Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1310 1314
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Journal of Cardiothoracic and Vascular Anesthesia
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Editorial
A Systematic Approach to the Treatment of Vasoplegia
Based on Recent Advances in Pharmacotherapy
VASOPLEGIA IS AN increasingly recognized challenge in
the perioperative environment, particularly given the increas-
ing amount of heart failure surgery, for which the incidence
may be 20% to 30%.1-3 Vasoplegia in adults has multiple
numerical definitions but is frequently defined as a normal or
high output state (cardiac index  2.2 L/min/m2) with diffi-
culty maintaining a mean arterial pressure (MAP) of 60
mmHg due to a low systemic vascular resistance (<800
dynes*sec/cm5) despite high-dose vasopressors (typically 0.5
mg/kg/min of norepinephrine equivalents).4,5 Vasoplegia
occurs in a multitude of scenarios, including cardiac surgery,
liver transplantation, sepsis, and anaphylaxis.5,6 Even though
currently there is no “standard of care” treatment algorithm for
vasoplegia, recent developments in pharmacotherapy now
allow treatment options for virtually all patients, but the indi-
vidual side effects of each agent must be considered.
Methylene Blue
Methylene blue (Provayblue; Cenexi, Fontenay-sous-Bois,
France) is commonly used in vasoplegia, but the risk of seroto-
nin syndrome due to monoamine oxidase inhibition properties
and hemolysis in glucose-6-phosphate dehydrogenase (G6PD)
deficiency (the most common enzymatic defect [5% of the
population]) are both important limitations.7,8 Patients at risk
for serotonin syndrome with methylene blue include those on
selective serotonin reuptake inhibitors (SSRIs); monoamine
oxidase inhibitors; meperidine; tramadol; phenylpiperidine
narcotics (eg, remifentanil, fentanyl, sufentanil); linezolid;
trazodone; and certain recreational substances such as lysergic
acid diethylamide and 3,4-methylenedioxymethamphetamine.9
Fortunately, it appears that the risk of serotonin syndrome in
patients concomitantly taking fentanyl and other serotonergic
medications is low.10 Reports of serotonin syndrome in
patients given methylene blue while on serotonin norepineph-
rine reuptake inhibitors, clomipramine, and SSRIs have been
published, and the US Food and Drug Administration (FDA)
DOI of original article: http://dx.doi.org/10.1053/j.jvca.2018.11.020.
https://doi.org/10.1053/j.jvca.2018.11.025
1053-0770/Ó 2018 Elsevier Inc. All rights reserved.
has issued a warning regarding the administration of methy-
lene blue to patients on these medications.11-13 Inhibition of
nitric oxide synthase and soluble guanylate cyclase is believed
to be the mechanism of blood pressure augmentation. In a ret-
rospective review of 88 patients receiving methylene blue for
postcardiotomy vasoplegic shock, 44.3% of patients responded
to methylene blue, with a response defined by a 20%
decrease in vasopressor requirement.14 Even though 2 weeks
of cessation is deemed acceptable for most SSRIs, particular
attention is paid to fluoxetine because the long half-life would
necessitate discontinuation 5 weeks before the administration
of methylene blue to avoid serotonin syndrome.13 The usual
dose is 1.5 to 2.5 mg/kg intravenously with or without an infu-
sion at 0.25 to 0.5 mg/kg/h for 4 to 6 hours.7
Hydroxocobalamin
Intravenous (IV) high-dose hydroxocobalamin (Cyanokit;
Meridian Medical Technologies, Columbia, MD) is FDA
approved for cyanide toxicity with the notable side effect of
extreme hypertension in 18% to 28% of patients, depending
on the dose used (5 or 10 g). The reason for hypertension is
believed to be via an inhibitory effect on nitric oxide syn-
thase.15 Hydroxocobalamin is not known to cause serotonin
syndrome and has been used for vasoplegia in patients at
risk of serotonin syndrome.16,17 The usual dose for vasople-
gia is 5 or 10 g IV over 15 minutes. No reports of hydroxo-
cobalamin causing hemolysis in patients with G6PD
currently exist. Hence, it may be a good substitute for
patients with vasoplegia and G6PD or increased risk for
serotonin syndrome. It is significantly more expensive than
methylene blue (approximately $1,200 v $100) and can
interfere with dialysis, falsely elevate hemoglobin and cre-
atinine levels, and alter activated partial thromboplastin
time and prothrombin time values for about 24 hours.16 Cur-
rently there are no randomized trials examining the effects
of high-dose hydroxocobalamin in vasoplegia, and data are
only available in case series and case reports, although a
small trial by Low et al. at Darmouth-Hitchcock Medical
Center is listed on ClinicalTrials.gov.16,18
 Editorial / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1310 1314 1311

Fig 1. Algorithm for vasoplegia based on medication side effects and limitations. *A hemoglobin transfusion threshold of 9 g/dL has not been shown to result in
worse outcomes versus 7.5 g/dL and may result in improved systemic vascular resistance (see article for references), possibly benefiting patients with vasoplegia.
AI, adrenal insufficiency; ATII, angiotensin II (Giapreza); G6PD, glucose-6-phosphate dehydrogenase; IV B12, intravenous high-dose hydroxocobalamin (Cyano-
kit); MB, methylene blue; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Angiotensin II hydrocortisone). A systematic review of 31,281 patients

IV synthetic human angiotensin II (Giapreza; La Jolla
Pharmaceutical, San Diego, CA) is FDA approved for use in
patients with septic or other forms of distributive shock.
Patients experiencing septic and distributive shock fre-
quently have depleted angiotensin II levels; it is believed
that the restoration of angiotensin II levels allows for
improved hemodynamics through enhanced vascular tone.19
The starting dose is 20 ng/kg/min, and it can be titrated
every 5 minutes (by at most 15 ng/kg/min at a time) up to
80 ng/kg/min but for maintenance should be at most 40 ng/
kg/min.20 For weaning, the minimum dose is 1.25 ng/kg/
min before stopping the infusion completely. 20 Although
the randomized, double-blind ATHOS-3 trial showed suc-
cess over norepinephrine in meeting a MAP target of 75
mmHg or 10 mmHg above the baseline MAP, approxi-
mately 30% of patients receiving angiotensin II did not
reach this endpoint.21 Alternative medications for vasople-
gia still are needed. The notable side effect of thromboem-
bolic events was found in the ATHOS-3 trial (12.9% with
angiotensin II v 5.1% with placebo).21 This adverse event
profile is a potential limitation in patients at risk for throm-
boembolism, particularly those being placed on mechanical
circulatory support or those with mechanical circulatory
support undergoing any procedures. The ATHOS-3 trial
excluded patients with asthma, with Raynaud’s syndrome,
and on high-dose corticosteroids (500 mg of daily
noted that with the exception of patients in refractory shock,
2 deaths occurred, 1 due to cerebral hemorrhage and the
other due to left ventricular failure in a patient with decom-
pensated heart failure (both deaths were described in pub-
lished work from 1965).22 In the same review, 55 of 115
patients in refractory shock treated with angiotensin II
died.22 High-quality studies in cardiac surgery are absent.
Vitamin C and Thiamine
IV vitamin C (Ascor; McGuff Pharmaceuticals, Inc., Santa
Ana, CA) recently has gained attention for the treatment of
sepsis and vasoplegia. Vitamin C is important in catechol-
amine synthesis, and this may explain the impressive reduction
in vasopressor requirements seen in a case series of cardiac
surgical patients receiving a dose of 1.5 g every 6 hours for
96 hours.23 The current literature and possible future directions
on the use of vitamin C in the critically ill, including in
patients with vasoplegia, recently has been summarized.24
Rarely, thiamine-depleted patients present for procedures. Car-
diovascular and neurologic symptoms, lactic acidosis, and
hypothermia may be present in thiamine-deficient patients
with rapid improvement after its administration.25 A small ran-
domized trial on thiamine in patients presenting for cardiac
surgery showed no difference in lactate levels or survival.26
1312 Editorial / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1310 1314

Vasoplegia algorithm in patients with risk or diagnosis of either serotonin syndrome

(taking SSRI, SNRI, or clomipramine) or G6PD Deficiency

Reactive airway disease or moderate to high risk for thrombosis?

Yes to one or
No to both
both
Not Improved Improved
IV B12 5-10 grams ATII drip 5 to 40ng/kg/min Monitor

Improved Not Acceptable risk

Improved not on ATII
Monitor Not Improved
and received B12
Reassess severity of reactive airway
disease or thrombosis risk if not on ATII
Unacceptably high
risk or on ATII
Reconsider anaphylaxis or adrenal insufficiency if not already treated. Avoid high dose
vitamin C in G6PD deficiency. Consider IV thiamine. Consider alternative diagnoses.
Fig 2. Vasoplegia algorithm for patients with either glucose-6-phosphate dehydrogenase deficiency or risk for serotonin syndrome. ATII, angiotensin II (Giapreza);
G6PD, glucose-6-phosphate dehydrogenase; IV B12, intravenous high-dose hydroxocobalamin (Cyanokit), SNRI, serotonin norepinephrine reuptake inhibitor;
SSRI, selective serotonin reuptake inhibitor.

Proposed Algorithm support, those with a history of thromboembolic phenomena,

The algorithm presented in Fig. 1 is based on the side effects
and limitations of methylene blue and synthetic human angio-
tensin II. The major decision points are related to the likelihood
of G6PD deficiency, which can be tested for via blood sample
preoperatively; the risk of serotonin syndrome (most concerning
would be patients on SSRIs, serotonin norepinephrine reuptake
inhibitors, and/or clomipramine); and the perceived thrombosis
risk. For example, in patients that are on mechanical circulatory
support or those being placed on mechanical circulatory
and those with asthma or active bronchospasm, angiotensin II
may be best avoided as an initial treatment. Fig. 2 and 3 offer
close-up views of the 2 subsections of the algorithm. The use of
vasopressin, norepinephrine, or phenylephrine are left to the dis-
cretion of the clinician because practice varies widely. The algo-
rithm addresses the possibility of anaphylaxis and adrenal
insufficiency because, although rare, they require different treat-
ments than other known forms of vasoplegia, at least ini-
tially.27,28 In the intensive care unit population, recent work by
Annane and Venkatesh suggest that hydrocortisone alone or in

Fig 3. Vasoplegia algorithm for patients without glucose-6-phosphate dehydrogenase deficiency and low risk for serotonin syndrome. ATII, angiotensin II (Giap-
reza); G6PD, glucose-6-phosphate dehydrogenase; IV B12, intravenous high-dose hydroxocobalamin (Cyanokit), SNRI, serotonin norepinephrine reuptake inhibi-
tor; SSRI, selective serotonin reuptake inhibitor.
 Editorial / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1310 1314
combination with fludrocortisone improves vasopressor require-
ments and, when the combination is utilized, there may even
have an effect on survival.27,28 Blood transfusion is controver-
sial, but normovolemic hemodilution decreases systemic vascu-
lar resistance and anemia may be a risk factor for vasoplegia.29
Although several recent large trials in cardiac surgical patients
did not show a difference in outcomes between a liberal or
restrictive hemoglobin threshold (7.5 g/dL v 9.0 g/dL and 7.5g/
dL v 9.5 g/dL), vasoplegic patients may benefit hemodynami-
cally from a modestly higher hemoglobin level; thus, a higher
goal is suggested in this algorithm.30-32
Few sources include a vasopressin-to-norepinephrine
conversion, and it is unclear how to convert between the
two. One source equates 0.04 U/min of vasopressin to 0.1
mg/kg/min of norepinephrine.4 Alternatively, in a cohort of
the VANISH trial deemed to have complications likely due
to vasopressor therapy, the mean doses of norepinephrine
and vasopressin in the intervention group were 0.06 U/min
(vasopressin) and 0.33 mg/kg/min (norepinephrine),
whereas the norepinephrine only group had an average
dose of 0.79 mg/kg/min.33 The MAP target was 65 to 75
mmHg in both groups; equating a combined dose of
0.06 U/min vasopressin with 0.33 mg/kg/min norepineph-
rine to 0.79 mg/kg/min of norepinephrine shows that
0.06 U/min of vasopressin is about 0.46 mg/kg/min of nor-
epinephrine in this population (assuming no synergy, which
may not be true). Hence, 0.04 U/min vasopressin is approx-
imately 0.3 mg/kg/min of norepinephrine, triple the afore-
mentioned reference. The true equivalence of 0.04 U/min
of vasopressin is likely between 0.1 mg/kg/min and 0.3 mg/
kg/min of norepinephrine.
Conclusion
Vasoplegia is a serious and life-threatening entity that con-
tinues to challenge providers. A quick guide with a decision
tree for use is necessary. Randomized trials to validate the use
of methylene blue, angiotensin II, and hydroxocobalamin in
patients with vasoplegia are absent, but given the paucity of
evidence, this approach provides a reasonable, easy-to-follow
framework for treatment.
Jamel P. Ortoleva, MD1
Frederick C. Cobey, MD, MPH, FASE
Department of Anesthesiology and Perioperative Medicine, Tufts Medical
Center, Boston, MA
E-mail address: jortoleva@tuftsmedicalcenter.org
(J.P. Ortoleva)
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