ARTICLE IN PRESS

Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 110

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Journal of Cardiothoracic and Vascular Anesthesia

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Review Article
Vasoplegia During Cardiopulmonary Bypass: Current
Literature and Rescue Therapy Options
Jamel Ortoleva, MD*, Alexander Shapeton, MDy,
Mathew Vanneman, MDz, Adam A. Dalia, MD, MBA, FASEz
,1

*
Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA
y
Department of Anesthesia, Critical Care and Pain Medicine, Veterans Affairs Boston Healthcare System,
Harvard Medical School, Boston, MA
z
Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Massachusetts General Hospital,
Harvard Medical School, Boston, MA

Vasoplegia syndrome in the cardiac surgical intensive care unit and postoperative period has been an area of interest to clinicians because of its
prevalence and effects on morbidity and mortality. However, there is a paucity of evidence regarding the treatment of vasoplegia syndrome dur-
ing cardiopulmonary bypass (on-CPB VS). This review aims to detail the incidence, outcomes, and possible treatment options for patients who
develop vasoplegia during bypass. The pharmacologic rescue agents discussed are used in cases in which vasoplegia during CPB is refractory to
standard catecholamine agents, such as norepinephrine, epinephrine, and phenylephrine. Methods to improve vasoplegia during CPB can be
both pharmacologic and nonpharmacologic. In particular, optimization of CPB parameters plays an important nonpharmacologic role in vasople-
gia during CPB. Pharmacologic agents that have been demonstrated as being effective in vasoplegia include vasopressin, terlipressin, methylene
blue, hydroxocobalamin, angiotensin II (Giapreza), vitamin C, flurbiprofen (Ropion), and hydrocortisone. Although these agents have not been
specifically evaluated for vasoplegia during CPB, they have shown signs of effectiveness for vasoplegia postoperatively to varying degrees.
Understanding the evidence for, dosing, and side effects of these agents is crucial for cardiac anesthesiologists when treating vasoplegia during
CPB bypass.
Ó 2019 Elsevier Inc. All rights reserved.

Key Words: vasoplegia; vasoplegia syndrome; hypotension during bypass; intraoperative vasoplegia; vasoplegia during bypass

VASOPLEGIA SYNDROME (VS) has been reported in up
to 20% of patients undergoing cardiac surgery,1 with even
higher rates in specific patient populations.2,3 Vasoplegia is
defined by a low mean arterial pressure (MAP), a normal or
elevated cardiac index (CI), and a low systemic vascular resis-
tance (SVR) that is refractory to conventional doses of com-
monly used vasopressors, such as norepinephrine.4,5 Vague
terms such as “low MAP” often appear in the literature regard-
ing this definition because institutional, regional, and clinical
practices vary with differing MAP goals ranging from 55 to 65
mmHg.4,5 Even though transient hypotension upon initiation
1 have used similar definitions.6-9 The lack of a universal defini-
Address reprint requests to Adam Dalia, MD, MBA, FASE, Department of
Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital,
55 Fruit St., Boston, MA 02114.
E-mail address: aadalia@mgh.harvard.edu (A.A. Dalia).
of cardiopulmonary bypass (CPB) commonly occurs because
of hemodilution and cardioplegia administration, this typically
resolves without intervention or with minimal doses of vaso-
pressors. In contrast to transient hypotension, vasoplegia dur-
ing CPB (on-CPB VS) refers to vasoplegia that occurs during
cardiac surgery exclusively on bypass that is refractory to
high-dose vasopressors. Although there is no broadly accepted
definition, for the purposes of the present review, on-CPB VS
is defined as a bypass flow sufficient for a CI
2.2 and a MAP
<60 mmHg despite high doses of vasopressors (0.2-0.5 mg/
kg/min norepinephrine equivalents).5 Other studies that have
examined vasoplegia both during CPB and in other settings
tion has resulted in significant heterogeneity in the reported
incidence and clinical outcomes of vasoplegia during cardiac
surgery across different studies.

https://doi.org/10.1053/j.jvca.2019.12.013
1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110
The pathophysiology and etiology of vasoplegia may occur
intraoperatively during CPB, after weaning from CPB, or postoper-
atively in the intensive care unit (ICU).5 The etiology of vasoplegia
is complex and not fully understood but likely involves nitric oxide
(NO) dysregulation, vasopressin depletion, endothelial dysfunction,
abnormal hydrogen sulfide metabolism, ascorbic acid sequestra-
tion, and prostaglandin release.5 Patients who specifically develop
hypotension or vasoplegia during CPB are at increased risk of
worse cardiac or neurologic outcomes compared with patients who
develop vasoplegia after completion of CPB, despite both cohorts
experiencing similar pathophysiologic mechanisms.10,11
Numerous patient-specific risk factors, such as sex, body mass
index, and presence of a left ventricular assist device, also correlate
with vasoplegia during CPB (Table 1).7,12 CPB itself may amplify
vasoplegia for the following 2 reasons. First, hemodilution from
crystalloid pump primes may reduce blood viscosity, reducing
overall vascular resistance. Second, blood interaction with CPB
components may result in the release of inflammatory mediators,
worsening vascular tone and resulting in hypotension. Because at
least part of the etiology of on-CPB VS is a result of direct patient
contact with the bypass machine, some cases of vasoplegia during
CPB may resolve after weaning from bypass; others, however,
may persist into the post-bypass and ICU periods.
Understanding the causes and treatment options for vasople-
gia during bypass is important because patients who develop
VS have significantly increased ICU length of stay (LOS), hos-
pital LOS, risk of kidney injury, and mortality.1 Although
numerous studies have investigated patients with postoperative
vasoplegia, the prevalence and clinical outcomes of patients
who develop on-CPB VS is less understood.1,4,5,14
The present review differs from previous reviews regarding
vasoplegia, which often is described postoperatively in the
ICU, because herein the incidence, outcomes, and possible
treatment options for patients who develop vasoplegia during
CPB are discussed. The pharmacologic treatment options for
on-CPB vasoplegia are similar to those used to treat vasoplegia
in the ICU. The pharmacologic rescue agents discussed are
agents used in cases in which vasoplegia during bypass is
refractory to standard doses of catecholamine agents such as
norepinephrine, epinephrine, and phenylephrine.
Prevalence and Outcomes of On-CPB VS
Few studies have examined the prevalence of vasoplegia
during CPB. Truby et al. assessed 138 patients undergoing
Table 1
Risk Factors for Vasoplegia During Cardiopulmonary Bypass7,13
Left ventricular ejection fraction >40%
Male sex
Elderly
Higher body mass index
Presence of left ventricular assist device
Longer duration of cardiopulmonary bypass
Hypotension immediately upon initiation of cardiopulmonary bypass
Perioperative angiotensin-converting enzyme inhibitor use
Infected endocarditis
orthotopic heart transplantation and found that 16% developed
vasoplegia during CPB.7 Compared with other heart transplan-
tation patients, patients with on-CPB VS had significantly lon-
ger ICU LOS, increased rates of renal replacement therapy,
and higher mortality at 30 and 60 days.7 Another study of 80
patients found that 10% of patients undergoing aortic valve
procedures developed on-CPB VS compared with 20% of
patients with prior cardiac surgery.8 Levin et al. assessed
2,800 patients undergoing cardiac surgery and found that 58%
experienced at least transient vasoplegia during bypass.13 The
higher frequency of vasoplegia in that study may have been
attributed to a broader definition of vasoplegia, which was
defined as any patient experiencing a >20% decrease in MAP
within 5 minutes of CPB initiation for more than 2 minutes.
Despite this broad definition, patients in the cohort who devel-
oped vasoplegia during bypass had increased rates of postoper-
ative vasoplegia, prolonged hospital stay, and death. In another
retrospective cohort study, Tsiouris et al. found that 20% of
cardiac surgical patients experienced vasoplegia; of these,
77% experienced vasoplegia intraoperatively.1 A majority of
these studies are heterogenous and restricted to smaller sub-
groups of cardiac surgical patients, impairing overall estima-
tion of the prevalence and clinical implications of vasoplegia
during CPB. Risk factors, prevalence, and outcomes for vaso-
plegia during CPB are derived from the literature and are pre-
sented in Tables 1 and 2.6-8,10,11,14,15
Effects of Hypotension During CPB
Large studies specifically investigating vasoplegia during
bypass are lacking, partially because a universally accepted
definition of vasoplegia is lacking. Alternatively, some larger
studies have evaluated the clinical outcomes of hypotension
during CPB (defined as a MAP <65 mmHg). Because pro-
longed hypotension is a necessary element of vasoplegia, out-
comes from these larger studies of on-CPB hypotension may
be extrapolated to patients who develop the refractory hypo-
tension central to vasoplegia during CPB.
Systemic hypotension may not necessarily result in end-organ
hypoperfusion. Local vascular autoregulation may result in
microvascular vasoconstriction in the setting of systemic hypo-
tension, maintaining adequate tissue perfusion. Despite possible
autoregulatory mechanisms, patients who experience on-CPB
hypotension may experience worse outcomes.7 In a large retro-
spective cohort of cardiac surgical patients, Sun et al. found that
patients with a MAP <65 mmHg during CPB were significantly
more likely to have end-organ injury, such as stroke, compared
with patients with a MAP >65 mmHg.11 The risk of stroke was
both MAP- and time-dependent during bypass; additional
reductions of MAP <65 mmHg and increased time with MAP
<65 mmHg were associated with incremental increases in
stroke risk. Importantly, this risk was only amplified with hypo-
tension during CPB; hypotension during either the pre- or post-
bypass period was not associated with stroke risk.
In another study, Gold et al. randomly assigned patients
undergoing coronary artery bypass grafting to a goal bypass
MAP of 50 to 60 mmHg (low-MAP group) or 80 to 100
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Table 2
Studies Involving On-CPB Hypotension or Vasoplegia With Prevalence and Outcomes

Study Study Type and Patients Reported Study Prevalence Study Definition of Hypotension Reported Study Outcomes
Population (Number) or Vasoplegia

Christakis et al.6 Prospective cohort; 555 28% of patients required Vasoplegia defined as >800 mg No difference in stroke
CABG patients >800 mg phenylephrine of phenylephrine to maintain a No difference in mortality
during CPB MAP >50 mmHg with a CI
>2.2 L/min/m2 during CPB
Gold et al.10 Randomized controlled 248 124 patients with MAP 50-60 Hypotension defined as “low” Increased rate of composite of
trial; CABG patients mmHg (“low” group), 124 MAP (50-60 mmHg) compared cardiovascular and neurologic
patients with MAP 80-100 with “high” MAP group (80- complications in “low” MAP
mmHg (“high” group) 100 mmHg) group
Levin et al.13 Retrospective cohort; 2,823 58% at least transient VS Hypotension defined as >2 min Increased risk of post-CPB VS
broad cardiac surgical with a MAP >20% baseline Increased LOS
patients within the first 5 min of CPB Increased mortality
Wittwer et al.8 Retrospective cohort; 30 10% in aortic valve surgery Vasoplegia defined as Not investigated
isolated aortic valve 20% in prior right-sided vasopressor amount/CPB time
surgery or redo cardiac congenital heart disease ratio >1 standard deviation
surgery after right-sided from mean
congenital heart disease
repair
Truby et al.7 Retrospective cohort; 138 16% of heart transplantation Vasoplegia defined as mean SVR Increased ICU LOS
heart transplantation patients <800 dynes s/cm5 despite CI Increased CVVH
patients >3 L/min/m2 and cumulative Increased mortality
dose of >1,500 mg
phenylephrine during CPB
Rettig et al.14 Retrospective cohort; 1,891 98% of patients with MAP Hypotension defined as duration No difference in acute kidney
CABG patients <50 mmHg, median and area under curve for MAP injury
duration 28 min <50 mmHg No other outcomes investigated
Vedel et al.15 Randomized controlled 192 98 patients goal MAP 40-50 Hypotension defined as “low” No difference in clinical stroke or
trial; CABG, aortic or mmHg (“low” group), 94 MAP (40-50 mmHg) compared MRI white matter infarct
mitral valve surgical patients goal MAP 70-80 with “high” MAP group (70-80 volume
patients mmHg (“high” group) mmHg) No difference in any secondary
outcomes (eg, hemodialysis,
myocardial infarction, death)
Sun et al.11 Retrospective cohort; 7,457 Not measured specifically Hypotension defined as duration Dose-dependent increased risk of
CABG or valve surgery and area under curve for MAP stroke with lower MAP (<65
<65 mmHg mmHg) and longer CPB times
with MAP <65 mmHg

Abbreviations: CABG, coronary artery bypass grafting; CI, cardiac index; CPB, cardiopulmonary bypass; CVVH, continuous veno-venous hemofiltration; ICU, intensive
care unit; LOS, length of stay; MAP, mean arterial pressure, MRI, magnetic resonance imaging; VS, vasoplegia syndrome; SVR, systemic vascular resistance.

mmHg (high-MAP group).10 Compared with patients assigned
to the high-MAP group, patients in the low-MAP group were
almost 3-fold more likely to experience either cardiac or neu-
rologic complications (4.8% v 12.9%). An important weakness
of this that trial was the wide target of CI during CPB (1.6-2.4
L/min/m2), implying that some results in the “low-MAP”
group may have been related to inadequate pump flow rates
using modern perfusion standards and therefore would not be
considered vasoplegia. The recent Perfusion Pressure Cerebral
Infarcts trial assigned 197 patients to a fixed CI of 2.4 L/min/
m2 during CPB and randomly assigned patients to a MAP goal
of 45 mmHg (low target) or 70 mmHg (high target) with vaso-
pressor administration.15 That trial found no difference in the
risk of clinical stroke or magnetic resonance imagingdetect-
able white matter changes, but it did not investigate any other
clinical outcomes. Given these data, it remains unclear
whether the administration of vasoactive agents to correct on-
CPB hypotension affects clinical outcomes. Large randomized
trials with broader outcome measures are needed to fully
address this question. Nonetheless, there is no current evidence
of harm using a vasopressor-based strategy to target a MAP of
65 mmHg during CPB periods with adequate flow rates.
Treatment Options for On-CPB VS
It is crucial when diagnosing vasoplegia during CPB to rule
out other causes of perceived hypotension, such as errors in
arterial line monitoring, anaphylaxis, aortic dissection,
mechanical failure of the bypass machine, improper cannula
size, erroneous medication administration, or unintentional
torsion/clamping of cannula. If these causes are ruled out, it is
imperative to evaluate the possible pharmacologic or nonphar-
macologic methods to reverse on-CPB VS.
Optimizing Bypass Parameters
Both vascular and nonvascular components contribute to a
patient’s MAP during bypass. The vascular components
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generally are nonmodifiable and include vessel length, diame-
ter and number of vessels, and precapillary shunting.16 The
nonvascular components include bypass flow rate, blood tem-
perature, hematocrit, and blood viscosity. Optimizing these
nonvascular components can curtail the duration and incidence
of vasoplegia during bypass. One of the common theorized
causes of on-CPB VS is the rapid change in viscosity of blood
upon initiation of bypass because of crystalloid volume prim-
ing of the pump.16 The hemodilution that occurs during bypass
reduces the viscosity of the circulating blood thereby decreas-
ing the patient’s resistance, which is reflected by a decrease in
the SVR. This is based on Poiseuille’s law/equation, where
(h) is blood viscosity and (R) is a patient’s SVR, as follows:
R ¼ ½8hL=pr 4
Because of this change in blood viscosity, ways to improve
on-pump hypotension is to either increase afterload with vaso-
active drugs (commonly phenylephrine), increase the viscosity
by retroactively priming the bypass circuit (autologous blood),
or transfuse packed red blood cells in anemic conditions. The
latter solution should be guided by the on-pump dilutional
hematocrit level or degree of unrelenting hypotension; close
monitoring of repeated decreases in the hematocrit level dur-
ing CPB can signal an unknown source of bleeding either at
the cannula site or in the thorax. A continued decrease in the
hemoglobin level should prompt an evaluation of the quality
of venous drainage and venous reservoir levels. Priming the
bypass circuit with exogenous blood to increase circuit volume
viscosity carries the usual risks as those for blood transfusion
but should be taken into consideration for patients at high risk
of bypass-induced vasoplegia (see Table 1).
Other bypass parameters that can be adjusted include pump
flow; the target CI can be increased if vasoplegia during bypass
is encountered. Increases in pump flow can lead to hemolysis
and manifest on-pump as hematuria or after separation of
bypass. Alternatively, pre-bypass if a patient has risk factors
for on-CPB VS, larger venous and arterial cannulae can be
placed to enable higher flow rates (see Table 1).16 Duration of
CPB is a variable that has been linked to vasoplegia and may
not be adjusted easily for open heart procedures but can be
suggested in possible off-pump scenarios, such as coronary
artery bypass grafting, if sustained hypotension is observed.
Adjusting Anesthetic Conditions During CPB
Certain anesthetic agents, such as propofol and volatile
anesthetics, during bypass can negatively affect MAP and
should be modified if vasoplegia during bypass is encoun-
tered.17 It is known that pharmacokinetic and pharmacody-
namics are altered during bypass.17 With the administration of
inhaled anesthetics, parameters such as oxygenator design, dis-
turbances in blood/gas partition coefficients, and tissue solubil-
ity are altered during bypass.17 Concurrently, intravenous
anesthetics experience changes in volume of distribution,
altered plasma protein binding, drug sequestration, lung isola-
tion, and altered drug clearance.17 If a potential cause of on-
CPB VS is attributed to the volatile anesthetic, a switch to total
intravenous anesthesia with fewer hemodynamic side effects
can be considered (remifentanil, dexmedetomidine, fentanyl,
midazolam, or ketamine). In addition, it should be noted that
patients undergoing hypothermic CPB require less anesthesia;
studies have shown that a lower dose of propofol is needed to
maintain a constant bispectral index.17 Potency of both inhaled
and intravenous anesthetics are increased in hypothermic con-
ditions and can lead to hypotension if levels are maintained at
the levels they were before bypass during normothermia.
Vasopressin and Terlipressin
Arginine vasopressin (vasopressin), also known as antidiu-
retic hormone, is a nonapeptide hormone produced endoge-
nously by the hypothalamus and stored in the posterior
pituitary, which serves a critical role in blood pressure regula-
tion, osmotic balance, and renal function. Terlipressin is a syn-
thetic prodrug analog of vasopressin, which is cleaved by
endothelial peptidases to its active form, lysine-vasopressin.18
Although terlipressin has been used successfully to treat post-
bypass vasoplegia, data directly comparing it to vasopressin in
this setting are lacking. In addition, terlipressin is not approved
by the U.S. Food and Drug Administration (FDA) for use in
the United States and Canada; however, it is commonly used
in Europe, Australia, and New Zealand. Binding to arginine
vasopressin receptor 1a appears to play the primary role in
treating vasoplegia because this mechanism promotes vaso-
constriction via a decrease in production of NO; terlipressin
has more selectivity for the arginine vasopressin receptor 1a
than does vasopressin.5
Landry et al.19 first identified that patients experiencing vas-
odilatory shock have a quantitative deficiency in circulating
vasopressin; Argenziano et al.20 later observed the same phe-
nomenon in patients experiencing cardiogenic shock. A defi-
ciency in circulating vasopressin was subsequently also
recognized as a factor in the development of post-bypass vaso-
plegia, leading some investigators to evaluate prophylactic
administration of vasopressin in cardiac surgery.21
An initial randomized controlled trial (RCT) exploring this
topic by Morales et al. demonstrated improved hemodynamics
and a decrease in inotropic requirements post-CPB in cardiac
surgical patients who were prophylactically treated with vaso-
pressin (0.03 U/min, initiated before CPB).22 Papadopolous
et al. later published an RCT confirming the findings of
Morales et al., in which they also reported significantly lower
rates of post-CPB vasodilatory shock and significantly lower
inotropic and catecholamine requirements in patients who
received prophylactic vasopressin.23 Neither trial specifically
addressed hemodynamics during CPB. More recently, investi-
gators in the VANCS (Vasopressin vs Norepinephrine in
Patients with Vasoplegic Shock after Cardiac Surgery) trial,
which randomly assigned more than 300 patients with post-
bypass vasoplegia to receive either norepinephrine or vaso-
pressin, demonstrated a significantly lower primary outcome
(composite mortality and severe complications) in the vaso-
pressin group.24
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At present, there are no RCTs or large retrospective studies
evaluating vasopressin or terlipressin to specifically treat vaso-
plegia during CPB. Given the existing literature, it is reason-
able to consider a prophylactic infusion of vasopressin before
initiation of CPB in patients with multiple risk factors for vas-
oplegia. Vasopressin should be considered as a first line agent
(along with phenylephrine and norepinephrine) for treating
vasoplegia on bypass and is FDA-approved for treatment of
vasoplegia.
Side effects of vasopressin include, but are not limited to,
myocardial ischemia, reductions in cardiac output and sys-
temic oxygen delivery, decreased platelet count and renal
blood flow, hyponatremia, splanchnic vasoconstriction, and
ischemic skin necrosis if administered through an infiltrated
peripheral intravenous line.24 The only absolute contraindica-
tion to vasopressin is hypersensitivity to the medication itself.
Terlipressin is contraindicated when there is hypersensitivity
to the medication; severe asthma; history of cerebral vascular
disease; and during pregnancy, for which terlipressin has been
shown to cause uterine contraction, increased intrauterine pres-
sure, and decreased uterine blood flow.25
Methylene Blue
Methylene blue acts as an inhibitor of NO synthase and solu-
ble guanylate cyclase, 2 enzymes involved in endothelial mus-
cle relaxation that are important in the cascade of refractory
vasodilatory shock.26 In cardiac surgical patients with vasodila-
tory shock refractory to catecholamines, approximately 40% of
patients have a positive blood pressure response to methylene
blue as defined by a decrease in vasopressor doses by at least
20%.27 In the literature, methylene blue has been used off-label
for cases of vasoplegia for nearly 2 decades.28 Intravenous
methylene blue comes as a 5 mL ampule with a total of 50 mg
in each vial, making a concentration of 10 mg/mL.
For patients experiencing on-CPB VS, there are very limited
data on the use of methylene blue. In a randomized trial of 30
patients receiving preoperative angiotensin-converting enzyme
(ACE) inhibitors divided in 1:1 fashion that could not be
blinded because of methylene blue coloring the urine, Maslow
et al. found that a dose of 3 mg/kg of methylene blue adminis-
tered after the initial dose of cardioplegia significantly
increased MAP during bypass.29 In that study, lactate levels in
the methylene blue group also were found to be lower, and
vasopressor requirements were reduced both during and after
separation from bypass. The increased dose of 3 mg/kg of
methylene blue was used because of the larger volume of dis-
tribution that is present in patients on bypass. A case report on
the use of methylene blue at 2 mg/kg added to the CPB prime
in a patient with infectious endocarditis described the resolu-
tion of severe vasodilation during and after bypass; of note,
before the induction of general anesthesia, the patient had a
blood pressure of 170/53 and was receiving no vasoactive
agents.30 Another case report described a patient undergoing
double lung transplantation who experienced vasoplegia on
bypass, and 2 mg/kg of methylene blue was administered,
which resulted in a significant reduction in vasopressor
5
requirements.31 A current ongoing randomized trial by Low
et al., the Hemodynamic effects of Methylene Blue versus
Hydroxocobalamin in Patients at Risk of Vasoplegia During
Cardiac Surgery (protocol NCT03446599), is being performed
to measure the hemodynamic effects of 2 mg/kg methylene
blue, 5 g hydroxocobalamin, or placebo (normal saline) during
and after CPB in patients at risk for vasoplegia. That trial is
scheduled to be completed by June 2020.
Before methylene blue use, flows should be maximized,
which typically, per the manufacturer, cannot be more than
approximately 6 L/min (ideally large cannulae are used in
patients at risk for vasoplegia); the administration of catechol-
amine and noncatecholamine vasoconstrictors should be
attempted; and other, more easily reversible causes of vasodila-
tory shock should be explored (eg, adrenal insufficiency, severe
anemia, and anaphylaxis).32 It is important to know the risks of
high flows, including hemolysis (although this ceases with the
termination of CPB), increased inflammation, and platelet acti-
vation and destruction. In addition, the off-label use of methy-
lene blue during CPB must be discussed with the surgeon and
the perfusion team so as not to respond to artefactual alterations
in oxygen sensors and to be prepared for possible rare side
effects, such as methemoglobinemia.32,33 Although limited,
there is some evidence that starting methylene blue early in the
diagnosis of vasoplegia may be beneficial.34
Methylene blue exhibits important side effects, which
include serotonin syndrome, hemolysis in patients experienc-
ing glucose-6-phosphate dehydrogenase deficiency (approxi-
mately 5% of the population), interference with pulse
oximetry, elevations in pulmonary vascular resistance through
inhibition of NO synthase, methemoglobinemia, and even
anaphylaxis.26,32,33,35 Given that the largest amount of
research on the subject has involved a dose of 3 mg/kg of
methylene blue for vasoplegia, the authors of the present
review recommend a 2 to 3 mg/kg dose for vasoplegia during
bypass. The use of a methylene blue infusion after this bolus
dose also is reasonable to maintain the hemodynamic response,
with typical dosing being 0.5 mg/kg/h for 6 hours.26
Hydroxocobalamin
Hydroxocobalamin is a highly bioavailable form of vitamin
B12 that currently carries FDA approval for the treatment of
only cyanide toxicity. An emerging off-label use for hydroxo-
cobalamin is rescue therapy in cases of vasoplegia post-bypass
or during liver transplantation when other therapies have been
unsuccessful or are contraindicated. Hydroxocobalamin and
other cobalamins are potent direct inhibitors of NO and NO
synthase. In addition, hydroxocobalamin directly binds sulfide
and increases elimination of hydrogen sulfide, an endothe-
lium-derived hyperpolarizing factor that has been shown to act
as an endogenous vasodilator36,37 This important mechanism
of action addresses a potential key cause of vasoplegia during
bypass—NO-mediated vasodilation.
Hydroxocobalamin in the post-CPB setting was first
described by Roderique et al. in 2014, and since then, several
other case reports and case series have been published.38 In the
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6 J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110
largest of these case series, Shah et al. reported that 24 of 33
(72.7%) patients diagnosed with vasoplegia after cardiac sur-
gery and treated with hydroxocobalamin had an improvement
in MAP and a decrease in vasopressor requirements.39 A
review by Shapeton et al. from early 2019 identified 7 individ-
ual case reports and 4 case series that described near universal
improvements in MAP and decreases in vasopressor require-
ments after treatment with hydroxocobalamin.40 Subsequently,
there has been rapid growth in this body of literature, with
Cios et al.,41 Armour et al.,42 and Feih et al.43 all publishing
separate case series with promising results.
As of publication of the present review, no RCTs or large ret-
rospective studies exist to assess efficacy, guide therapy, or
determine the most appropriate dosage for hydroxocobalamin in
the treatment of vasoplegia during bypass. Because high-quality
evidence is lacking, hydroxocobalamin should only be consid-
ered as a rescue agent in vasoplegia during bypass. Common
side effects such as chromaturia (red or orange), erythema, ele-
vated blood pressure, headache, rash, photosensitivity, and
injection site reactions have been reported. In addition, more
serious side effects such as anaphylaxis, angioedema, acute
renal failure, and severe hypertension also have been reported.
In patients with megaloblastic anemia, administration of
hydroxocobalamin must be approached with caution because it
can precipitate hypokalemia. However, the only known absolute
contraindication is hypersensitivity to hydroxocobalamin.
Hydroxocobalamin also is known to interfere with certain labo-
ratory values and equipment. Furthermore, hemoglobin, baso-
phils, creatinine, glucose, bilirubin, and alkaline phosphatase
may be falsely elevated for varying amounts of time after
administration, whereas hematocrit, leukocytes, and platelets do
not appear to be affected. Pertinent to the cardiac surgical popu-
lation, hydroxocobalamin also has been known to trigger the
false blood leak alarm in Fresenius (Fresenius Medical Care,
Bad Homburg, Germany) dialysis machines.40
Based on a review of published cases, the predominant dos-
ing regimen in use is 5 g administered intravenously over 15
minutes, with the option to give a second 5 g dose if the first
does not achieve the desired hemodynamic effect.40 Time to
peak effect has not been well-studied and appears to vary
greatly from patient to patient, as does onset of action (minutes
to hours).39
Angiotensin II
Patients undergoing CPB encounter a variety of physiologi-
cal insults that can lead to hypotension. One of these insults
includes hydrogen sulfide release, which can lead to the inhibi-
tion of endothelial ACE activity.44 In conjunction with pulmo-
nary endothelial injury and pulmonary isolation during CPB,
the level of ACE activity is greatly reduced.44,45 Because of
these derangements, vasoplegia during bypass may be cur-
tailed with angiotensin II (Giapreza; La Jolla Pharmaceutical,
San Diego, CA) administration. Angiotensin II acts directly on
the vessel wall to cause vasoconstriction and an increase in
MAP.40,44 Angiotensin II has been studied in vasoplegia dur-
ing septic shock and post-cardiac surgery, and the largest trial
to date is the ATHOS III (Angiotensin II for the Treatment of
High-Output Shock) trial that focused primarily on vasoplegia
in the ICU with 80.7% of patients enrolled experiencing sepsis
as the cause of vasodilatory shock.9 The trial involved 321
patients in vasodilatory shock who were assigned in a 1:1 ratio
to receive angiotensin II or a placebo. The primary end point
was a response to the medication at 3 hours measured by an
increase in MAP from baseline by 10 mmHg or to 75 mmHg
without increasing the baseline vasopressor doses. ATHOS III
comprised almost entirely (80%) patients diagnosed with sep-
tic shock, whereas only 19 patients were diagnosed with post-
operative vasoplegia.9 The results showed that patients in the
angiotensin II group reached the primary end point with statis-
tical significance (69.9% v 23.4%; p < 0.0001; odds ratio
7.95; 95% confidence interval 4.76-13.3).9 Although the
effects of the drug were measured over the span of hours to
days, it was noted that the MAP increased and the vasopressor
dosing decreased within the first 2 hours of medication admin-
istration. The trial also included 7 patients who were undergo-
ing extracorporeal membrane oxygenation (ECMO) therapy.46
All 7 patients who were treated with angiotensin II had a rapid
decline in vasopressor dose with a concomitant increase in
blood pressure; causes of vasoplegia during ECMO conditions,
such as activation of inflammatory mediators upon contact
with the circuit, more closely resemble CPB conditions.46
In a recent case report that described angiotensin II use for
post-CPB vasoplegia, the dose of norepinephrine was reduced
by 33.3% in the first hour and then by 88.9% in the second
hour.45 In a separate case series of 4 patients experiencing
post-CPB vasoplegia, angiotensin II was initiated at 20 ng/kg/
min and within 1 hour the MAP increased and the norepineph-
rine dose was reduced by 27.8%.44
The FDA-approved doses described in the literature for
distributive shock range from 10 to 40 ng/kg/min, with the
catecholamine-sparing effects noticed within an hour.44,45,47
The most serious side effect of angiotensin II is thromboem-
bolic events, and this risk/benefit should be seriously consid-
ered, especially during bypass.47 As a result of the
thrombosis risk noted in the ATHOS III trial, the use of
angiotensin II during CPB should not be considered a stan-
dard until additional studies are undertaken. In addition,
because of its expense ($1,500 per vial), it may not be on for-
mulary in every institution.
Vitamin C and Combination Therapy of Hydrocortisone,
Ascorbic Acid, and Thiamine (HAT)
Recent studies that have examined treatments for vasoplegia
also have focused on the off-label use of intravenous vitamin C
(ascorbic acid) because there is some evidence to suggest that
critically ill patients are deficient in this cofactor, resulting in
hypotension.48 Vitamin C plays a crucial role in dopamine, epi-
nephrine, vasopressin, and norepinephrine synthesis, and a defi-
ciency in this cofactor can lead to reduced levels of endogenous
catecholamines.49,50 Vitamin C also plays a role in increasing
receptor sensitivity to catecholamines, increasing microcircula-
tion, scavenging reactive oxygen, reducing nitric oxide
 ARTICLE IN PRESS
J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110
synthase, and decreasing histamine release.48 It has been
reported that patients experience a reduction in vitamin C after
CPB and that CPB plays a role in sequestering vitamin C, result-
ing in an ascorbic acid deficiency.51 This depletion has been
linked to vasoplegia postoperatively and could be a contributing
factor to vasoplegia during bypass.48 In the first report of vita-
min C administration for bypass-related vasoplegia, Wieruszew-
ski et al. described 3 cases of patients undergoing CPB ranging
from 55 minutes to 196 minutes who developed profound vaso-
plegia postoperatively.48 After initiation of vitamin C 1.5 g
intravenously every 6 hours, the vasopressor requirements to
maintain a MAP of 65 mmHg were reduced profoundly and as
early as 4 hours after administration.48 In 2 of the cases, this
reduction in vasopressor requirements was noted within 1 hour.
More recently, studies have examined the effect of HAT
therapy, which combines hydrocortisone, vitamin C (ascorbic
acid), and thiamine, for the treatment of severe sepsis and vas-
oplegia.52 The largest study regarding HAT therapy was pub-
lished in 2017 and was a retrospective before-after study of 94
patients with sepsis and vasoplegia.52 Even though the primary
end point was survival to hospital discharge, a secondary end
point was duration of vasopressor infusions. The 47 patients in
the treatment group had a mean duration of vasopressors of
18.3 § 9.8 hours compared with the 47 patients in the control
group who had a mean duration of vasopressors of 54.9 §
28.4 hours (p < 0.001).52 That study demonstrated a rapid
reduction in vasopressor dosing within 2 hours of administra-
tion of HAT therapy. Additional research regarding HAT ther-
apy for sepsis is ongoing and reportedly will be complete by
October 2021 as part of the Vitamin C, Thiamine, and Steroids
in Sepsis (VICTAS) trial (protocol NCT03509350); these
results may be pertinent to the treatment of vasopressor refrac-
tory hypotension during bypass.53
In both the case series and studies the described dosing of
vitamin C was 1.5 g intravenously every 6 hours for 96 hours
or until vasopressor discontinuation. A relevant side effect of
vitamin C, especially during CPB, is an observed decrease in
platelet activation and oxalate nephropathy. In addition, in
patients with glucose-6-phosphate dehydrogenase, vitamin C
administration can lead to hemolysis.50
Prostaglandin Inhibitors
As part of the protuberances experienced during CPB, an
increase in prostaglandins has been described as a potential
cause for vasoplegia during bypass.54,55 It is theorized that the
production of prostaglandins is increased because of the
inflammatory response of CPB. In addition, prostaglandin is
inactivated in the lungs, but because CPB bypasses the lungs,
this inactivation is reduced.54,55 For the treatment of CPB-
associated vasoplegia, a study in Japan examined the off-label
use of the nonsteroidal anti-inflammatory flurbiprofen
(Ropion; Tokyo, Japan) for its prostaglandin synthesis inhibi-
tion via inactivation of cyclooxygenase properties.54 In that
study 18 patients undergoing CPB were administered 50 mg of
flurbiprofen before the start of CPB and 50 to 100 mg of flurbi-
profen during CPB and were compared with a control group.
7
In both groups an alpha agonist analog was used to maintain
MAP >45 mmHg during CPB. The study group receiving flur-
biprofen had a higher MAP and lower rates of alpha agonist
infusion compared with the control group (57 § 4 mmHg v 48
§ 3 mmHg; p < 0.01).54 As a marker of perfusion, urine out-
put was examined and noted to be significantly greater in the
flurbiprofen group compared with the placebo group (503 §
179 mL/h v 354 § 112 mL/h; p < 0.01). No statistically signif-
icant difference was noted between the 2 groups with respect
to CPB time, aortic cross-clamp time, hematocrit, ejection
fraction, or demographic variables. Despite its possible utility
in the treatment of vasoplegia, the biggest limitation with this
drug class is both the half-life of 5.5 hours and its negative
effect on platelet function and bleeding, which is especially
important in cardiac surgery.54
Steroids
Inflammatory mediators released during the initiation of CPB
include tumor necrosis factor; interleukins (1, 6, and 10); leuko-
triene; cytokines; and endotoxin.5 Corticosteroids play a signifi-
cant role in reducing these inflammatory mediators, which
cause systemic hypotension. In addition, suppression of the
hypothalamic-pituitary-adrenal axis is observed as a result of
the stress conditions of CPB.56 The role of steroids in cardiac
surgery and septic shock vasoplegia has been examined exten-
sively.57-59 However, the use of steroids in the treatment of on-
CPB VS has not been clearly studied. Dexamethasone and
methylprednisolone were studied in the DECS (Dexamethasone
for Cardiac Surgery) and SIRS (Steroids in Cardiac Surgery) tri-
als, respectively, but neither trial found a significant benefit in
mortality for patients undergoing cardiac surgery.58,59 The pri-
mary focus of these studies was serious adverse outcomes such
as death and stroke but not vasoplegia.58,59
Hydrocortisone use for vasodilatory shock gained traction
after the results of the CORTICUS (Corticosteroid Therapy of
Septic Shock) trial.60 That study was an RCT involving 499
patients, with 251 receiving 50 mg of intravenous hydrocorti-
sone every 6 hours for 11 days. Although the primary end
point was mortality, the study did reveal that vasodilatory
shock was reversed faster with hydrocortisone administration
compared with placebo. The duration of vasodilatory shock
was statistically shorter in the hydrocortisone group than in the
placebo group (p < 0.001).5
It also should be noted that the 50 mg dosing regimen is
given over several days to hours, and this may not be as benefi-
cial in an acute setting during CPB unless the patient is
experiencing adrenal insufficiency.56 The threshold to admin-
ister corticosteroids in patients with vasoplegia during bypass
should be low because there is minimal risk to giving even
high doses of steroids with respect to infectious outcomes and
sternal complications.58,59
Conclusion and Future Investigations
The evidence to support various treatment strategies for
severe vasoplegia is minimal, but given the frequency and
 ARTICLE IN PRESS
8 J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110

Fig 1. Algorithm for vasoplegia during cardiopulmonary bypass. CI, cardiac index; MAP, mean arterial pressure;

need for systemic evaluation and treatment, a proposed algo-
rithm is presented in Fig 1. Additional studies are needed to
assess whether this proposed algorithm would affect clinical
outcomes. The very definition of what constitutes on-CPB
VS is not well-understood as evidenced by the wide range of
current definitions, which are highlighted in Table 2.
Although these rescue agents have been described in the liter-
ature for vasoplegia in the ICU, their validation in vasoplegia
during bypass has not been well-published and leaves room
for further clinical investigation (Table 3). Ongoing clinical
studies evaluating treatment for vasoplegia during bypass
hopefully will shed light on this understudied topic. It is
important for cardiac anesthesiologists to be familiar with
these rescue agents because they may become valuable thera-
pies in the armamentarium against vasoplegia during bypass
(see Table 4).

Table 3
Current Gaps in Evidence and Major Questions for Future Clinical Trials
Table 4
Regarding Vasoplegia During Cardiopulmonary Bypass
Rescue Agents and Relevant Dosing Derived From the Current Literature
Establishing a universal hemodynamic threshold defining vasoplegia during
Drug Dose
CPB
Examining the equipment differences among CPB circuits associated with Vasopressin 0.02-0.1 U/min
vasoplegia Terlipressin* 1-2 mg/kg/h
Studying the relationship between various MAP targets (eg, 50, 60, 65 mmHg) Methylene blue* 2-3 mg/kg over 10 minutes, followed by
and end-organ effects 0.5 mg/kg/h for 6 h
Validating an evidence-based algorithm for pharmacologic treatment of Hydroxocobalamin* 5 g infused over 15 min; may repeat once
vasoplegia during CPB Angiotensin II (Giapreza) 10-40 ng/kg/min
Identifying new pharmacologic treatment options for vasoplegia during CPB Vitamin C* 1.5 g intravenously every 6 h
Evaluating the association of pharmacologic therapy for vasoplegia during Flurbiprofen (Ropion)* 50-100 mg
CPB and postoperative outcomes Hydrocortisone 50-100 mg once, then 50 mg every 6 h
Abbreviations: CPB; cardiopulmonary bypass, MAP; mean arterial pressure. * Off-label use.
 ARTICLE IN PRESS
J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110
Conflict of Interest
The authors have no financial disclosures to report.
References
1 Tsiouris A, Wilson L, Haddadin AS, et al. Risk assessment and outcomes
of vasoplegia after cardiac surgery. Gen Thorac Cardiovasc Surg
2017;65:557–65.
2 Chan JL, Kobashigawa JA, Aintablian TL, et al. Characterizing predictors
and severity of vasoplegia syndrome after heart transplantation. Ann
Thorac Surg 2018;105:770–7.
3 de Waal EEC, van Zaane B, van der Schoot MM, et al. Vasoplegia after
implantation of a continuous flow left ventricular assist device: Incidence,
outcomes and predictors. BMC Anesthesiol 2018;18:185.
4 Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current con-
cepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4.
5 Shaefi S, Mittel A, Klick J, et al. Vasoplegia after cardiovascular proce-
dures-pathophysiology and targeted therapy. J Cardiothorac Vasc Anesth
2018;32:1013–22.
6 Christakis GT, Fremes SE, Koch JP, et al. Determinants of low systemic
vascular resistance during cardiopulmonary bypass. Ann Thorac Surg
1994;58:1040–9.
7 Truby LK, Takeda K, Farr M, et al. Incidence and impact of on-cardiopul-
monary bypass vasoplegia during heart transplantation. ASAIO J
2018;64:43–51.
8 Wittwer ED, Lynch JJ, Oliver WC Jr, et al. The incidence of vasoplegia in
adult patients with right-sided congenital heart defects undergoing cardiac
surgery and the correlation with serum vasopressin concentrations. J
Thorac Cardiovasc Surg 2014;148:625–30.
9 Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of
vasodilatory shock. N Engl J Med 2017;377:419–30.
10 Gold JP, Charlson ME, Williams-Russo P, et al. Improvement of outcomes
after coronary artery bypass. A randomized trial comparing intraoperative
high versus low mean arterial pressure. J Thorac Cardiovasc Surg
1995;110:1302–11;discussion 1311-4.
11 Sun LY, Chung AM, Farkouh ME, et al. Defining an intraoperative hypo-
tension threshold in association with stroke in cardiac surgery. Anesthesi-
ology 2018;129:440–7.
12 Chan JL, Kobashigawa JA, Aintablian TL, et al. Vasoplegia after heart
transplantation: Outcomes at 1 year. Interact Cardiovasc Thorac Surg
2017;25:212–7.
13 Levin MA, Lin HM, Castillo JG, et al. Early on-cardiopulmonary bypass
hypotension and other factors associated with vasoplegic syndrome. Circu-
lation 2009;120:1664–71.
14 Rettig TCD, Peelen LM, Geuzebroek GSC, et al. Impact of intraoperative
hypotension during cardiopulmonary bypass on acute kidney injury after cor-
onary artery bypass grafting. J Cardiothorac Vasc Anesth 2017;31:522–8.
15 Vedel AG, Holmgaard F, Rasmussen LS, et al. High-target versus low-tar-
get blood pressure management during cardiopulmonary bypass to prevent
cerebral injury in cardiac surgery patients: A randomized controlled trial.
Circulation 2018;137:1770–80.
16 Pappalardo F, Landoni G, Franco A, et al. Prolonged refractory hypoten-
sion in cardiac surgery after institution of cardiopulmonary bypass. J Car-
diothorac Vasc Anesth 2002;16:477–9.
17 Barry AE, Chaney MA, London MJ. Anesthetic management during car-
diopulmonary bypass: A systematic review. Anesth Analg 2015;120:
749–69.
18 Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: Pharmacol-
ogy and its clinical relevance. Anaesthesia 2004;59:993–1001.
19 Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contrib-
utes to the vasodilation of septic shock. Circulation 1997;95:1122–5.
20 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.
9
21 Morales DL, Gregg D, Helman DN, et al. Arginine vasopressin in the treat-
ment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac
Surg 2000;69:102–6.
22 Morales DL, Garrido MJ, Madigan JD, et al. A double-blind randomized
trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary
bypass. Ann Thorac Surg 2003;75:926–30.
23 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 graft-
ing-a double-blind randomized study. J Cardiothorac Surg 2010;5:17.
24 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.
25 Sarin SK, Sharma P. Terlipressin: An asset for hepatologists! Hepatology
2011;54:724–8.
26 Hosseinian L, Weiner M, Levin MA, et al. Methylene blue: Magic bullet
for vasoplegia? Anesth Analg 2016;122:194–201.
27 Mazzeffi M, Hammer B, Chen E, et al. Methylene blue for postcardiopul-
monary bypass vasoplegic syndrome: A cohort study. Ann Card Anaesth
2017;20:178–81.
28 Kofidis T, Struber M, Wilhelmi M, et al. Reversal of severe vasoplegia
with single-dose methylene blue after heart transplantation. J Thorac Car-
diovasc Surg 2001;122:823–4.
29 Maslow AD, Stearns G, Butala P, et al. The hemodynamic effects of meth-
ylene blue when administered at the onset of cardiopulmonary bypass.
Anesth Anal 2016;103:2–8;table of contents.
30 Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass
to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc
Surg 2003;125:426–7.
31 Carley M, Schaff J, Lai T, et al. Methylene blue for vasoplegia when on
crdiopulmonary bypass during double-lung transplantation. A A Case Rep
2015;5:127–30.
32 Ortoleva JP, Cobey FC. A systematic approach to the treatment of vasople-
gia based on recent advances in pharmacotherapy. J Cardiothorac Vasc
Anesth 2019;33:1310–4.
33 McRobb CM, Holt DW. Methylene blue-induced methemoglobinemia dur-
ing cardiopulmonary bypass? A case report and literature review. J Extra
Corpor Technol 2008;40:206–14.
34 Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene blue for vaso-
plegic syndrome after cardiac operation: Early edministration improves
survival. Ann Thorac Surg 2017;104:36–41.
35 Dewachter P, Mouton-Faivre C, Trechot P, et al. Severe anaphylactic
shock with methylene blue instillation. Anesth Analg 2005;101:149–50;
table of contents.
36 Weinberg JB, Chen Y, Jiang N, et al. Inhibition of nitric oxide synthase by
cobalamins and cobinamides. Free Radic Biol Med 2009;46:1626–32.
37 Mustafa AK, Sikka G, Gazi SK, et al. Hydrogen sulfide as endothelium-
derived hyperpolarizing factor sulfhydrates potassium channels. Circ Res
2011;109:1259–68.
38 Roderique JD, VanDyck K, Holman B, et al. The use of high-dose hydrox-
ocobalamin for vasoplegic syndrome. Ann Thorac Surg 2014;97:1785–6.
39 Shah PR, Reynolds PS, Pal N, et al. Hydroxocobalamin for the treatment of
cardiac surgery-associated vasoplegia: A case series. Can J Anaesth
2018;65:560–8.
40 Shapeton AD, Mahmood F, Ortoleva JP. Hydroxocobalamin for the treat-
ment of vasoplegia: A review of current literature and considerations for
use. J Cardiothorac Vasc Anesth 2019;33:894–901.
41 Cios TJ, Havens B, Soleimani B, et al. Hydroxocobalamin treatment of
refractory vasoplegia in patients with mechanical circulatory support. J
Heart Lung Transplant 2019;38:467–9.
42 Armour S, Armour TK, Joppa WR, et al. Use of hydroxocobalamin
(vitamin B12a) in patients with vasopressor refractory hypotension
after cardiopulmonary bypass: A case series. Anesth Analg 2019;129:
e1–4.
43 Feih JT, Rinka JRG, Zundel MT. Methylene blue monotherapy compared
with combination therapy with hydroxocobalamin for the treatment of
refractory vasoplegic syndrome: A retrospective cohort study. J Cardio-
thorac Vasc Anesth 2019;33:1301–7.
 ARTICLE IN PRESS
10 J. Ortoleva et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 110
44 Wieruszewski PM, Radosevich MA, Kashani KB, et al. Synthetic human
angiotensin II for postcardiopulmonary bypass vasoplegic shock. J Cardio-
thorac Vasc Anesth 2019;33:3080–4.
45 Evans A, McCurdy MT, Weiner M, et al. Use of angiotensin II for post car-
diopulmonary bypass vasoplegic syndrome. Ann Thorac Surg 2019;108:e5–7.
46 Ostermann M, Boldt DW, Harper MD, et al. Angiotensin in ECMO
patients with refractory shock. Crit Care 2018;22:288.
47 Bussard RL, Busse LW. Angiotensin II: A new therapeutic option for vaso-
dilatory shock. Ther Clin Risk Manag 2018;14:1287–98.
48 Wieruszewski PM, Nei SD, Maltais S, et al. Vitamin C for vasoplegia after
cardiopulmonary bypass: A case series. A A Pract 2018;11:96–9.
49 Chow JH, Abuelkasem E, Sankova S, et al. Reversal of vasodilatory
shock: Current perspectives on conventional, rescue, and emerging
vasoactive agents for the treatment of shock. Anesth Analg
2020;130:15–30.
50 Marik PE. Hydrocortisone, ascorbic acid and thiamine (HAT therapy)
for the treatment of sepsis. Focus on ascorbic acid. Nutrients
2018;14:10.
51 Rodemeister S, Duquesne M, Adolph M, et al. Massive and long-lasting
decrease in vitamin C plasma levels as a consequence of extracorporeal
circulation. Nutrition 2014;30:673–8.
52 Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and
thiamine for the treatment of severe sepsis and septic shock: A retrospec-
tive before-after study. Chest 2017;151:1229–38.
53 Hager DN, Hooper MH, Bernard GR, et al. The Vitamin C, Thiamine and
Steroids in Sepsis (VICTAS) protocol: A prospective, multi-center, dou-
ble-blind, adaptive sample size, randomized, placebo-controlled, clinical
trial. Trials 2019;20:197.
54 Takewa Y, Seki T, Tatsumi E, et al. Prostaglandin synthesis inhibitor
improves hypotension during normothermic cardiopulmonary bypass.
ASAIO J 2001;47:673–6.
55 Augoustides JG. Management of vasoplegia after cardiopulmonary bypass:
Role of prostaglandin inhibition. Ann Thorac Surg 2007;84:1796.;author
reply 1796.
56 Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: Pathophysiol-
ogy, risk factors and treatment. Am J Med Sci 2015;349:80–8.
57 Murphy GS, Whitlock RP, Gutsche JT, et al. Steroids for adult cardiac sur-
gery with cardiopulmonary bypass: Update on dose and key randomized
trials. J Cardiothorac Vasc Anesth 2013;27:1053–9.
58 Whitlock RP, Devereaux PJ, Teoh KH, et al. Methylprednisolone in
patients undergoing cardiopulmonary bypass (SIRS): A randomised, dou-
ble-blind, placebo-controlled trial. Lancet 2015;386:1243–53.
59 Dieleman JM, Nierich AP, Rosseel PM, et al. Intraoperative high-dose
dexamethasone for cardiac surgery: A randomized controlled trial. JAMA
2012;308:1761–7.
60 Moreno R, Sprung CL, Annane D, et al. Time course of organ failure in
patients with septic shock treated with hydrocortisone: Results of the Corti-
cus study. Intensive Care Med 2011;37:1765–72.