Journal of

Clinical Medicine

Review
Vasoplegic Syndrome after Cardiopulmonary Bypass in
Cardiovascular Surgery: Pathophysiology and Management in
Critical Care
Zied Ltaief 1, *, Nawfel Ben-Hamouda 1 , Valentina Rancati 2 , Ziyad Gunga 3 , Carlo Marcucci 2 , Matthias Kirsch 3
and Lucas Liaudet 1

1 Service of Adult Intensive Care, Lausanne University Hospital and University of Lausanne,
1010 Lausanne, Switzerland
2 Service of Anesthesiology, Lausanne University Hospital and University of Lausanne,
1010 Lausanne, Switzerland
3 Service of Cardiac Surgery, Lausanne University Hospital and University of Lausanne,
1010 Lausanne, Switzerland
* Correspondence: [email protected]

Abstract: Vasoplegic syndrome (VS) is a common complication following cardiovascular surgery with
cardiopulmonary bypass (CPB), and its incidence varies from 5 to 44%. It is defined as a distributive
form of shock due to a significant drop in vascular resistance after CPB. Risk factors of VS include
heart failure with low ejection fraction, renal failure, pre-operative use of angiotensin-converting
enzyme inhibitors, prolonged aortic cross-clamp and left ventricular assist device surgery. The
pathophysiology of VS after CPB is multi-factorial. Surgical trauma, exposure to the elements of the
CPB circuit and ischemia-reperfusion promote a systemic inflammatory response with the release of
cytokines (IL-1β, IL-6, IL-8, and TNF-α) with vasodilating properties, both direct and indirect through
the expression of inducible nitric oxide (NO) synthase. The resulting increase in NO production
Citation: Ltaief, Z.; Ben-Hamouda,
N.; Rancati, V.; Gunga, Z.; Marcucci,
fosters a decrease in vascular resistance and a reduced responsiveness to vasopressor agents. Further
C.; Kirsch, M.; Liaudet, L. Vasoplegic mechanisms of vasodilation include the lowering of plasma vasopressin, the desensitization of
Syndrome after Cardiopulmonary adrenergic receptors, and the activation of ATP-dependent potassium (KATP ) channels. Patients
Bypass in Cardiovascular Surgery: developing VS experience more complications and have increased mortality. Management includes
Pathophysiology and Management in primarily fluid resuscitation and conventional vasopressors (catecholamines and vasopressin), while
Critical Care. J. Clin. Med. 2022, 11, alternative vasopressors (angiotensin 2, methylene blue, hydroxocobalamin) and anti-inflammatory
6407. https://doi.org/10.3390/ strategies (corticosteroids) may be used as a rescue therapy in deteriorating patients, albeit with
jcm11216407 insufficient evidence to provide any strong recommendation. In this review, we present an update of
Academic Editor: Matthias Thielmann the pathophysiological mechanisms of vasoplegic syndrome complicating CPB and discuss available
therapeutic options.
Received: 27 September 2022
Accepted: 27 October 2022
Keywords: vasoplegic syndrome; cardio-pulmonary bypass; cardiac surgery; vasopressin;
Published: 29 October 2022
angiotensin 2; methylene blue; hydroxocobalamin; nitric oxide
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations. 1. Introduction
Vasoplegic syndrome (VS) complicating cardiopulmonary bypass (CPB) is a frequently
described syndrome with many used denominations: low vascular resistance syndrome,
Copyright: © 2022 by the authors.
catecholamine refractory vasoplegia, cardiac vasoplegia syndrome, inflammatory response
Licensee MDPI, Basel, Switzerland. to bypass, systemic inflammatory response syndrome (SIRS) after cardiac surgery, post
This article is an open access article perfusion syndrome and vasoplegic shock post-bypass [1–6]. The clinical pattern is that of a
distributed under the terms and distributive form of circulatory shock developing in the first 24 h after CPB [7], characterized
conditions of the Creative Commons by hypotension (mean arterial pressure < 65 mmHg resistant to fluid challenge), systemic
Attribution (CC BY) license (https:// vascular resistance < 800 dynes s/cm5 and a cardiac index > than 2.2 l/min/m2 [1,8].
creativecommons.org/licenses/by/ The incidence of VS after CPB varies from 5 to 44% [1,8] and it accounts for 4.6% of
4.0/). all forms of circulatory shock [9]. A higher incidence has been reported in patients with

J. Clin. Med. 2022, 11, 6407. https://doi.org/10.3390/jcm11216407 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022, 11, 6407 2 of 19

low preoperative left ventricular (LV) ejection fraction (EF) and in those undergoing LV
assist device surgery [10,11]. Several predisposing factors have been identified, such as
advanced age, prolonged aortic cross-clamp and CPB time, as well as the pre-operative
use of angiotensin-converting enzyme inhibitors (ACEI) and diuretics [8,10,12]. Patients
experiencing VS display an increased incidence of postoperative complications and, con-
sequently, a longer intensive care unit (ICU) stay [8], as well as greater post-operative
mortality (5.6–15%) [2,13] than in the overall cardiac surgery population (3.4–6.2%) [14,15].
Table 1 summarizes the main clinical characteristics, pathophysiological mechanisms, and
principles of management of VS after CPB.

Table 1. Vasoplegic shock after cardiopulmonary bypass—main characteristics.

Distributive Form of Circulatory Shock ≤ 24 h after CPB Initiation, Characterized by:

(1) MAP < 65 mmHg resistant to fluid challenge
Definition
(2) SVR < 800 dynes s/cm5
(3) CI > 2.2 L/min/m2 *
Predisposing factors
Patient-related factors Advanced age; anemia; low LVEF; renal failure
Pre-/peri-operative drugs Diuretics; sympatho-adrenergic inotropes; ACEI (controversial)
Operative factors CPB/aortic cross clamping time; redo surgery; combined surgery; LVAD surgery; HTx
Pathophysiology Systemic inflammatory response triggered by:
(1) Exposure of blood to the artificial surfaces of the extra-corporeal circuit;
(2) Surgical trauma;
(3) Ischemia/ reperfusion injury;
Initiating events (4) Oxidative stress;
(5) Release of endotoxin from the gut;
(6) Hemolysis;
(7) Reinfusion of cell saver blood
(1) Desensitization of adrenergic receptors;
(2) Increased NO biosynthesis;
(3) Low plasma vasopressin;
Mechanisms of pathological vasodilation (4) VSMC hyperpolarization due to opening of KATP channels;
(5) RAS dysfunction with low Ang2 (?);
(6) Excess H2 S generation (?);
(7) Endothelial glycocalyx alteration (?).

(1) More frequent postoperative bleeding;

Outcome (2) Increased incidence of organ dysfunction: renal, liver and respiratory failure;
(3) Prolonged mechanical ventilation and length of ICU/hospital stay;
(4) Higher mortality.

I. Ensure adequate cardiac preload and cardiac output

(1) Evaluate tissue perfusion by capillary refill time, mottling score, arterial lactate,
VA-PCO2 gap;
(2) Use dynamic indices of volume responsiveness.
Management II. Vasoactive drugs
(1) Conventional Vasopressors **: Norepinephrine; Vasopressin;
(2) Non-conventional Vasopressors *** (in refractory VS): Methylene Blue;
Hydroxocobalamin; Angiotensin 2.
III. Low doses of hydrocortisone ****
Abbreviations: ACEI: Angiotensin-Converting Enzyme Inhibitors; Ang 2: Angiotensin 2; CI: Cardiac Index; CPB:
CardioPulmonary Bypass; H2S: Hydrogen Sulfide; HTx: Heart Transplantation; ICU: Intensive Care Unit; MAP:
Mean Arterial Pressure; LVAD: Left Ventricular Assist Device; LVEF: Left Ventricle Ejection Fraction; NO: Nitric
Oxide; RAS: Renin−Angiotensin System; SVR: Systemic Vascular Resistance; VA−PCO2 gap: Venous to Arterial
Difference in the Partial Pressure of Carbon Dioxide; VS: Vasoplegic Syndrome; VSMC: Vascular Smooth Muscle
Cell. *: In some patients with severe cardiac dysfunction, vasoplegia may be present in spite of a low cardiac
output (CI < 2.2 L/min/m2 ). These patients therefore do not fulfill the complete hemodynamic criteria of pure
VS, and should be considered as presenting a mixed form of shock. **: Strong recommendation ***: Insufficient
evidence; risk of harm incompletely documented; can be used on a case−by−case basis as a rescue therapy; need
for additional adequately powered randomized controlled trials (RCTs). ****: Acts via anti−inflammatory actions
+ increased vascular responsiveness to vasoconstrictors; accelerates resolution of shock in sepsis, controversial
effects on mortality; precise role in VS post−CPB presently undefined; may be used as adjunctive treatment to
conventional vasopressors in refractory cases; need for additional adequately powered RCTs.
J. Clin. Med. 2022, 11, 6407 3 of 19

2. Pathophysiology of Vasoplegic Syndrome after CPB (Figure 2.9)

2.1. Physiology of Vascular Smooth Muscle Cell Contraction
The phosphorylation of the regulatory Myosin Light Chain (MLC) is the cornerstone
of smooth muscle contraction. Vasoconstricting agents such as norepinephrine, angiotensin
2 and vasopressin activate cell surface G-protein-coupled receptors (GPCRs) to induce an
increase in intracellular Ca++ concentration in vascular smooth muscle cells (VSMCs). In
turn, Ca++ binds to calmodulin, forming a complex activating MLC Kinase to promote
MLC phosphorylation, with subsequent actin-myosin interaction and smooth muscle
contraction [16]. In contrast, vasodilators such as nitric oxide (NO) and natriuretic peptides
trigger a guanylyl cyclase-dependent increase in cyclic guanosine monophosphate (cGMP),
which activates myosin phosphatase to dephoshorylate MLC, thereby preventing smooth
muscle contraction [17,18]. CPB promotes a series of pathophysiological mechanisms
concurring to alter smooth muscle Ca++ signaling and MLC phosphorylation, which may
ultimately result in a state of vasoplegia, characterized by pathological vasodilation and
reduced responsiveness to vasoconstrictors.

2.2. Inflammatory Pathways Triggered by CPB

Several mechanisms triggered at the time of CPB, and amplified upon its discontinua-
tion, concur to trigger a systemic inflammatory response: the exposure of blood components
to the artificial surfaces of the extracorporeal circuit, surgical trauma, organ ischemia, the
release of endotoxin from the gut into the circulation, and hemolysis with liberation of
free hemoglobin. Altogether, these mechanisms promote the activation of the complement
cascade and the expression of pro-inflammatory mediators, such as interleukin-1 beta
(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) [6,19,20]. IL-6 is no-
tably a potent inhibitor of vascular contraction by increasing the synthesis of cyclic AMP,
which promotes vasodilation by reducing myoplasmic [Ca++ ] [21,22]. Accordingly, higher
circulating levels of IL-6 have been associated with an increased incidence of VS and a
higher need for vasopressors after CPB [23,24]. Longer CPB and aortic cross-clamping
durations, combined surgery and redo intervention all predispose to a more intense inflam-
matory response and therefore represent independent risk factors for the development of
VS [25]. Following the discontinuation of CPB, systemic reperfusion promotes the genera-
tion of oxygen-free radicals and the amplification of the initial inflammation. Moreover, the
reinfusion of cell saver blood containing hemolyzed red blood cells, activated platelets and
denatured proteins, may also contribute to this response [4,26]. Ultimately, such systemic
inflammation engages a series of biological processes precipitating the loss of vascular tone,
as detailed below.

2.3. Adrenoreceptor Desensitization

Inflammatory cytokines such as IL-1β, IL-6 and TNFα impair adrenoreceptor-dependent
signaling by two mechanisms. The first one is related to a reduced expression of vascular
α1-adrenoreceptors, consecutive to suppressed promoter activity at the level of gene tran-
scription [27]. The second and most important mechanism relies in the desensitization of
the receptors, triggered by the excessive release of catecholamines in response to barore-
ceptor and cytokine-dependent stimulation of the central sympathetic system. In turn,
sustained adrenergic stimulation induces the phosphorylation of the G-protein coupled
adrenoreceptor through the activation of GPCR kinases, inhibiting catecholamine binding
and downstream signaling [26,28].

2.4. Increased Nitric Oxide Biosynthesis

Inflammatory cytokines stimulate the expression of the inducible isoform of NO
synthase (iNOS) through the activation of nuclear factor kappa B (NF-κB) [29]. In contrast
to the low amounts of NO released by the constitutive, calcium-dependent NOS isoforms,
the calcium-independent iNOS has the ability to produce copious quantities of NO over
prolonged periods of time [29]. Elevated iNOS expression has been reported in lung tissue
J. Clin. Med. 2022, 11, 6407 4 of 19

after CPB [30], and increased generation of NO has been shown to be proportional to the
duration of CPB [31].
Several mechanisms account for the vasodilatory properties of NO. First and most
importantly, NO activates soluble guanylyl cyclase in VSMCs to promote the formation of
cyclic GMP, leading to MLC dephosphorylation [29]. Secondly, NO (via cGMP) activates
adenosine triphosphate-sensitive potassium channels (KATP ) in VSMCs, causing K+ efflux
and membrane hyperpolarization. This results in the closure of voltage-activated calcium
(Ca++ ) channels, the reduction in cytosolic Ca++ and vasodilation [32]. These effects are
amplified by the ability of NO-cGMP to further promote K+ efflux by activating the vascular
calcium-activated potassium channels (KCa++ ) [32]. An additional mechanism of NO-
induced vasodilation is the generation of peroxynitrite, a strong oxidant and nitrating
species formed from the rapid reaction of NO with the superoxide anion radical (O2 − ).
Peroxynitrite contributes to vasoplegia by impairing bioenergetics in VSMCs, by activating
matrix metalloproteinases, and by inativating catecholamines and their receptors [29].

2.5. Relative Deficiency of Vasopressin

Inflammatory cytokines and sustained baroreceptor stimulation are responsible for
an overactivation of the central sympathetic system and the hypothalamo-pituitary axis,
with subsequent release of high levels of norepinephrine, epinephrine, cortisol, and va-
sopressin [26]. Persistent shock and hypotension result in the progressive decline in the
blood levels of these vasoactive mediators, a phenomenon particularly significant in the
case of vasopressin [26]. Circulating vasopressin levels during CPB have been measured
by Colson et al. in sixty-four consecutive patients. Patients developing VS displayed a
significant drop of plasma vasopressin 8 h after CPB in comparison to non-VS patients
(16 vs. 42 pmol/l, p = 0.01) [33]. Comparable results have been reported in patients with
septic shock [34,35]. In turn, such decrease in vasopressin abrogates its vasopressor effects,
which depend on the vascular V1 receptor (V1R), whose activation results in a protein
kinase C (PKC)-dependent increase in intracellular calcium, both directly via Ca++ channel
opening, and indirectly via KATP channel inhibition [36]. In addition, V1R-dependent PKC
activation may inhibit MLC phosphatase, reduce iNOS expression and NO formation in
response to inflammatory cytokines, promote the release of vasoconstrictors by endothe-
lial cells (endothelin-1) and platelets (thromboxane A2), and ultimately can increase the
vascular sensitivity to catecholamines [37–40].

2.6. Activation of KATP Channels and Membrane Hyperpolarization in VSMCs

The regulation of membrane potential in VSMCs depends on the activity of several
types of K+ channels whose opening promotes K+ efflux and membrane hyperpolarization,
resulting in the inhibition of Ca++ -channel-dependent cellular influx of Ca++ and subse-
quent vasodilation. These channels include voltage dependent (Kv), Ca++ activated (KCa),
inward rectifier (Kir) and ATP-sensitive (KATP ) K+ channels [41]. Among these channels,
the activation of KATP channel has been closely linked to the development of pathological
vasodilation and the induction of hypotension in various forms of distributive shock [17].
Several mechanisms may account for the activation of KATP channel in VS associated with
CPB, including NO release, vasopressin deficiency, hypoxia, acidosis and an increase in the
generation of hydrogen sulfide (see below) [17,36,42–45].

2.7. Dysfunction of the Renin-Angiotensin System

Angiotensinogen, an inactive peptide produced by the liver, is cleaved by renin into
angiotensin 1 (Ang1), and then to angiotensin 2 (Ang2) by the action of type 1 angiotensin-
converting enzyme (ACE 1) in the lung endothelium. In turn, Ang2 targets the vascular AT1
receptor, resulting in increased cytosolic Ca++ and vasoconstriction. Under conditions of
impaired ACE 1 activity (pulmonary dysfunction), Ang2 formation is prevented, and Ang1
is converted into the vasodilating derivative Ang1–7 by the type 2 ACE (ACE 2) [46,47]. Such
scenario might develop during the pulmonary exclusion associated with CPB, precipitating
J. Clin. Med. 2022, 11, 6407 5 of 19

vasoplegia by reducing ACE 1 activity and Ang2 formation, while increasing Ang1 and
Ang1–7 . In addition, this process may be amplified by the enhanced secretion of renin,
triggered in response to low Ang2 and reduced blood pressure, which further increases
Ang1 formation (“high renin shock”) [47].

2.8. Endothelial Glycocalyx Alteration

The glycocalyx is a complex layer of glycosaminoglycans and proteoglycans coating
the endothelial cell surface, with important components comprising heparan sulfate and
syndecan-1. Heparan sulfate plays an important role in the regulation of vascular tone by
modulating shear-stress dependent NO production, whereas syndecan-1 has been associ-
ated with anti-inflammatory effects by downregulating leukocyte adhesion and activation
at the surface of the endothelium [48,49]. Circumstantial evidence indicates that CPB may
induce damage to the glycocalyx, as reported in a pilot study by Boer et al., who found
that glycocalyx thickness was significantly reduced after the initiation of CPB, a change
which persisted after weaning and was associated with microcirculatory impairment [50].
Furthermore, Abou-Arab et al. reported that the plasma levels of syndecan-1 increased
after CPB, consistent with glycocalyx shedding. Interestingly, patients developing VS
had reduced baseline plasma syndecan-1 and a lesser increase after CPB, suggesting that
altered glycocalyx structure with reduced syndecan-1 might predispose to endothelial
inflammation and vasodilation after CPB [51].

2.9. Possible Role of an Excess Production of Hydrogen Sulfide

Hydrogen sulfide (H2 S) is a gaseous transmitter formed in the vascular system from
the metabolism of cysteine and homocysteine by the enzymes cystathionine-gamma-
lyase (CSE), cystathionine-beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase
(3-MST) [52]. In blood vessels, H2 S plays several homeostatic functions, notably acting
as a vasodilator. This effect is related, on one hand, to the activation of KATP channels
leading to membrane hyperpolarization [53], and on the other hand, to the enhancement,
via multiple mechanisms, of vascular NO signaling [52]. An increased formation of H2 S has
been demonstrated in various animal models of septic shock, which might participate to
the development of pathological vasodilation in such conditions [54]. Although not directly
demonstrated in the setting of CPB, one can assume that the prevailing inflammatory con-
ditions might enhance the synthesis of H2 S as reported in sepsis. This would be consistent
J. Clin. Med. 2022, 11, x FOR PEER REVIEW
with the notion that hydroxocobalamin, which can bind H2 S and4inhibitof 21 its effects, can
increase blood pressure in patients with severe VS post-CPB, as discussed later [55,56].

Figure 1. Pathophysiological mechanism of vasoplegia after cardio-pulmonary bypass. Under nor-

Figure 1. Pathophysiological mechanism of vasoplegia after cardio-pulmonary bypass. Under nor-
mal conditions, norepinephrine (NE), angiotensin 2 (Ang2) and vasopressin (VP) activate their re-
mal conditions,
spective receptors norepinephrine
in vascular smooth(NE), angiotensin
muscle cells, namely2the
(Ang2) and vasopressin
α1-adrenoreceptor, (VP)
the Ang2 activate
type I their respective
receptor (AT1R) and the vasopressin V1 receptor, to promote an increase in cytosolic Ca++, leading
to Myosin Light Chain (MLC) phosphorylation, actin-myosin interaction and smooth muscle con-
traction. In addition, vasopressin exerts indirect vasoconstrictor actions by inhibiting two physio-
logical mechanisms of vasodilation, including NO production and the opening of ATP-dependent
potassium channels (KATP). Following cardiopulmonary bypass (CPB), cytokine release and sus-
tained baroreceptor stimulation foster a down-regulation and desensitization of adrenergic recep-
J. Clin. Med. 2022, 11, 6407 6 of 19

receptors in vascular smooth muscle cells, namely the α1-adrenoreceptor, the Ang2 type I receptor
(AT1R) and the vasopressin V1 receptor, to promote an increase in cytosolic Ca++ , leading to Myosin
Light Chain (MLC) phosphorylation, actin-myosin interaction and smooth muscle contraction. In ad-
dition, vasopressin exerts indirect vasoconstrictor actions by inhibiting two physiological mechanisms
of vasodilation, including NO production and the opening of ATP-dependent potassium channels
(KATP ). Following cardiopulmonary bypass (CPB), cytokine release and sustained baroreceptor
stimulation foster a down-regulation and desensitization of adrenergic receptors, as well as a reduc-
tion in plasma VP, reducing catecholamine and vasopressin-mediated vasoconstriction. In addition,
inflammatory cytokines stimulate the expression of the inducible isoform of NO synthase (iNOS),
leading to excessive NO production. NO activates soluble guanylyl cyclase (GC), generating cyclic
GMP (cGMP), which dephosphorylates MLC with subsequent vasodilation. Moreover, NO activates
KATP channels, causing K+ efflux, membrane hyperpolarization, and the closure of Ca++ channels,
thereby reduce cytosolic Ca++ . KATP channels opening and membrane hyperpolarization can also
result from additional mechanisms, as indicated (*). NO further reacts with the superoxide anion
radical (O2 − ) to form peroxynitrite (PN), which contributes to vasodilation via multiple processes, as
indicated (**). CPB can also trigger alterations of the glycocalyx (favoring endothelial dysfunction
and vascular inflammation), promote the production of hydrogen sulfide (H2 S) with vasodilating
properties, and reduce Ang2 formation by type I angiotensin-converting enzyme (ACE 1). Solid lines
indicate activation; dashed lines indicate inhibition.

3. Predisposing Factors of Post-CPB Vasoplegic Syndrome

3.1. Patient-Related Factors
Several pre-operative conditions have been associated with an increased incidence of
VS post-CPB, including advanced age, recent myocardial infarction, anemia, and higher
perioperative risk score (Euro score) [25,57,58]. Heart failure with reduced ejection fraction
is of particular concern, as indicated by an increased incidence of VS up to 74% in patients
with poor LV function (EF < 37%) exposed to prolonged CPB duration [23]. In a prospective
cohort of 145 cardiac surgery patients, Argenziano et al. reported that an EF < 35% was
an independent risk factor for post-CPB VS, with a relative risk of 9.1 [10]. Additionally, a
low EF (<40%) has been correlated with the development of severe systemic inflammation
after CPB, as diagnosed by circulating levels of IL-6 > 1000 pg/mL [10,24]. In line with
these notions, patients undergoing heart transplantation [59] or LVAD surgery [60] are at
increased risk of VS. Pre-operative renal failure is another important risk factor, possibly
due to higher levels of pro-inflammatory cytokines and vascular endothelial dysfunction
in these patients [61]. In a meta-analysis including > 30,000 patients from 10 studies, Dayan
et al. reported that pre-operative renal failure was indeed the most significant independent
risk factor for VS, with an odds ratio of 1.47 (95% CI 1.17–1.86) [25].

3.2. Pre- and Peri-Operative Drug Therapies

The peri-operative use of ACE inhibitors (ACEI) has been reported as an independent
risk factor for VS after CPB in several observational studies [62], a concept substantiated by
the results of a recent meta-analysis of 10 observational case–control studies [63]. Although
these findings have led to the frequent practice to withdraw ACEI prior to cardiac surgery,
this issue remains highly controversial, as no association between ACEI and VS was
found in two randomized (but underpowered) controlled trials (RCTs) [64,65], and in the
previously mentioned meta-analysis by Dayan et al. [25]. The latter study pointed out the
large heterogeneity between studies (type and dose of ACEI used, definition of post-CPB
VS), making a clear statement impossible. Therefore, the precise link between ACEI and
VS after CPB remains uncertain, which underscores the need for large prospective RCTs to
address this issue.
The peri-operative use of diuretics is a further risk factor to consider, as empha-
sized in a retrospective analysis on 1992 patients showing an independent association
J. Clin. Med. 2022, 11, 6407 7 of 19

between diuretics and VS, with an odds ratio (OR) of 1.36 (1.07–2.38) [57]. Reduced car-
diac preload, as well as hyponatremia-dependent blunting of vasopressin secretion, could
explain, at least partly, this observation [57]. In contrast to ACEI and diuretics, treatment
with beta-blockers has been associated with a reduced incidence of VS in the meta-analysis
by Dayan et al. [25]. By preventing chronic stimulation of the sympathetic system, beta-
blockers might improve the sensitivity of adrenergic receptors and reduce the development
of vasoplegia after CPB [66].
A significant association between the preoperative use of inotropes and postopera-
tive vasoplegia has also been reported, primarily related to the use of sympathomimetic
inotropes (dobutamine), but not phosphodiesterase inhibitors (milrinone) [57]. Conversely,
milrinone may reduce the incidence of VS, as shown in patients undergoing cardiac trans-
plantation, through yet undefined mechanisms [67,68].

4. Outcome
Few studies reported data about the outcome of patients experiencing VS. Com-
pared to non-complicated postoperative course, patients with VS require higher inotropic
support, display more frequent bleeding complications, and have more organ dysfunc-
tion, including liver injury, renal and respiratory failure, as well as more frequent lactic
acidosis [8,25,33,69], translating into a prolonged duration of mechanical ventilation and
length of ICU stay [12,25]. Ultimately, such complications have a profound impact on sur-
vival, with reported mortality rates between 5.6 and 15%, as compared to 3.4 to 6.2% in the
overall population of cardiac surgery patients [2,13–15]. The ominous prognosis of VS has
been particularly underscored by Levin et al. in a retrospective cohort of 2823 adult cardiac
surgery patients. Those developing VS after the discontinuation of CPB were significantly
more likely to have a prolonged ICU stay length > 10 days or to die in hospital, with an
OR of 3.3 (p = 0.005) [12]. This was further substantiated by the very high mortality (25%)
reported in heart transplant recipients with post-operative VS, contrasting to 9% mortality
in those without VS [68].

5. Management
5.1. Peri-Operative Prevention
Patient care during the peri-operative period is crucial to reduce the risk of VS after
CPB. In this context, Van Vessem et al. proposed a risk score incorporating age, sex, the
type of surgery, the value of creatinine clearance and thyroxine levels, the presence of
anemia and the use of beta-blockers [58]. Using this score, the authors stratified the risk
of developing VS into low, intermediate, and high risk, with an observed incidence of VS
of 13, 39 and 65%, respectively. They suggested that, according to the calculated score,
preoperative measures such as hemodynamic optimization and improvement of renal
function could prove beneficial to reduce the risk of post-operative VS. This score should
now be validated in a prospective multicenter trial.
Given the lack of consensus regarding pre-operative drug management (use of di-
uretics, ACEI and beta-blockers), an individualized strategy should be implemented on a
case-by-case basis. With respect to surgery, beyond the obvious requirement to keep the
duration of CPB and aortic cross-clamping to a minimum, it has been suggested that the use
of minimal extracorporeal circulation (MECC) and of biocompatible, heparin-coated short
circuits, might limit inflammation by reducing the exposure to foreign surfaces [26]. In an
evidenced-based review of 98 RCTs evaluating various strategies to modulate inflammatory
response during CPB, Clive Landis et al. identified 8 RCTs examining MECC (median
sample size = 45) and 14 RCTs evaluating biocompatible circuits (median sample size = 38).
Although several trials reported a reduction in inflammation, the overall clinical benefits
were limited [70]. In a meta-analysis of 24 RCTs comparing MECC with conventional ECC,
Anastasiadis et al. reported that MECC was associated with significantly less systematic
inflammation, a reduced incidence of VS (OR 0.19, 95% CI 0.04–0.88, p = 0.03) and decreased
mortality [71]. These results must however be interpreted with caution, owing to the small
J. Clin. Med. 2022, 11, 6407 8 of 19

number of included patients in most studies evaluated and the heterogeneity of outcome
measurements. Therefore, doubt persists regarding the real impact of these strategies, and
additional, adequately powered RCTs are warranted to address their effectiveness.

5.2. Volume Resuscitation

The main goal of resuscitation in any form of circulatory shock is to ensure adequate
tissue perfusion and oxygen delivery to meet the tissue metabolic needs. Such requirement
implies the maintenance of sufficient cardiac output and perfusion pressure [72]. Fluid
resuscitation is crucial to maintain adequate preload and optimize cardiac output. Both
absolute (pre- and peri-operative fluid losses) and relative (venous vasodilation with
increased unstressed vascular volume) hypovolemia [73] may reduce venous return and
cardiac preload in the cardiac surgery patient. Although it is critical to recognize and
correct hypovolemia, avoiding fluid over-resuscitation is of paramount importance given
the harmful consequences of increased extravascular lung water, excessive cardiac filling
pressure and hemodilution [74–76]. Volume resuscitation should therefore be based on
the demonstration of insufficient perfusion, which can be clinically evaluated by the
mottling score and the capillary refill time [77], and biologically by the value of arterial
blood lactate and the venous-to-arterial difference in the partial pressure of carbon dioxide
(VA-pCO2 gap) [78].
It is generally admitted that beyond an initial fluid loading of 20–30 mL/kg, additional
fluids should be cautiously administered [79], and guided by dynamic indices (e.g., pulse
pressure variation, echographic indices of stroke volume variation) to confirm a positive
effect of fluid loading on cardiac output [75,80]. The technique of “mini fluid challenge” (ad-
ministration of 100 to 150 mL crystalloid fluid over 60 to 120 s) may be here interesting [81].
This was recently shown in a multicenter prospective study in surgical patients undergoing
laparotomy surgery [82], indicating that such challenge predicted fluid responsiveness,
defined by an increase in stroke volume index ≥ 10%, with high-sensitivity and specificity.
Cardiac surgical patients frequently display reduced hemoglobin concentrations post-
operatively, which could increase the risk of tissue hypoxia. Several RCTs therefore eval-
uated transfusions thresholds in this population. Although one RCT (TITRe2 study)
found reduced 90 d mortality (secondary outcome) when patients were transfused ac-
cording to a liberal (Hb 9 g/dL) vs. restrictive (Hb 7.5 g/dL) threshold, most RCTs and
meta-analyses indicate non-inferiority of restrictive strategies with respect to morbidity
and mortality [83–86]. Hence, current guidelines recommend a transfusion threshold of
7.5 g/dL in stable patients without evidence of tissue hypoxia [87,88]. However, no study
evaluated transfusion thresholds in the specific population of VS patients. It is noteworthy
that anemia can reduce systemic vascular resistance, both by reducing blood viscosity and
decreasing Hb-dependent inhibition of NO [89,90], which could contribute to aggravate hy-
potension in VS patients. Indeed, a direct relationship exists between Hb levels and blood
pressure [91]. Therefore, anemia may be less well-tolerated in post-operative patients with
VS, and transfusion thresholds might be higher in this setting, which should be evaluated
in future studies. For these reasons, we use a 9 g/dL transfusion threshold in VS patients
treated in our center.

5.3. Vasoactive Drugs

A mean arterial pressure (MAP) of 65–70 mm Hg is considered as the initial value
to target in circulatory shock, as higher values have not been associated with improved
survival [75,92,93]. After reaching such MAP, the appropriate target must be repeatedly
assessed, using the clinical and biochemical endpoints measures of tissue perfusion pre-
viously mentioned [94]. Although it has long been considered that vasopressors should
be initiated following adequate volume resuscitation, it is now recommended to start
vasoactive drugs together with volume resuscitation, as this strategy has been associated
with reduced short-term mortality in sepsis-associated vasoplegia [95]. Potential benefits
from early vasopressor use include a reduced need of fluids, via the mobilization of blood
J. Clin. Med. 2022, 11, 6407 9 of 19

from the unstressed and stressed vascular compartments, and an improved myocardial
perfusion through an increased diastolic pressure [96].

5.3.1. Norepinephrine
Norepinephrine (NE) targets the vascular α-1 adrenoreceptor to increase intracellular
Ca++ and promote vascular smooth muscle contraction. Although no mortality benefit
from its use in post-CPB VS has been demonstrated, NE remains the first line vasopres-
sor agent in most cardiac surgery centers, and is thus still considered as the standard of
care [97–100]. However, owing to its beta-adrenergic actions [97–100], NE may trigger
important side effects such as tachycardia, atrial fibrillation, increased myocardial oxygen
consumption, and hyperlactatemia [97–100]. Such detrimental effects are even more com-
mon with epinephrine and dopamine, which therefore are not recommended in the therapy
of VS [97–100]. It is also noteworthy that high doses NE may result in immunosuppression
predisposing to secondary infections [101]. Therefore, accumulating evidence indicates
that sympathetic overactivation should be avoided, and that a non-catecholaminergic vaso-
pressor (vasopressin) should be added early if MAP cannot be rapidly restored with NE, or
in case of side effects attributable to NE [97–100]. There is currently no recommendation
regarding the threshold dose of NE for the initiation of vasopressin, as such threshold
varied between 0.1 and 0.7 µg/kg/min across studies evaluating this issue [97–100].

5.3.2. Vasopressin
As previously mentioned, vasopressin (VP) promotes vasoconstriction via vascular
V1-receptor-dependent increase in cytosolic Ca++ , modulation of NO signaling, and im-
provement of catecholamine sensitivity. The reduced circulating levels of VP reported in
patients with VS after CPB (see above) provides a strong rationale for the therapeutic use
of exogenous VP in this setting. This was initially evaluated in a small prospective RCT
published in 1998 by Argenziano et al. [10]. Ten vasoplegic hypotensive patients following
LVAD surgery and treated with NE received VP (0.1 U/min) or saline placebo. In all
patients, VP significantly increased MAP while allowing a reduction in NE requirements,
an effect that was particularly marked in a subgroup of patients displaying inappropriately
low circulating levels of endogenous VP. Several subsequent studies in patients with va-
sodilatory shock confirmed similar findings, further reporting a reduced incidence of new
onset arrhythmias with VP in comparison to NE [102,103]. Additionally, various authors
reported that the systemic vasopressor effect of VP occurred in the absence of any negative
influence on pulmonary vascular resistance, thereby increasing right ventricular perfusion
pressure without increasing right ventricular afterload [104,105].
A large RCT (VANCS trial), including 300 patients with VS after cardiac surgery,
directly compared NE (10–60 µg/min) with VP (0.01–0.06 U/min) as first line vasopressor
to maintain a MAP of 65 mm Hg [13]. Patients in the VP arm had a significant reduction
(32% vs. 49%, p = 0.0014) of the primary outcome (a composite of 30 days mortality or
severe complications), mostly due to a marked reduction in acute renal failure (10% vs.
36%, p < 0.0001). In addition, VP was associated with a lower incidence of atrial fibrillation
(64% vs. 82%, p = 0.0004), and did not result in a greater occurrence of digital, mesenteric,
or myocardial ischemia.
Based on these data, and on meta-analyses confirming a reduced incidence of AF and
possible decreased incidence of acute kidney injury with VP [106–108], a recent expert
consensus [97] proposed the following recommendations. (1) To start or add VP to increase
MAP in case of adverse effects related to sympathoadrenergic drugs (strong recommenda-
tion, moderate level of evidence). (2) To use VP as a first line vasopressor therapy (weak
recommendation, moderate level of evidence). Furthermore, owing to the favorable profile
of action of VP on the pulmonary circulation, this expert consensus recommended the use
of VP (first line or added to norepinephrine) in cardiac surgical patients with right ventricle
dysfunction and/or pulmonary hypertension (weak recommendation, very low level of
evidence). Regarding the dose of VP, no definitive consensus has emerged so far, but due to
J. Clin. Med. 2022, 11, 6407 10 of 19

a dose-dependent increased risk of ischemic complications, doses higher than 0.06 U/min
should be avoided.

5.3.3. Angiotensin 2
The possibility that a disturbed renin angiotensin system leading to reduced Ang2
generation participates to VS after CPB (see above) suggests that exogenous Ang2 might be
a therapeutic option in this setting. Several case reports and small case series reported safe
and successful administration of Ang2, with significant hemodynamic improvement and
vasopressor sparing effect, in vasoplegic patients following cardiac surgery (see [47] for an
extensive recent review on this topics). The ATHOS-3 trial evaluated the effectiveness of
Ang2 (20–200 ng/kg/min) in refractory vasodilatory shock from various origins (primarily
septic shock) unresponsive to high dose of vasopressors [109]. The pre-defined hemody-
namic target (MAP increase of at least 10 mm Hg or an increase to at least 75 mm Hg after
3 h) was reached significantly more often with Ang2 than placebo (70 vs. 23%, OR 7.95,
95% CI 4.76–13.3, p < 0.001). A subsequent post hoc analysis in 16 patients with VS after
cardiac surgery showed that the end point was reached by 89% of patients treated with
Ang2, compared to 0% in those receiving the placebo, an effect achieved with very low
doses of Ang2 (5 ng/kg/min) in a majority of patients. In addition, there was a marked
vasopressor sparing effect of Ang2, with a 76.5% decrease in vasopressors, compared to a
7.8% increase in the placebo group (p = 0.0013) [110]. Taken together, these findings strongly
suggest that Ang2 may provide significant benefits in VS after CPB, and some have indeed
already incorporated Ang2 in their treatment algorithm [47]. However, current evidence
remains insufficient to make any recommendation [97], implying the need for additional
RCTs evaluating Ang2 in cardiac surgery patients [111].

5.3.4. Methylene Blue

Methylene blue (MB) is a thiazine dye used as an antidote to treat methemoglobine-
mia [112]. Owing to several pharmacological actions, MB increases vascular tone, a prop-
erty that led to evaluate MB for the therapy of vasoplegia associated with septic shock
or following CPB. MB acts by inhibiting NO-dependent vasodilation via three distinct
mechanisms: direct scavenging of NO, inhibition of NO synthase, and most significantly,
inhibition of guanylyl cyclase [97–100]. Several investigations in cardiac surgery patients
(reviewed in [113].
In spite of these encouraging results, data on clinical outcome with MB remain scarce
and contrasted. In a RCT comparing pre-operative MB (2 mg/kg over 30 min) vs. placebo in
patients at high risk of post-operative VS, Özal et al. reported a significant lower incidence
of VS (0% vs. 26%, p < 0.001), as well as lower ICU and hospital stay in the MB arm [114].
Levin et al. randomized 56 patients with established post-operative VS to receive either
MB (1.5 mg/kg) or placebo, and reported a significant reduction in mortality with MB (0%
vs. 21.4%, p = 0.01) [115–117]. In a retrospective analysis of 221 patients with per-operative
vasoplegia treated with MB (2 mg/kg), Kofler et al. reported improved hemodynamic
status, but unchanged 90-day mortality [113]. In contrast to these data, Weiner et al.
found, in a retrospective cohort of 226 patients with post-operative VS, that treatment with
MB (57 patients) was an independent predictor of in-hospital mortality (p = 0.007) and
post-operative complications (p = 0.001). In addition, Mehaffey et al. showed that MB
treatment, in a cohort of 118 patients, was associated with a high rate of post-operative
complications and mortality [118]. It must also be underscored that MB may be associated
with serious complications, including serotoninergic syndrome, acute hemolysis in patients
with G6PDH deficiency, and impaired splanchnic perfusion at high doses (7 mg/kg).
Therefore, given the lack of high-quality data, uncertainties regarding clinical out-
comes, the potential for severe side effects, unresolved issues regarding the timing (pre-,
per-, or post-operatively), dose and mode of administration (bolus vs. infusion), the use of
MB to treat VS after CPB is presently not recommended, unless as a rescue therapy in cases
with hypotension refractory to usual vasopressors [97].
J. Clin. Med. 2022, 11, 6407 11 of 19

5.3.5. Hydroxocobalamin
Hydroxocobalamin (vitamin B12) is used for the therapy of pernicious anemia and
in cyanide poisoning [119]. Several properties of hydroxocobalamin indicate that it may
increase vascular tone, including inhibition of NOS enzymes [120], direct NO inactiva-
tion [121] and reduction in H2 S toxicity through direct binding [122,123]. Hydroxocobal-
amin has been therefore evaluated for the treatment of refractory VS after CPB, using the
same protocol of administration as in cyanide poisoning (5 g administered by IV infusion
over 15 min). Several case reports showed that such regimen increased MAP and allowed
reduction in vasopressors [124], and comparable effects have been reported in small case
series [125,126]. In a retrospective study of 33 patients treated with hydroxocobalamin
for refractory hypotension during or after CPB, a pressor effect was noted in 24 patients,
albeit such response was highly heterogeneous [127]. Indeed, four distinct patterns were
identified, including no response (“poor responders”, 27%), brisk and sustained increase
(“responders”, 24%), progressive increase (“sustainers”, 27%) and brisk increase followed
by rebound hypotension (“rebounders”, 21%) [127]. Since such heterogeneity might be due,
partly, to the mode of administration (bolus), Seelhammer et al. evaluated the effects of
a continuous infusion of hydroxocobalamin (5 g over 6 h) post-operatively in 12 patients
with severe VS, showing that such regimen permitted a prolonged (>10 h) and significant
reduction in vasopressors in all patients [128].
To sum up current available data, hydroxocobalamin appears generally associated
with hemodynamic improvement and decreased vasopressor requirement in the setting of
VS after cardiac surgery, as reviewed recently by Shapeton et al. [124]. However, safety and
mortality data are lacking, and both the timing (pre- or post-operative) and mode (bolus
vs. continuous infusion) of administration remain to be established. Therefore, the use of
hydroxocobalamin should only be considered as a rescue strategy in deteriorating patients
refractory to usual vasopressors.

5.3.6. Vitamin C
Vitamin C (ascorbic acid) is a co-factor for several enzymes involved in the biosynthesis
of endogenous catecholamines [129], and it also increases the sensitivity of adrenorecep-
tors [130]. It is also a free radical scavenger and might therefore reduce oxidant-mediated
tissue injury, inflammation and endothelial dysfunction [131]. An important reduction in
plasma Vitamin C occurs following CPB, suggesting a potential therapeutic role from ex-
ogenous supplementation [132]. This was first assessed by Wieruszewski et al. in 3 patients
with severe VS after cardiac surgery. High dose Vitamin C (1500 mg iv every 6 h) allowed
to rapidly reduce vasopressors in all patients. Such approach was then evaluated in a RCT
including 50 cardiac surgery patients with VS [133]. Although Vitamin C was generally
well tolerated, it did not allow a statistically faster resolution of vasoplegia. It is also worth
to mention that a recent study in septic shock patients (LOVIT trial, 872 patients) did
not find any benefit from Vitamin C treatment (50 mg/kg q6 h for up to 96 h) [134]. In
contrast, patients treated with Vitamin C displayed significantly higher risk of death or
persistent organ dysfunction. Additionally, in another trial in septic shock, Vitamin C was
associated with a higher need for renal replacement therapy and greater positive fluid
balance [135]. Altogether, the results of these trials do not support the use of vitamin C
to treat vasodilatory shock, and therefore, it cannot be recommended in the setting of VS
after CPB.

5.4. Anti-Inflammatory Strategies

5.4.1. Corticosteroids
The interest of corticosteroids in the treatment of vasoplegia involves two main phar-
macological actions. The first one is related to their anti-inflammatory effects, leading
notably to a reduced expression of inflammatory cytokines, iNOS and cyclooxygenase-
2 [97,99,136]. The second one relies in the ability of corticosteroids to enhance the syn-
thesis of catecholamines and to increase the expression and sensitivity of adrenorecep-
J. Clin. Med. 2022, 11, 6407 12 of 19

tors [137,138]. In septic shock, the administration of low doses corticosteroids (hydrocor-
tisone) accelerates the reduction in vasopressors and the resolution of shock, albeit with
controversial effects on mortality, as shown in several major RCTs [139–142]. In cardiac
surgery, two large trials (SIRS trial -7507 patients, and DECS trial—4494 patients) evaluated
the effects of high doses corticosteroids (intraoperative methyprednisolone or dexametha-
sone) on mortality and major complications, and did not report any significant effects of the
interventions [143,144]. With respect to low doses hydrocortisone, several trials (extensively
reviewed in [145]) reported reduced inflammation, lower incidence of atrial fibrillation,
shortened ICU and hospital length of stay and reduced need of vasopressors. However,
none of the studies specifically addressed the role of low doses steroids in established
VS after cardiac surgery. Therefore, although low doses steroids appear safe and may
be associated with some beneficial effects, there is no evidence supporting their use to
specifically treat CPB-induced vasoplegia.

5.4.2. Extracorporeal Cytokine Adsorption Therapy

Extracorporeal cytokine adsorption therapy (ECAT) is a technique of extracorporeal
blood purification using specifically designed filters able to adsorb and remove inflam-
matory mediators from the circulation. This strategy has been applied to decrease inflam-
mation in sepsis, with promising results reported in a number of case reports and case
series. However, prospective RCTs failed to report any mortality benefit, some of them
showing instead potential harmful effects possibly related to the unselective removal of
anti-inflammatory mediators and drugs, notably antibiotics (see: [146] for extensive review
on this topic).
In the field of cardiac surgery, the largest RCT to date has been published by Diab et al.,
who compared ECAT using the CytoSorb® cytokine filter integrated to the CPB circuit
(n = 142 patients) with standard of care (n = 146 patients). Although patients in the inter-
vention arm displayed significantly lower levels of IL-1β and IL-18 at the end of CPB, they
did not differ from controls in terms of the primary outcome (post-operative change from
baseline in sequential organ failure assessment score), notably with respect to the use of
vasopressors [147]. In a systematic review including 5 RCTs (n = 163 patients) evaluating
ECAT in cardiac surgery, Goetz et al. reported no significant benefits from the technique
in terms of mortality and post-operative complications [148]. Moreover, a recent meta-
analysis of 8 trials in sepsis and 10 in cardiac surgery (total 875 patients), revealed (low
certainty of evidence) that the use of a cytokine filter might increase mortality in critically
ill patients with inflammatory conditions [149]. As a whole, these data indicate that the
efficacy and safety of ECAT remains not established. Therefore, its application in cardiac
surgical patients cannot be currently recommended.

5.5. Management of VS after CPB: Summary of Evidence and Current Recommendations (Table 1)
The aim of the management of VS is to restore organ perfusion pressure and adequate
oxygen delivery, by ensuring appropriate preload and by the administration of vasoactive
drugs, with the aim to maintain a MAP of 65 mm Hg. Among the panoply of available
agents, present evidence indicates that conventional vasopressors are recommended as
first line therapy [97]. In this respect, norepinephrine is generally considered as the stan-
dard of care. Vasopressin should be added to norepinephrine in case of untoward side
effects (tachycardia, atrial fibrillation) related to excessive sympathetic stimulation, or could
be used as the initial vasopressor, as supported by the recent VANCS clinical trial [13].
Non-conventional vasopressors, including Methylene Blue, Angiotensin 2 and Hydroxo-
cobalamin, have been increasingly used in refractory cases, but evidence is not sufficient
to make any recommendations. Therefore, while awaiting further RCTs to evaluate their
efficacy and safety, these drugs should only be introduced as a rescue therapy, on a case-
by-case basis. Low doses hydrocortisone may be associated with vasopressors in order
to potentiate their effects, due to their demonstrated role in shortening the duration of
vasoplegia in sepsis and their safety profile. However, evidence for their use in post-CPB
J. Clin. Med. 2022, 11, 6407 13 of 19

VS has not yet been demonstrated. Finally, in spite of some theoretical advantages, Vitamin
C and cytokine adsorption filters should not be used, owing to possible deleterious effects.

6. Conclusions and Perspectives

Vasoplegic syndrome is a frequent complication of cardiopulmonary bypass, with
significant impact on major clinical outcomes. It is of particular concern in patients with left
ventricular dysfunction or/and chronic renal failure, and it occurs more frequently after
complex surgery, left ventricular device implantation and heart transplantation. Systemic
inflammation, triggered by multiple mechanisms set in motion during CPB and after its
discontinuation, is the key pathophysiological event leading to vasoplegia, by promoting a
series of biological processes impairing the normal maintenance of vascular tone. Beyond
the obvious necessity to shorten, as much as possible, the duration of CPB to prevent or
reduce such deleterious consequences, therapy of established VS is based primarily on
adequate volume resuscitation and the use of vasoactive agents to maintain end-organ
perfusion and viability. It is puzzling that, in spite of the importance of this conundrum,
only very few and adequately powered controlled prospective studies have addressed the
question of the best regimen of vasoactive drugs to apply in this setting. Therefore, the
current recommended strategy relies only on low to moderate evidence indicating that
conventional vasopressors, which include norepinephrine and vasopressin, either alone
or in combination, should be used to restore vascular tone, whereas non-conventional
vasopressors (methylene blue, hydroxocobalamin and angiotensin 2) are not recommended,
except from extremely refractory situations.
While future studies will undoubtedly help optimize treatment algorithms, it must be
underscored that vasoplegic syndrome develops as a final common disorder precipitated
by an array of pathophysiological mechanisms. Such mechanistic diversity might hamper
the development of a unique therapeutic strategy similarly applicable to every single
patient (“one size fits all”). We may therefore hope that future developments in the field
of molecular diagnostics and precision medicine might allow decipher which mechanism
prevails in a given situation, and thereby tailor the therapeutic management to each
specific patient.

Author Contributions: Conceptualization and manuscript drafting, Z.L., N.B.-H. and L.L.; Final
draft reviewing and editing, V.R., Z.G., C.M. and M.K. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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