatric

Not established

Vasodilators

These agents relieve chest discomfort by improving myocardial oxygen supply, which, in turn,dilate epicardial and collateral vessels, improving blood supply to the ischemic myocardium.

Nitroglycerin (Nitro-Bid, Deponit)

Reduces preload and ventricular pressures, thus reducing myocardial oxygen demand. NTG

also promotes coronary vasodilatation, which promotes improved myocardial blood flow.Reflex tachycardia may be harmful, concomitant beta-blocker usage may offset this reaction.

Adult

400 mcg SL or spray q5min, repeated up to 3 timesIf symptoms persist, administer 5-10 mcg/min IV infusionTitrate dose to reduce MAP by 10%, relieve symptoms, limit adverse effects of hypotension(>30% reduction in MAP or

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Pediatric

Not established

Analgesics

These agents reduce pain, which decreases sympathetic stress, in addition to providing somepreload reduction.

Morphine sulfate (Astramorph, MS Contin, MSIR)

Reduces pain and possibly anxiety associated with angina pectoris. Use judiciously in setting ofhypotension.

Adult

2-4 mg IV q5-15min; titrate to

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