STATE OF THE ART

Vasoplegia During Cardiac

Surgery: Current Concepts and Management
Gregory W. Fischer, MD, and Mathew A. Levin, MD

Vasoplegic syndrome (VS) is a recognized and relatively common complication of cardiopulmo-

nary bypass (CPB), appearing with an incidence ranging between 5% and 25%. It is character-
ized by significant hypotension, high or normal cardiac outputs and low systemic vascular
resistance (SVR), and increased requirements for fluids and vasopressors during or after CPB.
Patients developing VS are at increased risk for death and other major complications following
cardiac surgery. This review will focus on the pathophysiology and contemporary strategies of
treating VS encountered after CPB.
Semin Thoracic Surg 22:140-144 © 2010 Elsevier Inc. All rights reserved.

Keywords: vasoplegia, cardiac surgery, cardiopulmonary bypass

Organ homeostasis is maintained by providing ade-
quate systemic blood flow and perfusion pressure.
This system depends upon a balance of vasoconstric-
tor and vasodilator influences. Under pathologic
conditions the influence of one of the antagonists can
outweigh the other, leading to perfusion compro-
mise at the end organ level. When blood flow falls
below a critical level resulting in inadequate oxygen
delivery to peripheral tissue, the situation is referred
to as “shock.” One form of shock that is encountered
under conditions of extreme vasodilation is referred
to as “vasoplegia.” In this circumstance, the organism
is incapable of achieving adequate perfusion pres-
sure because of a lack of vascular tone.
Vasoplegic syndrome (VS) is a recognized and rel-
atively common complication of cardiopulmonary
bypass (CPB), appearing with an incidence ranging
between 5% and 25%.1-3 It is characterized by sig-
nificant hypotension, high or normal cardiac out-
puts and low systemic vascular resistance (SVR), and
increased requirements for fluids and vasopressors
during or after CPB.4
PATHOPHYSIOLOGY AND RISK
FACTORS ASSOCIATED WITH VS
VS is multifactorial, resulting on the one hand
from pathologic activation of several vasodilator
Department of Anesthesiology, Mount Sinai Medical Cen-
ter, New York, New York.
Dr. Fischer reports receiving fees from Philips Medical.
Address reprint requests to Gregory W. Fischer, MD, De-
partment of Anesthesiology, Mount Sinai Medical Center,
One Gustave L. Levy Place, Box 1010, New York, NY
10029. E-mail: Gregory.fischer@mountsinai.org
mechanisms and on the other from resistance to va-
sopressors. These pathways are dynamic and an inter-
action between the two is commonly seen. Activation
of adenosine triphosphate-sensitive potassium chan-
nels (KATP channels) in the plasma membrane of vas-
cular smooth muscle, activation of the inducible
form of nitric oxide (NO) synthase, and deficiency of
the hormone vasopressin are the prime culprits re-
sponsible for derailment of vascular tone.
Physiological vasoconstrictors, such as norepi-
nephrine and angiotensin II, bind to and activate
receptors on the surface of vascular smooth-muscle
cells. These receptors then activate second messen-
ger systems, which in turn increase intracellular cal-
cium concentrations by opening membrane-bound
calcium channels. A complex formed between cal-
cium and calmodulin within the cytosol leads to the
activation of kinases, which in turn phosphorylate
the light chain of myosin. This phosphorylation of
myosin allows actin and myosin to interact and ulti-
mately contracts the muscle. Vasodilators, such as
atrial natriuretic peptide and NO, lead to the de-
phosphorylization of myosin thus preventing muscle
contraction.5
The etiology of VS is not completely elucidated. In
a recent review from our institution we examined the
incidence and risk factors associated with the devel-
opment of VS in patients undergoing cardiac surgery
with CPB.3 Two thousand eight hundred twenty-
three cardiac surgery cases were retrospectively
studied; we found an incidence of VS of 20.4%. Pa-
tient-specific risk factors for the development of VS
included the preoperative use of angiotensin-convert-
ing enzyme (ACE) inhibitors or beta-blockers, which

140 1043-0679/$-see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1053/j.semtcvs.2010.09.007

Figure 1. Illustration of AAC calculation. The AAC is significantly associated with the risk of developing
post-CPB vasoplegia. AAC, area above the curve; CPB, cardiopulmonary bypass; MAP, mean arterial
pressure; MMAP, median mean arterial pressure. (Reprinted with permission from Levin et al.3)
increased the relative risk for vasoplegia by 1.31 and
1.37, respectively. In addition, the investigators found
that patients with a higher additive euroSCORE or
the presence of pre-CPB hemodynamic instability
(defined as a requirement for vasoactive medica-
tions) had an increased risk for developing post-CPB
vasoplegia (odds ratio [OR] 1.15 per 1 point increase
in euroSCORE, and 3.59, respectively).
A patient independent risk factor was the type of
surgery being performed. Compared with coronary
artery bypass grafting, valve procedures and surgery
specifically intended for the treatment of heart fail-
ure were associated with an increased risk (OR 1.52
and 2.04, respectively); however, aortic surgery and
reoperations were protective against the develop-
ment of VS (OR for both, 0.48). The mechanism of
protection for these two groups remains speculative.
Perhaps the protective effect of hypothermia could
have played an important role, because hypothermic
management reduced the risk of VS (OR 1.11/per
one degree celsius increase in temperature while on
CPB).
The main focus of the aforementioned review,
however, was to explore the relationship between
the initial hemodynamic reaction to the commence-
ment of CPB and the likelihood of developing post-
CPB vasoplegia. The authors found that the severity
and duration of the decline in mean arterial pressure
(MAP) immediately after beginning CPB, as quanti-
fied by the area above the MAP curve (AAC), can be
used to identify patients likely to experience post-
CPB vasoplegia (Fig. 1). In addition to the initial
hemodynamic picture seen on CPB, the duration of
CPB significantly increased the risk of VS: for each
additional 30-minute interval on CPB, the risk of
vasoplegia increased by 38% (OR 1.38).
PROGNOSIS
VS carries a poor prognosis. Particularly, norepi-
nephrine refractory VS is associated with an increase
in morbidity and mortality.6,7 Catecholamine-refrac-
tory VS lasting for more than 36-48 hours has a
mortality rate as high as 25%.8 These results from
Seminars in Thoracic and Cardiovascular Surgery ● Volume 22, Number 2
VASOPLEGIA DURING CARDIAC SURGERY
other centers were confirmed by our data. Among
patients who developed post-CPB vasoplegia, 308 of
537 (57.4%) had a bad outcome (defined as either
death or a hospital length of stay ⬎10 days) versus
only 481 of 2099 (22.9%) of the nonvasoplegic pa-
tients.
TREATMENT
Standard of care for the treatment of intraopera-
tive or postoperative VS has been the administration
of vasoactive infusions like phenylephrine, norepi-
nephrine or vasopressin (Table 1). Although these
agents usually suffice to restore systemic hemody-
namics, vascular tone can be refractory to conven-
tional treatment in some instances.9 Furthermore,
high-dose vasoconstrictor therapy has serious side
effects, which can include the development of pe-
ripheral ischemia of the upper and lower extremities
or mesenteric ischemia, which can progress to the
development of mucosal injury, tissue necrosis, and
metabolic acidosis. Low-dose vasopressin, ⬍0.04 U
min⫺1 can be beneficial because vasoplegia has been
associated with a reduction in circulating endoge-
nous vasopressin levels.10 Morales et al showed sup-
port for the vasopressin hypothesis by demonstrat-
ing that compared to controls, patients given a
prophylactic vasopressin infusion (0.03 U/min)
starting 20 minutes prior to the onset of CPB re-
quired significantly less post-CPB vasopressor sup-
port.11 Greater dosages of vasopressin, ⬎0.04 U
min⫺1 have not been shown to be beneficial when
compared with norepinephrine alone, most likely
because of poor microcirculatory perfusion.12
An interesting alternative that has emerged as an
option for the treatment of vasopressor-resistant va-
soplegia is methylene blue. Classically, employed as
a medication for the treatment of methemoglobin-
emia as well as a dye in various medical procedures,
methylene blue blocks accumulation of cyclic
guanosine monophosphate (cGMP) by inhibiting the
enzyme guanylate through binding to the iron heme-
moiety.4,13,14 It competes directly with NO in its abil-
ity to activate this key enzyme, which in turn is re-
141
VASOPLEGIA DURING CARDIAC SURGERY

Table 1. List of Common Vasoconstrictors Used in VS

Agent Action/Receptor Site Dosage Side Effects
Phenylephrine ␣1-agonist 40-100 ␮g bolus Peripheral vasoconstriction, no
0.5-10 ␮g/min inotropic action
infusion
Norepinephrine ␣1, ␣2, and ␤1- 4-10 ␮g bolus Potent vasoconstrictor with potential
agonist 10-300 ng/kg/min gut ischemia, increases pulmonary
vascular resistancy, arrhythmias
Vasopressin V1, independent of 1-6 U/h infusion Mesenteric ischemia at doses
adrenergic ⬎6 U/h
receptors
Methylene blue Inhibition of guanylate 2 mg/kg bolus Hemolytic anemia in patients with
cyclase 0.5 mg/kg/h for 6 h G6PD deficiency
Greenish-blue coloration of urine
and skin
PVR, pulmonary vascular resistancy; G6PD, Glucose-6-phosphate dehydrogenase; VS, vasoplegic syndrome.

sponsible for producing cGMP. cGMP in turn is part
of the second messenger system that activates ki-
nases, which lead to the dephosphorylization of my-
osin and smooth muscle relaxation. Thus adminis-
tration of methylene blue results in reduced
responsiveness of vessels to cGMP dependent vaso-
dilators like NO and carbon monoxide.
Studies have shown that NO is not the only mech-
anism that can activate soluble guanylate cyclase.
Interleukins and oxygen free radicals can additionally
activate guanylate cyclase leading to vascular hypo-re-
activity in the absence of NO.15,16 Thus, methylene
blue’s unique ability to interact and inhibit soluble
guanylate cyclase, as the rate-limiting enzyme in the
cascade, may explain its superior ability to restore vas-
cular tone even when NO is not present.17
To date most literature has been published de-
scribing the post-CPB use of methylene blue as a
therapeutic intervention of last resort to reverse va-
soplegia. Several groups have reported that the post-
CPB administration of a single dose of methylene blue
in VS can restore SVR.1,2,4 The use of methylene blue
not only enabled a significant reduction in the dosage of
vasopressors required to maintain stabile hemodynam-
ics, it also reduced the time for which patients were
vasoconstrictor dependent. In a study of 638 pa-
tients, the methylene blue treatment group showed a
reduction in mortality of those patients fulfilling va-
soplegia criteria, compared with the placebo group
(0% vs 21.4%).2 Similar results were published by
Leyh.18 Kofidis et al19 successfully used methylene
blue for treatment of vasoplegia in a patient after a
heart transplant. Methylene blue has been adminis-
tered in most studies as a single dose (1.5-2 mg/kg)
to treat postoperative vasoplegia. Other authors have
reported using a maintenance infusion after the ap-
plication of the bolus.20
The literature also supports the use of methylene
blue during the intraoperative period. Grayling and
Deakin21 describe the use of methylene blue added
to the CPB circuit as prophylactic treatment of septic
endocarditis. Sparicio et al22 reported the periopera-
tive management of 2 patients who overdosed on
lithium. The hemodynamic picture in both patients
improved dramatically after receiving methylene
blue. Evora et al19 administered methylene blue to a
patient after an anaphylactic reaction to protamine.
Once again, the hemodynamic picture could only be
normalized after the administration of methylene
blue.
Recently, reports have started to show the benefit
of prophylactic use of methylene blue. Ozal et al23
conducted a randomized controlled study of 100
patients undergoing coronary artery bypass surgery
coronary artery bypass grafting who were at high risk
for VS (preoperative ACE inhibitors, calcium block-
ers, and heparin). Although it was impossible to
blind the clinicians to the group that received meth-
ylene blue, the treatment group showed a higher
SVR and required less inotropic support during sur-
gery. Remarkable was the fact that none of the pa-
tients in the treatment group developed vasoplegia,
whereas 26% (13/50) of the patients in the control
group became vasoplegic. Six of the 13 vasoplegic
patients were initially resistant to norepinephrine.
Four eventually improved whereas two continued to
deteriorate and died of multiorgan failure despite
late treatment with methylene blue. The result of this
study seems to suggest that early use of methylene
blue is preferred and that methylene blue is ineffec-
tive if used after multiorgan failure has already de-
veloped.
In another randomized controlled trial, Maslow
et al24 studied 30 patients who were at high risk of

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 VASOPLEGIA DURING CARDIAC SURGERY

developing vasoplegia (patients taking ACE inhibi-
tors within 24 hours before elective heart surgery
requiring CPB). They modified the protocol of pro-
phylactic use of methylene blue by initiating meth-
ylene blue administration after the onset of CPB. The
result of this study demonstrated that this treatment
protocol improved patient hemodynamics, in asso-
ciation with lower serum lactate levels. However, the
timing of methylene blue administration in this study,
which was initiated after an initial period of stabiliza-
tion on CPB (5 min), must be questioned, especially in
light of the data presented by Levin et al.3 Because of the
association of AAC and the risk of developing vasople-
gia in the post CPB setting, it would seem more logical
to administer methylene blue before the commence-
ment of CPB to prevent the hypotensive insult brought
on by CPB. Moreover, the study was underpowered
preventing it from evaluating the effects of the protocol
on patient outcomes.
One downside to administering methylene blue dur-
ing the pre-CPB period is the fact that a safety hazard for
patients is created because methylene blue administra-
tion interferes with pulse oximetry,25 leading to falsely
low readings. However, if additional modalities, such
as cerebral oximetry are used to monitor tissue oxygen-
ation levels, this downside may be mitigated.
FUTURE DIRECTIONS
Understanding the etiology of VS is the key to devel-
oping robust models that can preoperatively predict the
likelihood of patients becoming vasoplegic in the post-
CPB setting. Once such models have been created pa-
tients at high-risk for developing vasoplegia can be
identified, and the use of methylene blue can be prop-
erly evaluated using randomized controlled trials.
The development of intraoperative decision support
systems will further enable the precise identification of
patients at risk of VS. Such systems will analyze physi-
ological data in near-real time and provide notification
to the clinician about developing higher order trends
that are not immediately apparent on simple inspec-
tion. For example, the algorithm to calculate an AAC
and the subsequent statistical model presented by
Levin et al were developed using retrospective, histor-
ical data. Such models can be taken and adapted to
calculate an AAC “on the fly” within minutes of a pa-
tient going on CPB. If the AAC begins to become very
large, the system can send notifications (email, pager,
on-screen dialog box, etc.) to the perfusionist and an-
esthesiologist, suggesting early vasopressor support.
The clinician can then intervene early with the goal of
preventing post-CPB vasoplegia from developing. This
type of immediate feedback and targeted intervention is
a form of “personalized” medicine that will further im-
prove patient outcomes.
CONCLUSIONS
VS is a recognized and relatively common compli-
cation of CPB. Despite an incidence of 20%, associ-
ated with an increased likelihood of adverse out-
come when present, there is only limited data found
in the literature to guide clinical management. By the
use of large cohort studies with the aim of identifying
patients at highest risk for vasoplegia, we hope that
tailored protocols will be developed, which in turn
will result in improved outcomes.

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