Journal of

Personalized
Medicine

Review
Biochemical Changes in Cardiopulmonary Bypass in Cardiac
Surgery: New Insights
Luan Oliveira Ferreira 1,2, * , Victoria Winkler Vasconcelos 1 , Janielle de Sousa Lima 1 ,
Jaime Rodrigues Vieira Neto 1 , Giovana Escribano da Costa 1 , Jordana de Castro Esteves 1 ,
Sallatiel Cabral de Sousa 1 , Jonathan Almeida Moura 1 , Felipe Ruda Silva Santos 1 , João Monteiro Leitão Filho 1 ,
Matheus Ramos Protásio 3 , Pollyana Sousa Araújo 4 , Cláudio José da Silva Lemos 4 , Karina Dias Resende 1
and Dielly Catrina Favacho Lopes 2, *

1 Residency Program in Anesthesiology, João de Barros Barreto University Hospital, Federal University of Pará,
Belém 66073-000, Brazil; [email protected] (V.W.V.); [email protected] (J.d.S.L.);
[email protected] (J.R.V.N.); [email protected] (G.E.d.C.);
[email protected] (J.d.C.E.); [email protected] (S.C.d.S.);
[email protected] (J.A.M.); [email protected] (F.R.S.S.);
[email protected] (J.M.L.F.); [email protected] (K.D.R.)
2 Laboratory of Experimental Neuropathology, João de Barros Barreto University Hospital, Federal University
of Pará, Belém 66073-000, Brazil
3 Hospital Israelita Albert Einstein—HIAE, São Paulo 05652-900, Brazil; [email protected]
4 Department of Cardiovascular Anesthesiology, Hospital Clínicas Gaspar Vianna, Belém 66083-106, Brazil;
[email protected] (P.S.A.); [email protected] (C.J.d.S.L.)
* Correspondence: [email protected] (L.O.F.); [email protected] (D.C.F.L.)

Abstract: Patients undergoing coronary revascularization with extracorporeal circulation or car-

diopulmonary bypass (CPB) may develop several biochemical changes in the microcirculation that
lead to a systemic inflammatory response. Surgical incision, post-CPB reperfusion injury and blood
contact with non-endothelial membranes can activate inflammatory signaling pathways that lead to
the production and activation of inflammatory cells, with cytokine production and oxidative stress.
Citation: Ferreira, L.O.; Vasconcelos, This inflammatory storm can cause damage to vital organs, especially the heart, and thus lead to
V.W.; Lima, J.d.S.; Vieira Neto, J.R.; da
complications in the postoperative period. In addition to the organic pathophysiology during and
Costa, G.E.; Esteves, J.d.C.; de Sousa,
after the period of exposure to extracorporeal circulation, this review addresses new perspectives for
S.C.; Moura, J.A.; Santos, F.R.S.;
intraoperative treatment and management that may lead to a reduction in this inflammatory storm
Leitão Filho, J.M.; et al. Biochemical
Changes in Cardiopulmonary Bypass
and thereby improve the prognosis and possibly reduce the mortality of these patients.
in Cardiac Surgery: New Insights. J.
Pers. Med. 2023, 13, 1506. https:// Keywords: cardiopulmonary bypass; inflammation; lactate; cytokines; cardiac surgery
doi.org/10.3390/jpm13101506

Academic Editor: Michalina

Kołodziejczak
1. Introduction
Received: 30 July 2023 Cardiopulmonary bypass was used for the first time in cardiac surgery over 60 years
Revised: 19 August 2023 ago, and since then, many advances have occurred in the conduct of CPB and cardiac
Accepted: 23 August 2023 anesthesia [1]. CPB comprises a set of devices and techniques that replace cardiac and
Published: 18 October 2023
pulmonary function during surgery. Several cardiopulmonary bypass methods are used for
mechanical support of respiratory and cardiocirculatory failure, so that there is adequate
blood flow to supply oxygen to the vital organs [2]. CPB makes it easier for procedures
Copyright: © 2023 by the authors.
that need to enter the intracardiac space, such as valve replacement, to be performed with
Licensee MDPI, Basel, Switzerland. a reduced amount of blood and under controlled conditions [3].
This article is an open access article Substantial evidence from several studies on CPB reports that this procedure stimulates
distributed under the terms and the inflammatory process and that generates reactive oxygen and nitrogen species that
conditions of the Creative Commons overcome endogenous antioxidants, resulting in increased oxidative stress that significantly
Attribution (CC BY) license (https:// affects the rates of mortality and postoperative morbidity [1,3–8]. Several factors seem
creativecommons.org/licenses/by/ to be the cause of the systemic inflammatory reaction, such as blood contact with the
4.0/). CPB device’s surface, surgical trauma, endotoxemia, blood loss and ischemic reperfusion

J. Pers. Med. 2023, 13, 1506. https://doi.org/10.3390/jpm13101506 https://www.mdpi.com/journal/jpm

J. Pers. Med. 2023, 13, 1506 2 of 19

injury [9]. Thus, there is activation of the complement system and the immune system,
leukocytes and endothelial cells, which, in turn, are responsible for the release of multiple
pro-inflammatory cytokines [10]. Some deleterious effects that influence the high mortality
rate are related to the inflammatory response syndrome which, to a large extent, is related
to the interface of blood components, air and the artificial surfaces of the device [2,11].
Despite significant advances in recent years, oxidative stress and inflammation remain
major concerns when using CPB [12].
Cardiac surgery with cardiopulmonary bypass is associated with systemic inflamma-
tory response, a clinical condition that is characterized in some cases with severe hypoten-
sion due to low systemic vascular resistance during and after cardiopulmonary bypass, in
which some of these cases do not respond to volume or catecholamines. This condition
is known as vasoplegic syndrome [11,13]. The pathophysiology is complex and includes,
in addition to the intense inflammatory response, dysregulation of the vasodilator and
vasoconstrictor properties of vascular smooth muscle cells [11]. Although norepinephrine
is confirmed as a first-line therapy for the treatment of vasoplegia, currently, many ran-
domized studies have identified new adjuvant therapies to control metabolic and oxidative
stress as a pharmacological strategy to reduce the incidence of vasoplegic syndrome [11].
In this narrative review, we will present our study, focusing on the inflammatory re-
sponse, vasoplegic syndrome and new insights regarding adjuvant and non-catecholaminergic
treatment for the inflammatory response generated during the cardiopulmonary bypass method.

2. Search Strategy
We used PubMed, Web of Science and Embase to explore/find studies pertaining
to cardiopulmonary bypass. The search was implemented by using the following key-
words: “cardiopulmonary bypass”, “oxidative stress”, “inflammation”, “coagulation”,
“ischemia/reperfusion”, “vasoplegic syndrome”, “antioxidants”, “free radical”, “cardiac
surgery”, “lung/kidney injury”. In that context, we conducted a literature search in the
PubMed search engine (https://pubmed.ncbi.nlm.nih.gov (accessed on 27 June 2023)).
This narrative review is the result of the works having been thoroughly scrutinized by
specialists in the field, in order to critically include or exclude them.
In this review, we included all studies which involved cardiopulmonary bypass. We
did not restrict the types of articles, and we included peer-reviewed studies, book chapters,
reviews, letters to editors and animal studies. The studies included in this review were all
limited to English only. We excluded studies that did not focus on cardiopulmonary bypass
and non-English studies.

3. Pathophysiology of a Cardiopulmonary Bypass

During a CPB, the pumping functions of the heart are performed by a mechanical
pump and the functions of the lungs are replaced by a device capable of performing gas
exchange with the blood. In this context, to understand the systemic complications related
to this procedure, it is necessary to understand the blood circuit during cardiopulmonary
bypass [14].
In CPB, venous blood is diverted from the heart and lungs, arriving at the right atrium
of the patient through cannulas inserted in the superior and inferior vena cava. Through a
single channel, venous blood is taken to the oxygenator, a reservoir made of semipermeable
membranes to separate blood from oxygen and perform gas exchanges [15,16].
From the oxygenator, blood is directed to a part of the patient’s arterial system, usually
the ascending aorta, where it travels through the arterial system and is distributed to all
organs, supplying oxygen to the tissues for carrying out vital processes and removing the
carbon dioxide produced by them. After circulating through the tissue capillaries, the blood
returns to the superior and inferior vena cava system, where it is continuously redirected
to the CPB machine until the end of the surgery [16].
CPB control is carried out by means of a machine, which aspirates and propels the
blood. The machine consists of a control panel, oxygenator, reservoir, arterial pump that
 removing the carbon dioxide produced by them. After circulating through the tissue
capillaries, the blood returns to the superior and inferior vena cava system, where it is
J. Pers. Med. 2023, 13, 1506 continuously redirected to the CPB machine until the end of the surgery [16]. 3 of 19
CPB control is carried out by means of a machine, which aspirates and propels the
blood. The machine consists of a control panel, oxygenator, reservoir, arterial pump that
replaces the
replaces the contractile
contractile function
function ofof the
the heart,
heart, cardioplegia
cardioplegia (system
(system forfor mixing
mixing blood
blood and and
cardioplegicsolution)
cardioplegic solution)and andtubes
tubesororcannulas
cannulas(arterial
(arterialand
andvenous)
venous)[15].
[15].
After opening
After opening thethe patient’s
patient’s chest,
chest, the
the surgeon
surgeon introduces
introduces the the cannulas
cannulas intointo the
the right
right
atrium and
atrium and the
the inferior
inferiorand
andsuperior
superiorvena venacava.
cava. Thus,
Thus, oxygen-poor
oxygen-poor blood blood isis diverted
diverted and and
directed to a reservoir
directed reservoir (Figure
(Figure1). 1).InInthe
themachine,
machine, the
theheat exchanger
heat exchanger rewarms
rewarms or cools
or coolsthe
blood
the as needed.
blood as needed.Then, an oxygenator
Then, an oxygenator removes carbon
removes dioxide
carbon fromfrom
dioxide the blood and adds
the blood and
adds oxygen.
oxygen. After After that,blood
that, the the blood
passespasses
throughthrough
a filtera that
filterremoves
that removes air bubbles
air bubbles and
and other
other
emboli emboli
beforebefore returning
returning to theto the body
body throughthrough
a pump a pump that directs
that directs the blood
the blood to the to the
aorta.
aorta. [17].role
[17]. The Theofrole of arterial
arterial cannulation,
cannulation, performed
performed by inserting
by inserting a cannula
a cannula into aninto an artery,
artery, is to
is to return
return bloodblood
to thetopatient’s
the patient’s circulation.
circulation. BeforeBefore
returningreturning to thethe
to the body, body,
bloodtheisblood is
filtered
filtered
to ensureto ensure
that no that no particles,
particles, debris, debris, or gaseous
or gaseous emboli emboli
enter theenter the circulation
circulation [15,16].[15,16].

Figure 1. Activation of the coagulation pathway and oxidative stress in cardiopulmonary bypass
Figure 1. Activation of the coagulation pathway and oxidative stress in cardiopulmonary bypass
(CPB). The contact surface is responsible for producing activated factor XII (FXIIa), which induces
(CPB). The contact surface is responsible for producing activated factor XII (FXIIa), which induces
the intrinsic coagulation pathway, leading to thrombin formation. Factor XIIa converts the high-
the intrinsic coagulation
molecular-weight pathway,
kininogen (HMWK)leading
into to thrombin formation.
bradykinin. Bradykinin Factor XIIathe
stimulates converts
releasethe
of high-
nitric
molecular-weight kininogen (HMWK) into bradykinin. Bradykinin stimulates the
oxide and inflammatory cytokines. Cytokines stimulate the extrinsic pathway of coagulation release of nitric
and
oxide and inflammatory
potentiate the formation cytokines.
of thrombinCytokines stimulate and
and clot formation the extrinsic pathway
have direct effects of
oncoagulation
leukocytes. and
CPB
potentiate the formation
initiates multiple of thrombin
processes and clot
that stimulate theformation andof
production have directoxygen
reactive effects on leukocytes.
species (ROS).CPBThe
main forms of cardiac ROS are superoxide (O −) and hydrogen peroxide (H2O2).
initiates multiple processes that stimulate the production of reactive oxygen species (ROS). The main
2

forms of cardiac ROS are superoxide (O2 − ) and hydrogen peroxide (H2 O2 ).
The function of the arterial pump is to replace the function of the heart. It sends the
bloodThe function
from of the arterial
the reservoir pump isantoartificial
and ensures replace the function
blood of the The
circulation. heart. It sends
way the
in which
blood
blood from the reservoir
flow should and ensures
be provided, an artificial
continuous blood circulation.
or pulsatile, has been theThe way of
subject in debate,
which
blood
whichflow should
continues tobe provided,
this day [15]. continuous or pulsatile, has been the subject of debate,
which continues to this day [15].
3.1. Systemic Response to CPB
3.1. Systemic Response to CPB
In cardiac physiology, the cardiovascular system is a complex set of vessels, which
driven cardiac
In by the physiology,
heart, makethe cardiovascular
the system
blood circulate is a complex
throughout set of vessels,
the body. The veins which
are
driven by the heart, make the blood circulate throughout the body. The veins are responsible
responsible for the flow in centripetal way, whereas the arteries are responsible for the
for the flow in centripetal way, whereas the arteries are responsible for the flow in centrifu-
flow in centrifugal way. Within this system, the microcirculation—venules, arterioles and
gal way. Within this system, the microcirculation—venules, arterioles and capillaries—is
the place where gas exchange occurs and where the regulatory mechanisms of peripheral
blood flow are located [18].
During CPB, the physiology of the circulation is completely modified by the introduc-
tion of a non-pulsatile flow on the arterial side, which opposes an elevated venous pressure
on the venous side of the circulation. This situation generates adaptation mechanisms, thus
J. Pers. Med. 2023, 13, 1506 4 of 19

providing a “shunting” effect, sometimes harmful to the circulation, which may result in
the development of systemic inflammatory response syndrome (SIRS) [18].
It is believed that factors associated with CPB, such as hemodilution, contact activation
and induction of systemic inflammatory response, impair microcirculatory perfusion by
affecting both transport and diffusion of oxygen at the microvascular level [19].
Another form of damage to the microcirculation related to the use of CPB is the
formation of microbubbles, which circulate in the bloodstream and lodge in the capillaries,
causing obstruction, promoting ischemia, inflammation, complement activation, platelet
aggregation and clot formation [20]. In addition, CPB is responsible for other changes
in circulation, such as replacement of pulsatile physiological flow to continuous, which
increases the pressure on the venous side. In the microcirculation, the continuous flow
induces to phenotypic cell adaptation that also may result in the development of SIRS [18].
Hypothermia associated with cardiopulmonary bypass aims to reduce the metabolic
needs of patients, offering additional protection to the body, especially the vital organs,
avoiding anoxia injuries [21]. However, hypothermia reversibly inhibits clotting factors
and platelets, and rapid rewarming and hyperthermia are associated with brain injury [22].
In the first moments of CPB, hypotension is common due to the reduction in the
perfusion flow, the reduction in blood viscosity due to hemodilution, and the increase
in bradykinin. After this period, the body begins a compensatory response that, particu-
larly with hypothermia, the elevation of systemic vascular resistance and the absence of
pulsatility in the circulation, result in hypertension [23].
However, consequently, renal vasoconstriction occurs, predisposing the kidneys to
ischemia and injury [24]. In addition, hemodilution with crystalloid solutions, when in
excess, predisposes the patient to the formation of edema and watery diuresis rich in
electrolytes, favoring hydroelectrolytic imbalance [25,26].
Hemorrhagic disorders related to CPB are related to changes in blood clotting, since
blood circulates through tubes and devices that are non-endothelial surfaces. This imbal-
ance of blood hemostasis during CPB is the most common occurrence of thrombotic events,
while, after CPB, bleeding is usually reported [23,26,27].
Regarding the lungs, there is an increase in water leakage into the interstitium due to
inflammatory cells, surfactant inactivation and atelectasis and reduction in lung capacity,
which, together with exposure to hypothermia maintained during CPB, cause damage to
the pulmonary endothelium [28,29].

3.2. Metabolic Response

Patients undergoing CPB are subject to a significant hydroelectrolytic imbalance. The
migration of water between the different compartments depends on the concentration
of electrolytes for that the body’s water balance is maintained. Thus, when the patient
undergoes CPB, important imbalances may occur, such as excessive hydration, due to the
increased number of crystalloids in the perfusate [30].
The hyperhydrated patient may present facial or generalized edema, ascites, pleural
effusion, respiratory failure, asthenia, disorientation, delirium and seizures or other neuro-
logical manifestations. Hyperhydration is a complication that is accentuated in patients
with low amounts of proteins in the body, representing another risk factor for this indi-
vidual when performing surgical procedures, considering that the oncotic pressure of the
plasma is reduced and allows extravasation of liquids from the plasma to the interstitial
space, especially if the liquid supply is not adequately dimensioned [31,32].
In this context, sodium (Na+ ) is the main ion for sustaining water balance, since its
loss can cause a reduction in extracellular osmotic pressure and, consequently, cause the
transition from this compartment to the intercellular compartment. However, if there is
an increase in extracellular sodium levels, there is an increase in osmotic pressure and,
consequently, this results in the interstitial accumulation of water, with the development of
edema [31,32].
J. Pers. Med. 2023, 13, 1506 5 of 19

Another intracellular electrolyte is potassium (K+ ), which is responsible for conducting

the electrical impulse and performing muscle contraction. Its unbalanced extracellular
accumulation, characterized by hyperkalemia, and can be harmful, reducing electrical
conduction and myocardial contraction strength, that is, causing cardiac arrest, which
demonstrates its significance in cardiorespiratory surgical procedures in patients undergo-
ing CPB, especially during the infusion of the cardioplegia solution [31,32].
Other studies are in the same direction, highlighting calcium (Ca2+ ), as a fundamental
electrolytic substance for bone formation and blood flow regulation, meaning that its
lack characterizes hypocalcemia and can cause the same risks mentioned in relation to
hyperkalemia, that is, it can cause a cardiac arrest, resulting in death, and the balance of
the amount of calcium also tends to reduce the risk of blood clotting during and after the
surgery [31,32].
Magnesium (Mg2+ ) is an important electrolyte in activating metabolism, including
glycemic and protein metabolism, in addition to enabling neuromuscular contraction, but,
in high concentration, hypermagnesemia causes risks, with regard to unbalanced muscle
relaxation, such as in the heart muscles, as well as causing cardiac disorders related to the
process of electrical conduction [33].
Hydroelectrolytic alterations may therefore mean imminent risks to surgically assisted
cardiac patients, so that when undergoing CPB, the individual must have balanced systemic
functions or, on the contrary, when identifying the respective alterations, the artificial organs
must restore the balance [30].
An elevation of lactate levels (hyperlactatemia) is detectable in 10% to 20% of patients
undergoing CPB and is associated with adverse effects such as increased morbidity and
mortality [34]. Type A hyperlactatemia is the most common type in patients after cardiac
surgery and is strongly associated with metabolic acidosis. It results from anaerobic
metabolism, when the supply of oxygen is reduced below the requirement of cellular
metabolism, resulting in tissue hypoxia [35].
Some factors that lead to dysoxia during CPB and culminate in increased lactate levels
are comorbidities intrinsic to the patient, such as preoperative dehydration, high levels of
preoperative serum creatinine, active endocarditis, congestive heart failure, low left ventric-
ular ejection fraction, hypertension, atherosclerosis, low preoperative and perioperative
hemoglobin values and preoperative low cardiac output [36].
The reference range given for blood lactate is 0.5–2.2 mmol/L under certain physio-
logical conditions, with some variation between authors. Alert levels are usually defined
as being above 3 mmol/L during CPB, while other authors point out that a lactate peak
above 4.0 mmol/L is a better predictor of morbidity and mortality. And there are still
those who suggest that a situation of significant hyperlactatemia has a level greater than
5 mmol/L [37].
Lactate metabolism is closely related to glucose metabolism, as both compounds
are used to biosynthesize each other. Therefore, metabolic disorders that affect glucose
metabolism alter lactate homeostasis [38]. In cardiac surgeries, poor glycemic control is
associated with the induction of type B hyperlactatemia in the perioperative period and
studies show that low levels of glucose and high levels of lactate are closely related in these
patients and, commonly, levels are spontaneously regulated up to 24 h [39].

3.3. Systemic Inflammatory Reaction

CPB is associated with microvascular alterations in several pathological aspects. En-
dothelial cell injury and consequent acute inflammation with vascular damage, alteration
of the coagulation cascade, reperfusion injury and gaseous microemboli corroborate organ
dysfunctions during and after CPB [40].
The pathophysiology of the systemic inflammatory response to CPB is multifactorial
and can be divided into two main phases: “early” and “late”. The first phase occurs when
blood makes contact with non-endothelial surfaces of the system cannulas (“contact activa-
J. Pers. Med. 2023, 13, 1506 6 of 19

tion”). The late phase is caused by ischemia-reperfusion injury (I/R injury), endotoxemia,
coagulation disorders and heparin/protamine reactions [41].

3.4. Endothelial Injury

The endothelium is a participant in different physiological functions, including the
control of vascular tone and permeability, hemostasis and immune system responses. CPB
can lead to an inflammatory state similar to SIRS, with endothelial damage [42].
There are two main mechanisms of endothelial injury—neutrophil-mediated and
non-neutrophil-mediated. In the first, integrins on the surfaces of neutrophils bind to
molecules on endothelial cells, generating oxidative stress due to the reduction of ferric
iron to ferrous iron caused by superoxide anion, which is generated from xanthine oxidase,
produced by neutrophil elastase introduced into endothelial cells [40,43]. Neutrophil-
mediated endothelial cytotoxicity can also be caused by intracellular mechanisms involving
nitric oxide synthase [44].
In non-neutrophil-mediated injury, circulating pro-inflammatory cytokines (TNFa and
IL-1) directly stimulate endothelial cells, leading to a pathological increase in permeability,
causing tissue edema and impaired oxygen exchange, causing multiorgan dysfunction [45].

3.5. Alteration of the Coagulation Cascade

Contact with the artificial surface of the circuit leads to activation of the coagula-
tion cascades (Figure 1) and the alternative complement pathway. Activated factor XII
(XIIa) leads to the generation of bradykinin and the activation of the intrinsic coagulation
pathway; bradykinin is a potent vasoactive peptide that alters endothelial permeability,
smooth muscle tone and induces the production of cytokines and nitric oxide [46]. As
artificial surfaces, unlike the endothelium, have no regulatory molecules for suppressing
the complement system; they lead to an excessive inflammatory response and capillary
leakage, which has been demonstrated as a complication of cardiopulmonary bypass [46].
Furthermore, cytokines generated from brakinin induction may be able to activate
the extrinsic pathway of coagulation and leukocytes. Together, there is an increase in the
common pathway of coagulation, so activated factor X (FXa) converts prothrombin (II)
to thrombin (IIa), which then cleaves fibrinogen (I) to fibrin (Ia), resulting in subsequent
formation of clots [47,48]. Factor IIa increases the expression of adhesion molecules, such
as platelet activating factor (PAF), P-selectin and E-selectin by endothelial cells, increasing
adhesion and activation of defense cells, such as neutrophils [49].
The factor Xa and the thrombin formed, even with the administration of heparin, are
related to inflammatory processes and tissue remodeling. Thus, coagulation is closely
related to inflammatory processes during CPB [50].

3.6. Oxidative Stress

Aortic clamping in CPB blocks coronary flow with a decrease in oxygen supply
to myocytes, altering electrical activity and ceasing cardiac mechanical activity. This
maneuver of aortic clamping and subsequent removal of the clamp in CPB provides
favorable conditions for the formation of free radicals, triggering oxidative stress [12,51].
In ischemia, the supply of oxygen to the mitochondria ceases, interrupting the Krebs
cycle. Thus, the generation of ATP becomes primarily anaerobic. This change is accompa-
nied by an increase in cytosolic lactate and a reduction in intracellular pH. The reduction in
the cellular concentration of ATP interrupts the activity of active pumps that are important
in ionic homeostasis, such as the sodium and potassium pump and the sarcoplasmic reticu-
lum calcium,S ATPase, resulting in cytosolic overload of Na+ and Ca2+ , which prevents
cell repolarization, leading to contractile dysfunction. Additionally, high concentrations
of Ca2+ in the cytosol activate enzymes associated with lipid peroxidation, production of
reactive oxygen species (ROS), dysfunction of contractile proteins, loss of cell function and,
ultimately, cell death [52,53].
J. Pers. Med. 2023, 13, 1506 7 of 19

In tissue reperfusion with the end of aortic occlusion, it promotes the formation of ROS
in the cytosol, mitochondria, peroxisome, lysosomes and plasmatic membrane of polymor-
phonuclear leukocytes activated during the CPB ischemia period. Thus, the reintroduction
of the oxygen molecule in the ischemic heart tissue causes free radicals to react with polyun-
saturated fatty acids from the cell membrane. This starts a chain of oxygen-dependent
lipid deterioration where there formation of lipid peroxides and hydroxy-peroxides occurs,
which are generated rapidly by the NADPH oxidase complex in response to cytokines
that result in the generation of excessive amount of ROS, decreased membrane fluidity
and increased permeability and consequent damage to the cell membrane, contributing to
functional impairment in CPB [53–55].
When these ROS accumulate disproportionately to the body’s antioxidant capacity,
we are facing a situation called oxidative stress. The excess of reactive species causes
arrhythmias, reduction of the systolic function and change in the permeability of the my-
ocytes membrane. To avoid this, hydroperoxide radicals are removed from cells by enzyme
systems with antioxidant functions, generally present in the myocardium. These enzyme
systems with antioxidant action are responsible for limiting the intracellular accumulation
of reactive species during normal metabolism, reducing oxidative damage to proteins,
lipids and DNA [53–57].

4. Vasoplegic Syndrome Associate to CPB

One of the main changes that occur in patients undergoing cardiac surgery with car-
diopulmonary bypass is the vasoplegic syndrome. It is characterized as a circulatory shock,
of the distributive type, coursing with systemic vasodilation. It has a pathophysiology and
treatment similar to that of sepsis, with some peculiarities [58–61]. In this sense, the vasople-
gia observed after CPB can affect a considerable number of patients, with studies showing
an incidence greater than 50%, and is characterized by a low systemic vascular resistance,
with normal or slightly increased cardiac output that occurs in the first 24 h, associated
with a cardiac index (CI) greater than 2.2 L/kg/m2 . This drop in SVR leads to tissue hypop-
erfusion and progression to organ dysfunction [62,63]. The treatment of this condition is
based on the use of vasopressors to maintain mean arterial pressure within recommended
values, and recent research has associated the use of new, non-catecholaminergic strategies
as adjuvant treatments.
Furthermore, statistics indicate that approximately 25% of patients undergoing car-
diac surgery with cardiopulmonary bypass present vasoplegic syndrome, with variations
depending on the associated risk factors, and with high rates of morbidity and mortality in
these patients [64,65]. The mechanisms by which CPB leads to vasoplegia are multifactorial
and many signaling pathways are still being studied, but factors inherent to patients such
as obesity, diabetes, autoimmune diseases, intraoperative hyperthermia seem to contribute
to the increased incidence, in addition to the prolonged duration of CPB [64].

4.1. Regulatory Mechanisms: Vasoconstriction and Vasodilation

Physiologically, the dynamics of vascular smooth muscle contraction are strongly
linked to the calcium ion. It occurs due to an intracellular response to the increase in this
positive ion, which forms a complex with calmodulin, and this complex activates signaling
pathways that lead to the phosphorylation of the myosin light chain that will bind to actin,
promoting the shortening of muscle fibers and the contraction effect (Figure 2). There
are several ways in which increased intracytoplasmic calcium can occur; the main ones
are through G protein-linked receptors, of the Gq type, in which the activation of this
receptor internally signals the cell to mobilize calcium from the endoplasmic reticulum; the
responsible receptors are alpha-1 adrenergic receptor, vasopressin-1 receptor and type 1
angiotensin receptor [66,67].
 signaling pathways that lead to the phosphorylation of the myosin light chain that will
bind to actin, promoting the shortening of muscle fibers and the contraction effect (Figure
2). There are several ways in which increased intracytoplasmic calcium can occur; the
main ones are through G protein-linked receptors, of the Gq type, in which the activation
of this receptor internally signals the cell to mobilize calcium from the endoplasmic
J. Pers. Med. 2023, 13, 1506 8 of 19
reticulum; the responsible receptors are alpha-1 adrenergic receptor, vasopressin-1
receptor and type 1 angiotensin receptor [66,67].

Figure 2. Physiology of contraction and relaxation of vascular smooth muscle. Muscle contraction
Figure 2. Physiology of contraction and relaxation of vascular smooth muscle. Muscle contraction
occurs in response to the activation of receptors present in the membrane, such as the alpha-1
occurs in response to the activation of receptors present in the membrane, such as the alpha-1 adrener-
adrenergic receptor (a1R), the vasopressin-1 receptor (V1R) and the angiotensin type-1 receptor
gic receptor (a1R), the vasopressin-1 receptor (V1R) and the angiotensin type-1 receptor (AT1R); their
(AT1R); their activation by the selective agonist promotes the phosphorylation of the Gq protein and
activation by the selective agonist promotes the phosphorylation of the Gq protein and with that,
with that, the signaling pathway starts. With this, there is the release of calcium by the endoplasmic
the signaling
reticulum pathway
through starts. With this, there(IP3);
phosphatidylinositol-3 is the the
release of calcium
calcium by the
released inendoplasmic
the cytosol reticulum
binds with
through phosphatidylinositol-3 (IP3); the calcium released in the cytosol
calmodulin (CaM), forming the calcium-calmodulin complex that phosphorylates binds with calmodulin (CaM),
myosin and
forming the calcium-calmodulin complex that phosphorylates myosin and promotes
promotes contraction. On the other hand, the nitric oxide (NO) produced by the endothelium contraction.
On the the
reaches other hand, the
smooth nitric oxide
muscle, (NO) produced
converting GTP intobycGMP.
the endothelium reaches the smooth
cGMP dephosphorylates muscle,
myosin and
converting
promotes GTP into In
relaxation. cGMP. cGMPNO
addition, dephosphorylates myosin and
activates ATP-sensitive promoteschannels
potassium relaxation. In addition,
(KATP), leading
toNO activates ATP-sensitive
hyperpolarization potassium
and inhibition channels (KATP),
of vasoconstriction. leading to hyperpolarization
Angiotensin and inhibi-
II (AgII); norepinephrine (NE);
arginine-vasopressin (AVP);
tion of vasoconstriction. cyclic guanosine
Angiotensin monophosphate(NE);
II (AgII); norepinephrine (cGMP); guanosine triphosphate
arginine-vasopressin (AVP);
(GTP); diacyl glycerol
cyclic guanosine (DAG); phospholipase
monophosphate (cGMP); guanosineC (PLC); phosphatidylinositol-4,5-bisphosphate
triphosphate (GTP); diacyl glycerol (DAG);
(PIP2); protein kinase
phospholipase C (PKC).
C (PLC); phosphatidylinositol-4,5-bisphosphate (PIP2); protein kinase C (PKC).

Norepinephrine (NE),
Norepinephrine (NE),which
whichis isthethe
endogenous
endogenous ligand of the of
ligand alpha-1 adrenergic
the alpha-1 recep-
adrenergic
tor, is released from nerve endings originating from the sympathetic chain,
receptor, is released from nerve endings originating from the sympathetic chain, and and epinephrine,
a derivative a
epinephrine, ofderivative
NE, is released from
of NE, the adrenal
is released fromand is adrenal
the also capable
andofis binding to theof
also capable alpha-1
binding
adrenergic receptor. Arginine vasopressin (AVP) is released from
to the alpha-1 adrenergic receptor. Arginine vasopressin (AVP) is released from the hypothalamic axisthe
and angiotensin II is regulated as part of the renin–angiotensin–aldosterone axis [66,67]. All
these signals are regulated in response to stress and can be pharmacologically modulated.
To cause vasodilation or in the absence of vascular muscle contraction, it is possible to
block the receptors or through the production of nitric oxide (NO) [44,68]. It is produced
from the enzymatic induction of nitric oxide synthase (NOS), which converts L-arginine
into NO. There are three isoforms of NOS, eNOS, present in the endothelium and offer a
constant production of NO to endothelial cells that can rapidly diffuse to vascular smooth
muscle cells and exert its vasodilation effects [68]. The iNOS, enzyme is inducible via
oxidative stress and inflammatory cytokines (interleukin 1, tumor necrosis factor alpha and
interferon gamma) and can produce significantly higher levels of NO when compared to
J. Pers. Med. 2023, 13, 1506 9 of 19

eNOS [66,69–71]. These high levels of NO can react with superoxide, leading to peroxyni-
trite formation and cellular toxicity [72]. And, finally, nNOS, present in neuronal cells and
participates in functions such as neuronal plasticity and regulation of cerebral perfusion
pressure, with mechanisms of vasoconstriction and relaxation of cerebral arteries, but this
isoform of NOS participates in few of the systemic mechanisms of vasodilation induced by
NO [73].
NO promotes vasodilation through several methods, the main one being related to the
activation of guanalyl cyclase, an enzyme found in vascular smooth muscle that catalyzes
the dephosphorylation of guanosine triphosphate to cyclic guanosine monophosphate
(cGMP), which inhibits calcium entry through voltage-gated channels and activates intra-
cellular proteins that are cGMP-dependent [62]. NO also activates ATP-sensitive potassium
channels (KATP), which promote potassium efflux and induces the cell to a hyperpolar-
ized state. In a hyperpolarized state, the secondary intracellular cascade that leads to
vasoconstriction is inhibited [74].

4.2. Vasoplegia
These regulatory mechanisms of vasoconstriction are deregulated, to a greater or lesser
extent, during and after the cardiopulmonary bypass ends (Figure 3). The passage of blood
through CPB stimulates the activation of the complement cascade, production of ROS
species and release of inflammatory mediators, such as the triad of cytokines, interleukin-1
(IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [45,75–78]. All this
inflammatory biochemistry is capable of acting in specific areas of the brain such as the
locus coeruleus and the paraventricular nucleus of the hypothalamus, where the cells
responsible for the hypothalamic-pituitary-adrenal axis are located; they stimulate these
regions and lead to a reduction and desensitization of the alpha-1 adrenergic receptor and
an increase in the inflammatory state, thus forming a cycle that is difficult to overcome
(11). This reduction in receptors may be related to reduced gene expression in response to
inflammation [66] or, more significantly, receptor desensitization, triggered by exaggerated
catecholamine release in response to baroreflex-dependent stimulation [11,66].
These inflammatory mediators can also increase the production of nitric oxide (NO)
through the induction of iNOS by activating the nuclear factor, kappa B (NF-κB), which is a
vasodilator and, in excess, can result in vasoplegic shock [79–81]. As a response to shock,
the body stimulates the release of vasopressors via another region of the hypothalamus
and the renin–angiotensin–aldosterone system in the production of angiotensin II to try
to maintain the contraction of vascular smooth muscle and tissue perfusion, but in the
persistence of shock, these mechanisms suffer depletion and saturation [82,83]. Despite
this, vasopressin is of considerable importance in the process of controlling vasoplegia,
as it is capable not only of neutralizing the effects of NO, but also of decreasing NO
production [61,84].
Although the body maintains internal control mechanisms in response to vasoplegia,
such as the release of vasopressors and sustained activation of the sympathetic system [11],
recent studies have shown that circulating levels of vasopressin are reduced a few hours
after the cardiopulmonary bypass, suggesting that CPB may deplete this vasopressor
and contribute to the installation/maintenance of vasoplegic syndrome [85,86]. Not only
vasopressin, but the activity of several types of K+ channels promotes potassium efflux
and membrane hyperpolarization. Among these channels is the ATP-sensitive K+ channel
(KATP) [74]. Activation of this channel has been strongly linked to the development of
pathological vasodilation [62]. Several mechanisms may explain the activation of the
KATP channel in the vasoplegic syndrome associated with CPB, including NO release,
vasopressin deficiency, hypoxia and acidosis [62,86,87].
J. Pers. Med. 2023, 13, x FOR PEER REVIEW 10 of 20
J. Pers. Med. 2023, 13, 1506 10 of 19

Figure3.3.Pathophysiology
Figure Pathophysiologyofofvasoplegia.
vasoplegia.WithWiththe
thereturn
returnofofblood
bloodtotothe
thesystemic
systemiccirculation
circulationafter
after
passingthrough
passing throughthe theoxygenation
oxygenationmembrane
membrane during
during cardiopulmonary
cardiopulmonary bypass,
bypass, there
thereisisaadepletion
depletionof
ofthe
theendogenous
endogenousligands
ligandsofofthe
thealpha-1
alpha-1adrenergic
adrenergicreceptors, vasopressin-1
receptors, vasopressin-1 andand
the the
type-1 angiotensin
type-1 angio-
tensin receptor,
receptor, in addition
in addition to theto the downregulation
downregulation of the of the receptors
receptors themselves,
themselves, making making vasocon-
vasoconstriction
striction
an event anthat
event
is that is unlikely
unlikely to occur.
to occur. The reduction
The reduction in receptor
in receptor concentration
concentration leadsleads to a reduc-in
to a reduction
tion in intracellular calcium and with it, a reduction in contraction. In addition, CPB
intracellular calcium and with it, a reduction in contraction. In addition, CPB induces the production induces the
production of reactive oxygen species (ROS) and releases inflammatory mediators
of reactive oxygen species (ROS) and releases inflammatory mediators that can lead to the desensiti- that can lead to
the desensitization of adrenoreceptors and induces the production of nitric oxide (NO). NO leads
zation of adrenoreceptors and induces the production of nitric oxide (NO). NO leads to an increase in
to an increase in cGMP, which inhibits calcium in cells, leading to muscle relaxation. NO also acti-
cGMP, which inhibits calcium in cells, leading to muscle relaxation. NO also activates ATP-sensitive
vates ATP-sensitive potassium channels (KATP), leading to hyperpolarization and inhibition of vas-
oconstriction.channels
potassium NO further(KATP),
reactsleading
with thetosuperoxide
hyperpolarization and inhibition
anion radical (O2−) to formof vasoconstriction.
peroxynitrite (PN). NO
−
further reacts with the superoxide anion radical (O2 ) to form peroxynitrite (PN).
These inflammatory mediators can also increase the production of nitric oxide (NO)
In addition, the surgical incision is initially capable of triggering an inflammatory
through the induction of iNOS by activating the nuclear factor, kappa B (NF-κB), which
response, even if to a lesser extent, when compared to CPB. As the surgery progresses
is a vasodilator and, in excess, can result in vasoplegic shock [79–81]. As a response to
J. Pers. Med. 2023, 13, 1506 11 of 19

and the patient is coupled to the cardiopulmonary bypass system, systemic inflammatory
response syndrome can occur [80]. Of the generated cytokines, it is believed that interleukin-
6 is the one most associated with vasoplegia, as it is notably a potent inhibitor of vascular
contraction [64,88,89]. As the contact time of the blood with the CPB equipment is one
of the factors that contribute to the degree of the inflammatory response generated, as it
continues, the secondary immune response occurs as a result of the reinfusion of blood
from the circuit to the aorta. A cluster of hemolyzed cells and injured platelets stimulate
a secondary immune response leading to increased inflammation and subsequent loss of
vascular tone [80,90].
In refractory cases of vasoplegic syndrome, an increase in the dose of vasopressors is
necessary; however, without effect on mean arterial pressure levels, the patient can return
to CPB and a new attempt to withdraw from CPB can be performed. This may occur, as
the inflammatory state generated may be capable of inhibiting the response of adrenergic
receptors to catecholamines, through mechanisms that are still poorly understood [66].

5. Future Perspective and Antioxidant Agents

Although there are endogenous control systems to reduce the oxidative stress gen-
erated by cardiopulmonary bypass, they alone are often unable to attenuate the damage
caused [91]. There are considerable biochemical changes during and after the CPB, such as
oxygenation in non-endothelial membranes, reperfusion damage, absorption of nutrients
in the CPB circuit [91,92]. This context of inflammation and oxidative stress has been
associated with postoperative complications in these patients, such as atrial fibrillation,
acute kidney and lung and liver injury [12,51,93–95]. In this sense, several drugs with
antioxidant properties are being investigated, either as individual therapies or in combined
treatment to reduced oxidative damage.

5.1. Miniaturized Cardiopulmonary Bypass

The miniaturized cardiopulmonary bypass (mCPB) method was developed as a more
biocompatible alternative to conventional cardiopulmonary bypass [96]. It consists of a
small, closed, heparin-coated circuit in which venous blood is returned to a diffusion mem-
brane oxygenator through active drainage, which reduces mechanical trauma. Although
some studies have shown considerable benefit in relation to conventional systems, mainly
in the reduction of the inflammatory response and its associated complications [97,98],
meta-analyses of randomized clinical studies show contrasting results, in which there is no
significant difference in the incidence of primary outcomes such as stroke and mortality
among mCPB compared with the CPB [99].

5.2. Low-Level Light Therapy

As already mentioned, oxidative stress triggers several events that can lead to negative
outcomes in the patient [12]. Although new methods have been developed, such as mCPB
and materials with better biocompatibility, the results are still uncertain. In this regard,
although premature, the use of low-level light therapy (LLLT) in the red-to-near-infrared
radiation has shown promise [100–103]. The results of this method include a reduction in
the inflammatory response, as lipid peroxidation, and hemolysis during cardiopulmonary
bypass [100]. Furthermore, it has been shown to be important in also reducing platelet loss
and change of pattern of aggregation and CD62P (P-selectin) expression. This suggests that
LLLT can stabilize platelet function during CPB and decrease the side effects associated
with the interaction of cells with an non-endothelial surfaces [101].

5.3. Dexmedetomidine
Some anesthetics may extend clinical benefits beyond anesthesia and may also offer
anti-inflammatory support [104]. Dexmedetomidine (DEX), an alpha 2-adrenergic receptor
agonist, has been studied as a possible modulator of the inflammatory response caused
by cardiopulmonary bypass in cardiac surgery [105–107]. Bulow et al. [107] demonstrated
J. Pers. Med. 2023, 13, 1506 12 of 19

that the use of dexmedetomidine attenuated the increase in inflammatory cytokines (IL-
1β, IL-6, TNF-α and INF-γ) in patients undergoing cardiac surgery for up to 24 h after
CPB. In addition, randomized clinical studies have shown that in patients undergoing
cardiac surgery with CPB, the intraoperative administration of DEX reduced the levels of
pro-inflammatory cytokines during and after CPB, in addition to presenting possible renal
and cardiac protection [108–112].
Some mechanisms are suggested for this effect, such as the inhibition of noradrenaline
overflow and activation of the vagus nerve and the nicotinic acetylcholine receptor, which
are related to the suppression of inflammatory cytokines [113,114]. In this sense, DEX is
considered a promising candidate in modulating the inflammatory response, although more
studies are needed to explore the effect of dexmedetomidine on the long-term prognosis
of patients.

5.4. N-Acetylcysteine
N-acetylcysteine (NAC) is an acetyl derivative of L-cysteine with an active mercapto
group. Although it is widely used as a mucolytic in respiratory syndromes, it has recently
gained prominence, as studies have shown that the use of NAC prevents oxidative damage,
inhibits apoptosis and the inflammatory response, and promotes glutathione synthesis
in cells, one of the main endogenous antioxidants [115–118]. Regarding the heart, NAC
can improve the systolic function of myocardial cells and cardiac function, in addition to
protecting ventricular and vascular remodeling [115,119–122].
In addition, NAC has exhibited important effects by reducing the levels of lactate and
nitrogenous slags in the blood 24 h after cardiac surgery with CPB, suggesting a benefi-
cial effect on peripheral and renal tissue perfusion [123]. Furthermore, the prophylactic
use of NAC attenuates the liver damage induced by cardiopulmonary bypass during car-
diac surgery, in addition to reducing the incidence of acute kidney injury in this type of
surgery [93,124–126]. However, more clinical studies are needed to standardize necessary
doses and treatment times, as well as monitoring possible unwanted effects.

5.5. Nitric Oxide (NO)

NO has emerged as a promising alternative for protecting organs in cardiac surgeries,
especially the kidneys and the heart itself. NO is formed in the human body from the
oxidation of L-arginine via NO synthases, which are present in three isoforms (neuronal,
endothelial and inducible) [127,128]. Administered via inhalation, it generates selective
pulmonary vasodilation, whereas, due to its short half-life, it does not have systemic action.
However, its metabolites can circulate throughout the body and act on more distant organs.
Currently, inhaled NO is not recommended for routine use in patients under mechanical
ventilation, but it is commonly used in pulmonary arterial hypertension crises and in
persistent hypoxemia in acute respiratory distress syndrome (ARDS) [127].
For a long time, the possible deleterious effects of NO on cardiac muscle were marked,
due to the formation of free radicals from its degradation. However, more robust studies
have shown worsening of ischemia/reperfusion injuries when NO synthases are inhibited
and improved outcomes with the administration of exogenous NO [127,129].
The clinical applicability of exogenous NO in the context of cardiac surgeries with
PCB still has few studies, but with promising results. In randomized clinical trials of NO
administration in patients undergoing cardiac surgery with CPB, the development of acute
kidney injury was lower compared to the placebo groups [130,131]. In addition, recent
studies have shown that the use of NO during CPB can contribute to cardioprotection, with
significant reductions in troponin I levels and of the low cardiac output syndrome [132–135].
Thus, even with increasing evidence, there remain significant gaps, and more high-
quality, multicenter, high-volume research is needed in both adult and pediatric populations.
J. Pers. Med. 2023, 13, 1506 13 of 19

5.6. Vitamin C
Ascorbic acid has a great ability to donate electrons, which makes it a potent antioxi-
dant capable of interrupting cascades of free radicals that cause lipid peroxidation. It also
contributes to the immune system in processes such as neutrophil chemotaxis, phagocyto-
sis by lymphocytes and cell renewal [136,137]. In addition, vitamin C can phosphorylate
the signaling pathway in erythrocytes, in addition to stimulating endothelial nitric oxide
production, which can reduce blood loss and vasoplegic syndrome [138,139].
Furthermore, studies have been demonstrated the benefit of vitamin C supplementa-
tion, contributing to the reduction of arrhythmias (mainly atrial fibrillation) and duration
of mechanical ventilation, ICU and hospital stay, despite not having demonstrated an
improvement in mortality [138–142]. Although its use is promising, even with limitations,
studies that assess the form of administration, whether in bolus or continuous infusion,
before, during or after CPB are necessary to better assess the effectiveness of vitamin
C supplementation.

5.7. Vitamin E
Vitamin E comes in different forms (isomers), with α-tocopherol having the highest
antioxidant potential. These isomers are present in cell membranes and have an antioxidant
action by inhibiting lipid peroxidation. It has already been demonstrated that serum levels
of vitamin E are reduced during and after cardiac surgery; however, the primary outcomes
linked to its supplementation are still conflicting despite good experimental results, mainly
linked to α-tocopherol [143–146].

6. Conclusions
Cardiac surgery using cardiopulmonary bypass, although not perfect, remains es-
sential within intraoperative management. The inflammatory state and the production
of reactive oxygen species and oxidative stress remain challenges within the medical
sciences. In addition, the use of pharmacological strategies with antioxidant potential
that aim to reduce these radicals have a promising potential in reducing CPB compli-
cations such as the vasoplegic syndrome. Thus, more research needs to be carried out,
whether in basic science or randomized controlled clinical studies, in addition to more rigid
intraoperative management.

Author Contributions: Conceptualization, L.O.F., P.S.A., K.D.R. and D.C.F.L.; methodology, V.W.V.,
J.d.S.L., J.R.V.N., G.E.d.C. and J.d.C.E.; writing, L.O.F., S.C.d.S., J.A.M. and F.R.S.S.; draft preparation,
J.M.L.F.; writing—review and editing, L.O.F. and M.R.P.; visualization, C.J.d.S.L.; supervision, K.D.R.
and D.C.F.L. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded in part by PROPESP-UFPA.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Conflicts of Interest: The authors declare no conflict of interest.

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