Use of Vasopressors and Inotropes - UpToDate
Use of Vasopressors and Inotropes - UpToDate
Use of Vasopressors and Inotropes - UpToDate
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INTRODUCTION
Vasopressors are a powerful class of drugs that induce vasoconstriction and thereby elevate
mean arterial pressure (MAP). Vasopressors differ from inotropes, which increase cardiac
contractility; however, many drugs have both vasopressor and inotropic effects. Although
many vasopressors have been used since the 1940s, few controlled clinical trials have directly
compared these agents or documented improved outcomes due to their use [1]. Thus, the
manner in which these agents are commonly used largely reflects expert opinion, animal
data, and the use of surrogate end points, such as tissue oxygenation, as a proxy for
decreased morbidity and mortality.
Basic adrenergic receptor physiology and the principles, complications, and controversies
surrounding use of vasopressors and inotropes for treatment of shock are presented here.
Issues related to the differential diagnosis of shock and the use of vasopressors in patients
with septic shock are discussed separately. (See "Definition, classification, etiology, and
pathophysiology of shock in adults" and "Evaluation and management of suspected sepsis
and septic shock in adults".)
Beta adrenergic — Beta-1 adrenergic receptors are most common in the heart and mediate
increases in inotropy and chronotropy with minimal vasoconstriction. Stimulation of beta-2
adrenergic receptors in blood vessels induces vasodilation.
Calcium sensitizers — Some agents increase the sensitivity of the myocardial contractile
apparatus to calcium, causing an increase in myofilament tension development and
myocardial contractility (eg, pimobendan, levosimendan). These agents have additional
pharmacologic properties, such as phosphodiesterase inhibition, which may increase
inotropy and vasodilation and contribute significantly to their clinical profile, the details of
which are discussed separately.
Angiotensin — Angiotensin receptors (AT1 and AT2) are G-coupled protein receptors with
angiotensin II as their ligand. Angiotensin II is a vasoconstrictor that is part of the renin-
aldosterone-angiotensin (RAAS) system. When receptors are stimulated, cytosolic calcium
concentration increases to mediate vasoconstrictive effects as well as aldosterone and
vasopressin secretion [5].
PRINCIPLES
Hypotension may result from hypovolemia (eg, exsanguination), pump failure (eg, severe
medically refractory heart failure or shock complicating myocardial infarction), or a
pathologic maldistribution of blood flow (eg, septic shock, anaphylaxis). (See "Definition,
classification, etiology, and pathophysiology of shock in adults" and "Inotropic agents in
heart failure with reduced ejection fraction".)
Vasopressors are indicated for a decrease of >30 mmHg from baseline systolic blood
pressure, or a mean arterial pressure <60 mmHg when either condition results in end-organ
dysfunction due to hypoperfusion. Hypovolemia should be corrected prior to the institution
of vasopressor therapy [6]. (See "Treatment of severe hypovolemia or hypovolemic shock in
adults".)
The rational use of vasopressors and inotropes is guided by three fundamental concepts:
● One drug, many receptors – A given drug often has multiple effects because of actions
upon more than one receptor. As an example, dobutamine increases cardiac output by
beta-1 adrenergic receptor activation; however, it also acts upon beta-2 adrenergic
receptors and thus induces vasodilation and can cause hypotension.
● Dose-response curve – Many agents have dose-response curves, such that the primary
adrenergic receptor subtype activated by the drug is dose-dependent. As an example,
dopamine stimulates beta-1 adrenergic receptors at doses of 2 to 10 mcg/kg per
minute, and alpha adrenergic receptors when doses exceed 10 mcg/kg per minute.
● Direct versus reflex actions – A given agent can affect mean arterial pressure (MAP)
both by direct actions on adrenergic receptors and by reflex actions triggered by the
pharmacologic response. Norepinephrine-induced beta-1 adrenergic stimulation alone
normally would cause tachycardia. However, the elevated MAP from norepinephrine's
alpha-adrenergic receptor-induced vasoconstriction results in a reflex decrease in heart
rate. The net result may be a stable or slightly reduced heart rate when the drug is
used.
PRACTICAL ISSUES
Fluids may be withheld in patients with significant pulmonary edema due to the acute
respiratory distress syndrome (ARDS) or heart failure (HF). In patients with a pulmonary
artery catheter, pulmonary capillary wedge pressures (PCWP) of 18 to 24 mmHg are
recommended for cardiogenic shock [8], and 12 to 14 mmHg for septic or hypovolemic shock
[9]. (See "Pulmonary artery catheterization: Interpretation of hemodynamic values and
waveforms in adults".)
Selection and titration — Choice of an initial agent should be based upon the suspected
underlying etiology of shock (eg, dobutamine in cases of cardiac failure without significant
hypotension, epinephrine for anaphylactic shock). The dose should be titrated up to achieve
effective blood pressure or end-organ perfusion as evidenced by such criteria as urine output
or mentation. If maximal doses of a first agent are inadequate, then a second drug should be
added to the first. In situations where this is ineffective, such as refractory septic shock,
anecdotal reports describe adding a third agent, although no controlled trials have
demonstrated the utility of this approach.
This was demonstrated in a study that monitored plasma factor Xa levels in three groups of
hospitalized patients following the initiation of prophylactic low molecular weight heparin
[17]. Patients who required vasopressor support (dopamine >10 mcg/kg per minute,
norepinephrine >0.25 mcg/kg per minute, or phenylephrine >2 mcg/kg per minute) had
decreased factor Xa activity compared to both intensive care unit (ICU) patients who did not
require vasopressors and routine postoperative control patients. The clinical significance of
the decrease in plasma factor Xa levels was not determined.
The authors of the study suggested that patients might need higher doses of LMW heparin
to attain adequate thrombosis prophylaxis. Another approach is to change subcutaneous
medications to an intravenous form whenever a patient is receiving vasopressor therapy.
Frequent re-evaluation — Critically ill patients may undergo a second hemodynamic insult
which necessitates a change in vasopressor or inotrope management. The dosage of a given
agent should not simply be increased because of persistent or worsening hypotension
without reconsideration of the patient's clinical situation and the appropriateness of the
current strategy.
ADRENERGIC AGENTS
Although SVR elevation increases cardiac afterload, most studies document that cardiac
output (CO) is either maintained or actually increased among patients without pre-existing
cardiac dysfunction [4,19]. The drug is contraindicated if the SVR is >1200 dynes x sec/cm5.
Epinephrine — Epinephrine (Adrenalin) has potent beta-1 adrenergic receptor activity and
moderate beta-2 and alpha-1 adrenergic receptor effects. Clinically, low doses of epinephrine
increase CO because of the beta-1 adrenergic receptor inotropic and chronotropic effects,
while the alpha adrenergic receptor-induced vasoconstriction is often offset by the beta-2
adrenergic receptor vasodilation. The result is an increased CO, with decreased SVR and
variable effects on the MAP [3].However, at higher epinephrine doses the alpha-adrenergic
receptor effect predominates, producing increased SVR in addition to an increased CO.
Epinephrine is most often used for the treatment of anaphylaxis, as a second line agent
(after norepinephrine) in septic shock, and for management of hypotension following
coronary artery bypass grafting.
Dopamine — Dopamine (Intropin) has a variety of effects depending upon the dose range
administered. It is most often used as a second-line alternative to norepinephrine in patients
with absolute or relative bradycardia and a low risk of tachyarrhythmias. Weight-based
administration of dopamine can achieve quite different serum drug concentrations in
different individuals [21], but the following provides an approximate description of effects:
● At doses >10 mcg/kg per minute, the predominant effect of dopamine is to stimulate
alpha-adrenergic receptors and produce vasoconstriction with an increased SVR [26,27].
However, the overall alpha-adrenergic receptor effect of dopamine is weaker than that
of norepinephrine, and the beta-1 adrenergic receptor stimulation of dopamine at
doses >2 mcg/kg per minute can result in dose-limiting dysrhythmias.
In practical terms, the dose-dependent effects of dopamine mean that changing the dose of
the drug is akin to switching vasopressors. Conversely, simply increasing the dose of
dopamine without being cognizant of the different receptor populations activated can cause
untoward results.
The usual dose range for dopamine is 2 to 20 mcg/kg per minute, although doses as high as
130 mcg/kg per minute have been employed [28]. When used for cardiac failure, dopamine
should be started at 2 mcg/kg per minute and then titrated to a desired physiologic effect
rather than depending on the predicted pharmacologic ranges described above.
Dobutamine is most frequently used in severe, medically refractory heart failure and
cardiogenic shock and should not be routinely used in sepsis because of the risk of
hypotension. Dobutamine does not selectively vasodilate the renal vascular bed, as
dopamine does at low doses. (See "Inotropic agents in heart failure with reduced ejection
fraction".)
The effects of vasopressin and terlipressin in vasodilatory shock (mostly septic shock) were
evaluated in a systematic review that identified 10 relevant randomized trials (1134 patients)
[44]. A meta-analysis of six of the trials (512 patients) compared vasopressin or terlipressin
with placebo or supportive care. There was no significant improvement in short-term
mortality among patients who received either vasopressin or terlipressin (40.2 versus 42.9
percent, relative risk 0.91, 95% CI 0.79-1.05). However, patients who received vasopressin or
terlipressin required less norepinephrine. A second randomized trial compared vasopressin
with norepinephrine in 409 patients with septic shock. Although vasopressin did not improve
mortality or the number of kidney failure-free days, it may have been associated with a
reduction in the rate of kidney failure requiring renal replacement therapy (25 versus 35
percent) [45]. Further studies are needed before vasopressin can replace norepinephrine as
the first-choice agent for those with septic shock. (See 'Choice of agent in septic shock'
below.)
The effects of vasopressin may be dose dependent. A randomized trial compared two doses
of vasopressin (0.0333 versus 0.067 IU/min) in 50 patients with vasodilatory shock who
required vasopressin as a second pressor agent [46]. The higher dose was more effective at
increasing the blood pressure without increasing the frequency of adverse effects in these
patients. However, doses of vasopressin above 0.04 units/min have been associated with
coronary and mesenteric ischemia and skin necrosis in some studies [47-50], although some
of these studies were in animals and necrosis in humans may also have been due to
coexisting conditions (eg, disseminated intravascular coagulation). However, doses higher
than the therapeutic range (0.04 units/min) are generally avoided for this reason unless an
adequate mean arterial pressure (MAP) cannot be attained with other vasopressor agents.
When weaning, we generally attempt to wean off vasopressin before norepinephrine.
NONADRENERGIC AGENTS
NOS inhibitors — Nitric oxide overproduction appears to play a major role in vasodilation
induced by sepsis (see "Pathophysiology of sepsis"). Studies of nitric oxide synthase (NOS)
inhibitors such as N-monomethyl-L-arginine (L-NMMA) in sepsis demonstrate a dose-
dependent increase in systemic vascular resistance (SVR) [56]. However, cardiac index (CI)
and heart rate (HR) decrease, even when patients are treated concomitantly with
norepinephrine or epinephrine. The increase in SVR tends to be offset by the drop in CI, such
that mean arterial pressure (MAP) is only minimally augmented. The clinical utility of this
class of drugs remains unproven.
Further trials will be required to compare angiotensin II with other vasopressor agents and
to examine its effects in populations other than those with vasodilatory shock before it can
be routinely used as a second line agent for the treatment of shock.
COMPLICATIONS
Vasopressors and inotropic agents have the potential to cause a number of significant
complications, including hypoperfusion, dysrhythmias, myocardial ischemia, local effects,
and hyperglycemia. In addition, a number of drug interactions exist.
The initial findings are dusky skin changes at the tips of the fingers and/or toes, which may
progress to frank necrosis with autoamputation of the digits. Compromise of the renal
vascular bed may produce renal insufficiency and oliguria, while patients with underlying
peripheral artery disease may develop acute limb ischemia.
Inadequate mesenteric perfusion increases the risk of gastritis, shock liver, intestinal
ischemia, or translocation of gut flora with resultant bacteremia. Despite these concerns,
maintenance of MAP with vasopressors appears more effective in maintaining renal and
mesenteric blood flow than allowing the MAP to drop, and maintenance of MAP with
vasopressors may be life-saving despite evidence of localized hypoperfusion [18,63].
Dysrhythmias — Many vasopressors and inotropes exert powerful chronotropic effects via
stimulation of beta-1 adrenergic receptors. This increases the risk of sinus tachycardia (most
common), atrial fibrillation (potentially with increased atrioventricular nodal [A-V] conduction
and therefore an increased ventricular response), re-entrant atrioventricular node
tachycardia, or ventricular tachyarrhythmias.
Adequate volume loading may minimize the frequency or severity of dysrhythmias. Despite
this, dysrhythmias often limit the dose and necessitate switching to another agent with less
prominent beta-1 effects. The degree to which the agent affects the frequency of
dysrhythmias was illustrated by a randomized trial of 1679 patients with shock [30].
Dysrhythmias were significantly more common among patients who received dopamine than
among those who received norepinephrine (24.1 versus 12.4 percent).
Hyperglycemia — Hyperglycemia may occur due to the inhibition of insulin secretion. The
magnitude of hyperglycemia generally is minor and is more pronounced with
norepinephrine and epinephrine than dopamine [23]. Monitoring of blood glucose while on
vasopressors can prevent complications of untreated hyperglycemia.
CONTROVERSIES
Several controversies exist regarding the use of vasopressors and inotropic agents in
critically ill patients. Most stem from the relative paucity of large-scale studies comparing
similar patient populations treated with different regimens. The development of clear
definitions for the systemic inflammatory response syndrome, sepsis, and septic shock is a
step forward toward comparative trials among standardized patient populations. (See
"Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and
prognosis".)
Choice of agent in septic shock — The optimal agent in patients with septic shock is
unknown and practice varies considerably among experts. However, based upon meta-
analyses of small randomized trials and observational studies, a paradigm shift in practice
has occurred such that most experts prefer to avoid dopamine in this population and favor
norepinephrine as the first-choice agent the details of which are discussed separately. (See
"Evaluation and management of suspected sepsis and septic shock in adults", section on
'Vasopressors'.)
"Renal dose" dopamine — Dopamine selectively increases renal blood flow when
administered to normal volunteers at 1 to 3 mcg/kg per minute [66,67]. Animal studies also
suggest that low-dose dopamine in the setting of vasopressor-dependent sepsis helps
preserve renal blood flow [68]. (See "Renal actions of dopamine" and "Possible prevention
and therapy of ischemic acute tubular necrosis".)
However, a beneficial effect of low or "renal dose" dopamine is less proven in human patients
with sepsis or other critical illness. Critically ill patients who do not have evidence of renal
insufficiency or decreased urine output will develop a diuresis in response to dopamine at 2
to 3 mcg/kg per minute, with variable effects on creatinine clearance, but the benefit of this
diuresis is questionable [12,25]. The intervention is not entirely benign because hypotension
and tachycardia may ensue. One small study demonstrated that the addition of low dose
dopamine to patients receiving other vasopressors increases splanchnic blood flow but does
not alter other indices of mesenteric perfusion, such as gastric intramucosal pH (pHi) [69].
At present, there are no data to support the routine use of low dose dopamine to prevent or
treat acute renal failure or mesenteric ischemia. In general, the most effective means of
protecting the kidneys in the setting of septic shock appears to be the maintenance of mean
arterial pressure (MAP) >60 mmHg while attempting to avoid excessive vasoconstriction (ie,
the systemic vascular resistance [SVR] should not exceed 1300 dynes x sec/cm5) [7,14,70,71].
Supranormal cardiac index — Elevation of the cardiac index with inotropic agents to
supranormal values (ie, >4.5 L/minute per m2) potentially increases oxygen delivery to
peripheral tissues. In theory, increased oxygen delivery may prevent tissue hypoxia and
improve outcomes, and initial studies appeared to support this hypothesis [72-74]. However,
later larger trials showed that goal-oriented hemodynamic therapy to increase either cardiac
index to >4.5 L/min per m2 or oxygen delivery to >600 to 650 mL/min per m2 with volume
expansion or dobutamine resulted in either no improvement or worsened morbidity or
mortality [15,16,75]. Therefore, the routine administration of vasopressors or inotropes to
improve cardiac output or oxygen delivery to supranormal levels is not advocated. (See
"Oxygen delivery and consumption".)
The American Thoracic Society (ATS) statement on the detection, correction, and prevention
of tissue hypoxia, as well as other ATS guidelines, can be accessed through the ATS web site
at www.thoracic.org/statements.
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sepsis in children and
adults".)
● Principles – Vasopressors are indicated for an MAP <60 mmHg, or a decrease of systolic
blood pressure that exceeds 30 mmHg from baseline, when either condition results in
end-organ dysfunction due to hypoperfusion. (See 'Principles' above.)
● Practical issues – Hypovolemia should be corrected prior to the institution of
vasopressor therapy for maximum efficacy. Patients should be re-evaluated frequently
once vasopressor therapy has been initiated. Common issues that arise include
tachyphylaxis, which may require dose titration, and additional hemodynamic insults,
which should be recognized and managed. (See 'Practical issues' above.)
● Choosing an agent – Choice of an initial agent should be based upon the suspected
underlying etiology of shock (eg, dobutamine for cardiogenic shock without significant
hypotension, norepinephrine for septic and cardiogenic shock with hypotension,
epinephrine for anaphylactic shock). (See 'Practical issues' above and "Prognosis and
treatment of cardiogenic shock complicating acute myocardial infarction", section on
'Vasopressors and inotropes'.)
Range of
United
Usual maximum
States
Agent Initial dose maintenance doses used in
trade
dose range refractory
name
shock
All doses shown are for intravenous (IV) administration in adult patients. The initial doses
shown in this table may differ from those recommended in immediate post-cardiac arrest
management (ie, advanced cardiac life support). For details, refer to the UpToDate topic
review of post-cardiac arrest management in adults, section on hemodynamic considerations.
Vasopressors can cause life-threatening hypotension and hypertension, dysrhythmias, and
myocardial ischemia. They should be administered by use of an infusion pump adjusted by
clinicians trained and experienced in dose titration of intravenous vasopressors using
continuous noninvasive electronic monitoring of blood pressure, heart rate, rhythm, and
function. Hypovolemia should be corrected prior to the institution of vasopressor therapy.
Reduce infusion rate gradually; avoid sudden discontinuation.
Vasopressors can cause severe local tissue ischemia; central line administration is preferred.
When a patient does not have a central venous catheter, vasopressors can be temporarily
administered in a low concentration through an appropriately positioned peripheral venous
catheter (ie, in a large vein) for less than 24 hours. The examples of concentrations shown in
this table are useful for peripheral (short-term) or central line administration. Closely monitor
catheter site throughout infusion to avoid extravasation injury. In event of extravasation,
prompt local infiltration of an antidote (eg, phentolamine) may be useful for limiting tissue
ischemia. Stop infusion and refer to extravasation management protocol.
Vasopressor infusions are high-risk medications requiring caution to prevent a medication
error and patient harm. To reduce the risk of making a medication error, we suggest that
centers have available protocols that include steps on how to prepare and administer
vasopressor infusions using a limited number of standardized concentrations. Examples of
concentrations and other detail are based on recommendations used at experienced centers;
protocols can vary by institution.
D5W: 5% dextrose water; MAP: mean arterial pressure; NS: 0.9% saline.
Dopamine (mcg/kg/min)*
0.5 to 2 0 + 0 ++ CO
5 to 10 + ++ 0 ++ CO ↑, SVR ↑
10 to 20 ++ ++ 0 ++ SVR ↑↑
+++: very strong effect; ++: moderate effect; +: weak effect; 0: no effect; SVR: systemic vascular
resistance; CO: cardiac output.