Rev Esp Anestesiol Reanim.

2019;66(5):277---287

Revista Española de Anestesiología

y Reanimación
www.elsevier.es/redar

REVIEW

Vasoplegic syndrome in cardiac surgery: Definitions,

pathophysiology, diagnostic approach and
management夽
D.M. Orozco Vinasco a,∗ , C.A. Triana Schoonewolff b , A.C. Orozco Vinasco c

a
Departamento de Anestesia Cardiovascular, Clínica Colsubsidio Calle 100, Instituto del Corazón de Bucaramanga sede Bogotá,
Bogotá, Colombia
b
Departamento de Anestesia Cardiovascular, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia
c
Departamento de Anestesia, Hospital Universitario Severo Ochoa, Leganés Madrid, Spain

Received 7 September 2018; accepted 24 December 2018

Available online 30 April 2019

KEYWORDS Abstract Vasoplegic syndrome is a state of vasopressor resistant systemic vasodilation in the
Cardiac surgical presence of a normal cardiac output. Its definition, pathophysiology, risk factors, diagnosis and
procedures; therapeutic approach will be reviewed in this paper. It occurs frequently during cardiac surgery
Intra-operative and is associated with high morbidity and mortality. A search in the LILACS, MEDLINE, and
complications; GOOGLE SCHOLAR databases was conducted to find the most relevant papers during the last 18
Cardiopulmonary years.
bypass; Prompt identification and diagnosis of patients at risk must be undertaken in order to imple-
Vasoconstrictors; ment an optimal therapeutic approach. This latter includes early treatment with vasopressors
Vasoplegia; with different mechanisms of action.
Vasoplegic syndrome © 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published
by Elsevier España, S.L.U. All rights reserved.

PALABRAS CLAVE Síndrome vasopléjico en cirugía cardíaca: definición, fisiopatología, enfoque

Procedimientos diagnóstico y manejo
quirúrgicos cardíacos;
Resumen El síndrome vasopléjico constituye un estado de vasodilatación sistémica refractaria
Complicaciones
al uso de vasopresores en presencia de gasto cardíaco normal. En el presente artículo se revis-
intraoperatorias;
ará la definición, fisiopatología, factores predisponentes el enfoque diagnóstico y terapéutico
Derivación
del mismo. Su ocurrencia es frecuente en el perioperatorio de cirugía cardíaca y se asocia
cardiopulmonar;

夽
Please cite this article as: Orozco Vinasco DM, Triana Schoonewolff CA, Orozco Vinasco AC. Síndrome vasopléjico en cirugía cardíaca:
definición, fisiopatología, enfoque diagnóstico y manejo. Rev Esp Anestesiol Reanim. 2019;66:277---287.
∗ Corresponding author.

E-mail address: damorov@yahoo.com (D.M. Orozco Vinasco).

2341-1929/© 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published by Elsevier España, S.L.U. All rights
reserved.
278 D.M. Orozco Vinasco et al.

Vasoconstrictores;
Vasoplejía;
Síndrome vasopléjico
a incrementos en morbimortalidad. Se llevó a cabo una búsqueda en las bases de datos LILACS,
MEDLINE y GOOGLE SCHOLAR abarcando los artículos relevantes durante los últimos 18 años.
Se debe identificar los pacientes de riesgo en aras de realizar un diagnóstico y tratamiento
precoz con vasopresores con diferentes mecanismos de acción.
© 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Publicado
por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction Table 1 Diagnostic criteria of vasoplegic syndrome.

Vasoplegic syndrome (VS) is a condition in which deep SAP <80 mmHg

arteriolar vasodilatation causes pathological low systemic
vascular resistance, severe hypotension in the presence
of normal or increased cardiac output (CO), and partial
or no response to management with vasopressors. SV has
been described in severe sepsis, anaphylaxis, intoxication,
pancreatitis, different states of shock, and often in the peri-
operative period of cardiac surgery. In the latter context,
the use of extracorporeal circulation triggers an exagger-
ated inflammatory response, which is considered the main
factor in the genesis of VS.
The vast majority of patients undergoing cardiac surgery
present some degree of vasodilation that easily reverses
with the administration of low-dose vasopressors. How-
ever, in 5---25% of these patients, vasodilation continues
beyond the first 6 postoperative hours, becoming severe and
refractory to conventional management. If it persists for
36---48 h, prognosis worsens, and the mortality rate increases
by 16---27%. Other complications will also occur, particularly
kidney failure, which prolong the length of both ICU and
hospital stay, with the corresponding increase in resources.
VS is a potentially reversible condition if optimal treat-
ment is initiated before the onset of refractory shock. This
therapeutic window appears to be limited to the first post-
operative day.1 For these reasons, we believe it is important
to describe the state of the knowledge of a syndrome that
has so far been poorly defined. In this article, we will review
the definition, pathophysiology, predisposing factors, and
the diagnostic and therapeutic approach to SV in the periop-
erative period of cardiac surgery, and propose a treatment
algorithm.
We searched the LILACS, MEDLINE and GOOGLE SCHOLAR
databases for articles in both English and Spanish using
the following search terms: cardiac surgery/adverse
effects; cardiopulmonary bypass/adverse effects; vaso-
constrictors/therapeutic use; vasoplegia/etiology; vasople-
gia/physiopathology; vasoplegia/therapy articles published
between 2000 and 2018 were considered.
CI >2.2 l/min
CVP <5 mmHg
PAOP <10 mmHg
SVR <800 dynes s cm−5
Norepinephrine >0.5 ␮g/k/min
CI: cardiac index; CVP: central venous pressure; MAP: mean arte-
rial pressure; PAOP: pulmonary artery occlusion pressure; SAP:
systolic arterial pressure; SVR: systemic vascular resistance.
Source: authors.
manifests clinically as hypotension in the presence of nor-
mal CO, although no universal diagnostic criteria have been
defined to accurately diagnose this condition. Although all
the articles retrieved define vasoplegia as a state of vasodil-
atation and hyperdynaemia,1---3 the diagnostic criteria vary
greatly, not only in terms of the variables used, but also
in the cut-off point. According to some authors, the most
widely used variable is mean arterial pressure (MAP),1 while
others rely on systolic pressure. Likewise, CO,3 the car-
diac index (CI)2 and the stroke volume have been used
interchangeably, with different cut points. There is also no
clear definition of high-dose vasopressors, with doses ran-
ging from 0.5 ␮g/kg/min to 1 ␮g/kg/min4 norepinephrine.
The parameter with the greatest consensus appears to be
systemic vascular resistance (SVR), for which a cut-off value
of 800 dynes s cm−5 is generally accepted.1---4 Table 1 shows
the diagnostic criteria most frequently found in the scien-
tific literature. Some authors also include elevation of lactic
acid and oliguria.3 By way of synthesis, therefore, we will
use the following definition of SV in cardiac surgery: systolic
arterial pressure (SAP) less than 80 mmHg, CI greater than
2.2 l/m2 , with normal or decreased filling pressures, SVR less
than 800 dynes s cm−5 , in a patient receiving norepinephrine
infusion greater than 0.5 ␮g/kg/min.
Pathophysiology and risk factors

Endothelial dysfunction leads to arteriolar dilatation and

Vasoplegic syndrome in cardiac surgery
Definition
VS can be defined as a state of tissue hypoperfusion caused
by vasodilatation refractory to the use of vasopressors. It
loss of autoregulation, which are the causes of VS; however,
the underlying biochemical mechanisms have not been fully
clarified. Recent research has identified cellular signals that
initiate and amplify the vasodilator pathways involved.2,4
These appear to operate synergistically or concurrently,
so VS is the result of multiple events that occur at the
Vasoplegic syndrome in cardiac surgery
endothelial level. Homeostasis mechanisms are disturbed
during cardiopulmonary bypass (CPB), triggering a systemic
inflammatory response, which is divided into 2 fundamental
phases: early and late.5 The early phase involves activa-
tion of the contact system (composed of factor xii, factor
xi, prekallikrein and high molecular weight kininogen) as a
consequence of the exposure of blood to artificial surfaces.
At the same time, coagulation and the complement system
are activated, leading to a marked increase in fibrinolysis.5
At the cellular level, lymphocytes, monocytes, neu-
trophils, platelets and endothelial cells are activated.
Mastocyte degranulation leads to the release of proin-
flammatory cytokines, such as interleukin 4 (IL-4), IL-10,
interferon gamma (IFN-␥) and tumour necrosis factor alpha
(TNF-␣).5,6 The late phase of the inflammatory response
to CPB is the results of ischaemia and reperfusion caused
by aortic detachment and the recruitment of previ-
ously unperfused vascular beds. Ischaemia and reperfusion
cause endothelial damage by activating and amplifying the
humoral response of the complement system and the release
of oxygen free radicals. After CPB, there is a marked
increase in immunomodulators such as atrial natriuretic
peptide and IL-1, which can cause vasodilation by increas-
ing the production of cyclic guanosine monophosphate
(cGMP).
Nitric oxide (NO) is also closely related with the devel-
opment of VS. NO is produced following activation of the
2 types of NO synthase (NOS): endothelial (eNOS) and
inducible (iNOS). INOS is produced in vascular smooth mus-
cle cells and by the release of inflammatory mediators such
as TNF-␣ and IFN-␥. NO activates guanylyl cyclase, which
in turn initiates the production of cGMP and inhibits the
contractile activity of the vascular smooth muscle, thus
causing vasodilation.6
Underlying mechanisms unrelated to NO are also
thought to be involved in the pathophysiology of VS,
such as bradykinin, a vasodilator peptide whose degrada-
tion is inhibited by angiotensin converting enzyme (ACE)
inhibitors, hypothermia and CPB. Bradykinin and other adju-
vant factors promote the release of endothelium-derived
hyperpolarizing factor, which in turn activates the adeno-
sine triphosphate-sensitive potassium channel in cardiac
myocytes and further negativizes the resting membrane
potential, inhibiting aperture of the L-type calcium chan-
nel. This mechanism explains the catecholamine resistance
that characterises VS.2,3,5
Finally, hormonal factors have also been put forward,
since some studies have shown that absolute or relative defi-
ciency of hormones is involved in the regulation of blood
pressure, such as vasopressin, thyroxine and cortisol.
VS has traditionally been associated with patients under-
going on-pump heart surgery. However, it has also be found
in 2.8% of patient undergoing coronary revascularization
surgery without CPB,7 which suggests the existence of other
triggering mechanisms. This suggests that VS could be a
common final pathway, in which multiple factors cause
endothelial dysfunction, leading to vasodilation and loss of
autoregulation.
279
Risk factors
CPB, which generates the systemic inflammatory response
discussed above, is the main risk factor for VS. However,
other CPB-related variables that also appear to cause VS
need to be discussed. The duration of CPB, the presence
of hypotension and body temperature during CPB can also
contribute to the development of SV. A recent article pub-
lished in this journal found that CPB lasting more than
100 min (RR 1.02), MAP of less than 50 mmHg (RR 1.7), and
a body temperature of 34.4 (RR 1.2) were associated with
the appearance of VS.8
Determining the influence of haematocrit levels is even
more problematic, as several factors need to be taken
into account. Haemoglobin is a natural scavenger of free
radicals, so decreased levels could worsen the endothe-
lial lesion. Preoperative anaemia is a marker of chronic
disease in which persistent inflammation together with vaso-
pressin and thyroxine deficiency are known to be involved.
Moreover, blood products administered to treat anaemia,
by virtue of their immunomodulatory effects, would acti-
vate inflammatory pathways that could further worsen the
condition.4
VS presents in the most seriously ill patients, which
means that patients that develop this syndrome have a high
Euroscore and lower ejection fraction.4,5 The incidence of
VS in patients with normal systolic function is 3.3%12 com-
pared with 44.4% in patients with ventricular dysfunction.
Moreover, the incidence of VS among patients with ventri-
cular assist devices is as high as 42%, probably due to chronic
disease and inflammation.1---7
It is logical to assume that vasodilators, such as phos-
phodiesterase inhibitors, nitrates, beta-blockers, calcium
channel blockers and amiodarone, among others,3---5 would
trigger VS, but this has not been demonstrated. However,
administration of ACEIs in the 24 h prior to the proce-
dure is a documented risk factor, with an incidence of
26.9%.9
Other drugs, such as intravenous heparin infusion or pro-
tamine, have been implicated in the pathogenesis of VS, but
the evidence is sketchy to say the least. Some authors claim
that the calcium chelating action of heparin can promote
VS, in the absence of other plausible mechanisms. Others
suggest that this is merely an association, not a causative
factor, since patients who enter the operating room with
heparin infusion are often more seriously ill (acute coro-
nary syndrome, prosthetic thrombosis, etc.). Protamine has
occasionally been mentioned as a risk factor for VS, but it
is at present the only known antidote for heparin, mak-
ing it impossible to compare groups that have and have
not received this drug. Heparin-related anaphylactic reac-
tions are not believed to cause the syndrome, and although
they exhibit the same haemodynamic changes, these are
usually transient and respond well to treatment. Vasodila-
tors are not the only drugs involved in the development of
VS; chronic preoperative use of inotropics also seems to be
a trigger, presumably due to downregulation of adrenergic
receptors.
280
The type of surgery and the indication also play an
important role, insofar as VS is more common in open
heart procedure10 than in coronary revascularization surgery
(RR 0.45). In the latter intervention, it is more frequent
in on-pump procedures (RR 2.3).7,11 With regard to the
indication for surgery, there is evidence that patients under-
going valve replacement surgery for endocarditis are at
greater risk compared to patients with other indications.12
Patients undergoing surgery for terminal heart failure have
the highest incidence of VS, particular those undergoing ven-
tricular assist device implantation, followed by ventricular
restoration.13
The literature is unclear regarding the relative value of
each risk factor, and whether multiple risk factors in the
same individual have an accumulative effect. A recent study
by van Vessem et al.13 proposes a mathematical formula for
predicting VS in patients undergoing surgery for heart fail-
ure. However, this model has not yet been validated by other
groups, and is only applicable in this subgroup of patients.
A risk prediction instrument suitable for a broader popula-
tion is a needed to optimise therapeutic efforts to minimise
outcomes associated with SV.
Diagnosis
VS is a diagnosis of exclusion that requires a high index
of suspicion and consideration of predisposing factors. The
diagnostic approach must be based on the different stages of
the perioperative period, and certain differential diagnoses
can be ruled out depending on the stage of the procedure
(Table 2):
--- During CPB: although VS can occur at any time during the
perioperative period, CPB is the most powerful trigger.
The earliest sign is persistently low MAP despite adequate
blood flow. At this point, other causes, such as errors in
arterial or venous cannulation, aortic dissection, exces-
sive or drug-induced haemodilution (inhalational agents,
vasodilators, antiarrhythmics), must be ruled out.
--- Weaning from CPB: during this phase, VS mimics vol-
ume deficit. Haemodynamic findings will be low MAP
accompanied by low central venous pressure (CVP) and
pulmonary artery occlusion pressure (PAOP). The key to
differentiating VS from hypovolaemia is CO: in the case
of hypovolaemia, CO will be low while in the case of
vasoplegic shock it will typically be increased.
Table 2 Differential diagnoses.
During CPB After CPB
Errors in arterial or Regional wall motion dysfunction
venous cannulation
Excessive haemodilution Valvular mismatch
Drug reactions Right ventricular failure
Aortic dissection Drugs (protamine)
Occult bleeding (thorax) Anaphylaxis
Occult or obvious bleeding
Source: authors.
D.M. Orozco Vinasco et al.
Transoesophageal echocardiography in vasoplegic
syndrome
Although the thermodilution method for CO determination
using a pulmonary artery catheter (PAC) continues to be
the gold standard, its use has declined in recent decades in
favour of the routine use of intraoperative transoesophageal
ultrasound. This technique correlates with measurements
obtained from a PAC, provides detailed information about
cardiac anatomy, systolic and diastolic function, and can be
used to evaluate the surgical repair.
If VS is suspected, the first step is to rule out alterations
such as regional wall motion disorders, valvular maladjust-
ment and acute right ventricular dysfunction, which may
require restart of CPB. In the postoperative period, transtho-
racic assessment may be sufficient if the ultrasound window
is adequate. The echocardiographic images are compatible
with those showing severe hypovolaemia with dysfunction
of the papillary muscles in the transgastric short axis. CO,
calculated with pulsed Doppler using transgastric long-axis
or 5-chamber views, is increased, unlike volume deficit, in
which CO will be depressed.
When the patient is evaluated with the chest closed, sig-
nificant variations in the collapse of the inferior vena cava
and the aortic valve velocity time integral (VTI).
Pharmacology of vasopressors in vasoplegic
syndrome
The cornerstones of VS management are vasopressors, which
restore vascular tone. The many vasopressors currently
available can be divided into catecholamines, hormones
and NO inhibitors, depending of their mechanism of action
(Table 3).
Catecholamines
This group includes drugs that exert their action by stim-
ulating adrenergic receptors to activate L-type calcium
channels, producing an increase in cytosolic calcium and
a concomitant contraction of the vascular smooth mus-
cle. The haemodynamic profile of each catecholamine
differs, depending on its activation of different adrenergic
receptors.16
This group includes phenylephrine and norepinephrine as
pure vasoconstrictors, and adrenaline and dopamine, which
have mixed effects (inotropic and vasopressor). Very high
doses of these drugs are usually required to achieve target
blood pressure due to resistance to catecholamine treat-
ment inherent to the severe form of VS.14,15
Norepinephrine: blood pressure is increased following
stimulation of ␣1-adrenergic receptors in vascular smooth
muscle and ␤1receptors in the kidney, with the subsequent
release of angiotensin ii. Several studies have evaluated
the haemodynamic effects of this drug during the post-CPB
period, finding an increase in MAP and left ventricular work,
without affecting CVP, PAOP or CI.14
Phenylephrine: a pure ␣1-adrenergic receptor agonist.
Its haemodynamic effects are limited to increasing MAP, with
few effects on other parameters. CI can decrease, although
this is not always observed in the few studies in cardiac
surgery published to date.15
Vasoplegic syndrome in cardiac surgery
Table 3 Vasopressors in vasoplegic syndrome.
Drug Action/receptor
Phenylephrine Alpha-1 agonist
Norepinephrine Alpha-1, alpha-2 and beta-1 agonist
Adrenalin Alpha-1, alpha-2 and beta-1 agonist
Vasopressin V1, non-adrenergic receptors
Terlipressin V2, non-adrenergic receptors
Methylene blue Guanylyl cyclase inhibitor
Source: authors.
Dopamine: a natural catecholamine that binds to ␣
and ␤ adrenergic receptors, showing greater affinity for
␤ at low doses, and a predominance of ␣ effects at high
doses (10 ␮g/kg/min). Several studies have described its
haemodynamic effects in the post-CPB period as an increase
in MAP with variable effects on CI and a marked increase in
pulmonary pressures, heart rate, and the incidence of atrial
fibrillation (AF).16
Adrenaline: a powerful ␣ and ␤ adrenergic agonist, which
exerts its action by a dual mechanism of vasoconstriction
and increased CO. Its haemodynamic effects are similar
to norepinephrine, except for increased heart rate.17,22
Adrenaline has traditionally been thought to produce lactic
acidosis due to visceral hypoperfusion; however, this theory
has been re-evaluated in recent years.14
Adverse effects. Because catecholamines share a common
mechanism of action, their adverse effects are also common
to all. These are due to cytosolic calcium overload, which
promotes diastolic dysfunction, tachycardia, the develop-
ment of arrhythmias and intestinal, kidney and cutaneous
hypoperfusion.14---16 The effects are more or less severe
depending on the different receptor affinity of the particular
catecholamine used. Dopamine is more closely associated
with AF,16 tachycardia and increased pulmonary pressures,
while adrenaline is usually linked with the development of
lactic acidosis, but this does not appear to be due to tissue
hypoperfusion.
There is also a linear relationship between the need for
inotropic drugs and mortality, ICU stay and hospital stay,
although this could be due to the fact that the most seriously
ill patients require more inotropes, and may not be an effect
of the therapy itself.17
Hormones
Vasopressin, terlipressin (a prodrug of the former) and
angiotensin II are non-adrenergic vasopressors, although
they do increase cytosolic calcium. They are more effec-
tive than catecholamines in restoring vascular tone because
they do not depend on calcium L-type channels to exert their
action.18
Vasopressin: has a multisystemic action, such as stimu-
lation of gluconeogenesis, platelet aggregation and release
of adrenocorticotropin. It produces its effects through V1
and V2 receptors. V1 receptors enhance conservation of
water by inhibiting aquaporin in the collecting ducts, and
V2 receptors cause vasoconstriction via the phosphatidyl-
inositol pathway. When used for treatment, vasopressin
exhibits an interesting therapeutic profile due to its benefi-
cial effect on pulmonary hypertension and its catecholamine
281
Dose
40---100 ␮g bolus 0.5---10 ␮g/min infusion
4---10 ␮g bolus0.5---0. ␮g/kg/min infusion
40---100 ␮g bolus 0.5---10 ␮g/min infusion
1---6 IU/h infusion
1 mg bolus
1---100 ␮g bolus 0.25---1 mg/kg/h over 6 h
saving effect in the perioperative period of cardiac surgery.
When used as a prophylactic, vasopressin has been effective
in preventing VS during implantation of ventricular assist
devices in high-risk cases and in patients on ACE inhibitors.
When used as rescue strategy in cardiogenic shock refrac-
tory to catecholamines, it seems to offer greater benefits in
comparison with high-dose norepinephrine.19---27
In summary, the haemodynamic effects of vasopressin in
VS involve an increase in MAP without increasing CI, and a
modest decrease in heart rate and the incidence of arrhyth-
mias. They have also been shown to significantly reduce
the need for norepinephrine (33---66%). Several studies have
focused on organ function and perfusion during vasopressin
therapy. In the context of VS, prospective studies show a
significant decrease in postoperative kidney failure, which
in turn reduces mortality rates, without reaching statistical
significance.29
Terlipressin: a prodrug of vasopressin, with the same
haemodynamic profile. However, it is a selective V2 receptor
agonist, and therefore is a pure vasoconstrictor.
Concerns have been voiced regarding the safety of this
drug. The fact that terlipressin has no vasodilatory effect
on the kidneys suggests that it could increase the incidence
of kidney failure, although this has not been demonstrated
in the few available clinical studies. Another problem is its
prolonged half-life, which complicates both titration and
suspension of the drug. Its dosage form is also unclear (bolus
vs. continuous infusion). Two prospective clinical studies
(NCT03038503 and NCT02468063) currently under way are
expected to settle these questions.4,30
Angiotensin II: its use in cardiac surgery in patients with
VS refractory to catecholamines receiving ACEIs or amio-
darone has not been substantiated, although in these cases,
infusion of angiotensin II restored vascular resistance. More
evidence is needed to establish whether angiotensin II should
be a first-line treatment for iatrogenic vascular deficiency.
The best available evidence is derived from the ATHOS 3
study in patients with septic shock, so these results cannot
be extrapolated to the perioperative scenario. It should be
noted that in the angiotensin II arm, MAP targets at 3 h was
achieved more frequently than in controls.4,5
Adverse effects. Unlike catecholamines, hormones are
non-adrenergic vasopressors, and do not cause tachycar-
dia, arrhythmias (in fact, 2 studies showed a decrease in
the incidence of AF in the postoperative period of cardiac
surgery), or diastolic changes. However, high afterload can
cause low CO, a situation that has been documented in hypo-
volaemic patients and in those with low baseline CO. These
adverse effects have been described in all types of shock
282
(septic, haemorrhagic, cardiogenic, etc.). In the case of post
cardiac surgery VS, there is no evidence that treatment with
vasopressin and analogues increases the risk of mortality
or hypoperfusion28 ; on the contrary, they seem to protect
against kidney failure.29
Nitric oxide inhibitors
Methylene blue: a useful alternative in cases of vasopressor-
resistant vasoplegia in the context of cardiac surgery,31 since
it has beneficial effects on NO metabolism, the endothe-
lium, and vascular smooth muscle. It has a powerful direct
inhibitory effect on eNOS and probably on iNOS, and blocks
cGMP formation (the second pathway involved in the reg-
ulation of smooth muscle contraction) by decreasing the
action of guanylyl cyclase. These effects are mediated
by iron oxidation. Methylene blue, therefore, is able to
restore vascular tone in both dependent and independent NO
pathways. Methylene blue has been widely used in various
types of vasoplegia in cardiac surgery, such as: vasoplegia
refractory to catecholamines, heart transplant, surgery for
heart failure, and in drug reactions (protamine, amiodarone,
aprotinin).32---35 It should be noted that the benefit of this
drug is greater when it is used early (intraoperatively vs.
postoperatively).
The foregoing has led some authors to evaluate its use
as a prophylactic during CPB priming, despite the contro-
versy surrounding this indication. The literature on this
subject consists basically of case series involving patients
with endocarditis. Ozal et al.,36 Maslow et al.37 and Grayling
and Deakin12 all report good outcomes. Cho et al.,38 how-
ever, found that prophylaxis with methylene blue does not
significantly reduce vasopressor requirements or improve
haemodynamic variables in the same population. The defini-
tive role of methylene blue could emerge from 3 ongoing
studies (NCT03038503, NCT01797978 and NCT03120637).
Many different treatment regimens for the management
VS in cardiac surgery have been proposed, the most common
being intravenous infusion of 1---2 mg/kg for 10---30 min and
0.25---1.0 mg/kg/h for 6 h if the condition persists.
Adverse effects. The adverse effects of methylene blue
are not common, but can be serious. In animal models,
40 mg/kg has been found to be lethal, and it is recommended
not to exceed 5---7 mg/kg per day in humans.30
Side effects are dose-dependent, the most frequent
being nausea, vomiting, dyspnoea, urine discolouration,
angina, increased pulmonary pressure, and interference
with pulse oximetry readings. It has also been associated
with cardiac arrhythmias at high doses. Methylene blue is
a monoamine oxidase inhibitor, and should therefore be
administered with caution in patients receiving serotonin
reuptake inhibitors. In patients with glucose 6-phosphate
dehydrogenase deficiency, it can trigger haemolytic crises.
Methylene blue metabolites can accumulate in patients
with kidney failure, so the dose should be adjusted
accordingly. Other effects described are coma and methe-
moglobinaemia. In a recent meta-analysis that included
5 studies, the authors concluded that methylene blue is
effective in increasing MAP without increasing the risk of
mortality.30
D.M. Orozco Vinasco et al.
Evidence for the use of vasopressors in vasoplegic
syndrome
Although there is a considerable body of literature on VS,
this mostly consists of cases reports, reviews and patient
series, and the few studies performed are small with insuffi-
cient statistical power. Another factor to take into account
is that some of the recommendations have been extrapo-
lated from studies performed in septic patients or patients
with VS with different aetiologies.
Egi et al.15 conducted a systematic review of VS in
cardiac surgery from 1980 to 2006, and found only 37 ran-
domised clinical trials in which vasopressors were compared
in the postoperative period of cardiac surgery. The stud-
ies available were heterogeneous, and therefore unsuitable
for a meta-analysis, but those that were included in the
review compared norepinephrine, dopamine, vasopressin,
adrenaline, terlipressin, phenylephrine, angiotensin II and
methylene blue. The authors put forward several conclu-
sions, among them, that there is insufficient evidence to
recommend any particular vasopressor. They ratified the
adverse effects of dopamine, which is associated with
a higher incidence of tachycardia, increased pulmonary
pressures, and incidence of AF. Although norepinephrine
causes a decrease in mixed venous saturation when com-
pared with adrenaline, it is associated with higher pH and
base excess. Of particular interest is the fact that the combi-
nation of a second vasopressor with a different mechanism
of action may be superior to high-dose monotherapy, and
the use of vasoactive substances in VS in the postopera-
tive period of cardiac surgery is not associated with visceral
hypoperfusion. With regard to non-conventional vasopres-
sors, the authors conclude that the prophylactic use of
vasopressin decreases catecholamine consumption and pos-
sibly the incidence of VS, and that methylene blue can
reduce the duration of VS. A recent study in a retrospec-
tive cohort of patients, meanwhile, showed that methylene
blue may be associated with higher mortality; however,
patients receiving this therapy were more seriously ill than
controls.39
In a systematic review of non-adrenergic vasopressors,
Belletti et al. found a clear haemodynamic benefit for this
therapy, with a trend towards a decrease in mortality.18
Since the publication of this systematic review, the VASST40
and VANISH41 studies (septic patients), and the VANCS29
(postoperative cardiac surgery) study have evaluated the
role of vasopressin in VS. All these found a lower inci-
dence of renal failure, and the VANCS study also reported
a decrease in mortality, apparently linked to less need for
dialysis among patients assigned to the vasopressin group.
Due to the absence of prospective randomised studies in
methylene blue, it is currently only used as a coadjuvant or
rescue therapy in case of partial response or failure of the
existing therapy.
The main therapeutic objective is to achieve sufficient
perfusion pressure to maintain organ homeostasis. A MAP
of 65 mmHg is based on studies in patients with sepsis and
cardiogenic shock, but is not specifically VS.
Initial management with vasoactive amines is still the
first line treatment. Extrapolating the evidence from stud-
ies in sepsis suggests that norepinephrine would be the
Vasoplegic syndrome in cardiac surgery 283

DURING CPB

RISK FACTORS
DRUGS PATIENT SURGICAL
ACEI High Euroscore Heart failure surgery

PDE inhibitors Endocarditis Endocarditis

Inotropic dependence LVEF < 35% Prolonged CPB

STATUS DURING CPB

SVR < 800 dynes•sec•cm-5

RULE OUT AND TREAT
Cannulation errors MAP < 50mmHg
Severe anaemia (Hct < 20%)
Occult bleeding Inexplicable increase in volume requirements
Aortic dissection
Drugs

Norepinephrine up to 0.05 mcg/kg/min

Yes NO
Continue existing MAP 65 mmHg Vasopressin 0.03 IU/kg/h
management strategy SVR > 800 dynes•sec•cm-5 Consider terlipressin 1 mg

Continue existing
Yes Reevaluate
MAP 65 mmHg
management strategy
SVR > 800 dynes•sec•cm-5

Hydrocortisone 50 – 100 mg every 6 h.

Adjust vasopressin for MAP 65 mmHg.
2 mg/kg bolus methylene blue over 15 minutes.
Consider 0.25 mg/hour infusion up to 7 mg/kg
over 24 h.

CPB WEANING

CPB WEANING
Frequency and rate according to pathology.
Optimise preload by passing venous return to heart.
Adjust inotropes and vasopressors according to real time TOE and pulmonary
pressures.

MAP 65 mmHg
SVR > 800 dynes•sec•cm-5
CI 2.2 L/m2
Vasopressin < 5 IU/h
Norepinephrine < 0.5 mcg/kg/min
Yes
TOE
RULE OUT AND TREAT
Rule out: left ventricula
failure, cor pulmonale,
surgical problems
VS: imaging shows
hypovolaemia (left cavity
obliteration) with CI 2.2
l/m2 measured in deep
transgastric view with
NO
pulsed wave Doppler.

STABLE UNSTABLE
Titrate fluids using dynamic Titrate fluids using dynamic parameters.
parameters. Hydrocortisone 50 – 100 mg every 6 h.
Hydrocortisone 50 – Adjust vasopressin to MAP 65 mmHg. 2 mg/kg bolus
100 mg every 6 h. Continue methylene blue over 15 minutes.
vasopressin 12 – 24 h. Consider 0.25 mg/hour infusion up to 7 mg/kg over
24 h.

Figure 1 Proposed management algorithm for VS. ACEI: angiotensin converting enzyme inhibitors; CPB: cardiopulmonary bypass;
DTV: deep transgastric view; HCT: haematocrit; LVEF: left ventricular ejection fraction; MAP: mean arterial pressure; PDE: phos-
phodiesterase; SVR: systemic vascular resistance; TOE: transoesophageal ultrasound.
284
recommended treatment, as it has advantages over other
catecholamines in terms of efficacy and possibly lower
mortality. High-dose norepinephrine in monotherapy has
2 disadvantages: on the one hand, poor response due
to the calcium channel inactivation typical of VS, and
on the other, myocardial calcium overload that causes
diastolic dysfunction, arrhythmias and down regulation of
adrenergic receptors. With norepinephrine doses of over
0.75 ␮g/kg/min, mortality can reach up to 86% in patients
with multiple organ dysfunction, so the concomitant use
of another vasopressor with an alternative mechanism of
action is recommended2 . Vasopressin and methylene blue,
which use non-L-type calcium channel pathways, can be
effective alternatives in this context. Of these, there is
high quality evidence to support the use of vasopressin,
while methylene blue is only used as a coadjuvant or rescue
therapy.42
Therapeutic approach
Ideally, a preoperative strategy to prevent VS should be
implemented; however, this is not always feasible, since
the presence of one or more risk factors does not pre-
dict development of the syndrome. Although van de Messe’s
mathematical formula is interesting, it is only applicable
in heart failure surgery. If the use of beta-blockers and
ACEIs is a proven risk factor,43 would preoperative suspen-
sion be justified? The Coronary Revascularization Guidelines
of the American Heart Association recommend continua-
tion of beta-blockers in the perioperative period of coronary
revascularization surgery in all patients without contraindi-
cations. This is a type I recommendation to prevent AF, and
a type II recommendation to reduce mortality in patients
with ejection fraction greater than 30%. Preoperative dis-
continuation of beta-blockers to prevent VS is not currently
recommended.44 ACEIs are an established risk factor for VS,
and their suspension 24 h prior to cardiac surgery is consid-
ered adequate.45---48
Despite the absence of specific recommendations in car-
diac surgery, we propose the algorithm shown in Fig. 1, based
on an analysis of the available evidence, as an intraopera-
tive clinical approach to VS. The algorithm is drawn from
clinical trials, most of which involve surgical patients, with
some recommendations drawn from studies in septic shock
(specifically, the choice of norepinephrine as a first line
vasopressor, and the indication of corticoids in refractory
shock).
VS can occur at any time during the patient’s evolu-
tion, but CPB is the most important trigger. For this reason,
SVRs should be carefully monitored while the patient is on
pump; if these are abnormally low (after ruling out excessive
haemodilution, drugs, anaemia, etc.), norepinephrine infu-
sion should be started to achieve a target MAP of 65 mmHg.
A detailed discussion of the ideal MAP in CPB is beyond
the scope of this article. The MAP level recommended was
drawn from a recent study that found that a MAP of less
than 65 mmHg to be a risk factor for stroke.49 It should
be noted that although the diagnostic criterion for VS is
SAP, this parameter is not applicable during CPB due to the
absence of cardiac impulse; therefore, MAP, which is used in
D.M. Orozco Vinasco et al.
algorithms for managing patients in shock, was used instead
of SAP in our algorithm.
If more than 0.5 ␮g/kg/min adrenaline is required,
continuous infusion of vasopressin should be started. Ter-
lipressin in 1 mg boluses could be an alternative, although
more evidence is needed to recommend this approach.
After CPB, if the diagnosis of VS has been confirmed,
fluid replacement should be guided by dynamic preload
parameters (passive leg lift while the thorax is open, or
changes in aortic valve VTI with closed thorax). Methy-
lene blue is reserved for patients requiring more than
0.5 ␮g/kg/min norepinephrine combined with high-dose
vasopressin to maintain target MAP. In these cases, a
2 mg/kg bolus of methylene blue is given as rescue ther-
apy, which significantly increases SVR and reduces the need
for haemodynamic support in most patients. If vasoplegia
persists, an infusion of 0.25 mg/kg/h methylene blue should
be started.
Several studies, most in septic shock patients, sup-
port the use of corticosteroids in shock refractory to
catecholamines. However, the 2 leading studies in car-
diac surgery, DECS and SIRS, did not find any benefit in
terms of mortality or morbidity, and therefore the rou-
tine use of steroids in cardiac surgery is not recommended.
It should be noted that neither study analysed the inci-
dence or severity of VS, nor did they document any
detrimental effects that would conclusively advise against
corticosteroids.50,51 Weighing up the potential benefits in
terms of response to catecholamines in the absence of seri-
ous complications, hydrocortisone administration at doses
of 50---100 mg c/6---8 h could be a reasonable strategy.
Other treatments
Other approaches to VS management have also been
explored. Recent research points to alternative therapeutic
targets, for example, studies performed with high doses of
vitamins such as hydroxocobalamin and high-dose ascorbic
acid.
The accepted indication for hydroxocobalamin is the
management of cyanide poisoning, and one of its known
adverse effects is the development of severe hypertensive
crises. The proposed mechanism is direct antagonism of NO
and inhibition of NOS. The best available evidence in car-
diac surgery is a case series of 33 patients published by
Shah et al.,52 in which lower vasopressor requirement was
observed. Hydroxocobalamin could be considered an alter-
native to methylene blue in patients at risk of serotonin
syndrome.53
Ascorbic acid has antioxidant properties and regulates
microvasculature metabolism. In a retrospective study in
severe septic shock, ascorbic acid, in association with hydro-
cortisone and thiamine, showed a significant reduction in
mortality and need for vasopressors. It is impossible to
know which of these drugs had the greatest impact on the
results, and it is not clear whether these findings can be
generalised to other patient subgroups. More studies are
needed before ascorbic acid can be recommended as a
vasopressor.5
Vasoplegic syndrome in cardiac surgery
Conclusions
VS is a common occurrence in the perioperative period of
cardiac surgery, and has an established epidemiology and
prognosis. It significantly increases morbidity and mortality,
but is reversible if treated aggressively during the first 6 h.
Unfortunately, the syndrome has yet to be clearly
defined, although experts agree that it is a hyperdynamic
state involving a decrease in SVR due to pathological vasodi-
lation. Researchers need to reach a consensus on a more
precise definition of VS.
The diagnosis of VS is one of exclusion, requiring a high
index of suspicion. The routine use of intraoperative tran-
soesophageal echocardiography is recommended, both to
rule out other differential diagnoses, and for a prompt iden-
tification of the syndrome.
The treatment is based on restoring vascular tone through
the early use both adrenergic and non-adrenergic vasopres-
sors. In summary, the best strategy should include:
a. Identification of risk factors and preoperative optimisa-
tion.
b. Use of catecholamines as first line treatment, avoiding
dopamine, since the development of AF in the postopera-
tive period of cardiac surgery is associated with greater
mortality and hospital stay. Norepinephrine, which has
few cardiac effects, is probably the best therapeutic
option.
c. Early use of a vasopressor with alternative mechanism of
action (vasopressin).
d. Reserve methylene blue for rescue therapy.
e. Corticoids as adjuvants to improve response to cate-
cholamines.
f. Evaluate the use of other alternative therapies, such as
hydroxocobalamin and ascorbic acid.
Funding
No external funding.
Conflicts of interest
None declared.
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