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Review Article

Pharmacologic agents for acute


hemodynamic instability:Recent
advances in the management of
perioperative shock- Asystematic
review
Steven T. Morozowich1,2, Harish Ramakrishna1,2
Department of Anesthesiology, Mayo Clinic College of Medicine, 2Department of Anesthesiology, Division of
1

Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Phoenix, Arizona, USA

ABSTRACT Despite the growing body of evidence evaluating the efficacy of vasoactive agents in the management of
hemodynamic instability and circulatory shock, it appears no agent is superior. This is becoming increasingly
accepted as current guidelines are moving away from detailed algorithms for the management of shock,
and instead succinctly state that vasoactive agents should be individualized and guided by invasive
hemodynamic monitoring. This extends to the perioperative period, where vasoactive agent selection and
use may still be left to the discretion of the treating physician with a goal-directed approach, consisting of
close hemodynamic monitoring and administration of the lowest effective dose to achieve the hemodynamic
goals. Successful therapy depends on the ability to rapidly diagnose the etiology of circulatory shock and
thoroughly understand its pathophysiology as well as the pharmacology of vasoactive agents. This review
focuses on the physiology and resuscitation goals in perioperative shock, as well as the pharmacology and
recent advances in vasoactive agent use in its management.

Received: 240815 Key words: Circulatory shock; Hemodynamic instability; Perioperative period; Perioperative shock; Vasoactive
Accepted: 250915 agent

INTRODUCTION Conventionally, these agents are used in


a supportive context with the assumption
Circulatory shock is defined as inadequate that clinical recovery will be facilitated
oxygen delivery to the tissues, typically in by their temporary use. [7,8] Despite using
the setting of hypotension.[1] The current these drugs since the 1940s, their use today
definition of hypotension varies, but a
systolic arterial blood pressure<90mmHg Address for correspondence: Dr.Harish Ramakrishna,
and/or a mean arterial blood pressure(MAP) Mayo Clinic College of Medicine, Department of
Access this article online Anesthesiology, Division of Cardiovascular and Thoracic
<6070mmHg is generally accepted.[13] If Anesthesiology, Mayo Clinic, Phoenix, Arizona, USA.
Website: www.annals.in Email:Ramakrishna.Harish@Mayo.edu
circulatory shock is not corrected rapidly,
PMID:
*** tissue hypoxia and cellular death ensue. The
DOI: mortality associated with circulatory shock This is an open access article distributed under the terms of the
10.4103/0971-9784.166464 Creative Commons AttributionNonCommercialShareAlike 3.0
in the intensive care unit ranges from 16% in License, which allows others to remix, tweak, and build upon the
Quick Response Code:
those with trauma/hypovolemic shock,[4] 48% work noncommercially, as long as the author is credited and the
new creations are licensed under the identical terms.
in those with cardiogenic shock,[5] and up to
60% in those with septic shock.[6] Inevitably, For reprints contact: reprints@medknow.com
these patients will present perioperatively
Cite this article as: Morozowich ST, Ramakrishna H.
and will require ongoing management with Pharmacologic agents for acute hemodynamic instability: Recent
vasoactive agents, a term collectively referring advances in the management of perioperative shock- A systematic
review. Ann Card Anaesth 2015;18:543-54.
to vasopressor and inotrope medications.

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Morozowich and Ramakrishna: Recent advances in perioperative shock management

remains guided largely by opinion.[8,9] In the general refractory hypotension despite a normal or elevated
population of critically ill patients with circulatory CO and DO2. Although the CO and DO2 are normal,
shock, surveys have shown that agent selection is hypotension below the normal organ autoregulatory
based on clinical experience and preference[10] and, range (e.g.MAP<6065mmHg) still results in impaired
interestingly, despite the growing body of evidence, organ blood flow.[1719] This occurs because the absolute
this practice has recently been validated.[11] Similarly, organ perfusion pressure(or driving pressure) is too
perioperative studies have demonstrated significant low, and the normal autoregulatory decrease in organ
variability in agent selection in cardiac surgery.[1214] In vascular resistance is insufficient to restore normal
a recently published metaanalysis of 23 randomized organ blood flow.[18] This relationship is expressed by
controlled trials comparing commonly used vasoactive relating Ohms law to fluid flow:[20]
agents(dopamine, norepinephrine, epinephrine,
phenylephrine, vasopressin, and terlipressin), Organ blood flow =(Organ perfusion pressure)/(organ
either alone or in combination with dobutamine or vascular resistance)
dopexamine for the management of hypotensive shock
showed no difference in mortality based on agent use Organ perfusion pressure is the difference between
and concluded that currently, there is no sufficient organ arterial and venous pressure. Because normal
evidence that any of the agents are clearly superior.[11] organ venous pressure is typically negligible, the organ
However, the presumption is that current vasoactive perfusion pressure is usually equal to the organ arterial
agent selection for the management of circulatory pressure, which is the MAP, thus demonstrating the
shock is based on correctly identifying the underlying direct relationship between organ blood flow and MAP:
physiologic deficit and choosing a drug with the optimal
pharmacologic properties to manage it, thus a thorough Organ blood flow=MAP/(organ vascular resistance)
understanding of these concepts is required.
The resuscitation goals intended to preserve organ
PHYSIOLOGY oxygen delivery in all types of circulatory shock are:
Primary resuscitation: Rapidly reestablish
Most causes of circulatory shock are characterized normal organ perfusion pressure with an
by low cardiac output(CO). CO is the product of MAP>6065mmHg[2,17,19]
stroke volume(SV) and heart rate(HR) and is a major Secondary resuscitation: Rapidly reestablish
determinant of MAP and the delivery of oxygen(DO2): adequate DO2.[22]

CO=SVHR. An MAP>6065mmHg must be achieved in primary


resuscitation to maintain vital cerebral and coronary
MAP=COSVR. perfusion.[17,19] Because CO is a determinant of both
MAP and DO 2 , further resuscitation focused on
DO2=CaO2CO(in dL/min). augmenting CO is preferred.[23,24] However, MAP is
the product of CO and SVR, therefore transiently
Thus, optimizing SV and HR will improve CO, MAP, and increasing the SVR with vasopressors to achieve an
DO2, keeping in mind that SV and overall myocardial MAP>6065mmHg is acceptable while secondary
performance is determined by five other factors in resuscitation is ongoing.[25,26] Achieving the MAP goal
addition to inotropy(contractility) that requires of 6065mmHg quickly has recently been underscored
consideration:(1) HR and rhythm(atrioventricular by a retrospective study of critically ill patients where
synchrony),(2) myocardial blood flow,(3) preload, an MAP<50mmHg in a subset of comorbid patients
(4) afterload, and(5) diastolic function. However, was found to result rapidly in cardiac arrest, likely
depending on the underlying cause of shock, the as a consequence of coronary hypoperfusion. [27]
sympathetic nervous system compensation intended to Following successful primary resuscitation, secondary
restore normal organ perfusion pressure is manifested resuscitation involves first ensuring adequate volume
in different ways[Table1].[15,16] In the example of status(correcting hypovolemia) then, subsequently
distributive shock, the underlying pathophysiology administering other vasoactive agents if necessary
prevents the compensatory increase in SVRseen while monitoring the resuscitation endpoints proved
in most types of circulatory shock, resulting in in goaldirected therapy(GDT).[22,28,29]

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Morozowich and Ramakrishna: Recent advances in perioperative shock management

Table1: Types of circulatory shock and their clinical picture


Type of MAP CO DO2 CVP MPAP PCWP SVR Common clinical Treatmentb
shock examples
Hypovolemic Hemorrhage Volume
Capillary leak resuscitation
Obstructive Pulmonary embolus Inotropes
Tension pneumothorax
Cardiogenic Myocardial infarction Inotropes
Arrhythmia
Distributive Systemic inflammatory Vasopressors
response syndromea
Anaphylaxis
a
Sepsis and trauma, bTreatment of the underlying cause of circulatory shock is the primary objective and pharmacologic therapy with
vasopressors and/or inotropes is used as a temporizing measure to maintain organ perfusion pressure(MAP >65 mmHg) and CO while the
underlying process is corrected. MAP: Mean arterial pressure, CO: Cardiac output, CVP: Central venous pressure, MPAP: Mean pulmonary
artery pressure, PCWP: Pulmonary capillary wedge pressure, SVR: Systemic vascular resistance, DO2: Delivery of oxygen, : Increased,
: Decreased, : No change. Hadian M, Pinsky MR. Functional hemodynamic monitoring. Curr Opin Crit Care 2007;13:31823

PERIOPERATIVE GOALDIRECTED THERAPY Regarding the end points of resuscitation used in GDT,
rightsided filling pressures poorly predict preload[46,47]
GDT, initially brought to the forefront in the management and although minimally invasive hemodynamic monitors
of sepsis,[22] has continued to evolve[2,30] and is now are becoming widely available, most of these indirectly
being expanded to the perioperative period. Although monitor endpoints and require further study. In contrast,
the concept in septic shock has recently been called intraoperative transesophageal echocardiography(IOTEE)
into question[31,32] and may not be superior to clinical in highrisk patients can quickly and accurately diagnose
judgment(usual care) and/or the utilization of the etiology of intraoperative hypotension and allows
other less invasive resuscitation endpoints(such the clinician to rapidly assess the results of intervention
as lactate),[33] it seems plausible that after years of by monitoring cardiac volume/preload and function
integrating GDT protocols into physician education and as well as utilizing Doppler to quantitate SV and CO.
practice that these methods now reflect usual care, Although conclusive study demonstrating the efficacy
thereby potentially biasing their results. The evolving of IOTEE in perioperative GDT is currently lacking, the
concept of perioperative GDT currently includes early use of ITOEE in septic shock has been shown to
the use of fluids and/or vasoactive agents to achieve change management by limiting fluid administration
hemodynamic endpoints and minimize postoperative and initiating early inotropic support in patients with
complications and has recently been reviewed.[34] With left ventricular (LV) systolic dysfunction, who otherwise
emerging evidence demonstrating the adverse effects of would not have met Surviving Sepsis Campaign criteria
aggressive fluid resuscitation perioperatively[3541] and for inotropic therapy.[48] Furthermore, IOTEE is considered
metaanalysis favoring goaldirected versus liberal fluid by many as the gold standard to assess intraoperative
therapy,[42] initiating perioperative GDT to optimize hemodynamic instability and monitor preload, [47,49]
fluid status and hemodynamics, with the appropriate therefore its use in perioperative GDT is plausible.
use of fluids as well as the use of earlier/preemptive
inotropes and vasopressors, is likely the paradigm of OVERVIEW OF VASOACTIVE AGENTS
the future. This is supported by recent metaanalysis
suggesting that although GDT does not improve Vasopressors
mortality, it may reduce complications and hospital Vasopressors are primarily used in cardiopulmonary
length of stay[43] and subsequent metaanalysis found resuscitation(CPR) and in the treatment of circulatory
a reduction in cardiovascular complications with this shock, where the main clinical benefit of raising the
practice.[44] However, a followup large, randomized trial MAP is to restore rapidly organ perfusion pressure.
of perioperative GDT in highrisk patients undergoing However, some vasopressors have inotropic properties
noncardiac surgery did not definitely support the as well, and the predominant effect is usually
practice but did demonstrate a nonsignificant trend dosedependent. In CPR, vasopressors cause profound
supporting GDT. [45] Therefore, at this point, no systemic vasoconstriction that preferentially increases
consensus on the true benefit of perioperative GDT coronary perfusion pressure in an attempt to restore
exits, but further prospective study is underway. myocardial blood flow, oxygen delivery, and the return

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Morozowich and Ramakrishna: Recent advances in perioperative shock management

of spontaneous circulation.[50,51] In circulatory shock properties). Further classification of these agents is


characterized by refractory hypotension, vasopressors illustrated in Figure1 and their standard dosing,
are used in a supportive context until definitive therapy receptor binding, and adverse effects are listed in
can be initiated, with the assumption that clinical Table2.[8] Although some adrenergic agents stimulate
recovery will be facilitated by temporarily restoring many receptors producing various cardiovascular
and maintaining normal organ perfusion pressure.[7,8] effects, their vasopressor actions are mediated via
alpha1 receptors resulting in arterial and venous
In the example of distributive shock, vasopressors vascular smooth muscle contraction and an increase
correct the underlying deficit in SVR, thus restoring in systemic and pulmonary vascular resistance and
organ perfusion pressure.[52,53] The importance of organ venous return.[8,55,56] The nonadrenergic agents such
perfusion pressure has recently been emphasized as as vasopressin, exerts its vasopressor effects through
vasopressors are now being recommended as secondary V1 receptor stimulation resulting in vascular smooth
agents where the indication is less obviousCirculatory muscle contraction,[8] and methylene blue scavenges
shock characterized by low CO and persistent nitric oxide and inhibits nitric oxide synthesis, thus
hypotension that is refractory to conventional treatment. reversing the vasodilatory effects of nitric oxide on the
Historically, vasopressors have been used with extreme endothelium and vascular smooth muscle.
caution in this setting to avoid the complications
associated with excessive vasoconstriction(increasing Inotropes
systemic and organ vascular resistance beyond normal Inotropy (contractility) refers to the force and velocity
physiologic values) such as further impairment of CO, of cardiac muscle contraction, and the term inotrope
DO2, and organ blood flow, together possibly increasing generally refers to a drug that produces positive
mortality.[23,24] However, excessive vasoconstriction inotropy (increased contractility). Inotropes differ from
primarily occurs when these agents are given in the vasopressors, which primarily produce vasoconstriction
setting of inadequate volume resuscitation with or and a subsequent rise in MAP. As with vasopressors,
without preexisting low CO. [54] Considering this, some inotropes have vasopressor properties as well,
patients receiving vasoactive agents require careful and the predominant effect is usually dosedependent.
monitoring and frequent reevaluation, so these agents In circulatory shock characterized by low CO
can be titrated to the minimal effective dose. (e.g.,cardiogenic and obstructive shock), the main
clinical benefit of increasing contractility with inotropes
Vasopressor agents are broadly classified below by is to increase SV and CO to restore adequate DO2 to
their clinical effect as:(1) Pure vasoconstrictors or vital organs until definitive therapy can be initiated.[7,8]
(2) inoconstrictors(vasoconstrictors with inotropic
All inotropes increase CO by increasing the force
of contraction of cardiac muscle, but the other
determinants of myocardial performance are variably
affected. For example, some inotropes directly increase
HR, some indirectly decrease HR(reflex), while others
have no effect, some inotropes increase venous tone
(venoconstriction) and arterial tone(afterload) while
others decrease these through vasodilation, and some
improve diastolic function. Therefore, any given agent
may have multiple and dosedependent effects to be
considered. In cardiogenic shock, the failing ventricle
is very sensitive to afterload, so inotropes that produce
systemic vasodilation(inodilators) should be firstline
Figure1: Vasopressor classification[8,91]a: Adrenergic agents
mimic sympathetic nervous system stimulation and are also agents as long as systemic hypotension does not occur.
termed sympathomimetics; b: Catecholamines structurally Although supraphysiologic goals for CO have not shown
contain a catechol group and are rapidly metabolized by
catecholOmethyltransferase and monoamine oxidase benefit and may cause harm,[23,57,58] maximal doses of a
corresponding to their short duration of action(12min), making first agent are inadequate to meet goals, then a second
them ideal agents for titration; c: Noncatecholamines have
longer durations of action(approximately 515min) since they drug should be added, with consideration given to agents
are not metabolized by catecholOmethyltransferase with different mechanisms of action to maximize effects.

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Table2: Standard dosing of vasoactive agents, their receptor binding(or mechanism of action), and
major adverse effects
Drug IV infusion dose* Receptor activity or mechanism Adverse effects
of action
Alpha1 Beta1 Beta2 Dopamine
Isoproterenol >0.15 mcg/kg/min 0 ++ ++ 0 Arrhythmias, myocardial ischemia,
hypotension
Milrinone Load 20-50 mcg/kg then Phosphodiesterase inhibitor Hypotension
0.25-0.75 mcg/kg/min
Levosimendan 12-24 mcg/kg then Calciumsensitizer Hypotension
0.05-0.2 mcg/kg/min
Dobutamine 2-20 mcg/kg/min ++ + 0 Arrhythmias, tachycardia, myocardial
ischemia, hypotension
Dopamine 1-5 mcg/kg/min ++ Arrhythmias, myocardial ischemia,
5-10 mcg/kg/min + ++ + ++ hypertension, tissue ischemia
10-20 mcg/kg/min ++ ++ + ++
Epinephrine 0.01-0.03 mcg/kg/min ++ + 0 Arrhythmias, myocardial ischemia,
0.03-0.1 mcg/kg/min + ++ + 0 hypertension, hyperglycemia,
hypermetabolism/lactic acidosis
>0.1 mcg/kg/min ++ ++ + 0
Norepinephrine Start 0.01 mcg/kg/min and titrate ++ ++ 0 Arrhythmias, hypertension, tissue
to effect (max 30 mcg/min) ischemia
Phenylephrine 0.15-0.75 mcg/kg/min ++ 0 0 0 Bradycardia, hypertension, excessive
vasoconstriction
Vasopressin 0.010.04 units/min V1 receptor agonist Hypertension, excessive vasoconstriction
*Doses are guidelines and the actual administered dose should be determined by patient response; ++: Potent, +: Moderate,
: Minimal, 0: None, IV: Intravenous. Schlichtig R, Kramer DJ, Pinsky MR. Flow redistribution during progressive hemorrhage is
a determinant of critical O2 delivery. JAppl Physiol 1991;70:16978

Inotropes are broadly classified below by their


clinical effects as:(1) Inodilators agents that produce
inotropy and vasodilation or[2] inoconstrictors agents
that produce inotropy and vasoconstriction. Further
classification of these agents is illustrated in Figure2.[8]
The commonly used adrenergic agents stimulate the
adrenergic receptors as listed in Table3 to produce
their cardiovascular effects.[8] The standard dosing of
inotropes, their receptor binding(or mechanism of
action), and adverse effects are listed in Table2.[8,21]
Figure2: Inotrope classification.[8,91] a: Adrenergic agents
mimic sympathetic nervous system stimulation and are also
COMMON VASOACTIVE AGENTS AND LITERATURE REVIEW termed sympathomimetics; b: Catecholamines structurally
contain a catechol group and are rapidly metabolized by
catecholOmethyltransferase and monoamine oxidase
Pure vasoconstrictors corresponding to their short duration of action(12min), making
Phenylephrine stimulates only alpha receptors them ideal agents for titration; c: Noncatecholamines have
longer durations of action(approximately 515min) since they
resulting in arterial and venous vasoconstriction, are not metabolized by catecholOmethyltransferase
clinically producing an increase in SVR, MAP,
venous return, and baroreceptormediated reflex addition, the use of phenylephrine to maintain
bradycardia. The increase in SVR(afterload) hemodynamic stability during liver transplantation
and reflex bradycardia may decrease CO, so has demonstrated less blood loss and lower
phenylephrine should only be used transiently in lactate levels compared to inotropes, an effect
general and with caution in patients with preexisting attributable to its ability to increase vascular
cardiac dysfunction(low CO).[59,60] Perioperatively, resistance and thus reduce portal blood flow.[61]
phenylephrine is used to correct hypotension, Phenylephrine is considered a firstline agent in
improve venous return, and decrease the HR in hyperdynamic(normal CO) septic shock as it
patients with various cardiac conditions(e.g.aortic restores SVR and organ perfusion pressure.[2,52] Also,
stenosis and hypertrophic cardiomyopathy).[8] In phenylephrines reflex bradycardia may prove

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Table3: Adrenergic receptors with Vasopressin is primarily indicated in distributive


cardiovascular effects shock, usually as a secondary agent, [2] but its
Adrenergic Location Cardiovascular ability to increase MAP and not adversely impact
receptor effects CO has recently been demonstrated in refractory
Beta1 Myocardium Inotropy
(increased contractility)
cardiogenic shock,[75] underscoring the physiologic
Chronotropy importance of maintaining organ(myocardial)
(increased heart rate) perfusion pressure.[8] Considering this, the use of
Dromotropy vasopressin has shown utility perioperatively, where
(increased conduction)
its preemptive use in highrisk patients undergoing
Beta2 Systemic arterioles Vasodilation
cardiac surgery has demonstrated hemodynamic
Pulmonary arterioles
Veins stability after cardiopulmonary bypass and an
Alpha1 Systemic arterioles Vasoconstriction adrenergic agent sparing effect.[76] Moreover, recent
(receptor density)* invitro study[55] supports the emerging clinical
Skin (high) observations[77] that compared to adrenergic agents
Skeletal muscle (high) such as norepinephrine, vasopressin produces
Abdominal viscera/
splanchnic (moderate)
selective systemic vasoconstriction, with minimal
Kidney (moderate) effect on the pulmonary vasculature. This has
Myocardium (minimal) significant application, particularly in cardiac
Brain (minimal) surgery, where vasopressin would improve right
Pulmonary arterioles ventricular(RV) function by increasing coronary
Veins perfusion without altering RV afterload, suggesting
*Vasoconstriction of vascular beds with moderate and high it may be the drug of choice to improve MAP in
alpha1 receptor density allows the redistribution of blood
flow to vital organs with minimal receptor density (brain and the setting of RV failure. Its 3060min duration
myocardium), and is the basis for adrenergic vasopressor of action is much longer than adrenergic agents,
use in cardiopulmonary resuscitation. During progressive
hemorrhage, the fraction of CO distributed to the dermal/ making titration more challenging
skin, splanchnic, and renal vascular beds declines while Methylene blue inhibits the vasodilatory effects
the fraction of CO distributed to the brain and myocardium
increases.a,b CO: Cardiac output. Kaihara S, Rutherford RB, of nitric oxide on the endothelium and vascular
Schwentker EP, Wagner HN, Jr. Distribution of cardiac output
in experimental hemorrhagic shock in dogs. JAppl Physiol smooth muscle. Historically, methylene blue has
1969;27:21822. bSchlichtig R, Kramer DJ, Pinsky MR. Flow not been considered a vasoactive agent, but its
redistribution during progressive hemorrhage is a determinant
of critical O2 delivery. JAppl Physiol 1991;70:16978 expanding use in vasoplegic syndrome prompted
its inclusion here. Vasoplegic syndrome is generally
useful in the treatment of hypotension caused by defined as an MAP<50mmHg with a low SVR
tachyarrhythmias or when tachyarrhythmias occur (<600800 dynes/s/cm5) despite vasoactive agent
in response to other vasoactive agents used in the administration.[78,79] The syndrome is also typically
treatment of circulatory shock[2] accompanied by low filling pressures(central
Vasopressin (antidiuretic hormone) levels are venous pressure<510mmHg, pulmonary capillary
increased in response to early shock to maintain wedge pressure<10mmHg).[78,79] The incidence
organ perfusion,[62] but levels fall dramatically as of vasoplegic syndrome in cardiac surgery varies
shock progresses.[63,64] Unlike the adrenergic agents, but has been reported as high as 42% in comorbid
vasopressin does not stimulate adrenergic receptors patients undergoing ventricular assist device
and is not associated with their adverse effects,[65] placement[80] and the mortality may be as high as
and its vasopressor effects are relatively preserved 25%.[81] Methylene blue has been used as a rescue
during hypoxemic and acidemic conditions, agent for perioperative vasoplegic syndrome in
making it useful in refractory circulatory shock and multiple clinical scenarios including cardiac surgery,
CPR,[6572] specifically asystole.[73] Vasopressin, due to protamine reaction, sepsis, and anaphylaxis.[8184] It
its alternate mechanism of action, not only improves has even been used prophylactically in highrisk
hemodynamics but also improves the vascular patients undergoing cardiac surgery.[79] Suggested
response to adrenergic agents, allowing a reduction risk factors for perioperative vasoplegic syndrome
in their dosing [67,70,74] which may reduce the in cardiac surgery have been reviewed, and include
adverse effects seen with adrenergic agents, this is preoperative LV ejection fraction<35%, ventricular
commonly referred to as an adrenergic sparing effect. assist device implantation, prolonged CPB, and

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the preoperative use of intravenous heparin, venous return and CO.[93] Consequently, the degree
angiotensinconverting enzyme inhibitors, calcium of splanchnic vasoconstriction appears to be greater
channel blockers, and betablockers.[81] The dose than with equipotent doses of norepinephrine or
of methylene blue varies in the literature but in dopamine in patients with severe shock,[94] thus
cardiac surgery, a dose of 1.52.0mg/kg IV infused limiting its liberal use among clinicians. However,
over1h is generally acceptable.[85,86] In some cases, recent prospective study in critically ill patients
this initial bolus is followed by a continuous demonstrated no difference in 28 and 90days
infusion. Methylene blue has a rapid onset, but mortality compared to norepinephrine when using
unlike most vasoactive agents, it has a long halflife MAP as the sole endpoint, thus tempering the
of approximately 5.25h.[87] It is eliminated by the theoretical safety concerns held by many[95]
kidney and is contraindicated in renal failure Norepinephrine has potent alpha1, modest beta1,
and should be avoided in patients with known and minimal beta2 activity.[8] Thus, norepinephrine
glucose6phosphate dehydrogenase deficiency.[81] produces powerful vasoconstriction and a reliable
Adverse effects have been reviewed and include increase in SVR and MAP, but a less pronounced
transient color change of the skin and urine to increase in HR and CO, compared to epinephrine.[96]
greenishblue, cardiac arrhythmias(transient Therefore, caution must be used in the setting of
nodal rhythm and ventricular ectopy), coronary the failing ventricle. Reflex bradycardia usually
vasoconstriction, decreased CO, increased PVR, occurs in response to the increased MAP, such that
and decreased renal and mesenteric blood its modest beta1 chronotropic effect is mitigated,
flow; however, these effects were transient and and the HR remains relatively unchanged. Because
dose dependent(usually at doses>2mg/kg).[81] norepinephrine is the predominant endogenous
Although the use of perioperative methylene blue adrenergic agent and sepsis can lead to its
is currently controversial,[88] a recent metaanalysis depletion, its use as the firstline agent in septic
of randomized controlled trials in hypotensive shock has been argued as intuitive.[97,98] Current
patients demonstrated no harm.[89] Therefore, due Surviving Sepsis Campaign guidelines support
to the high mortality associated with perioperative its use as the firstline agent, [2] especially in
vasoplegic syndrome, the use of methylene blue as hyperdynamic(normal CO) septic shock because of
a rescue agent should be considered in the setting its ability to increase SVR and MAP, thus correcting
of refractory hypotension. the physiologic deficit in organ perfusion pressure,
compared to other agents that instead increase
Inoconstrictors MAP by increasing CO(e.g.,dopamine).[23,58,99]
Epinephrine, in low doses, increases CO Although its recommendation in cardiogenic shock
because beta1 inotropic and chronotropic no longer formally exists, it may still be useful in
effects predominate, while the minimal alpha1 the presence of severe hypotension(systolic blood
vasoconstriction is offset by beta2 vasodilation, pressure<70mmHg) in the setting of LV systolic
resulting in increased CO with decreased SVR and dysfunction due to its ability to improve MAP,
variable effects on the MAP.[90] At higher doses, thereby restoring coronary and organ perfusion
alpha1 vasoconstrictive effects predominate, pressure[100]
producing increased SVR, MAP, and CO.[8] Thus, in Dopamine is the immediate precursor to
the acutely failing ventricle(e.g.,low CO syndrome norepinephrine and is characterized by
after cardiac surgery), epinephrine maintains dosedependent effects that are due to both direct
coronary perfusion pressure and CO. Epinephrine is receptor stimulation and indirect effects[8] due to
used in CPR to restore coronary perfusion pressure norepinephrine conversion and release.[101] Doses
and in the management of symptomatic bradycardia <5mcg/kg/min stimulate dopamine receptors
unresponsive to atropine or a temporizing measure and have minimal cardiovascular effects. At
while awaiting the availability of a pacemaker.[92] moderate doses between 5 and 10mcg/kg/min,
It is a secondline agent in septic[2] or refractory dopamine weakly binds to beta1 receptors,
circulatory shock and is the drug of choice in promotes norepinephrine release, and inhibits
anaphylaxis because of its efficacy to maintain norepinephrine reuptake in presynaptic sympathetic
MAP, partly due to its superior recruitment of nerve terminals, resulting in increased inotropy and
splanchnic reserve(about 800mL), compared to chronotropy, and a mild increase in SVR via alpha1
other vasoactive agents, which helps to restore adrenergic receptor stimulation.[8] At higher doses

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of 1020mcg/kg/min, alpha1 receptormediated The net result is increased HR, CO, and decreased
vasoconstriction dominates.[8] Dopamine remains SVR with or without a small reduction in MAP.
the treatment for symptomatic bradycardia Dobutamine is frequently used to treat low CO
unresponsive to atropine or as a temporizing following cardiac surgery primarily due to its
measure while awaiting the availability of inotropic and pulmonary vasodilatory effects.[106]
a pacemaker. [92] Otherwise, the clinical use Although its recommendation in cardiogenic shock
of dopamine continues to decline due to its no longer formally exists, it may still be useful in
indirect effects, significant variations in plasma early cardiogenic shock without evidence of organ
concentrations in patients receiving the same dose, hypoperfusion.[100] However, if organ hypoperfusion
and recent study demonstrating a higher incidence is present, an inoconstrictor should be chosen to
of arrhythmia and higher mortality in cardiogenic[102] restore organ perfusion pressure.[100] Dobutamine
and septic shock. [103] Consequently, previous remains recommended therapy in septic shock with
recommendations for its use in cardiogenic shock low CO[2]
with SBP 70100mmHg with signs or symptoms Milrinone, a nonadrenergic phosphodiasterase
of endorgan compromise,[100] based on its alpha1 inhibitor, increases intracellular levels of myocardial
activity to correct the deficit in organ perfusion and vascular smooth muscle cAMP by inhibiting
pressure, have been removed. [104] Also citing its breakdown, leading to increased myocardial
this evidence, dopamine is no longer a firstline contractility and smooth muscle relaxation resulting
treatment for septic shock, but may be reserved in pulmonary and systemic vasodilation. Thus,
for select patients with a low risk of arrhythmia milrinone improves RV function in the setting
who present with hypodynamic(low CO) septic of pulmonary hypertension,[106] more so than the
shock and/or bradycardia,[2] as dopamine increases adrenergic inodilators. In addition, milrinone
inotropy and chronotropy(thereby increasing CO uniquely improves diastolic relaxation(lusitropy).
and MAP) with a minimal increase in SVR Being a nonadrenergic agent, it has the advantage
Ephedrine acts primarily on alpha and beta of not being affected by betablocker use or the
receptors,[105] similar to epinephrine but with less characteristic diminished beta receptor responses
potency. Ephedrine also releases endogenous seen in chronic heart failure and does not produce
norepinephrine from sympathetic neurons and the adverse effects associated with betareceptor
inhibits norepinephrine reuptake, accounting for stimulation.[8,106] Milrinones vasodilatory properties
additional indirect alpha and beta receptor effects. limit its use in hypotensive patients,[107] and its
Ephedrines combined effects result in an increased 3060min halflife is significantly longer than the
HR, CO, and MAP. Ephedrine is a noncatecholamine adrenergic inodilators[106]
and because of its longer duration of action, its L e v o s i m e n d a n i s a n o n a d r e n e r g i c
dependence on endogenous norepinephrine for calciumsensitizing agent that produces inotropy
its indirect effects and its potential to therefore by calcium sensitization of myocardial contractile
deplete norepinephrine, it is not ideal for infusion proteins, without increasing intracellular calcium,
and is therefore rarely used except in the setting of and vasodilatation within the systemic and
transient anesthesiarelated hypotension. pulmonary circulation, by activation of adenosine
triphosphatesensitive potassium channels. [108]
Inodilators Levosimendan produces similar clinical effects to
Isoproterenol has potent beta1 and beta2 activity milrinone,[109,110] but is also limited by hypotension
with virtually no alpha activity. Its principal and a long duration of action(80h due to active
actions are inotropy, chronotropy, and systemic metabolites). Levosimendan is a relatively new
and pulmonary vasodilation.[8] Despite its inotropy, agent and is not currently approved for use in the
the systemic vasodilation decreases venous return, United States.
resulting in a minimal increase in CO and a drop
in MAP.[8] Because of this, isoproterenol is limited CONCLUSION
to situations where hypotension and shock result
from bradycardia or heart block[92] Despite the growing body of evidence evaluating the
Dobutamine primarily stimulates beta1 and beta2 efficacy of vasoactive agents in the management of
receptors resulting in increased chronotropy, circulatory shock, it appears no agent is superior, and
inotropy, and systemic and pulmonary vasodilation. the recent metaanalysis of 23 randomized controlled

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