Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Contents lists available at ScienceDirect

journal homepage: www.jcvaonline.com

Review Article

Vasoplegia After Cardiovascular Procedures—

Pathophysiology and Targeted Therapy
Shahzad Shaefi, MD, MPHn,1, Aaron Mittel, MD†, John Klick, MD‡,
Adam Evans, MD, MBA§, Natalia S. Ivascu, MD¶,
Jacob Gutsche, MD‖, John G.T. Augoustides, MD‖
n
Divisions of Cardiac Anesthesia and Critical Care, Department of Anesthesia, Critical Care and Pain
Medicine, Beth Israel Deaconess Medical Center, Boston, MA
†
New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY
‡
Case Western Reserve University School of Medicine, Cleveland, OH
§
Departments of Cardiothoracic Surgery and Anesthesiology, Perioperative, and Pain Medicine, Icahn School of
Medicine, Mount Sinai Hospital, New York, NY
¶
Weill Cornell Medicine, New York, NY
‖
Cardiovascular and Thoracic Section, Department of Anesthesiology and Critical Care, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA

Vasoplegic syndrome, characterized by low systemic vascular resistance and hypotension in the presence of normal or supranormal cardiac
function, is a frequent complication of cardiovascular surgery. It is associated with a diffuse systemic inflammatory response and is mediated
largely through cellular hyperpolarization, high levels of inducible nitric oxide, and a relative vasopressin deficiency. Cardiopulmonary bypass is
a particularly strong precipitant of the vasoplegic syndrome, largely due to its association with nitric oxide production and severe vasopressin
deficiency. Postoperative vasoplegic shock generally is managed with vasopressors, of which catecholamines are the traditional agents of choice.
Norepinephrine is considered to be the first-line agent and may have a mortality benefit over other drugs. Recent investigations support the use of
noncatecholamine vasopressors, vasopressin in particular, to restore vascular tone. Alternative agents, including methylene blue, hydro-
xocobalamin, corticosteroids, and angiotensin II, also are capable of restoring vascular tone and improving vasoplegia, but their effect on patient
outcomes is unclear.
& 2017 Elsevier Inc. All rights reserved.

Key Words: pathophysiology of vasoplegic shock; cardiopulmonary bypass; nitric oxide; vasopressin; methylene blue; angiotensin II; hydroxocobalamin

VASODILATORY SHOCK is a common complication of
major cardiovascular surgery, affecting 5% to 45% of proce-
dures.1–4 In the majority of these cases, shock is limited in
severity and duration. However, a subset of patients exhibit
profound vasoplegia, which carries with it significant morbid-
ity and mortality.1 Its pathophysiology often is assumed to be
1
Address reprint requests to Shahzad Shaefi, MD, MPH, Beth Israel
Deaconess Medical Center, Rosenberg 660, 1 Deaconess Road., Boston,
MA 02215.
E-mail address: sshaefi@bidmc.harvard.edu (S. Shaefi).
similar to sepsis-induced vasodilatory shock, although the
inciting factor and some mediators may differ. Management of
vasoplegic shock is largely via pharmacologic therapy in the
form of vasopressor medications. Several recent trials have
investigated the role of these drugs and the use of nonvaso-
pressor adjuncts. These adjuncts occasionally lead to relatively
rapid hemodynamic improvement where more traditional
agents have failed. Particular attention recently has been
directed toward methylene blue and hydroxocobalamin,
among others. The findings from recent trials and the
emergence of potentially new therapies are the impetus for

http://dx.doi.org/10.1053/j.jvca.2017.10.032
1053-0770/& 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032

2 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
this review and will be discussed in conjunction with an
overview of the basic mechanism and approach to the
management of vasoplegia after cardiovascular surgery.
Methodology
Even though postoperative vasoplegia is a common clinical
problem, it has not been the focus of large-scale investigations.
Indeed, an August 2017 search of the PubMed database using
the terms “cardiovascular surgery AND vasoplegia” limited to
publications in English and research conducted on humans
returned only 58 citations, many of which were case reports or
editorial opinions. Given the sparse results from this broad-
based inquiry, the authors instead chose to query their author
group for inclusion of impactful publications that focus on the
recognition and management of vasoplegia. Ultimately, this
pragmatic search strategy netted several recent clinical trials
with a focus on the diagnosis, pathophysiology, and treatment
of vasoplegic shock. This review therefore brings attention to
evidence-based approaches used by this expert group of
writers.
Vasoplegia Definition and Risk Factors
Definition
Vasoplegic syndrome, also sometimes termed vasodilatory
or distributive shock, is characterized by end-organ hypoper-
fusion due to profoundly low systemic vascular resistance
(SVR) despite normal or supranormal cardiac output.1
Although postcardiotomy vasoplegia is a well-documented
entity, the lack of a strict definition has hampered more robust
investigation and accounts for its wide purported range of
incidence. Generally, the syndrome is recognized by a
persistent need for high-dose vasopressor drugs to maintain
appropriate blood pressure.
The low SVR state described in vasoplegic syndrome is
found in a number of disease entities, including sepsis,
glucocorticoid deficiency, hepatic failure, or long-lasting
severe shock of any cause.5 Sepsis is the most common cause
of vasoplegia and therefore has been the focus of many clinical
trials.5 However, even though the hemodynamic consequences
are similar, the differences between sepsis and cardiac
surgery–related vasoplegia remain relatively unexplored.
Therefore, it is prudent to acknowledge that treatments for
sepsis, and the evidence supporting those choices, may not be
entirely generalizable to a postoperative population.
Incidence, Risk Factors, and Outcomes
Vasoplegic syndrome is common after major cardiovascular
surgery and is associated with poor outcomes, largely due to
end-organ failure. Patients exhibiting postoperative vasoplegia
experience high rates of renal failure, prolonged hospital stays,
and death.6 Although the rate of postcardiac surgery
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
vasoplegia hovers somewhere in the range of 5% to 25% in
groups without preoperative features of risk, in those with
known predisposing factors, this rate is anywhere from 30% to
50%.6,7 Many preoperative factors have been associated with a
higher incidence of postoperative vasoplegia, namely preo-
perative use of angiotensin-converting enzyme inhibitors,
preoperative use of beta-blockers, and higher comorbid disease
burden before surgery.7 Patients with low preoperative systolic
ejection fraction consistently have shown a high affinity for the
development of vasoplegia.2 Intraoperative aspects such as the
need for vasopressors before or during cardiopulmonary
bypass (CPB), warmer core temperatures while on bypass,
and longer duration of CPB also confer a greater risk of
developing vasoplegia.2
Pathophysiology of Vasoplegia
Cellular Physiology
From a cellular perspective, vasodilatory shock is complex
but is fundamentally a deficit in vascular smooth muscle
contraction. In general, vascular smooth muscle contracts
when intracellular calcium levels rise, through surface-receptor
binding and opening of voltage-gated calcium channels (where
angiotensin and catecholamines bind). This rise in cytoplasmic
calcium concentration generates a stepwise reaction in which
calcium phosphorylates myosin, which in turn catalyzes the
cross-linking of myosin-actin filaments and generates the
contraction of the muscle and vasoconstriction.5
This process is balanced by regulatory vasodilatory mole-
cules, such as nitric oxide (NO) or atrial natriuretic peptide.
These molecules trigger vasodilation via several mechanisms,
all leading to a rise in intracellular cyclic guanosine monopho-
sphate (cGMP) concentrations. Inverse to the contractile
process, this results in activation of myosin phosphatase,
dephosphorylation of myosin, and vasodilation (Fig 1).5
Thus, the downstream effect of vasoconstriction is depen-
dent on the influx of calcium into the cytoplasm via voltage-
gated channels. If these channels are deactivated, such as may
occur with intracellular acidosis or depletion of adenosine
triphosphate (ATP) through membrane hyperpolarization,
vasoconstriction will not be possible even if the cell is exposed
to high levels of catecholamines. High levels of other
compounds, including NO, atrial natriuretic peptide, adeno-
sine, and others, also can lead to activation and prolonged
opening of these channels. Presumably, this is an important
physiologic mechanism to counteract periods of temporary
local tissue ischemia. However, this can become counter-
productive if prolonged periods of vasodilation lead to a
persistently low pressure system and compromise of flow to
other vessel beds.7
NO, implicated as an activator of ATP-sensitive potassium
channel (KATP) channel opening, is a particularly important
intercellular mediator of vasodilatory shock. NO is synthesized
by the nitric oxide synthase (NOS) family of enzymes, which
 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]] 3

Fig 1. The cellular mechanisms of vasodilatory shock. Vascular smooth muscle contracts when intracellular calcium levels rise and lead to cross-linking of actin
and newly phosphorylated myosin. This process is triggered after vasoconstrictive mediators, such as angiotensin II or catecholamines, bind to surface receptors.
Inversely, vasodilation occurs when molecules such as nitric oxide or atrial natriuretic peptide yield an increase in intracellular cyclic guanosine monophosphate
and subsequent dephosphorylation of myosin.

are differentiated by their typical organ location and baseline
activity. Constitutive, calcium-dependent isoforms of NOS are
responsible for constant, low-level NO production, which is
important for interneuronal signaling, regional blood flow
autoregulation, and immunologic modulation. Inducible, cal-
cium-independent NOS isoforms (iNOS) synthesize NO on
demand and take several hours to respond to physiologic
stress. This inducible NOS often is implicated as the mediator
of distributive shock and may precipitate mitochondrial
dysfunction, apoptosis, and multiorgan failure. However, it
plays important physiologic roles and perhaps should be
thought of as a “necessary poison,” having both direct and
indirect injurious and protective effects.8 For example, induc-
tion of NOS is important to increase myocardial NO levels,
which encourages left ventricular relaxation and appropriate
filling during diastole.9,10 Ultimately, NO increases intracel-
lular cGMP (thereby decreasing myosin phosphorylation),
inactivates calmodulin, and encourages opening of calcium-
sensitive potassium efflux channels (KCA channels) to blunt
the effects of vasoconstriction. Thus, the presence of NO leads
to a state in which vascular smooth muscle contraction is
antagonized.6
In addition to membrane hyperpolarization and high concen-
trations of NO, vasopressin is an important modulator of
vasodilation. Prolonged shock is associated with a relative
vasopressin deficiency, which may be inadequate for the
severity of physiologic stress.11 Initially, vasopressin serum
concentrations are quite high in acute hypotension but gradually
taper to lower-than-normal levels. This drop off is believed to
be caused by a depletion of neurohypophyseal stores after
prolonged arterial baroreflex stimulation.11,12 This is mechan-
istically important because vasopressin directly inactivates KATP
channels,13 blunts the NO-induced increase in cGMP (by
binding to AVPR1 receptors), and reduces NO synthesis.14
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
Vasopressin thus mitigates the effects of membrane hyperpolar-
ization, myosin dephosphorylation, and NO accumulation and is
an important modulator of vasomotor tone.5
Precipitants of Vasoplegia During Cardiovascular Surgery
Triggering factors for vasoplegia after cardiovascular sur-
gery are poorly understood. Considerable investigation into the
underlying mechanism has been performed, largely focusing
on the physiologic response to extracorporeal circulation. CPB
causes a broad-based immunologic response secondary to
ischemia-reperfusion injury of the heart and lung, endotoxin
release from mucosal surfaces, and complement cascade
activation after exposure of blood to the CPB circuitry.15
These processes result in increased production of oxygen free
radicals, endothelins, NO, platelet activating factors, throm-
boxane A2, prostaglandins, a wide variety of cytokines, and
other vasoactive molecules. Of particular interest, CPB leads
to increased production of inducible NO, the concentration of
which directly correlates with the length of CPB.16 High serum
concentrations of these molecules also have been found to
correlate with the development of the systemic inflammatory
response syndrome, supporting the hypothesis that postopera-
tive vasoplegia is, at least in part, an inflammatory response.17
The downstream effects of these inflammatory and vasoactive
agents are variable (eg, potential vasoconstriction or vasodila-
tion differs by concentration and physiologic action of each
molecule), but lead to derangement of baseline vascular
reactivity and tone.16 Possibly, patients with chronically high
levels of inflammatory mediators, such as those with preexist-
ing heart failure, may be particularly prone to a predominantly
vasodilatory effect.18 This may explain why patients with
reduced ejection fraction are more likely to develop vasoplegia
after CPB.2
4 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Nevertheless, a generalized inflammatory response with
increased NO production is not the sole cause of post-CPB
vasoplegia. Indeed, poor neurohumoral control of vascular
tone in the form of a vasopressin deficiency plays a significant
role. Serum vasopressin levels are known to increase during
CPB, and in patients who do not develop vasoplegia, they
remain elevated or normal postoperatively. However, serum
vasopressin concentrations in patients who develop postopera-
tive vasodilation have been found to be inappropriately low,
suggesting a chronic depletion of neurohypophyseal vasopres-
sin stores. This relative vasopressin deficiency is similar but
more severe than that seen in septic shock, suggesting that
CPB is a particularly stressful trigger and can lead to severe
vasoplegia in susceptible patients (Fig 2).5,6,19,20
Thus, the development of postoperative vasoplegic shock is
likely secondary to the coupling of a profound inflammatory
response and a potential for relative vasopressin deficiency.
These are themselves caused by the immunologic reaction that
occurs in response to CPB and other nonspecific perioperative
triggers in the background of chronic cardiovascular neurohu-
moral stress. When these risk factors are combined with
patient-specific risk factors, such as an extensive noncardiac
disease burden or need for complex surgical repair, there is a
high likelihood of developing postoperative vasoplegic shock.
Management of Vasoplegia
Early management of the postoperative vasoplegic syn-
drome focuses on recognition of the problem. Namely, the
clinician should confirm the presence of hypotension, low
SVR, and normal/supranormal cardiac output. Alternative
etiologies of vasodilatory shock should be considered; early
administration of antibiotics is important if infection is
suspected.21,22 It may be necessary in some patients, such as
those who have had long aortic cross-clamp times or have
undergone complex procedures, to transduce central (eg,
femoral) pressure because it may be significantly higher than
radial artery pressure. This is a common issue after CPB and
may mitigate the need for aggressive anti-vasoplegic ther-
apy.23 Ultimately, an adequate understanding of the existence
and severity of vasoplegia is important in order to guide
therapy.
Prevention
In an ideal setting, the clinician caring for the patient at risk
of postoperative vasoplegia would be able to intervene before
the onset of shock. However, many of the risk factors
previoulsy listed are not modifiable in the immediate pre-
operative period or are inherent components of the surgical
procedure to be performed. Furthermore, the pathophysiology
of the vasoplegic syndrome is nuanced and associated with
basic physiologic mechanisms of homeostasis. Manipulation
of these mechanisms generally has not been associated with
clinical benefit, such as unsuccessful trials of NO antagon-
ism.10 One group of investigators did find a reduction in the
incidence of postoperative shock after empiric, early adminis-
tration of vasopressin to patients at high risk of postoperative
vasoplegia.24 However, it is difficult to determine whether this
approach was reflective of a particular preventative benefit

Fig 2. Mechanisms of cardiopulmonary bypass-related vasoplegia. Cardiopulmonary bypass triggers a profound inflammatory reaction that results in increased
production of nitric oxide, depletion of ATP, and increased acidemia of vascular smooth muscle, resulting in a decrease in phosphorylation of myosin and
subsequent vasodilation. Simultaneously, neurohypophyseal stores of endogenous vasopressin are depleted rapidly, compounding the vasodilatory effect and
creating vasoplegic shock. ATP, adenosine triphosphate; cGMP, cyclic guanosine monophosphate; H þ , hydrogen ion; KATP, ATP-sensitive potassium channel.

Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032

 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
from vasopressin as opposed to treatment of unrecognized
shock with any vasopressor.25 Others have advocated that
angiotensin-converting enzyme inhibitors should be withheld
preoperatively from patients at high risk of perioperative
vasoplegia.26 However, the appropriate timeline to withhold
administration of these agents and the potential outcomes
associated with this approach have not been investigated.
Thus, the clinician with concern for potential vasoplegia
should be aware of the treatment options described in the
following.
Fluid and Blood Product Resuscitation
Identifying fluid responsiveness is an important component
of early treatment of postoperative vasoplegia. Due to
perioperative hemorrhage, hypovolemia may be concomitant
with vasoplegic shock; judicious transfusion of blood pro-
ducts should be used to correct severe anemia. Generally,
restrictive transfusion strategies are preferred over more
liberal strategies.26 However, overly aggressive fluid resusci-
tation (beyond 20-30 mL/kg) leads to excessive vascular
shear stress, unnecessary increases in cardiac filling pres-
sures, and harmful accumulations of extravascular lung
water.27 Ultimately, inordinate fluid administration is asso-
ciated with increased mortality in pure vasodilatory shock
and should be avoided.28
Vasoactive Drugs
The cornerstone of vasoplegic shock management is the use
of vasoactive agents to restore vascular tone. These agents act
on various receptors to increase SVR and raise mean arterial
pressure (MAP), and thus are broadly termed “vasopressors.”
Catecholamines are the mainstay of treatment but may be
required in high doses and may yield insufficient hemody-
namic stability. Other, noncatecholamine vasopressors histori-
cally have not been used for vasodilatory shock but may be
particularly beneficial and have been more intensely scruti-
nized in recent years; they are described here (Table 1).
An important caveat to the decision to choose any one
particular vasoactive agent over another is the observation
that many of these recommendations are based on results
from randomized trials of vasopressors for septic shock.
Thus, although likely generalizable to patients with post-
CPB vasoplegia, they may not be directly comparable. This
is particularly important when considering the potential for
concomitant cardiogenic shock. Ventricular dysfunction is
common after cardiovascular surgery and in sepsis.29 Thus,
even though increasing SVR remains the goal of treating
vasoplegic states, the use of vasopressors must be balanced
with the need to ensure appropriate left ventricular afterload
to allow for effective end-organ perfusion. Even though
outside the scope of this review, assessment of cardiac
performance (such as that which is easily performed with
echocardiography) therefore is a critical component of mana-
ging vasoplegia.30
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
5
Catecholamines
Catecholamines exert their physiologic effects by modula-
tion of adrenergic receptors. Traditionally they have been the
agents of choice to treat vasodilatory shock. Norepinephrine,
phenylephrine, epinephrine, and dopamine all have been used
successfully to increase MAP without limiting end-organ
perfusion. Norepinephrine has been studied extensively in
sepsis-induced vasodilatory shock. It may provide a mortality
benefit compared with other catecholamines and is the
recommended first-line agent specifically in septic
shock.22,31,32 However, trials comparing norepinephrine with
combinations of other catecholamines, such as epinephrine or
dobutamine, have failed to show a definitive benefit.33 On the
other hand, dopamine carries an increased risk of arrhythmia
and mortality compared with norepinephrine in randomized
controlled trials and probably should not be used as a first-line
agent.34
A frequent concern about using high-dose vasopressors is
the potential for severe peripheral vasoconstriction and end-
organ injury. However, there is insufficient evidence to
support this theory. Nevertheless, the need for high-dose
catecholamines should prompt the clinician to consider switch-
ing to, or adding, a noncatecholaminergic agent.35
Vasopressin
The use of noncatecholaminergic agents for the treatment of
vasodilatory shock bypasses some of the difficulties when
dealing with severe vasoplegia, including membrane hyperpo-
larization and associated catecholamine resistance.5 Noncate-
cholamines also may simply exert a synergistic effect and
allow for reduced doses of any one particular agent, creating a
more balanced approach to vasopressor therapy.35 This per-
haps is especially notable with vasopressin, the use of which is
biochemically supported by the presence of a vasopressin
deficiency after CPB.6,19
Vasopressin binds to AVPR1a, AVPR1b, and AVPR2;
oxytocin; and purinergic receptors. The AVPR1a receptor is
especially important because it promotes vasoconstriction by
inhibiting KATP channel opening and reduces NO production,
providing an entirely catecholamine-independent mechanism
of mediating vasodilation. Several recent randomized con-
trolled trials focused explicitly on outcomes after use of
vasopressin for septic shock. In the VASST trial, patients
with septic shock who already were receiving norepinephrine
were randomly assigned to either norepinephrine or vasopres-
sin. The investigators did not identify a difference in their
primary outcome of mortality between the groups at 28 days
but did observe a significant reduction in catecholamine dose
necessary to achieve target MAP in the vasopressin group and
did not identify harm associated with vasopressin.36 Of note,
post hoc analysis of VASST found improved renal outcomes
in patients in the vasopressin group who had mild kidney
injury at enrollment.37 The 2016 VANISH trial explored this
finding further. Powered primarily to detect a difference in
renal failure between vasopressin and norepinephrine for
 6
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032

Table 1
Vasoactive Drugs for the Management of Vasoplegia

Suggested Dose Advantages Disadvantages Evidence

Catecholamines
Norepinephrine 0.01-0.1 mg/kg/min Increases MAP predominantly via High doses may be required to achieve hemodynamic Recommended first-line agent based on RCTs of septic shock.
continuous infusion increased SVR but may also provide goals in severe vasoplegia May have mortality benefit over other catecholamines used
inotropic support in isolation.

S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]

Phenylephrine 0.5-5 mg/kg/min Increases MAP by increasing SVR Few studies support its use as a single agent Retrospectively associated with decreased survival compared
continuous infusion with norepinephrine
Epinephrine 0.01-0.5 mg/kg/min Increases MAP and provides inotropic Few studies focus on its use as a first-line agent for Comparable in efficacy to combination of norepinephrine and
continuous infusion support vasodilatory shock dobutamine when both vasopressor and inotropic support
required
Dopamine 0-20 mg/kg/min Dose-dependent increases in SVR and Increased risk of arrhythmia compared with other Meta-analysis of RCTs suggests increased risk of mortality
continuous infusion inotropy catecholamines compared with norepinephrine
Noncatecholamines
Vasopressin 1.2-6.0 U/h continuous Reduces catecholamine dose required to As a first-line agent, no significant mortality benefit Use is supported by several RCTs and the observation of
infusion achieve MAP goal compared with norepinephrine severe vasopressin deficiency post-CPB
May reduce severity of renal failure
Terlipressin 1.3 mg/kg/h continuous Comparable with vasopressin but has a More selective than vasopressin for AVPR1 receptors, Small studies suggest it is equally as effective as
infusion longer half-life theoretically causing profound SVR increase and norepinephrine for raising MAP
decrease in CO
Methylene blue 1.5-2 mg/kg bolus In single boluses, may rapidly improve May precipitate serotonergic syndrome and hemolytic No high-quality RCTs investigating its use
MAP in severe vasoplegia anemia and interferes with pulse oximetry Retrospectively associated with mortality benefit when given
early in vasoplegic shock
Hydroxocobalamin 5 g infusion over Raises MAP and avoids some risks More expensive than methylene blue Only described in case reports
5 min associated with methylene blue Not well-investigated
Angiotensin II Continuous infusion May dramatically improve MAP and Limited data One recent RCT suggested hemodynamic improvement
starting at 20 ng/kg/ reduce catecholamine requirements May interfere with endogenous vasopressin synthesis compared with placebo
min
Corticosteroids Varies by study and Likely hasten the resolution of shock Not associated with mortality benefit in either septic No studies have specifically investigated their use in post-CPB
drug of choice shock or in non-vasoplegic cardiac surgery vasoplegia
Hydrocortisone 50 mg populations
q 6 h is frequently
chosen
Vitamin C 6 g intravenous bolus May hasten the reversal of shock when Limited safety and efficacy data One recent retrospective study suggested hemodynamic and
per day combined with hydrocortisone and mortality benefit in septic shock patients
thiamine

NOTE. Vasoactive agents useful for the treatment of vasoplegic syndrome after cardiovascular surgery. As described in the text, catecholamines (norepinephrine in particular) are the mainstay of therapy.
Noncatecholamines, particularly vasopressin, may provide benefit by reducing the catecholamine dose required to achieve hemodynamic goals. Evidence supporting the use of any particular noncatecholamine,
aside from vasopressin, is relatively weak.
Abbreviations: CO, cardiac output; RCT, randomized controlled trial.
 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
septic shock, the authors randomly assigned patients to
vasopressin and hydrocortisone, vasopressin and placebo,
norepinephrine and hydrocortisone, or norepinephrine and
placebo. There was no significant difference in renal failure
between the vasopressin and norepinephrine groups, but
dialysis was used less frequently in the groups that received
vasopressin, which suggests it may reduce the severity of renal
failure compared with norepinephrine.38 Ultimately, VASST
and VANISH were large, well-performed trials that failed to
identify a definite benefit of vasopressin over catecholamines
for septic-type vasodilatory shock, although the observation
that vasopressin may limit the severity of renal failure is
intriguing.
Of importance, the vasopressin deficiency seen after CPB is
even more severe than that seen during septic shock. Patients
with post-CPB vasoplegia therefore may theoretically obtain
greater benefit from vasopressin administration than the septic
shock population.19 Several small, early trials demonstrated
vasopressin to be safe and potentially effective after CPB but
generally were underpowered to address clinical outcomes and
did not include head-to-head comparison with norepinephr-
ine.19,39 To address these issues, Hajjar et al conducted the
recent VANCS trial, in which patients with post-CPB vaso-
plegic shock were randomly assigned to vasopressin or
norepinephrine as a primary agent. Patients who were ran-
domly assigned to vasopressin demonstrated a significant
reduction in a composite end point of 30-day mortality or
severe postoperative complications, driven almost exclusively
by a decrease in the occurrence of acute renal failure.40
Taken as a group, VASST, VANISH, and VANCS represent
a large population of patients with either septic or CPB-induced
vasoplegic shock who generally benefit from vasopressin as a
single or additive vasopressor. However, this largely is limited
to a reduction in the need for catecholamines or a decrease in
the severity or incidence of renal failure, rather than an
improvement in mortality. Nevertheless, a reduction in renal
failure (and the potential need for dialysis) is an important
finding that should promote the perioperative use of vasopres-
sin. The results of the VANCS trial are especially encouraging
in patients with vasoplegia after cardiac surgery and lend
support to the practice of early, and possibly preferential, use
of vasopressin over catecholamines.
Methylene blue
Several endogenous compounds, including NO, carbon
monoxide, and oxygen-free radicals, produce local vascular
vasodilation, which may be an important counterbalance of
systemic vasoconstriction in early shock states but can become
pathologic if widespread vasodilation results in global hypo-
perfusion. Most of these substances, of which NO has been the
most extensively investigated, mediate vasodilation via cGMP
second messenger pathways and thus are broadly antagonized
by agents that disrupt this signaling cascade.41 Methylene blue
is one of these agents and, more than any other drug, often is
considered to be a rescue agent capable of treating post-CPB
vasoplegia. It directly competes with NO for activation of
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
7
guanylyl cyclase, the enzyme responsible for synthesizing cGMP
from guanosine triphosphate (GTP). Furthermore, it inhibits
inducible NO synthase, potentially reducing the upswing in NO
concentration that occurs with CPB and other physiologic stress.
Methylene blue therefore prevents NO-mediated dephosphoryla-
tion of myosin and associated vasodilation.5 However, the
potential downstream effects of its broad-sweeping action on
basic physiologic mechanisms of vascular reactivity are
unknown.
Adverse reactions with methylene blue are uncommon but
can be serious. They largely are explained by the global
antagonism of NO-mediated vasodilation and include coronary
vasoconstriction, decreases in splanchnic blood flow, and
increases in pulmonary vascular resistance. Furthermore,
methylene blue is reduced in red blood cells to leukomethy-
lene blue, which requires nicotinamide adenine dinucleotide
phosphate (NADPH). This can precipitate hemolytic anemia,
especially in patients with G6PD deficiency. Methylene blue
and leukomethylene blue are excreted in the urine, reliably
coloring urine green. Methylene blue also interferes with pulse
oximetry readings, even though this is transient, and has been
associated with a nonspecific elevation in liver function tests.42
In addition, methylene blue is a potent inhibitor of monoamine
oxidase and may precipitate serotonin syndrome, particularly
in patients taking selective serotonin reuptake inhibitors. Even
though these side effects are uncommon, they are relatively
wide ranging and associated with severe disruption of normal
cardiovascular physiology.43
Early case reports identified successful use of methylene
blue to rapidly reverse severe vasoplegia after CPB with only
single 1.5 to 2 mg/kg boluses.44,45 These reports prompted
small-scale prospective interventional studies that confirmed
methylene blue’s ability to rapidly and dramatically improve
MAPs of post-CPB vasoplegic patients and suggested a
possible mortality benefit of the drug.46–49 Retrospectively,
methylene blue may be most efficacious if administered early in
the course of vasoplegic shock (eg, while still in the operating
room as opposed to postoperatively), when it may reduce the
risk of mortality or end-organ failure.50 However, not all studies
have been supportive of the use of methylene blue. In one
retrospective analysis, methylene blue was associated with an
increased likelihood of developing renal failure and mortality.
However, the vasoplegic patients in that study who had received
methylene blue were sicker than their counterparts who were not
given the drug, and the authors were not able to solidify their
findings with propensity matching.51
Without question, readily available noncatecholamine vaso-
pressors (eg, vasopressin and methylene blue) have a role in
treating post-CPB vasoplegia. However, until more rigorous
trials are performed, they are limited to additive and/or rescue
roles. A recent systematic review and meta-analysis, which did
not include the VANISH or VANCS trials but did include
more than 1,600 patients in 20 trials, concluded that vaso-
pressin, terlipressin (discussed later), and/or methylene blue
improved survival compared with catecholamines. However,
this analysis incorporated patients with diverse etiologies of
vasoplegic shock and included some potentially biased studies.
8 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
In addition, neither vasopressin, terlipressin, nor methylene
blue was superior to catecholamines when analyzed indepen-
dently.52 Thus, evidence supports the use, but not superiority,
of noncatecholamine vasopressors to improve outcomes in
vasodilatory shock.
Corticosteroids
The use of corticosteroids to treat vasodilatory shock has
been controversial for several decades and is based on the
assumption that the hypothalamic-pituitary-adrenal axis may
be suppressed in periods of critical illness. Putatively, corti-
costeroids ameliorate the underlying inflammatory process that
causes loss of vascular tone and may increase the efficacy of
vasopressors by increasing the expression of vascular adrener-
gic receptors. However, clinical investigations of corticoster-
oids for vasoplegia have not shown a mortality benefit but
have found an increased risk of infection. This was most
recently demonstrated in the CORTICUS trial, published in
2008, which evaluated the use of a 5-day course of 50 mg of
hydrocortisone every 6 hours in patients with septic shock.
The authors found no significant mortality benefit with
hydrocortisone compared with placebo, both in patients who
were unresponsive to corticotropin stimulation and in those
who were responsive (presumably adrenally suppressed and
not suppressed, respectively). However, patients who received
hydrocortisone had more rapid reversal of shock.53 This
finding also was seen in an earlier trial, published in 2002,
which also found a mortality benefit with corticosteroids in
corticotropin nonresponders who were hypotensive despite
fluid resuscitation and administration of vasopressors. In
addition, formative work precluding the VANISH trial demon-
strated evidence for interaction of corticosteroids and vaso-
pressin, with a halving of vasopressin dose in those receiving
steroids, interestingly without a change in overall vasopressin
levels. Cumulatively, these studies support the notion that
corticosteroids may hasten the resolution of vasodilatory
shock, even though they do not provide an overall mortality
benefit, possibly unless the patient is hypotensive despite
vasopressors.54
The use of corticosteroids for treatment of nonseptic
vasoplegic shock has not been evaluated explicitly. However,
their role in the cardiac surgery population must be considered
in light of the potential for increased perioperative complica-
tions (including delayed wound healing, poor glucose control,
and gastrointestinal bleeding) and recent findings from the
2015 SIRS trial.55 In that trial, methylprednisolone did not
confer a benefit with respect to mortality or end-organ function
when given before and during CPB to high-risk patients
undergoing cardiac surgery.55 Similarly, the earlier DECS trial
did not find significant benefit from intraoperative use of
dexamethasone given to patients undergoing cardiac surgery
with use of CPB.56 However, both the DECS and SIRS trials
were designed to detect a reduction of adverse outcomes
(eg, death, stroke, myocardial infarction) rather than the
effect on vasoplegia. In summary, neither of these studies
focused explicitly on postoperative vasoplegic shock. Thus,
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
it is plausible that corticosteroids may hasten reversal of
post-CPB shock, as they do in sepsis, but fail to reduce
mortality rates.
Future Directions
Several potential therapies have not permeated into conven-
tional practice yet but are supported by case series or early
investigations. They may become viable treatment options in
the near future and are discussed here.
Vitamin C
Vitamin C (ascorbic acid) has known anti-inflammatory
effects and may improve autoregulation of microcirculatory
blood flow. These qualities, putatively similar to those of
corticosteroids, may reduce the dose of vasopressors required
to achieve hemodynamic goals.57 A recent preliminary, retro-
spective study of patients with severe septic shock identified a
dramatic reduction in mortality in patients who were treated
with a daily intravenous combination of 6 g vitamin C, 50 mg
hydrocortisone every 6 hours, and 200 mg thiamine every 12
hours. Of importance to the present review, the authors of this
trial found a significant and rapid reduction in vasopressor
requirements in patients who received the study regimen.57
The effects of the individual agents (eg, vitamin C without use
of hydrocortisone) on hemodynamics is unknown. Ultimately,
the generalizability of these results to a postcardiotomy
population is unclear. Future research may encourage the use
of vitamin C as another noncatecholamine vasopressor.
Hydroxocobalamin
There are isolated case reports of hydroxocobalamin’s
successful use in the setting of vasoplegic syndrome.58,59
Although traditionally used in the treatment of cyanide
poisoning, the mechanisms of hydroxocobalamin-induced
hypertension are yet to be fully elucidated but may lie in its
ability to bind the vasodilatory compound hydrogen sulfide.
Unlike methylene blue, it does not carry a risk of serotonin
syndrome, although it is more expensive and may cause
chromaturia.60 In terms of dosing, successive aliquots of 250
mg of intravenous hydroxocobalamin have been administered
alongside infusions of 500 mg/h in liver transplantation. The
same group has reported the use of 5 g administered
intravenously over 15 minutes in the cardiac surgical setting.61
Although premature to advocate for its widespread use,
hydroxocobalamin may be another possible rescue therapy in
the setting of profound refractory vasoplegia.
Terlipressin
Terlipressin is an established vasopressin analog used
primarily outside of North America with similar pharmacody-
namic properties to vasopressin. However, it has a much
longer half-life than vasopressin (4-6 h as opposed to 6 min)
and thus can be intermittently bolused without the need for
 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
continuous infusion. In addition, it has preferential selection
for AVPR1-type receptors and thus may allow for more
selective vasoconstriction, without NO liberation that may
occur with agonization of AVPR2 receptors. Small studies
comparing terlipressin and norepinephrine have shown them to
be equally effective at raising MAP.62 However, the isolated
increase in SVR that occurs with terlipressin, without perhaps
being offset by beta-adrenergic effects of norepinephrine or
AVPR2 effects of vasopressin, possibly could be harmful.
Because of its long half-life, long-lasting reduction in cardiac
index and oxygen delivery caused by high SVR could be
detrimental and may require the addition of an inotropic
agent.63 When compared head-to-head with vasopressin,
terlipressin performed similarly but was associated with a
reduction in platelet counts.62,64 Ultimately, larger controlled
trials need to be performed before terlipressin can be con-
sidered an appropriate anti-vasoplegia agent.
Angiotensin II
Angiotensin II is an endogenous hormone that makes up a
component of the renin-angiotensin-aldosterone axis and is a
direct, potent vasoconstrictor. It has a serum half-life of
approximately 30 seconds, though up to 30 minutes of effect
while in parenchymal tissue. Angiotensin II has wide-ranging
homeostatic effects, including stimulation of aldosterone
release and antidiuretic hormone secretion. Much of its
downstream effects are designed to increase sodium and water
retention while ensuring appropriate vascular tone, and there-
fore recently it has been scrutinized as a possible noncatecho-
lamine rescue vasopressor. Chawla et al performed a small
study of angiotensin II, starting at 20 ng/kg/min, versus
placebo to evaluate the concomitant need for norepinephrine
and found a significant, dramatic reduction in norepinephrine
requirement in the group receiving angiotensin II.65 A follow-
up trial randomly assigned patients with septic shock to either
angiotensin II or placebo with a primary end point of an
increase in MAP at 3 hours after infusion. Although somewhat
limited, with an inclusion criterion of a relatively normotensive
MAP range of 55 to 70 mmHg, the results were encouragingly
in favor of angiotensin II.66 Additional research is needed to
determine the effects of angiotensin II on patient outcomes
before it can be added to the anti-vasoplegia armamentarium.
The role of exogenous vasopressin, if combined with angio-
tensin II, also needs to be elucidated because angiotensin II
naturally encourages the release of vasopressin from the
neurohypophysis.
Conclusion
Vasoplegic shock is common after cardiovascular surgery.
Even though it often is a component of the inflammatory
response that occurs with CPB, alternative diagnoses with
similar presentations, such as sepsis, should be considered.
After appropriate fluid resuscitation has been performed,
vasopressors become the primary form of treatment. Catecho-
lamines, norepinephrine in particular, are the best studied and
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
9
are the suggested first-line treatment agents. Recent investiga-
tions have supported the use of noncatecholamine drugs,
especially when used in conjunction with norepinephrine.
Vasopressin and methylene blue are relatively well-studied
and are attractive additive and/or rescue agents. Both of these
drugs and other agents capable of increasing SVR may see
expanded roles in the near future when treating severe
vasoplegia.
References
1 Gomes WJ, Carvalho AC, Palma JH, et al. Vasoplegic syndrome after
open heart surgery. J Cardiovasc Surg 1998;39:619–23.
2 Levin MA, Lin HM, Castillo JG, et al. Early on-cardiopulmonary bypass
hypotension and other factors associated with vasoplegic syndrome.
Circulation 2009;120:1664–71.
3 Mets B, Michler RE, Delphin ED, et al. Refractory vasodilation after
cardiopulmonary bypass for heart transplantation in recipients on combined
amiodarone and angiotensin-converting enzyme inhibitor therapy: A role for
vasopressin administration. J Cardiothorac Vasc Anesth 1998;12:326–9.
4 Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: Pathophysiol-
ogy, risk factors and treatment. Am J Med Sci 2015;349:80–8.
5 Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J
Med 2001;345:588–95.
6 Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current
concepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4.
7 Weis F, Kilger E, Beiras-Fernandez A, et al. Association between
vasopressor dependence and early outcome in patients after cardiac
surgery. Anaesthesia 2006;61:938–42.
8 Szabo C. Role of poly(ADP-ribose) synthetase activation in the suppres-
sion of cellular energetics in response to nitric oxide and peroxynitrite.
Biochem Soc Trans 1997;25:919–24.
9 Hauser B, Bracht H, Matejovic M, et al. Nitric oxide synthase inhibition in
sepsis? Lessons learned from large-animal studies. Anesth Analg
2005;101:488–98.
10 Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized,
placebo-controlled, double-blind study of the nitric oxide synthase
inhibitor 546C88: Effect on survival in patients with septic shock. Critical
Care Med 2004;32:21–30.
11 Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency
contributes to the vasodilation of septic shock. Circulation 1997;95:1122–5.
12 Wilson MF, Brackett DJ, Tompkins P, et al. Elevated plasma vasopressin
concentrations during endotoxin and E. coli shock. Adv Shock Res 1981;6:
15–26.
13 Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K(þ)-channel
activities of cultured smooth muscle cells from porcine coronary artery.
Am J Physiol 1992;263:H491–6.
14 Umino T, Kusano E, Muto S, et al. AVP inhibits LPS- and IL-1beta-
stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells.
Am J Physiol 1999;276:F433–41.
15 Hall RI, Smith MS, Rocker G. The systemic inflammatory response to
cardiopulmonary bypass: Pathophysiological, therapeutic, and pharmaco-
logical considerations. Anesth Analg 1997;85:766–82.
16 Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmon-
ary bypass: Mechanisms involved and possible therapeutic strategies.
Chest 1997;112:676–92.
17 Kerbaul F, Guidon C, Lejeune PJ, et al. Hyperprocalcitonemia is related to
noninfectious postoperative severe systemic inflammatory response syn-
drome associated with cardiovascular dysfunction after coronary artery
bypass graft surgery. J Cardiothorac Vasc Anesth 2002;16:47–53.
18 Sundaram V, Fang JC. Gastrointestinal and liver issues in heart failure.
Circulation 2016;133:1696–703.
19 Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory
shock after cardiac surgery: Identification of predisposing factors
and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116:
973–80.
10 S. Shaefi et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
20 Colson PH, Bernard C, Struck J, et al. Post cardiac surgery vasoplegia is
associated with high preoperative copeptin plasma concentration. Crit Care
2011;15:R255.
21 Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis
of early goal-directed therapy for septic shock: The ARISE, ProCESS and
ProMISe Investigators. Intensive Care Med 2015;41:1549–60.
22 Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign:
International Guidelines for management of sepsis and septic shock: 2016.
Critical Care Med 2015;45:486–552.
23 Fuda G, Denault A, Deschamps A, et al. Risk factors involved in central-
to-radial arterial pressure gradient during cardiac surgery. Anesth Analg
2016;122:624–32.
24 Papadopoulos G, Sintou E, Siminelakis S, et al. Perioperative infusion of
low- dose of vasopressin for prevention and management of vasodilatory
vasoplegic syndrome in patients undergoing coronary artery bypass grafting:
A double-blind randomized study. J Cardiothorac Surg 2010;5:17.
25 Lange M, Aken HV, Westphal M. Role of vasopressinergic V1 receptor
agonists in the treatment of perioperative catecholamine-refractory arterial
hypotension. Best Pract Res Clin Anaesthesiol 2008;22:369–81.
26 Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion
after cardiac surgery. N Engl J Med 2015;372:997–1008.
27 Marik PE. Early management of severe sepsis: Concepts and controversies.
Chest 2014;145:1407–18.
28 Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: A
positive fluid balance and elevated central venous pressure are associated
with increased mortality. Critical Care Med 2011;39:259–65.
29 Vieillard-Baron A, Caille V, Charron C, et al. Actual incidence of global
left ventricular hypokinesia in adult septic shock. Critical Care Med
2008;36:1701–6.
30 Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;369:
1726–34.
31 Vail E, Gershengorn HB, Hua M, et al. Association between US
norepinephrine shortage and mortality among patients with septic shock.
JAMA 2017;317:1433–42.
32 De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and
norepinephrine in the treatment of shock. N Engl J Med 2010;362:779–89.
33 Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine
versus epinephrine alone for management of septic shock: A randomised
trial. Lancet 2007;370:676–84.
34 De Backer D, Aldecoa C, Njimi H, et al. Dopamine versus norepinephrine
in the treatment of septic shock: A meta-analysis. Crit Care Med 2012;40:
725–30.
35 Egi M, Bellomo R, Langenberg C, et al. Selecting a vasopressor drug for
vasoplegic shock after adult cardiac surgery: A systematic literature
review. Ann Thorac Surg 2007;83:715–23.
36 Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine
infusion in patients with septic shock. N Engl J Med 2008;358:877–87.
37 Gordon AC, Russell JA, Walley KR, et al. The effects of vasopressin on
acute kidney injury in septic shock. Intensive Care Med 2010;36:83–91.
38 Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early
vasopressin vs norepinephrine on kidney failure in patients with septic
shock: The VANISH randomized Clinical Trial. JAMA 2016;316:509–18.
39 Morales DL, Garrido MJ, Madigan JD, et al. A double-blind randomized
trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary
bypass. Ann Thorac Surg;75:926–30.
40 Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Vasopressin versus
norepinephrine in patients with vasoplegic shock after cardiac surgery: The
VANCS randomized controlled trial. Anesthesiology 2017;126:85–93.
41 Schmidt HH. NO., CO and .OH. Endogenous soluble guanylyl cyclase-
activating factors. FEBS Lett 1992;307:102–7.
42 Shanmugam G. Vasoplegic syndrome—the role of methylene blue. Eur J
Cardiothorac Surg 2005;28:705–10.
43 Wolvetang T, Janse R, Ter Horst M. Serotonin syndrome after methylene
blue administration during cardiac surgery: A case report and review.
J Cardiothorac Vasc Anesth 2016;30:1042–5.
Please cite this article as: Shaefi S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.10.032
44 Kofidis T, Struber M, Wilhelmi M, et al. Reversal of severe vasoplegia
with single-dose methylene blue after heart transplantation. J Thorac
Cardiovasc Surg 2001;122:823–4.
45 Yiu P, Robin J, Pattison CW. Reversal of refractory hypotension with
single-dose methylene blue after coronary artery bypass surgery. J Thorac
Cardiovasc Surg 1999;118:195–6.
46 Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces
mortality and morbidity in vasoplegic patients after cardiac surgery. Ann
Thorac Surg 2004;77:496–9.
47 Leyh RG, Kofidis T, Struber M, et al. Methylene blue: The drug of choice
for catecholamine-refractory vasoplegia after cardiopulmonary bypass?
J Thorac Cardiovasc Surg 2003;125:1426–31.
48 Maslow AD, Stearns G, Butala P, et al. The hemodynamic effects of
methylene blue when administered at the onset of cardiopulmonary bypass.
Anesth Analg 2006;103:2–8.
49 Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue
administration in patients at high risk for vasoplegic syndrome during
cardiac surgery. Ann Thorac Surg 2005;79:1615–9.
50 Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene blue for
vasoplegic syndrome after cardiac operation: Early administration
improves survival. Ann Thorac Surg 2017;104:36–41.
51 Weiner MM, Lin HM, Danforth D, et al. Methylene blue is associated with
poor outcomes in vasoplegic shock. J Cardiothorac Vasc Anesth 2013;27:
1233–8.
52 Belletti A, Musu M, Silvetti S, et al. Non-adrenergic vasopressors in
patients with or at risk for vasodilatory shock: A systematic review and
meta-analysis of randomized trials. PloS One 2015;10:e0142605.
53 Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients
with septic shock. N Engl J Med 2008;358:111–24.
54 Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low
doses of hydrocortisone and fludrocortisone on mortality in patients with
septic shock. JAMA 2002;288:862–71.
55 Whitlock RP, Devereaux PJ, Teoh KH, et al. Methylprednisolone in
patients undergoing cardiopulmonary bypass (SIRS): A randomised,
double-blind, placebo-controlled trial. Lancet 2015;386:1243–53.
56 Dieleman JM, Nierich AP, Rosseel PM, et al. Intraoperative high-dose
dexamethasone for cardiac surgery: A randomized controlled trial. JAMA
2012;308:1761–7.
57 Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C and
thiamine for the treatment of severe sepsis and septic shock: A retro-
spective before-after study. Chest 2017;151:1229–38.
58 Burnes ML, Boettcher BT, Woehlck HJ, et al. Hydroxocobalamin as a
rescue treatment for refractory vasoplegic syndrome after prolonged
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2016;31:1012–4.
59 Roderique JD, VanDyck K, Holman B, et al. The use of high-dose
hydroxocobalamin for vasoplegic syndrome. Ann Thorac Surg 2014;97:
1785–6.
60 Geraci MJ, McCoy SL, Aquino ME. Woman with red urine: Hydro-
xocobalamin-induced chromaturia. J Emerg Med 2012;43:e207–9.
61 Akinosoglou K, Alexopoulos D. Use of antiplatelet agents in sepsis: A
glimpse into the future. Thromb Res 2014;133:131–8.
62 Morelli A, Ertmer C, Rehberg S, et al. Continuous terlipressin versus
vasopressin infusion in septic shock (TERLIVAP): A randomized, con-
trolled pilot study. Crit Care 2009;13:R130.
63 Morelli A, Ertmer C, Lange M, et al. Effects of short-term simulta-
neous infusion of dobutamine and terlipressin in patients with
septic shock: The DOBUPRESS study. Br J Anaesth 2008;100:
494–503.
64 Marks JA, Pascual JL. Selepressin in septic shock: Sharpening the VASST
effects of vasopressin? Crit Care Med 2014;42:1747–8.
65 Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II
for the treatment of high-output shock (ATHOS trial): A pilot study. Crit
Care 2014;18:534.
66 Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment
of vasodilatory shock. N Engl J Med 2017;377:419–30.