Approach Considerations

The initial management of patients with cardiogenic pulmonary edema (CPE)

should address the ABCs of resuscitation, that is, airway, breathing, and
circulation. Oxygen should be administered to all patients to keep oxygen
saturation at greater than 90%. Any associated arrhythmia or MI should be
treated appropriately.
Methods of oxygen delivery include the use of a face mask, noninvasive
pressure-support ventilation (which includes bilevel positive airway pressure
[BiPAP] and continuous positive airway pressure [CPAP]), and intubation and
mechanical ventilation. Which method is used depends on the presence of
hypoxemia and acidosis and on the patient's level of consciousness. For
example, intubation and mechanical ventilation may become necessary in
cases of persistent hypoxemia, acidosis, or altered mental status.[10, 11]
The use of noninvasive pressure support ventilation in acidotic patients with
severe acute cardiogenic pulmonary edema does not appear to be
associated with adverse outcomes (early mortality and intubation rates) in
these patients.[12]
Following initial management, medical treatment of CPE focuses on 3 main
goals: (1) reduction of pulmonary venous return (preload reduction), (2)
reduction of systemic vascular resistance (afterload reduction), and, in some
cases, (3) inotropic support. Preload reduction decreases pulmonary capillary
hydrostatic pressure and reduces fluid transudation into the pulmonary
interstitium and alveoli. Afterload reduction increases cardiac output and
improves renal perfusion, which allows for diuresis in the patient with fluid
overload.
Patients with severe LV dysfunction or acute valvular disorders may present
with hypotension. These patients may not tolerate medications to reduce
their preload and afterload. Therefore, inotropic support is necessary in this
subset of patients to maintain adequate blood pressure.
Patients who remain hypoxic despite supplemental oxygenation and patients
who have severe respiratory distress require ventilatory support in addition
to maximal medical therapy.
Ultrafiltration
Ultrafiltration is a fluid removal procedure that is particularly useful in
patients with renal dysfunction and expected diuretic resistance.
Intra-aortic balloon pumping
Intra-aortic balloon pumping (IABP) can be employed to achieve
hemodynamic stabilization in the patient before definitive therapy. The IABP
decreases afterload as the pump deflates; during diastole, the pump inflates
to improve coronary blood flow.

Diet
Patients admitted with heart failure or pulmonary edema should be given a
low-salt diet to minimize fluid retention. Closely monitor their fluid balance.
Ventilatory Support
Noninvasive pressure-support ventilation
Consider noninvasive pressure-support ventilation (NPSV) early when
treating patients with severe CPE.
In NPSV, the patient breathes through a face mask against a continuous flow
of positive airway pressure. NPSV maintains the patency of the fluid-filled
alveoli and prevents them from collapsing during exhalation. As a result, the
patient saves energy that would have been spent trying to reopen collapsed
alveoli. NPSV improves pulmonary air exchange, and it increases
intrathoracic pressure with reduction in preload and afterload.
Several studies suggest that NPSV is associated with decreased length of
stay in the ICU, decreased need for mechanical ventilation, and decreased
hospital costs. A few clinical trials showed that in patients with CPEmainly
defined as having severe dyspnea, oxygen saturation of less than 90%, and
basal ralesearly and prehospital NPSV treatment by paramedics is safe and
associated with faster improvement of oxygen saturation.[13, 14] However,
the mortality and the need for intensive care did not differ between the
patients who were treated with NPSV and those who were treated with a
Venturi face mask in most of those studies. Indeed, a more recent study that
evaluated the safety and efficacy of implementing prehospital CPAP for the
treatment of acute (CPE) and acute exacerbations of chronic obstructive
pulmonary disease (AECOPD) found no benefit in morbidity, mortality, and
length of hospital stay.[15]
CPAP and BiPAP
Two types of NPSV are CPAP and BiPAP. In CPAP, a single airway pressure is
maintained throughout all phases of the respiratory cycle. In BiPAP, high
pressures can be applied during inspiration and low pressures, during
expiration, increasing the patient's comfort.[10]
A randomized trial comparing CPAP, noninvasive intermittent positive
pressure ventilation (NIPPV), and standard oxygen therapy in 1069 patients
with acute cardiogenic pulmonary edema demonstrated no mortality benefit
from noninvasive ventilation, but improvements were seen in
symptomatology and oxygenation.[16]

Although CPAP improves the condition of patients with cardiogenic

pulmonary edema and has been associated with a reduced need for tracheal
intubation, its use fails to reduce short-term mortality in this setting.[17]
In one small study, researchers compared CPAP with BiPAP and found that
BiPAP was associated with more rapid improvement in vital signs but also
with an increased rate of MIs.[18] Moreover, patients who received BiPAP
initially had more chest pain than did patients who received CPAP. Other
randomized clinical trials, however, did not show an increased rate of MI in
patients who received CPAP or BiPAP compared with those who received
oxygen by means of a face mask.
As of now, the data are insufficient to compare the efficacy and safety of
BiPAP with those of CPAP. Therefore, the authors suggest that CPAP be the
preferred method employed when NPSV is used unless the patient has
obstructive airway disease.
Mechanical ventilation
In general, use endotracheal intubation and mechanical ventilation when
patients with CPE remain hypoxic despite maximal noninvasive supplemental
oxygenation, when patients have evidence of impending respiratory failure
(eg, lethargy, fatigue, diaphoresis, worsening anxiety), or when patients are
hemodynamically unstable (eg, hypotensive, severely tachycardic).
Mechanical ventilation maximizes myocardial oxygen delivery and
ventilation. Positive end-expiratory pressure is generally recommended to
increase alveolar patency and to enhance oxygen delivery and carbon
dioxide exchange.
Preload Reduction
Nitroglycerin
Nitroglycerin (NTG) is the most effective, predictable, and rapidly-acting
medication available for preload reduction. Several studies demonstrated
greater efficacy and safety and a faster onset of action with NTG than with
furosemide or morphine sulfate. The use of sublingual NTG is associated with
preload reduction within 5 minutes and with some afterload reduction.
Topical NTG may be as effective as sublingual NTG in most patients with CPE,
but it should be avoided in patients with severe LV failure, because of poor
skin perfusion (manifesting as skin pallor or mottling) and resultant poor
absorption.
Intravenous (IV) NTG at high dosages provides rapid and titratable preload
and afterload reduction and is excellent monotherapy for patients with
severe CPE. IV NTG can be started with 10mcg/min and then rapidly

uptitrated to more than 100mcg/min. The other alternative is NTG given as 3

mg IV boluses every 5 minutes.
The antianginal dose of NTG of 0.4 mg every 5 minutes has the
bioequivalence of an NTG IV infusion of less than 80 mcg/min. Therefore, the
dosage of NTG for patients with CPE is higher than the standard antianginal
dosage would be.
Considering the short half-life of nitrates, physicians should be comfortable
with the high dosage for CPE, especially in most patients with CPE, who
present with a hyperadrenergic state and moderately elevated blood
pressure. However, nitrates should not be used in hypotensive patients, and
they should be used with extreme caution in patients with aortic stenosis and
pulmonary hypertension.
Diuretics
Loop diuretics have been considered the cornerstone of CPE treatment for
many years. Furosemide is used most commonly. Loop diuretics are
presumed to decrease preload through 2 mechanisms: diuresis and direct
vasoactivity (venodilation).
In most patients, diuresis does not occur for at least 20-90 minutes;
therefore, the effect is delayed. Loop diuretics affect the ascending loop of
Henle; therefore, the diminished renal perfusion in CPE may delay the onset
of effects of loop diuretics.
Many patients with CPE do not have fluid overload. Continued use of
diuretics in these patients after their acute symptoms have resolved may be
associated with adverse outcomes, including electrolyte derangements,
hypotension, and worsening renal function (GFR) as a result of
tubuloglomerular feedback.
The presumption that these medications have a direct vasoactive
(venodilating) effect has been questioned. Some studies demonstrated initial
adverse hemodynamic consequences (eg, elevations of PCWP, LV filling
pressure, heart rate, and systemic vascular resistance) after the
administration of IV furosemide, perhaps due to direct neurohormonal
stimulation.
Premedication with drugs that decrease preload (eg, NTG) and afterload (eg,
angiotensin-converting enzyme [ACE] inhibitors) before the administration of
loop diuretics can prevent potential adverse hemodynamic changes.
Morphine sulfate
The use of morphine sulfate in CPE for preload reduction has been
commonplace for many years, but good evidence supporting a beneficial

hemodynamic effect is lacking. Data suggest that morphine sulfate may

contribute to a decrease in cardiac output and that it may be associated with
an increased need for ICU admission and endotracheal intubation.
Adverse effects (eg, nausea and vomiting, local or systemic allergic
reactions, respiratory depression) may outweigh any potential benefit,
especially given the availability of medications that are more effective than
morphine in reducing preload (eg, NTG).
Any beneficial hemodynamic effect from morphine is probably due to
anxiolysis, with a resulting decrease in catecholamine production and a
decrease in systemic vascular resistance. An alternative can be low-dose
benzodiazepines (eg, lorazepam 0.5mg IV) in patients who are extremely
anxious. This alternative reduces the risk of respiratory depression in
patients whose condition responded to initial therapy.
Nesiritide
Nesiritide is recombinant human BNP that decreases PCWP, pulmonary
artery pressure, RA pressure, and systemic vascular resistance while
increasing the cardiac index and stroke volume index. Therapy with nesiritide
has decreased plasma renin, aldosterone, norepinephrine, and endothelin-1
levels and has reduced ventricular ectopy and ventricular tachycardia. Heartrate variability also improves with nesiritide.[19, 20, 21]
Most of the beneficial effects of nesiritide were shown in the landmark
Vasodilation in the Management of Acute Congestive Heart Failure (VMAC)
study. Investigators compared IV nesiritide with IV NTG. IV nesiritide was
associated with some hypotension but was otherwise well tolerated.
However, the VMAC study also showed a trend toward increased mortality in
the IV nesiritide group compared with the patients receiving IV NTG, although
the difference was not statically significant (90-day mortality, 19% for
nesiritide vs 13% for NTG). The most important limitation of this study was
the use of suboptimal dosages of IV NTG (mean 30-40 mcg/min) because the
dosage was based on physician's decision and not on a protocol.
A later meta-analysis of 3 randomized trials of 485 patients receiving
nesiritide and 377 patients not receiving nesiritide showed a 7.2% 30-day
mortality with nesiritide versus 4% without nesiritide.[22]
In most large clinical trials nesiritide has not had a significant effect on renal
function. In one of the largest studies of nesiritide to date, the Acute Study of
Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND
HF), nesiritide had a neutral effect on survival and rehospitalization and a
small effect on dyspnea when used in combination with other treatments.
[23] In the study, which was powered to show the effects of the drug on

survival and renal function, no association was found between use of

nesiritide and deteriorating renal function, although use of this agent was
associated with a slight increase in hypotension. The investigators
recommended against the routine use of nesiritide in the broad population of
patients with acute heart failure.[23]
Afterload Reduction
ACE inhibitors
ACE inhibitors are generally considered the cornerstones for treating chronic
CHF, and studies have demonstrated excellent results with ACE inhibitors for
the treatment of acute decompensated CHF and CPE. The use of ACE
inhibitors in CPE is associated with reduced admission rates to ICUs and
decreased endotracheal intubation rates and length of ICU stay.
The hemodynamic effects of ACE inhibitors include reduced afterload,
improved stroke volume and cardiac output, and a slight reduction in
preload. The last effects happen when renal perfusion improves after cardiac
output improves and diuresis occurs.
Enalapril 1.25 mg IV or captopril 25 mg, given sublingually, result in
hemodynamic and subjective improvements within 10 minutes.
Improvements occur much more slowly with the oral route.
Angiotensin II receptor blockers
Angiotensin II receptor blockers (ARBs) have comparable beneficial effects in
heart failure. Studies have proposed a role for ACE inhibitors and ARBs in
preventing structural and electrical remodeling of the heart, resulting in a
reduced incidence of arrhythmias.
The Valsartan Heart Failure Trial (Val-HeFT) showed that valsartan reduces
the incidence of atrial fibrillation (AF) by 37%. (BNP level and advanced age
were the strongest independent predictors for AF occurrence.)[24] Similarly,
the Candesartan in Heart Failure: Assessment in Reduction of Mortality and
Morbidity (CHARM) trial showed a reduction in the onset of AF in patients
who were treated with Candesartan compared with placebo, with a median
follow-up period of 37.7 months.[25]
Nitroprusside
Nitroprusside results in simultaneous preload and afterload reduction by
causing direct smooth-muscle relaxation, with an increased effect on
afterload. Afterload reduction is associated with increased cardiac output.
The potency and rapidity of onset and offset of effect make this an ideal
medication for patients who are critically ill. It may induce precipitous falls
and labile fluctuations in blood pressure; intra-arterial blood pressure
monitoring is often recommended.

Nitroprusside should generally be avoided in the setting of acute MI. Its use
is associated with the shunting of blood away from ischemic myocardium
toward healthy myocardium (ie, coronary steal syndrome), which potentiates
ischemia.
If nitroprusside is used, convert therapy to oral or alternative IV vasodilator
therapy as soon as possible, because prolonged high-dose use is associated
with thiocyanate and cyanide toxicity, particularly in patients with significant
hepatic or renal dysfunction. Use in pregnancy is associated with fetal
thiocyanate toxicity. Prolonged infusion can induce tolerance, and reflex
tachycardia may occur.
Catecholamines
Inotropic support is usually used when preload- and afterload-reduction
strategies are not successful or when hypotension precludes the use of these
strategies. Two main classes of inotropic agents are available: catecholamine
agents and phosphodiesterase inhibitors (PDIs). Calcium-sensitizer agents
are a new class of medications that have notably beneficial effects in acute
decompensated heart failure; these drugs are under investigation.
Dobutamine
Dobutamine, a catecholamine agent, mainly serves as a beta1-receptor
agonist, though it has some beta2-receptor and minimal alpha-receptor
activity. IV dobutamine induces significant positive inotropic effects, with
mild chronotropic effects. It also induces mild peripheral vasodilation
(decrease in afterload). The combination effect of increased inotropy with
decreased afterload significantly increases cardiac output. Combination use
with IV NTG may be ideal for patients with MI and CPE and mild hypotension
to simultaneously reduce preload and increase cardiac output. In general,
avoid dobutamine in patients with moderate or severe hypotension (eg,
systolic BP < 80 mm Hg), because of the peripheral vasodilation.
Dopamine
The vascular and myocardial receptor effects of dopamine, a catecholamine
agent, are dose dependent. Low dosages of 0.5-5 mcg/kg/min stimulate
dopaminergic receptors in the renal and splanchnic vascular beds, causing
vasodilation and increasing diuresis. Moderate dosages of 5-10 mcg/kg/min
stimulate beta-receptors in the myocardium, increasing cardiac contractility
and heart rate.
High dosages of 15-20 mcg/kg/min stimulate alpha-receptors, resulting in
peripheral vasoconstriction (increased afterload), increased blood pressure,
and no further improvement in cardiac output.

Moderate and high dosages are arrhythmogenic and increase myocardial

oxygen demand (with the potential for myocardial ischemia). Therefore, use
these dosages only in patients with CPE who cannot tolerate dobutamine
because of severe hypotension (eg, systolic blood pressure 60-80 mm Hg)
Norepinephrine
Norepinephrine, a catecholamine agent, primarily stimulates alpha receptors,
significantly increasing afterload (and the potential for myocardial ischemia)
and reducing cardiac output. Norepinephrine is generally reserved for
patients with profound hypotension (eg, systolic blood pressure < 60 mm
Hg). After blood pressure is restored, add other medications to maintain
cardiac output.
Phosphodiesterase inhibitors
PDIs increase the level of intracellular cyclic adenosine monophosphate
(cAMP) by preventing the breakdown of cAMP to 5'AMP. This results in a
positive inotropic effect on the myocardium, in peripheral vasodilation
(decreased afterload), and in a reduction in pulmonary vascular resistance
(decreased preload). Unlike the catecholamine inotropes, PDIs do not depend
on adrenoreceptor activity. Therefore, patients are less likely to develop
tolerance to PDIs than they are to other medications. (Tolerance to
catecholamine inotropes can rapidly develop by means of a down-regulation
of adrenoreceptors.)
PDIs are less likely than catecholamine inotropes to cause the adverse
effects that are typically associated with adrenoreceptor activity (eg,
increased myocardial oxygen demand, myocardial ischemia).
Several direct comparisons of PDIs (milrinone) to dobutamine in patients with
CPE demonstrated that milrinone produced equal or greater improvements in
stroke volume, cardiac output, PCWPs (preload), and systemic vascular
resistance (afterload). However, milrinone was associated with the same or
more tachycardia and with an increased incidence of tachyarrhythmias.
Furthermore, the use of milrinone in the Outcomes of a Prospective Trial of
Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIMECHF) study did not reduce hospital length of stay and was associated with a
significant increase in adverse events compared with placebo.[26]
All known IV inotropic agents are associated with an increased long-term
mortality compared with placebo and therefore should be reserved for
patients with heart failure and a markedly depressed cardiac index and
stroke volume.
Calcium sensitizers

Levosimendan is a calcium sensitizer that is used in several European

countries to manage moderate to severe heart failure. It has inotropic,
metabolic, and vasodilatory effects. Levosimendan increases contractility by
binding to troponin C. It does not increase myocardial oxygen demand, and it
is not a proarrhythmogenic agent.[27, 28, 29]
Levosimendan opens potassium channels sensitive to adenosine
triphosphate (ATP), causing peripheral arterial and venous dilatation. It also
increases coronary flow reserve. Moreover, studies have shown
levosimendan to have an anti-inflammatory effect.
Overall, levosimendan has been an effective and safe alternative to
dobutamine. The most common adverse effects of levosimendan treatment
are hypotension and headache. A randomized clinical studythe Survival of
Patients With Acute Heart Failure in Need of Intravenous Inotropic Support
(SURVIVE) trialdemonstrated no mortality benefit from levosimendan in
comparison with dobutamine in patients with acute decompensated CHF.[30]
Tolvaptan
Tolvaptan is an oral vasopressin V2-receptor antagonist that was evaluated in
a large (4133 patients), randomized, double-blind, placebo-controlled trial in
patients with acute clinically decompensated CHF. This study, the Efficacy of
Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan
(EVEREST), demonstrated no mortality or CHF hospitalization benefit at a
median follow-up of 9.9 months. However, patients randomized to tolvaptan
demonstrated early (1-7 d) improvements in body weight, dyspnea, serum
sodium, and edema, as compared with placebo.[31, 32]