Use of Vasopressors and Inotropes

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Use of vasopressors and inotropes

Author: Scott Manaker, MD, PhD
Section Editor: Polly E Parsons, MD
Deputy Editor: Geraldine Finlay, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2022. | This topic last updated: Apr 15, 2022.
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".)
PHYSIOLOGIC MECHANISMS OF VASOCONSTRICTION
The main categories of adrenergic receptors relevant to vasopressor activity are the alpha-1,
beta-1, and beta-2 adrenergic receptors, as well as the dopamine receptors [2,3].
Alpha adrenergic — Activation of alpha-1 adrenergic receptors, located in vascular walls,

induces significant vasoconstriction. Alpha-1 adrenergic receptors are also present in the
heart and can increase the duration of contraction without increased chronotropy. However,
clinical significance of this phenomenon is unclear [4].
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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.
Dopamine — Dopamine receptors are present in the renal, splanchnic (mesenteric),

coronary, and cerebral vascular beds; stimulation of these receptors leads to vasodilation. A
second subtype of dopamine receptors causes vasoconstriction by inducing norepinephrine
release.
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
Use of vasopressors and inotropic agents requires attention to a number of issues:
Volume resuscitation — Adequate intravascular volume resuscitation, when time permits,

is crucial prior to the initiation of vasopressors. As an example, most patients with septic
shock require at least 2 liters of intravenous fluid in order for vasopressors to be maximally
effective [7]. Vasopressors will be ineffective or only partially effective in the setting of
coexistent hypovolemia.
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.
Route of administration — Vasopressors and inotropic agents should be administered

through an appropriately positioned central venous catheter, if available. This facilitates

more rapid delivery of the agent to the heart for systemic distribution and eliminates the risk
of peripheral extravasation. When a patient does not have a central venous catheter,
vasopressors and inotropic agents can be administered through an appropriately positioned
peripheral intravenous catheter temporarily, until a central venous catheter is inserted
[10,11]. (See "Overview of complications of central venous catheters and their prevention in
adults" and "Overview of central venous access in adults".)
Tachyphylaxis — Responsiveness to these drugs can decrease over time due to

tachyphylaxis. Doses must be constantly titrated to adjust for this phenomenon and for
changes in the patient's clinical condition [12,13].
Hemodynamic effects — Mean arterial pressure (MAP) is influenced by systemic vascular

resistance (SVR) and cardiac output (CO). In situations such as cardiogenic shock, elevating
SVR increases afterload and the work of an already failing heart, thus potentially lowering
CO. Some authors recommend keeping the SVR approximately 700 to 1000 dynes x sec/cm5
to avoid excessive afterload and to minimize complications from profound vasoconstriction
(calculator 1) [14]. However, there is no consensus regarding an ideal target cardiac index
(CI). Studies that have attempted to maintain a supraphysiologic CI of >4 to 4.5 L/minute per
m2 have not shown consistent benefit [15,16]. (See "Oxygen delivery and consumption".)
Subcutaneous delivery of medications — Critically ill patients often receive

subcutaneously injected medications, such as heparin and insulin. The bioavailability of
these medications can be reduced during treatment with vasopressors due to cutaneous
vasoconstriction.
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
Adrenergic agents, such as phenylephrine, norepinephrine, dopamine, and dobutamine, are

the most commonly used vasopressor and inotropic drugs in critically ill patients ( table 1).
These agents manifest different receptor selectivity and clinical effects ( table 2).
Norepinephrine — Norepinephrine (Levophed) acts on both alpha-1 and beta-1 adrenergic

receptors, thus producing potent vasoconstriction as well as a modest increase in cardiac
output [6]. A reflex bradycardia usually occurs in response to the increased mean arterial
pressure (MAP), such that the mild chronotropic effect is canceled out and the heart rate
remains unchanged or even decreases slightly. Norepinephrine is the preferred vasopressor
for the treatment of septic shock. (See 'Choice of agent in septic shock' below and
"Evaluation and management of suspected sepsis and septic shock in adults".)
Phenylephrine — Phenylephrine (Neo-Synephrine) has purely alpha-adrenergic agonist

activity and therefore results in vasoconstriction with minimal cardiac inotropy or
chronotropy. MAP is augmented by raising systemic vascular resistance (SVR) [18]. The drug
is useful in the setting of hypotension with an SVR <700 dynes x sec/cm5 (eg, hyperdynamic
sepsis, neurologic disorders, anesthesia-induced hypotension). A potential disadvantage of
phenylephrine is that it may decrease stroke volume, so it is reserved for patients in whom
norepinephrine is contraindicated due to arrhythmias or who have failed other therapies.
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.
Other disadvantages of epinephrine include dysrhythmias (due to beta-1 adrenergic

receptor stimulation) and splanchnic vasoconstriction. The degree of splanchnic
vasoconstriction appears to be greater with epinephrine than with equipotent doses of

norepinephrine or dopamine in patients with severe shock [20], although the clinical
importance of this is unclear.
Ephedrine — Similar to epinephrine, ephedrine acts primarily on alpha- and beta-adrenergic

receptors, but with less potency. It also has an effect by leading to release of endogenous
norepinephrine. Ephedrine is rarely used except in the setting of post-anesthesia-induced
hypotension.
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 of 1 to 2 mcg/kg per minute, dopamine acts predominantly on dopamine-1

receptors in the renal, mesenteric, cerebral, and coronary beds, resulting in selective
vasodilation. Some reports suggest that dopamine increases urine output by
augmenting renal blood flow and glomerular filtration rate, and natriuresis by
inhibiting aldosterone and renal tubular sodium transport [22-24]. These effects may
be blunted by haloperidol and other butyrophenones [24]. However, the clinical
significance of these phenomena is unclear, and some patients may develop
hypotension at these low doses [25]. (See "Renal actions of dopamine".)
● At 5 to 10 mcg/kg per minute, dopamine also stimulates beta-1 adrenergic receptors

and increases cardiac output, predominantly by increasing stroke volume with variable
effects on heart rate [26]. Doses between 2 and 5 mcg/kg per minute have variable
effects on hemodynamics in individual patients: vasodilation is often balanced by
increased stroke volume, producing little net effect upon systemic blood pressure.
Some mild alpha adrenergic receptor activation increases SVR, and the sum of these
effects is an increase in MAP.
● 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 — Dobutamine (Dobutrex) is not a vasopressor but rather is an inotrope that

causes vasodilation. Dobutamine's predominant beta-1 adrenergic receptor effect increases
inotropy and chronotropy and reduces left ventricular filling pressure. In patients with heart
failure this results in a reduction in cardiac sympathetic activity [29]. However, minimal
alpha- and beta-2 adrenergic receptor effects result in overall vasodilation, complemented
by reflex vasodilation to the increased CO. The net effect is increased CO, with decreased SVR
with or without a small reduction in blood pressure.
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".)
Isoproterenol — Isoproterenol (Isuprel) also is primarily an inotropic and chronotropic

agent rather than a vasopressor. It acts upon beta-1 adrenergic receptors and, unlike
dobutamine, has a prominent chronotropic effect. The drug's high affinity for the beta-2
adrenergic receptor causes vasodilation and a decrease in MAP. Therefore, its utility in
hypotensive patients is limited to situations in which hypotension results from bradycardia.
Contraindications and interactions — Several conditions or medications require avoidance

of specific agents:
● In patients with cardiogenic shock, norepinephrine is preferred over dopamine as the

first-line vasopressor because a subgroup analysis from a randomized trial found that
patients with cardiogenic shock who received dopamine had a higher mortality than
those who received norepinephrine [30]. In addition, dysrhythmias were more common
in the dopamine group.
● Patients with pheochromocytoma are at risk of excessive autonomic stimulation from

adrenergic vasopressors.
● Dobutamine is contraindicated in the setting of idiopathic hypertrophic subaortic

stenosis.
● Patients receiving monoamine oxidase inhibitors are extremely sensitive to

vasopressors and, therefore, require much lower doses.

VASOPRESSIN AND ANALOGS
Vasopressin (antidiuretic hormone) is used in the management of diabetes insipidus and

esophageal variceal bleeding; however, it may also be helpful in the management of
vasodilatory shock ( table 1). Although its precise role in vasodilatory shock remains to be
defined, it is primarily used as a second-line agent in refractory vasodilatory shock,
particularly septic shock or anaphylaxis that is unresponsive to epinephrine [31-37]. It is also
used occasionally to reduce the dose of the first-line agent. Terlipressin, a vasopressin
analog, has been assessed in patients with vasodilatory shock [38-43], but it is not available
in the United States.
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.
Based upon clinical experience, hypotension appears to be common following withdrawal of

vasopressin. To avoid this, the dose can be slowly tapered by 0.01 units/minute every 30 to
60 minutes [51,52].

Other potential adverse effects of vasopressin include hyponatremia, pulmonary

vasoconstriction, and diabetes insipidus [47-50,53]. Terlipressin appears to have a similar
side effect profile to vasopressin. In a meta-analysis of four trials (431 patients) that was
conducted as part of the systematic review described above, there was no significant
difference in the frequency of adverse events among patients who received either
vasopressin or terlipressin (10.6 versus 11.8 percent, relative risk 0.90, 95% CI 0.49-1.67) [44].
NONADRENERGIC AGENTS
A number of agents produce vasoconstriction or inotropy through nonadrenergic

mechanisms, including phosphodiesterase inhibitors and nitric oxide synthase inhibitors,
calcium sensitizers, or angiotensin II.
PDE inhibitors — Phosphodiesterase (PDE) inhibitors, such as inamrinone (formerly known

as amrinone) and milrinone, are nonadrenergic drugs with inotropic and vasodilatory
actions. In many ways, their effects are similar to those of dobutamine but with a lower
incidence of dysrhythmias. PDE inhibitors most often are used to treat patients with
impaired cardiac function and medically refractory heart failure, but their vasodilatory
properties limit their use in hypotensive patients [26]. Inamrinone is no longer available in
North America and most/all other countries so the only intravenous PDE inhibitor used in
the US is milrinone. (See "Inotropic agents in heart failure with reduced ejection fraction".)
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) [54]. 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.
Calcium sensitizers — Several agents increase myocardial contractility (eg, pimobendan,

levosimendan) but conclusive evidence of improved outcomes with their use is lacking
[55,56].
Angiotensin II — Preliminary trials have reported an adequate vasopressor effect when

synthetic angiotensin II is exogenously administered for vasodilatory shock (eg, septic shock)
[57,58]. Best supporting its role as a vasopressor agent is a randomized trial of 344 patients
with vasodilatory shock (80 percent had sepsis and patients had a normal cardiac output)
already receiving high dose norepinephrine or similar vasopressor equivalent [59]. When
compared with placebo, angiotensin II resulted in a greater proportion of patients achieving
a 10 mmHg or greater increase in the baseline mean arterial pressure (MAP) or more or an
increase in the MAP to 75 mmHg or higher (70 versus 23 percent), at three hours. There was
no effect on mortality or on the sequential organ failure assessment score. Serious adverse
events were no different among the groups. Angiotensin II resulted in less background
vasopressor use and higher heart rates but did not result in life-threatening
tachyarrhythmias. 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.
Hypoperfusion — Excessive vasoconstriction in response to hypotension and vasopressors

can produce inadequate perfusion of the extremities, mesenteric organs, or kidneys.
Excessive vasoconstriction with inadequate perfusion, usually with an systemic vascular
resistance (SVR) >1300 dynes x sec/cm5, commonly occurs in the setting of inadequate
cardiac output or inadequate volume resuscitation.
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 [18,60].
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
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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).
Myocardial ischemia — The chronotropic and inotropic effects of beta-adrenergic receptor

stimulation can increase myocardial oxygen consumption. While there is usually coronary
vasodilation in response to vasopressors [61], perfusion may still be inadequate to
accommodate the increased myocardial oxygen demand. Daily electrocardiograms on
patients treated with vasopressors or inotropes may screen for occult ischemia, and
excessive tachycardia should be avoided because of impaired diastolic filling of the coronary
arteries.
Local effects — Peripheral extravasation of vasopressors into the surrounding connective

tissue can lead to excessive local vasoconstriction with subsequent skin necrosis. To avoid
this complication, vasopressors should be administered via a central vein whenever possible.
If infiltration occurs, local treatment with phentolamine (5 to 10 mg in 10 mL of normal
saline) injected subcutaneously can minimize local vasoconstriction [62].
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 [63,64]. Animal studies also
suggest that low-dose dopamine in the setting of vasopressor-dependent sepsis helps
preserve renal blood flow [65]. (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) [66].
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) [7,14,67,68].
Optimal dosage — Although norepinephrine doses of up to 100 mcg/min in adults are

typically used in refractory shock and as salvage therapy in combination with a second
vasopressor agent, there is no well-established maximum dose. Several studies have
suggested improved tissue perfusion when higher doses of norepinephrine (up to 350
mcg/min) are used [14,68] but no survival benefit of high-dose norepinephrine has been
conclusively proven.
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 [69-71]. 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 [15,16,72]. 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.
SOCIETY GUIDELINE LINKS
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".)
SUMMARY AND RECOMMENDATIONS
● Definition – Vasopressors are a powerful class of drugs that induce vasoconstriction

and elevate mean arterial pressure (MAP). (See 'Introduction' above.)
● Physiology – Alpha-1 adrenergic receptors induce vasoconstriction, while beta-1

receptors induce inotropy plus chronotropy, and beta-2 receptors induce vasodilation.
One subtype of dopamine receptor induces norepinephrine release with subsequent
vasoconstriction, although many dopamine receptors induce vasodilation. Some
agents increase the sensitivity of the myocardial contractile apparatus to calcium while
others cause direct vasoconstriction via angiotensin II receptor stimulation. (See
'Physiologic mechanisms of vasoconstriction' above.)
● 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'.)
● Complications – Complications of vasopressor therapy include hypoperfusion

(particularly affecting the extremities, mesentery or kidneys), dysrhythmias, myocardial

ischemia, peripheral extravasation with skin necrosis, and hyperglycemia. (See

'Complications' above.)
Use of UpToDate is subject to the Terms of Use.
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Topic 1619 Version 42.0

GRAPHICS
Vasopressors and inotropes in treatment of acute hypotensive states and

shock: Adult dose and selected characteristics
United Range of
Usual
States maximum dose
Agent Initial dose maintenance
trade used in
dose range
name refractory shock
Vasopressors (alpha-1 adrenergic)
Norepinephrine Levophed 5 to 15 mcg/minute 2 to 80 mcg/minute 80 to

(noradrenaline) (0.05 to (0.025 to 250 mcg/minute (1
0.15 mcg/kg/minute) 1 mcg/kg/minute) to
3.3 mcg/kg/minute
Cardiogenic shock: Cardiogenic shock:
0.05 mcg/kg/minute 0.05 to
0.4 mcg/kg/minute
Epinephrine Adrenalin 1 to 15 mcg/minute 1 to 40 mcg/minute 40 to

(adrenaline) (0.01 to (0.01 to 160 mcg/minute
0.2 mcg/kg/minute) 0.5 mcg/kg/minute) (0.5 to
2 mcg/kg/minute)

Phenylephrine Neo- 40 to 20 to 80 to
Synephrine, 160 mcg/minute 400 mcg/minute 730 mcg/minute
Vazculep until stabilized (0.25 to (1.1 to
(alternatively, 0.5 to 5 mcg/kg/minute) 9.1 mcg/kg/minute
2 mcg/kg/minute)

Dopamine Inotropin 2 to 2 to 20 mcg/kg/minute

5 mcg/kg/minute 20 mcg/kg/minute

Antidiuretic hormone
Vasopressin Pitressin, 0.03 units/minute 0.01 to Doses

(arginine- Vasostrict 0.04 units/minute >0.04 units/minute
vasopressin) (not titrated) can cause cardiac
ischemia and
should be reserved
for salvage therapy
Inotrope (beta1 adrenergic)
Dobutamine Dobutrex Usual: 2 to 2 to 20 mcg/kg/minute

5 mcg/kg/minute 10 mcg/kg/minute
(range: 0.5 to
5 mcg/kg/minute;
lower doses for less
severe cardiac
decompensation)

Inotrope (nonadrenergic, PDE3 inhibitor)
Milrinone Primacor 0.125 to 0.125 to 0.75 mcg/kg/minut

0.25 mcg/kg/minute 0.75 mcg/kg/minute

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.
Prepared with data from:

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of
sepsis and septic shock: 2016. Crit Care Med 2017; 45:486.
2. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011; 183:847.
3. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.
Graphic 99963 Version 20.0

Vasoactive medication receptor activity and clinical effects
Receptor activity
Predominant clinical
Drug
Alpha- Beta- Beta- effects
Dopaminergic
1 1 2
Phenylephrine +++ 0 0 0 SVR ↑ ↑, CO ↔/↑
Norepinephrine +++ ++ 0 0 SVR ↑ ↑, CO ↔/↑
Epinephrine +++ +++ ++ 0 CO ↑ ↑, SVR ↓ (low dose) SVR/↑

(higher dose)
Dopamine (mcg/kg/min)*
0.5 to 2. 0 + 0 ++ CO
5. to 10. + ++ 0 ++ CO ↑, SVR ↑
10. to 20. ++ ++ 0 ++ SVR ↑ ↑
Dobutamine 0/+ +++ ++ 0 CO ↑, SVR ↓
Isoproterenol 0 +++ +++ 0 CO ↑, SVR ↓
+++: Very strong effect; ++: Moderate effect; +: Weak effect; 0: No effect; SVR: systemic vascular
resistance; CO: cardiac output.
* Doses between 2. and 5. mcg/kg/min have variable effects.
Graphic 63100 Version 2.0

Contributor Disclosures
Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in
medical negligence matters [General pulmonary and critical care medicine]; National Board for
Respiratory Care [Director].
All of the relevant financial relationships listed have been mitigated. Polly E
Parsons, MD No relevant financial relationship(s) with ineligible companies to disclose. Geraldine
Finlay, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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PHYSIOLOGIC MECHANISMS OF VASOCONSTRICTION

Alpha adrenergic — Activation of alpha-1 adrenergic receptors, located in vascular walls,

Dopamine — Dopamine receptors are present in the renal, splanchnic (mesenteric),

Calcium sensitizers — Some agents increase the sensitivity of the myocardial contractile

Use of vasopressors and inotropic agents requires attention to a number of issues:

Volume resuscitation — Adequate intravascular volume resuscitation, when time permits,

Route of administration — Vasopressors and inotropic agents should be administered

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Tachyphylaxis — Responsiveness to these drugs can decrease over time due to

Hemodynamic effects — Mean arterial pressure (MAP) is influenced by systemic vascular

Subcutaneous delivery of medications — Critically ill patients often receive

Frequent re-evaluation — Critically ill patients may undergo a second hemodynamic insult

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Adrenergic agents, such as phenylephrine, norepinephrine, dopamine, and dobutamine, are

Norepinephrine — Norepinephrine (Levophed) acts on both alpha-1 and beta-1 adrenergic

Phenylephrine — Phenylephrine (Neo-Synephrine) has purely alpha-adrenergic agonist

Epinephrine — Epinephrine (Adrenalin) has potent beta-1 adrenergic receptor activity and

Other disadvantages of epinephrine include dysrhythmias (due to beta-1 adrenergic

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Ephedrine — Similar to epinephrine, ephedrine acts primarily on alpha- and beta-adrenergic

● At doses of 1 to 2 mcg/kg per minute, dopamine acts predominantly on dopamine-1

● At 5 to 10 mcg/kg per minute, dopamine also stimulates beta-1 adrenergic receptors

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Dobutamine — Dobutamine (Dobutrex) is not a vasopressor but rather is an inotrope that

Isoproterenol — Isoproterenol (Isuprel) also is primarily an inotropic and chronotropic

Contraindications and interactions — Several conditions or medications require avoidance

● In patients with cardiogenic shock, norepinephrine is preferred over dopamine as the

● Patients with pheochromocytoma are at risk of excessive autonomic stimulation from

● Dobutamine is contraindicated in the setting of idiopathic hypertrophic subaortic

● Patients receiving monoamine oxidase inhibitors are extremely sensitive to

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VASOPRESSIN AND ANALOGS

Vasopressin (antidiuretic hormone) is used in the management of diabetes insipidus and

Based upon clinical experience, hypotension appears to be common following withdrawal of

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Other potential adverse effects of vasopressin include hyponatremia, pulmonary

A number of agents produce vasoconstriction or inotropy through nonadrenergic

PDE inhibitors — Phosphodiesterase (PDE) inhibitors, such as inamrinone (formerly known

NOS inhibitors — Nitric oxide overproduction appears to play a major role in vasodilation

Calcium sensitizers — Several agents increase myocardial contractility (eg, pimobendan,

Angiotensin II — Preliminary trials have reported an adequate vasopressor effect when

Hypoperfusion — Excessive vasoconstriction in response to hypotension and vasopressors

Dysrhythmias — Many vasopressors and inotropes exert powerful chronotropic effects via

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Myocardial ischemia — The chronotropic and inotropic effects of beta-adrenergic receptor

Local effects — Peripheral extravasation of vasopressors into the surrounding connective

Hyperglycemia — Hyperglycemia may occur due to the inhibition of insulin secretion. The

"Renal dose" dopamine — Dopamine selectively increases renal blood flow when

Optimal dosage — Although norepinephrine doses of up to 100 mcg/min in adults are

Supranormal cardiac index — Elevation of the cardiac index with inotropic agents to

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Definition – Vasopressors are a powerful class of drugs that induce vasoconstriction

● Physiology – Alpha-1 adrenergic receptors induce vasoconstriction, while beta-1

● Principles – Vasopressors are indicated for an MAP <60 mmHg, or a decrease of

● Practical issues – Hypovolemia should be corrected prior to the institution of

● Complications – Complications of vasopressor therapy include hypoperfusion

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ischemia, peripheral extravasation with skin necrosis, and hyperglycemia. (See

Use of UpToDate is subject to the Terms of Use.

2. AHLQUIST RP. A study of the adrenotropic receptors. Am J Physiol 1948; 153:586.