Official Reprint From Uptodate ©2016 Uptodate: Scott Manaker, MD, PHD Polly E Parsons, MD Geraldine Finlay, MD

06/10/2016 Use of vasopressors and inotropes UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
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: Sep 2016. | This topic last updated: Sep 13, 2016.
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".)
RECEPTOR PHYSIOLOGY — The main categories of adrenergic receptors relevant to vasopressor activity
are the alpha1, beta1, and beta2 adrenergic receptors, as well as the dopamine receptors [2,3].
Alpha adrenergic — Activation of alpha1 adrenergic receptors, located in vascular walls, induces significant
vasoconstriction. Alpha1 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].
Beta adrenergic — Beta1 adrenergic receptors are most common in the heart and mediate increases in
inotropy and chronotropy with minimal vasoconstriction. Stimulation of beta2 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.
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 due to systolic dysfunction".)
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 endorgan dysfunction due to hypoperfusion.
Hypovolemia should be corrected prior to the institution of vasopressor therapy [5]. (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 beta1 adrenergic receptor
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activation; however, it also acts upon beta2 adrenergic receptors and thus induces vasodilation and can
cause hypotension.
● Doseresponse curve – Many agents have doseresponse curves, such that the primary adrenergic
receptor subtype activated by the drug is dosedependent. As an example, dopamine stimulates beta1
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.
Norepinephrineinduced beta1 adrenergic stimulation alone normally would cause tachycardia. However,
the elevated MAP from norepinephrine's alphaadrenergic receptorinduced 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 — Repletion of adequate intravascular volume, 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 [6]. 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 [7], and 12 to 14
mmHg for septic or hypovolemic shock [8]. (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 endorgan
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. (See "Complications of central venous catheters and their prevention" and "Overview of central
venous access".)
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 [9,10].
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) [11]. 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 [12,13]. (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 [14]. 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 reevaluation — 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 alpha1 and beta1 adrenergic receptors, thus
producing potent vasoconstriction as well as a modest increase in cardiac output [5]. 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 (NeoSynephrine) has purely alphaadrenergic agonist activity and
therefore results in vasoconstriction with minimal cardiac inotropy or chronotropy. MAP is augmented by
raising systemic vascular resistance (SVR) [15]. The drug is useful in the setting of hypotension with an SVR
<700 dynes x sec/cm5 (eg, hyperdynamic sepsis, neurologic disorders, anesthesiainduced 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 [16].
Although SVR elevation increases cardiac afterload, most studies document that cardiac output (CO) is either
maintained or actually increased among patients without preexisting cardiac dysfunction [4,17]. The drug is
contraindicated if the SVR is >1200 dynes x sec/cm5.
Epinephrine — Epinephrine (Adrenalin) has potent beta1 adrenergic receptor activity and moderate beta2
and alpha1 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 receptorinduced
vasoconstriction is often offset by the beta2 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 beta1 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 [18], although the
clinical importance of this is unclear [16].
Ephedrine — Similar to epinephrine, ephedrine acts primarily on alpha and betaadrenergic 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 postanesthesiainduced hypotension.
Dopamine — Dopamine (Intropin) has a variety of effects depending upon the dose range administered. It is
most often used as a secondline alternative to norepinephrine in patients with absolute or relative bradycardia
and a low risk of tachyarrhythmias. Weightbased administration of dopamine can achieve quite different
serum drug concentrations in different individuals [19], but the following provides an approximate description
of effects:
● At doses of 1 to 2 mcg/kg per minute, dopamine acts predominantly on dopamine1 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 [2022]. These effects may be
blunted by haloperidol and other butyrophenones [22]. However, the clinical significance of these
phenomena is unclear, and some patients may develop hypotension at these low doses [23]. (See "Renal
actions of dopamine".)
● At 5 to 10 mcg/kg per minute, dopamine also stimulates beta1 adrenergic receptors and increases
cardiac output, predominantly by increasing stroke volume with variable effects on heart rate [24]. 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 alphaadrenergic
receptors and produce vasoconstriction with an increased SVR [24,25]. However, the overall alpha
adrenergic receptor effect of dopamine is weaker than that of norepinephrine, and the beta1 adrenergic
receptor stimulation of dopamine at doses >2 mcg/kg per minute can result in doselimiting dysrhythmias.
In practical terms, the dosedependent 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 [26]. 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 beta1 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 [27]. However, minimal alpha and beta2 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 due
to systolic dysfunction".)
Isoproterenol — Isoproterenol (Isuprel) also is primarily an inotropic and chronotropic agent rather than a
vasopressor. It acts upon beta1 adrenergic receptors and, unlike dobutamine, has a prominent chronotropic
effect. The drug's high affinity for the beta2 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 firstline
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 [16,28]. 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 secondline agent in refractory vasodilatory shock, particularly septic shock or anaphylaxis
that is unresponsive to epinephrine [2934]. It is also used occasionally to reduce the dose of the firstline
agent. Terlipressin, a vasopressin analog, has been assessed in patients with vasodilatory shock [3540], 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) [41]. A metaanalysis of six of
the trials (512 patients) compared vasopressin or terlipressin with placebo or supportive care. There was no
significant improvement in shortterm mortality among patients who received either vasopressin or terlipressin
(40.2 versus 42.9 percent, relative risk 0.91, 95% CI 0.791.05). 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 failurefree days, it may have been associated with a reduction in the rate of kidney failure
requiring renal replacement therapy (25 versus 35 percent) [42]. Further studies are needed before
vasopressin can replace norepinephrine as the firstchoice 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 [43]. 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 0.03 units/min have
been associated with coronary and mesenteric ischemia and skin necrosis in other studies [16,4447] and are
avoided unless an adequate mean arterial pressure (MAP) cannot be attained with other vasopressor agents.
Rebound hypotension appears to be common following withdrawal of vasopressin. To avoid rebound
hypotension, the dose is slowly tapered by 0.01 units/min every 30 minutes.
Other potential adverse effects of vasopressin include hyponatremia and pulmonary vasoconstriction [16,44
47]. Terlipressin appears to have a similar side effect profile to vasopressin. In a metaanalysis 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 0.491.67) [41].
NONADRENERGIC AGENTS — A number of agents produce vasoconstriction or inotropy through
nonadrenergic mechanisms, including phosphodiesterase inhibitors and nitric oxide synthase inhibitors (table
1).
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 [24]. (See "Inotropic agents in heart failure due to systolic
dysfunction".)
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 NmonomethylL
arginine (LNMMA) in sepsis demonstrate a dosedependent increase in systemic vascular resistance (SVR)
[48]. 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.
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 lifesaving despite evidence of localized hypoperfusion
[15,49].
Dysrhythmias — Many vasopressors and inotropes exert powerful chronotropic effects via stimulation of
beta1 adrenergic receptors. This increases the risk of sinus tachycardia (most common), atrial fibrillation
(potentially with increased atrioventricular nodal [AV] conduction and therefore an increased ventricular
response), reentrant 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 beta1 effects. The degree
to which the agent affects the frequency of dysrhythmias was illustrated by a randomized trial of 1679 patients
with shock [28]. 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 betaadrenergic receptor stimulation can
increase myocardial oxygen consumption. While there is usually coronary vasodilation in response to
vasopressors [50], 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 [51].
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 [21]. 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 largescale 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 metaanalyses 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 firstchoice agent.
● Firstline agent – Data that support norepinephrine as a firstline agent in septic shock are derived from
numerous trials that have compared one vasopressor to another in septic shock [11,28,49,5255]. These
trials included norepinephrine versus phenylephrine [56], norepinephrine versus vasopressin [42,5759],
norepinephrine versus terlipressin [35,60], norepinephrine versus epinephrine [61], and vasopressin
versus terlipressin [62]. While some of the comparisons found no convincing difference in mortality, length
of stay in the ICU or hospital, or incidence of kidney failure [42,63], two 2012 metaanalyses have
reported increased mortality among patients who received dopamine during septic shock compared to
those who received norepinephrine (53 to 54 percent versus 48 to 49 percent) [52,64]. Although the
causes of death in the two groups were not directly compared, both metaanalyses identified arrhythmic
events were about twice as common with dopamine than norepinephrine.
However, the initial choice of vasopressor in patients with sepsis is often individualized and determined by
additional factors including the presence or absence of coexistent etiologies or conditions contributing
shock. For example, in patients with septic shock associated with a high cardiac output (also known as
“hyperdynamic” septic shock or “warm” sepsis) who also have significant tachycardia (eg, fast atrial
fibrillation, sinus tachycardia >160/minute) or in those who develop tachycardia with norepinephrine,
agents that completely lack beta adrenergic effects (eg, phenylephrine, vasopressin) may be preferred.
This preference is based upon the rationale that the predominant physiological abnormality is low
systemic vascular resistance and the addition of agents with any beta adrenergic activity may worsen
tachycardia and prompt further decompensation.
● Secondline agent – The addition of a second agent may be required and, again, should be individualized
taking into account the patient's clinical status (eg, the presence of heart failure, tachycardia, arrhythmias,
additional etiologies for shock, underlying ischemia). For example, vasopressin or terlipressin may be
beneficial, when added to other vasopressor agents, such as norepinephrine [16]. In contrast, these
agents should be avoided in those with active organ ischemia. As another example, for patients with
refractory septic shock associated with a low cardiac output (also known as “hypodynamic” septic shock
or “cold” sepsis), an inotropic agent is often added to norepinephrine; we typically add epinephrine,
although dobutamine is an alternative. (See 'Epinephrine' above and 'Dobutamine' above.)
● Thirdline agent – For patients who remain hypotensive despite two vasopressors, there is no evidence
that adding a third vasopressor is superior to trying an alternative combination of vasopressors (ie,
switching from norepinephrine plus vasopressin to norepinephrine plus phenylephrine).
"Renal dose" dopamine — Dopamine selectively increases renal blood flow when administered to normal
volunteers at 1 to 3 mcg/kg per minute [65,66]. Animal studies also suggest that lowdose dopamine in the
setting of vasopressordependent sepsis helps preserve renal blood flow [67]. (See "Renal actions of
dopamine" and "Possible prevention and therapy of postischemic (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 [9,23]. 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) [68].
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) [6,11,69,70].
Optimal dosage — Several studies have suggested improved tissue perfusion when higher doses of
norepinephrine (up to 350 mcg/min) are used [11,70]. However, no survival benefit of highdose
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 [7173]. However, later larger trials showed that goaloriented 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
[12,13,74]. 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.
SUMMARY AND RECOMMENDATIONS
● Vasopressors are a powerful class of drugs that induce vasoconstriction and elevate mean arterial
pressure (MAP). (See 'Introduction' above.)
● Alpha1 adrenergic receptors induce vasoconstriction, while beta1 receptors induce inotropy plus
chronotropy, and beta2 receptors induce vasodilation. One subtype of dopamine receptor induces
norepinephrine release with subsequent vasoconstriction, although many dopamine receptors induce
vasodilation. (See 'Receptor physiology' above.)
● Vasopressors are indicated for a MAP <60 mmHg, or a decrease of systolic blood pressure that exceeds
30 mmHg from baseline, when either condition results in endorgan dysfunction due to hypoperfusion.
(See 'Principles' above.)
● Hypovolemia should be corrected prior to the institution of vasopressor therapy for maximum efficacy.
Patients should be reevaluated 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.)
● 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'.)
● For patients with septic shock, we recommend norepinephrine as the firstline agent (Grade 1B).
Alternative agents include epinephrine or, for patients with tachyarrhythmias, phenylephrine. Addition of a
second or third agent should be individualized; vasopressin may be of benefit if the adrenergic agent is
inadequate in those with hyperdynamic septic shock while an inotropic agent may be appropriate in those
with hypodynamic septic shock. (See 'Adrenergic agents' above and 'Nonadrenergic agents' above and
'Choice of agent in septic shock' above.)
● 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.)
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Topic 1619 Version 22.0
GRAPHICS
Vasopressors and inotropes in treatment of acute hypotensive states and shock:
Adult dose and selected characteristics
Range of
Usual maximum Role in therapy
US trade
Agent Initial dose maintenance doses used and selected
name
dose range in refractory characteristics
shock
Vasopressors (alpha1 adrenergic)
Norepinephrine Levophed 8 to 12 2 to 4 35 to 100 Initial vasopressor of

(noradrenaline) mcg/minute (0.1 mcg/minute mcg/minute (0.5 choice in septic,
to 0.15 (0.025 to 0.05 to 0.75 cardiogenic, and
mcg/kg/minute) mcg/kg/minute) mcg/kg/minute; hypovolemic shock.
A lower initial up to 3.3 Wide range of doses
dose of 5 mcg/kg/minute utilized clinically.
mcg/minute may has been needed Must be diluted; eg, a
be used, eg, in rarely) usual concentration is
older adults 4 mg in 250 mL of
D5W or NS (16
micrograms/mL).
Epinephrine Adrenalin 1 mcg/minute 1 to 10 10 to 35 Initial vasopressor of

(adrenaline) (0.014 mcg/minute mcg/minute choice in anaphylactic
mcg/kg/minute) (0.014 to 0.14 (0.14 to 0.5 shock.
mcg/kg/minute) mcg/kg/minute) Typically an addon
agent to
norepinephrine in
septic shock when an
additional agent is
required and
occasionally an
alternative firstline
agent if
norepinephrine is
contraindicated.
Increases heart rate;
may induce
tachyarrhythmias and
ischemia.
Elevates lactate
concentrations during
initial administration
(ie, may preclude use
of lactate clearance
goal); may decrease
mesenteric perfusion.
Must be diluted; eg, a
usual concentration is
1 mg in 250 mL D5W
(4 micrograms/mL).
Phenylephrine Neo 100 to 180 20 to 80 80 to 360 Pure alphaadrenergic

Synephrine, mcg/minute until mcg/minute mcg/minute (1.1 vasoconstrictor.
Vazculep stabilized (0.25 to 1.1 to 6 Initial vasopressor
(alternatively, mcg/kg/minute) mcg/kg/minute); when
0.5 to 2 Doses >6 tachyarrhythmias
mcg/kg/minute) mcg/kg/minute preclude use of
do not increase norepinephrine.
efficacy Alternative
according to vasopressor for
product patients with septic
information in shock who: (1)
the United States develop
tachyarrhythmias on
norepinephrine, (2)
have persistent shock
despite use of two or
more
vasopressor/inotropic
agents including
vasopressin (salvage
therapy), or (3) high
cardiac output with
persistent
hypotension.
May decrease stroke
volume and cardiac
output in patients
with cardiac
dysfunction.
May be given as bolus
dose of 50 to100
micrograms to
support blood
pressure during rapid
sequence intubation.
10 mg in 250 mL
D5W or NS (40
micrograms/mL).
Dopamine Inotropin 2 to 5 5 to 20 20 to >50 A secondline agent

mcg/kg/minute mcg/kg/minute mcg/kg/minute to norepinephrine in
highly selected
patients (ie, low risk
of tachyarrhythmias
or bradycardia
induced
hypotension).
More adverse effects
(eg, tachycardia,
arrhythmias
particularly at doses
≥20 mcg/kg/minute)
and failed therapy
than norepinephrine.
May be useful in
selected patients (eg,
with compromised
systolic function or
bradycardia at low
risk for
tachyarrhythmias).
Lower doses (eg, 1 to
3 mcg/kg/minute)
should not be used
for renal protective
effect and can cause
hypotension during
weaning.
400 mg in 250 mL
D5W (1.6 mg/mL);
use of a commercially
available prediluted
solution is preferred.
Antidiuretic hormone
Vasopressin Pitressin, 0.03 units per 0.03 to 0.04 0.04 to 0.07 Addon to another

(arginine Vasostrict minute units per minute units/minute; vasopressor (eg,
vasopressin) (alternatively (not titrated) Doses >0.04 norepinephrine) to
0.01 to 0.03 units/minute can augment efficacy and
units/minute cause cardiac decrease initial
initially) ischemia and vasopressor
should be requirement. Not
reserved for recommended as a
salvage therapy replacement for a
firstline vasopressor.
Pure vasoconstrictor;
may decrease stroke
volume and cardiac
output in myocardial
dysfunction or
precipitate ischemia
in coronary artery
disease.
25 units in 250 mL
D5W or NS (0.1
units/mL).
Inotrope (beta 1 adrenergic)
Dobutamine Dobutrex 0.5 to 1 2 to 20 20 to 40 Initial agent of choice

mcg/kg/minute mcg/kg/minute mcg/kg/minute; in cardiogenic shock
(alternatively, Doses >20 with low cardiac
2.5 mcg/kg/minute output and
mcg/kg/minute are not maintained blood
in more severe recommended in pressure.
cardiac heart failure and Addon to
decompensation) should be norepinephrine for
reserved for cardiac output
salvage therapy augmentation in
septic shock with
myocardial
dysfunction (eg, in
elevated left
ventricular filling
pressures and
adequate MAP) or
ongoing
hypoperfusion
despite adequate
intravascular volume
and MAP.
Increases cardiac
contractility and rate;
may cause
hypotension and
tachyarrhythmias.
Must be diluted; a
250 mg in 500 mL
D5W or NS (0.5
mg/mL); use of a
commercially available
prediluted solution is
preferred.
Inotrope (nonadrenergic, PDE 3 inhibitor)
Milrinone Primacor Optional loading 0.125 to 0.75 Alternative for short

dose: 50 mcg/kg mcg/kg/minute term cardiac output
over 10 minutes augmentation to
(usually not maintain organ
given) perfusion in
cardiogenic shock
refractory to other
agents.
Increases cardiac
contractility and
modestly increases
heart rate at high
doses; may cause
peripheral
vasodilation,
hypotension, and/or
ventricular
arrhythmia.
Renally cleared; dose
adjustment in renal
impairment needed.
40 mg in 200 mL
D5W (200
micrograms/mL); use
of a commercially
available prediluted
solution is preferred.
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 postcardiac arrest management (ie, advanced cardiac life
support). For details, refer to the UpToDate topic review of postcardiac arrest management in adults, section
on hemodynamic considerations.
Vasopressors can cause lifethreatening 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) until a central venous
catheter is inserted. The examples of concentrations shown in this table are useful for peripheral (shortterm)
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, if available) may be useful for
limiting tissue ischemia. Stop infusion and refer to extravasation management protocol.
Vasopressor infusions are highrisk 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 vary.
D5W: 5% dextrose water; MAP: mean arterial pressure; NS: 0.9% saline.
Data from:
1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of
severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580.
2. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011; 183:847.
3. Lexicomp Online. Copyright © 19782016 Lexicomp, Inc. All Rights Reserved.
Graphic 99963 Version 6.0
Vasoactive medication receptor activity and clinical effects
Receptor activity
Drug Predominant clinical effects
Alpha1 Beta1 Beta2 Dopaminergic
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.
* Doses between 2. and 5. mcg/kg/min have variable effects.
Graphic 63100 Version 1.0
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06/10/2016 Use of vasopressors and inotropes UpToDate

Norepinephrine Levophed 8 to 12 2 to 4 35 to 100 Initial vasopressor of

Epinephrine Adrenalin 1 mcg/minute 1 to 10 10 to 35 Initial vasopressor of

Phenylephrine Neo 100 to 180 20 to 80 80 to 360 Pure alphaadrenergic

Dopamine Inotropin 2 to 5 5 to 20 20 to >50 A secondline agent

Vasopressin Pitressin, 0.03 units per 0.03 to 0.04 0.04 to 0.07 Addon to another

Dobutamine Dobutrex 0.5 to 1 2 to 20 20 to 40 Initial agent of choice

Milrinone Primacor Optional loading 0.125 to 0.75 Alternative for short

Phenylephrine +++ 0 0 0 SVR ↑ ↑, CO ↔/↑

Norepinephrine +++ ++ 0 0 SVR ↑ ↑, CO ↔/↑

Epinephrine +++ +++ ++ 0 CO ↑ ↑, SVR ↓ (low dose) SVR/↑ (higher dose)

Dobutamine 0/+ +++ ++ 0 CO ↑, SVR ↓

Isoproterenol 0 +++ +++ 0 CO ↑, SVR ↓

You might also like

Official Reprint From Uptodate ©2016 Uptodate: Scott Manaker, MD, PHD Polly E Parsons, MD Geraldine Finlay, MD

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Copyright

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Official Reprint From Uptodate ©2016 Uptodate: Scott Manaker, MD, PHD Polly E Parsons, MD Geraldine Finlay, MD

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Copyright:

Available Formats

06/10/2016 Use of vasopressors and inotropes ­ UpToDate

Norepinephrine Levophed 8 to 12 2 to 4 35 to 100 Initial vasopressor of

Epinephrine Adrenalin 1 mcg/minute 1 to 10 10 to 35 Initial vasopressor of

Phenylephrine Neo­ 100 to 180 20 to 80 80 to 360 Pure alpha­adrenergic

Dopamine Inotropin 2 to 5 5 to 20 20 to >50 A second­line agent

Vasopressin Pitressin, 0.03 units per 0.03 to 0.04 0.04 to 0.07 Add­on to another

Dobutamine Dobutrex 0.5 to 1 2 to 20 20 to 40 Initial agent of choice

Milrinone Primacor Optional loading 0.125 to 0.75 Alternative for short­

Phenylephrine +++ 0 0 0 SVR ↑ ↑, CO ↔/↑

Norepinephrine +++ ++ 0 0 SVR ↑ ↑, CO ↔/↑

Epinephrine +++ +++ ++ 0 CO ↑ ↑, SVR ↓ (low dose) SVR/↑ (higher dose)

Dobutamine 0/+ +++ ++ 0 CO ↑, SVR ↓

Isoproterenol 0 +++ +++ 0 CO ↑, SVR ↓

You might also like

06/10/2016 Use of vasopressors and inotropes UpToDate

Phenylephrine Neo 100 to 180 20 to 80 80 to 360 Pure alphaadrenergic

Dopamine Inotropin 2 to 5 5 to 20 20 to >50 A secondline agent

Vasopressin Pitressin, 0.03 units per 0.03 to 0.04 0.04 to 0.07 Addon to another

Milrinone Primacor Optional loading 0.125 to 0.75 Alternative for short