CARDIAC UPDATE
From the 12th Annual Scientific Assembly of the American College of Emergency Medicine
Amal Mattu, MD, Associate Professor and Program Director, Emergency Medicine Residency, University of
Maryland School of Medicine, Baltimore
| WINNING AT FAILURE: MODERN MANAGEMENT OF CARDIOGENIC PULMONARY EDEMA
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| Typical case: 65-yr-old man presents to emergency department (ED) with shortness of breath (progressing over past day
but worsened over past several hours); multiple cardiac risk factors; diaphoretic but has normal mental status (so hypercarbia
not concern); afebrile; tachycardic; severely hypertensive; tachypneic; hypoxic; on lung examination, patient has
“crackles up to his ears”; jugular venous distention (JVD); chest x-ray shows clear-cut pulmonary edema (PE); monitor
shows sinus tachycardia; electrocardiography (ECG) nonspecific, ie, no ST segment elevation or depression; patient on
100% oxygen non-rebreather mask and bilateral intravenous (IV) lines
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| Options for optimal management of patient in next 5 to 10 min: morphine; furosemide (Lasix) or diuretic of
choice; morphine plus furosemide; nitroglycerin plus one of above; nesiritide plus one of above; none of above
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| Pathophysiology: lungs can be thought of as bucket partially filled with fluid; when patient in PE, fluid level increased;
3 mechanisms responsible for homeostasis of fluid in lungs—1) preload; 2) left ventricular (LV) contractility; 3) afterload;
process leading to PE starts with dysfunction in one of these mechanisms, ie, increased preload or afterload, or
decompensation of already poor cardiac function, resulting in LV dysfunction; in 99% of cases, regardless of which problem
started process, by time patient presents with PE, all 3 mechanisms have gone awry
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| Goals of treatment: 1) decrease preload; 2) decrease afterload; 3) improve LV contractility, ie, provide inotropic support
(not required in majority of patients; agents that improve inotropic support best avoided because of adverse effects);
when first 2 goals of treatment met, contractility improves
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| Comments: studies indicate that 40% to 50% of patients who arrive in ED with cardiogenic pulmonary edema (CPE) not
fluid overloaded, but simply have fluid in “the wrong bucket”; thus, goal of management should be, fluid redistribution,
rather than fluid removal
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Preload Reduction
| Morphine: advantages—histamine effect (causes some venodilation that presumably reduces preload); anxiolytic effect
(decreases catecholamines, resulting in decreased afterload); disadvantages—side effects (eg, nausea, vomiting, rash, urticaria;
may increase catecholamines); respiratory depression and myocardial depression at high doses; limited data
supporting efficacy in decreasing preload; assumption that administration of morphine decreases preload extrapolated from
Vismara et al (1976) study that evaluated venous tone in wrist and forearm veins of PE patients after receiving IV morphine;
however, numerous Swann-Ganz catheter studies evaluating central circulation have found no evidence that morphine reduces
preload, and mounting evidence it increases rates of intubation, admission to intensive care unit (ICU), development
of cardiogenic shock, and mortality; when used for anxiolysis, morphine does decrease catecholamines (and theoretically,
afterload), but side effects may cause afterload to get worse; if patient truly requires anxiolytic, give small dose of benzodiazepine
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| Furosemide: reduces preload through diuresis and direct vasoactive effect; however, studies show patients with CPE often
have only 20% of normal renal blood flow (RBF); this can result in overadministration of diuretic, leading to hypotension
1 day later; conclusion that direct vasoactive reduces preload within minutes, extrapolated from studies
evaluating effect of furosemide on forearm and wrist veins ; however, Swann-Ganz catheter studies found no evidence of
immediate benefit, and most have demonstrated initial adverse hemodynamic effect, with reduction in preload occurring
only after diuresis (60 to 90 min later)
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| Summary for furosemide: decreases preload but only through diuresis (which is delayed effect); no consistent data
supporting immediate direct preload-reducing effect; produces initial adverse hemodynamic effects, including increases
in afterload and reductions in stroke volume (SV) and cardiac output; conclusion—furosemide should be considered
third-line medication for treatment of CPE
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| Nitroglycerin (NTG): drug of choice for preload reduction; in multiple head to head studies, proven superior to morphine
and furosemide; advantages—rapid, reliable preload reduction; multiple forms of administration; high doses reduce
afterload as well; be aggressive in giving IV NTG, ie, 60 to 100 µg/ min, or give sublingual (SL) dose; short half-
life limits adverse effects; cautions—avoid in patients with hypotension; valvular problems (acute mitral regurgitation
[MR], aortic stenosis, or pulmonary hypertension); patients on sildenafil (Viagra) or other erectile dysfunction medications
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| Summary for NTG: better and safer than morphine or furosemide for preload reduction;SL dosing provides rapid and
effective initiation of treatment; follow with topical NTG (if symptoms moderate) or with aggressive IV administration
(if symptoms severe); conclusion—NTG should be considered first-line prehospital and ED therapy for moderate or severe
congestive heart failure (CHF) decompensations
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Afterload Reduction
| Overview: results in improved cardiac output; restores RBF; NTG (at high doses) excellent single agent for simultaneous
preload and afterload reduction; nitroprusside “outstanding” afterload reducer but not used very often; hydralazine also
excellent for afterload reduction but can produce reflux tachycardia; not well-studied in acutely decompensated patients;
angiotensin-converting enzyme (ACE) inhibitors treatment of choice (along with β-blockers) for chronic CHF exacerbations
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| ACE inhibitors for CPE: 2 main formulations IV enalapril or SL captopril
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 | Studies: Barnett et al (1991)—SL captopril (25 mg given if blood pressure [BP] >110 mm Hg, 12.5mg if <110 mm Hg);
reduced afterload and preload within 10 min; hemodynamically stable, even in borderline BP patients; 12 additional
patients who were extremely hypoxic had such significant resolution of symptoms within 15 min, they avoided intubation
(8 of 12 had abrupt increase in diuresis without use of diuretic, due to improved RBF); Langes et al (1993)—IV
captopril infusion; onset of action in 6 min; decreased preload and afterload; no adverse effects; Varriale et al
(1993)—1.25 mg IV enalapril given to patients with severe CHF and MR; improved CO and SV; reduced afterload
and preload, and decreased magnitude of MR; no adverse effects; Sacchetti et al (1991)—patients treated with SL
captopril in ED had one quarter rates of intubation and ICU admission seen without captopril; dosage—SL captopril
25 mg; IV enalapril 1.25-mg single dose; hemodynamic and subjective improvements within 15 min; also works in
fluid overloaded patients, eg, noncompliant dialysis patients; Southall et (2004)—looked at safety of ED use of SL
captopril in New York Heart Association (NYHA) Class IV patients; patients who received 25-mg dose in ED had no
increased incidence of hypotension or need for vasopressors, and, in patients admitted to ICU, length of stay decreased
from 3 days to 1 day
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| Summary for ACE inhibitors: produce rapid reduction in afterload and preload; very safe; hemodynamicaly stable;
decrease bed utilization, hospital costs, need for intubation, ICU use; combination with NTG exceeds benefit of either
drug alone; work well as single agent in patients who cannot tolerate nitrates; conclusion—should be considered second-line
agents for decompensated CFH patients; can be used safely in patients with hyperkalemia; avoid in patients with
history of allergic reaction to ACE inhibitors
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Combination Preload and Afterload Reduction
| Natriuretic peptides: hormone-like substances produced by myocardium that modulate fluid balance (diuresis, vasodilation,
venodilation); normally activated and synthesized by ventricle in times of stress; however, in patients with decompensated
CHF, heart may not be able to produce adequate concentrations of natriuretic peptides
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| Nesiritide: recombinant form of B-type natriuretic peptide; early studies in patients with decompensated CHF reported
decreases in preload and afterload (although majority of subsequent studies show primarily preload reduction), no increase
in heart rate or arrhythmias, and symptomatic improvement
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| Vasodilation in the Management of Acute Congestive heart failure (VMAC) study (2002): randomized double-blind placebo-controlled
trial of IV nesiritide vs NTG; investigators concluded that, when added to standard care in patients
hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and “some self-reported
symptoms” more effectively than IV NTG or placebo; problems with study—manufacturer supported; nesiritide
added to standard treatment (morphine, furosemide and low-dose NT, not optimal treatment; patients given ACE inhibitors
or vasodilators eliminated from study; no mention of noninvasive ventilation; no subjective improvement in
status at 3 hr and 24 hr; some improvement in “global clinical status,” (nonvalidated scoring system not described in
study); issues raised in further analysis of study—cost-effectiveness (nesiritide 40 times more expensive than
NTG); patients who received nesiritide had 2-day longer hospital stay; readmission rate decreased but trend towards
increased mortality; 2 meta-analyses by Sackner-Bernstein found nesiritide associated with increased 30-day mortality
and worsening renal function; package insert for nesiritide admits VMAC study does not constitute adequate effectiveness
comparison with NTG; VMAC shows only that nesiritide better than placebo
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| Summary for nesiritide: does provide preload reduction, but unproven in optimally treated patients; while nesiritide
theoretically “makes sense,” before physicians adopt its use, manufacturers and supporters of drug must prove it clearly
better than optimal use of less expensive drugs
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| Treatment choices: include catecholamines (dopamine, dobutamine), phosphodiesterase inhibitors (amrinone, milrinone),
intra-aortic balloon pump (in patients who have cardiogenic shock)
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| Catecholamines: disadvantages—cause tachycardia; increase myocardial ischemia; not associated with improvements
in outcome (“they improve the numbers but not mortality”); patients with severe CHF often taking β-blockers (suppress
effects of inotropic agents), and tend to have chronically elevated levels of endogenous catecholamines (so they develop
tachyphylaxis quickly); so dopamine and dobutamine do not work in these patients
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| Milrinone: works through nonandrenergic system to decrease preload, afterload, and increase cardiac output; in 7 studies
comparing milrinone to dobutamine in patients with severe decompensated CHF, milrinone proved much better in reducing
preload and afterload, and increasing cardiac output; however, most recent study found milrinone produced no mortality
benefit; speaker recommends physicians use whatever they are comfortable with for inotropic support
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| Noninvasive positive pressure ventilation: continuous positive airway pressure (CPAP) or bilevel positive airway
pressure (BiPAP); “outstanding modality”; prevents collapse of fluid-filled alveoli; multiple studies show CPAP and BiPAP
decrease work of breathing, improve air exchange, preload, afterload, and CO, reduce need for intubation, length of
ICU stay, and hospital costs; in addition, 2 recent review articles demonstrated that routine use of CPAP and BiPAP in
decompensated CHF patients in ED associated with improvements in mortality; bear in mind that noninvasive ventilation
only currently available treatment that has been demonstrated to improve mortality; thus, physicians should be much
more aggressive about using it routinely in these patients; use early to maximize benefit
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Prehospital Diagnosis and Empiric Treatment
| Study by Hoffman (1998): of patients with presumed prehospital PE, found that 25% who received furosemide became
hypotensive and required fluid repletion (significant electrolyte problems common as well); almost 25% of patients misdiagnosed
(did not have PE) and inappropriately treated with furosemide and/or morphine (leading to worse outcome);
Kosowsky et al study of prehospital use of CPAP found that 32% of patients with presumed PE in firld misdiagnosed; however,
treatment with CPAP produced no adverse effects; Wuerz et al evaluated outcomes in 600 patients with presumed prehospital
PE; found 18% misdiagnosed and inappropriately treated with morphine or furosemide; (most had asthma, chronic
obstructive pulmonary disease [COPD], or pneumonia); patients who received only NTG had 2% mortality; if treated with
morphine and/or furosemide, mortality increased to 22%; study also found that patients with asthma, COPD or pneumonia
who received bronchodilators had 3% mortality; if CHF patients misdiagnosed and inappropriately treated with bronchodilators,
no adverse effects; in most recent study of presumed prehospital PE, 42% misdiagnosed and inappropriately treated
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| Summary for prehospital treatment: misdiagnosis common; when in doubt, treat with nitrates, bronchodilators,
and/or noninvasive ventilation; avoid morphine and furosemide
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| Concluding summary: NTG first-line agent; ACE inhibitors second-line agent (in addition to or instead of NTG); furosemide
third-line agent (after preload and afterload reduction); no indication for use of morphine; nesiritide still requires
more studies, currently not recommended for treatment; for inotropic support, use what you are comfortable with;
noninvasive ventilation definitely recommended; prehospital treatment (misdiagnosis and inappropriate treatment with
morphine and furosemide associated with markedly increased morbidity and mortality; misdiagnosis rate 18% to 42% in
studies; NTG, bronchodilators, and noninvasive ventilation probably safest approach); speaker’s approach to initial case
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Educational Objectives
| The goal of this activity is to provide an update on the modern management of cardiogenic pulmonary edema (CPE). After
hearing and assimilating this program, the listener will be able to:
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| 1. Describe the limitations of morphine and furosemide in the management of CPE
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| 2. Identify medications available for rapid preload reduction and afterload reduction.
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| 3. Explore and compare the advantages and disadvantages of the agents currently available for inotropic support
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| 4. Discuss the use of noninvasive positive pressure ventilation.
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| 5. Explain the difficulties and unreliability of prehospital diagnosis of PE, as well as the best and safest approach to prehospital
treatment.
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Discussed on This Program
Amrinone Lactate [Inocor]
Captopril [Capoten]
Diazepam [Diastat, Diazepam Intensol, Valium]
Diphenhydramine HCl [Benadryl; other trade names and formulations]
Dobutamine [Dobutrex]
Dopamine HCl [Intropin, Dopamine HCl in 5% Dextrose]
Enalapril maleate [Vasotec, Vasotec I.V.]
Furosemide [Lasix]
Hydralazine HCl [Apresoline]
Lorazepam [Ativan, Lorazepam Intensol]
Milrinone lactate [Primacor]
Morphine sulfate [Astramorph PF, Avinza, Duramorph, Infumorph, Infumorph 200, Infumorph 500, Kadian, MSIR, MS
Contin, Oramorph SR, RMS, Roxanol, Roxanol 100, Roxanol T]
Nesiritide [Natrecor]
Nitroglycerin [Nitrobid, Nitrobid IV, Nitrogard, Nitroglyn, Nitrol, Nitrolingual, Nitrong, NitroQuick, Nitrostat, Nitrotab,
Nitro-Time, Tridil]
Nitroprusside sodium [Nitropress, Sodium Nitroprusside]
Sildenafil citrate [Viagra]
Vasopressin (8-arginine-vasopressin) [Pitressin]
Suggested Reading
Barnett JC et al: Sublingual captopril in the treatment of acute heart failure. Curr Ther Res 49:274, 1991; Colucci WS
et al: Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med
343:246, 2000; Cross AM et al: Non-invasive ventilation in acute respiratory failure: a randomized comparison of continuous
positive airway pressure and bi-level positive airway pressure. Emerg Med J 20:531, 2003; Francis GS et al: Acute
vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral
axis. Ann Intern Med 103:1, 1985; Hoffman JR, Reynolds S: Comparison of nitroglycerin, morphine and furosemide
in treatment of presumed pre-hospital pulmonary edema. Chest 92:586, 1987; Ikram H et al: Haemodynamic and
hormone responses to acute and chronic frusemide therapy in congestive heart failure. Clin Sci (Lond) 59:443, 1980; Kiely J
et al: The role of furosemide in the treatment of left ventricular dysfunction associated with acute myocardial infarction. Circulation
48:581, 1973; Kosowsky JM et al: Prehospital use of continuous positive airway pressure (CPAP) for presumed
pulmonary edema: a preliminary case series. Prehosp Emerg Care 5:190, 2001; Kraus PA et al: Acute preload effects of
furosemide. Chest 98:124, 1980; Langes K et al: Efficacy and safety of intravenous captopril in congestive heart failure.
Curr Ther Res 53:167, 1993; Lappas DG et al: Filling pressures of the heart and pulmonary circulation of the patient with
coronary-artery disease after large intravenous doses of morphine. Anesthesiology 42:153, 1975; Levitt MA: A prospective,
randomized trial of BiPAP in severe acute congestive heart failure. J Emerg Med 21:363, 2001; Mattu A et al: Modern
management of cardiogenic pulmonary edema. Emerg Med Clin North Am 23:1105, 2005; Nelson GI et al:
Haemodynamic effects of frusemide and its influence on repetitive rapid volume loading in acute myocardial infarction. Eur
Heart J 4:706, 1983; Peacock WF et al: Morphine for acute decompensated heart failure: valuable adjunct or a historical
remnant? Acad Emerg Med 12(suppl 1):97, 2005; Pickkers P et al: Direct vascular effects of furosemide in humans. Circulation
96:1847, 1997; Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment
of decompensated congestive heart failure: a randomized controlled trial. JAMA 287:1531, 2002; Sacchetti et al:
Effect of ED management on ICU use in acute pulmonary edema. Am J Emerg Med 17:571, 1991; Sackner-Bernstein
JD et al: Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation
111:1487, 2005; Sackner-Bernstein JD et al: Short-term risk of death after treatment with nesiritide for decompensated
heart failure: a pooled analysis of randomized controlled trials. JAMA 293:1900, 2005; Southall JC et al: ACE inhibitors
in acutely decompensated congestive heart failure. Acad Emerg Med 11:503, 2004; Timmis AD et al: Haemodynamic effects
of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure. Br
Med J 280:980, 1980; Ullman E et al: Electrocardiographic manifestations of pulmonary embolism. Am J Emerg Med
19:514, 2001; Varriale P et al: Hemodynamic response to intravenous enalaprilat in patients with severe congestive heart
failure and mitral regurgitation. Clin Cardiol 16:235, 1993; Varriale P et al: Short-term intravenous milrinone for severe
congestive heart failure: the good, the bad, and not so good. Pharmacotherapy 17:371, 1997; Vismara LA et al: The effects
of morphine on venous tone in patients with acute pulmonary edema. Circulation 54:335, 1976; Widger HN et al:
Pressure support noninvasive positive pressure ventilation treatment of acute cardiogenic pulmonary edema. Am J Emerg
Med 19:179, 2001; Wuerz RC, Meador SA: Effects of prehospital medications on mortality and length of stay in congestive
heart failure. Ann Emerg Med 21:669, 1992.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue the speaker reports
nothing to disclose.
Dr. Mattu spoke at High Risk Emergency Medicine, held May 24-26, 2006, in San Francisco, CA, and sponsored by
the University of California, San Francisco, School of Medicine. The Audio-Digest Foundation thanks Dr. Mattu and
the University of California, San Francisco, School of Medicine for their cooperation in the production of this program.
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