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Inflammation & Cell Signaling 2014; 1: e75. doi: 10.14800/ics.75; © 2014 by Elif Doğan Baki, et al.
http://www.smartscitech.com/index.php/ics
REVIEW
Effects of anesthetic choice on inflammatory response in
cardiac surgery
Elif Doğan Baki1, Remziye Gül Sivaci1, Serdar Kokulu1, Yüksel Ela1, Mustafa Aldemir2
1
Afyon Kocatepe University, Faculty of Medicine, Department of Anesthesiology and Reanimation, 03200, Afyon, Turkey
Afyon Kocatepe University, Faculty of Medicine, Department of Cardiovascular Surgery, 03200, Afyon, Turkey
2
Correspondence: Elif Dogan Baki
E-mail: [email protected]
Received: January 31, 2014
Published online: March 04, 2014
Cardiac surgery is associated with the development of a systemic inflammatory response. The cytokine response in
cardiac surgery patients is well explained and is dominated by the pro-inflammatory cytokines tumour necrosis
factor (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and the antiinflammatory cytokine interleukin-10 (IL-10).
The release of these cytokines has been related to the development of complications after cardiopulmonary bypass
(CPB). In addition to many factors, choice of anesthetic agents affects immune response in cardiac surgery. This
article summarizes recently published literature concerning inflammatory cytokines associated with
cardiopulmonary bypass, use of anesthetic management techniques and their effects on inflammatory response in
cardiac surgery.
Keywords:
anesthesia; cardiac surgery; inflammation
To cite this article: Baki E, et al. Effects of anesthetic choice on inflammatory response in cardiac surgery. Inflamm Cell
Signal 2014; 1: e75. doi: 10.14800/ics.75.
Copyright: © 2014 The Authors. Licensed under a Creative Commons Attribution 4.0 International License which allows
users including authors of articles to copy and redistribute the material in any medium or format, in addition to remix,
transform, and build upon the material for any purpose, even commercially, as long as the author and original source are
properly cited or credited.
Introduction
Cardiopulmonary bypass (CPB) conduces to the release
of antiinflammatory cytokines that intervene the
inflammatory response observed during and after open
heart surgery [1].
CPB may especially activate the inflammatory response
over at least three different mechanisms. One mechanism
includes direct “contact activation” of the immune system
following exposure of blood to the foreign surfaces of the
CPB circuit. A second mechanism involves ischemiareperfusion injury to vital organs as a result of aortic crossclamping. There is a changing in perfusion of a lot of
organs such as intestines, kidneys, brain, and myocardium
resulting in cellular ischaemia before and after the initiation
of CPB. The third mechanism involves systemic
endotoxemia resulting from gut translocation of endotoxin
across a damaged mucosal barrier compromised following
splanchnic hypoperfusion. Endotoxemia may indirectly
activate the inflammatory cascade [2, 3].
Actuation of the complement cascade occurs and
secretion of interleukin 6 (IL-6), interleukin 8 (IL-8) and
tumour necrosis factor (TNF-α) also begins [4]. Due to the
inflammatory cascades, severe amplification begins to
produce multi-organ system dysfunction such as
coagulopathy, respiratory failure, myocardial dysfunction,
renal insufficiency, and neurocognitive defects [5].
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Inflammation & Cell Signaling 2014; 1: e75. doi: 10.14800/ics.75; © 2014 by Elif Doğan Baki, et al.
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Although the nature of peroperative cytokine response
seems to be specially identified by direct surgical trauma,
anesthesia regiments may perform a modifying effect [6,7].
Anesthetic regiments for cardiac surgery have developed
over the years, range from primarily volatile inhalation
anesthesia to high dose opioid, total intravenous anesthesia.
In recent years total intravenous anesthesia with short
acting agents and a combination of volatile agents with
intravenous anesthesia has become most popular [8].
Cytokines associated with CPB
Cytokines are a wide and swiftly growing group of
polypeptides manufactured by several diverse cell types
and necessary for optimum function of the immune system
[9]. TNF-α, IL-6, IL-8, and interleukin-1β (IL-1β) are the
major pro-inflammatory cytokines response to cardiac
surgery [2, 9, 10]. The proinflammatory cytokine response is
balanced by a phased antiinflammatory cytokine response
with soluble cytokine receptors, cytokine receptor
antagonists, and antiinflammatory cytokines. The prime
antiinflammatory cytokines are interleukin-10 (IL-10),
interleukin-1 receptor antagonist (IL-1ra), and TNF soluble
receptors 1 and 2 (TNFsr 1 and 2) [2].
TNF-α is made by activated monocytes and
mononuclear phagocytes, and it has a significant role in
inflammation [11]. Plasma levels of TNF-α increase with
CPB [12] and increase faster than other cytokines, showing
its role as a pioneer in the inflammatory response. It has a
big role in rised microvascular permeability [13] and is liable
for the post CPB weight gain, worse respiratory index and
prolonged hospital stay [14]. TNF-α can engender
hypotension, coagulopathy and renal dysfunction and its
increased levels are closed with systemic inflammatory
response syndrome/multiple organ dysfunction syndrome
(SIRS/MODS) [15].
IL-6 is a proinflammatory cytokine and is one of the
prime mediators in the acute phase response causing a host
of organ involvement, chiefly including the respiratory
system and the central nervous system [3]. It is the major
predictor within the pro-inflammatory cytokines of LV
systolic dysfunction, myocardial ischaemic episodes,
reduction in systemic vascular resistance, need for
vasopressor support, and cardiovascular abnormalities and
associated with mortality rates in inflammatory states like
sepsis [16, 17]. High levels of IL-6 are also significantly
associated with hepatic and renal dysfunction [18].
IL-8 is a proinflammatory cytokine, and its level
increases in cardiac surgeries with CPB. Elevated IL-8
levels associated with respiratory dysfunction, length of
inotropic support and were inversely related to the ratio of
PaO2 to FIO2 [19].
IL-10 is a powerful anti-inflammatory cytokine made by
monocytes and macrophages that inhibits production of
pro-inflammatory cytokines such as TNF-α, IL-6, IL-8 and
IL-1β [20] and also provides protection from ischaemia and
reperfusion (I/R) injury [21].
High dose opioid anesthesia
Since the 1980s, high-dose opioid methods have been
used in cardiac anesthesia due to their good circulatory
stability and stress reduction characteristics [22]. However
pure high-dose opioid anesthesia (e.g., fentanyl, 50-100
mcg/kg, or sufentanyl, 15-25 mcg/kg) performs longer
postoperative respiratory depression (12-24 h) and is
associated with an unacceptably high incidence of patient
awareness during surgery. Also muscle rigidity during
induction and prolonged postoperative ileus are undesired
effects of this regimen. Moreover, simultaneous
administration of benzodiazepines with large doses of
opioids can produce hypotension with myocardial
depression. When short acting agents, such as sufentanil or
remifentanil are used instead of fentanyl, patients generally
regain consciousness and can be extubated earlier. [8].
Opioids have many effects on the immune system,
intervened indirectly over the central nervous system or
through direct interactions with the cellular immune system
[23, 24]. Fentanyl increases concentrations of IL-1ra in in
vitro monocyte cultures [25].
Guggenberger and colleagues [26] compared the effects
of remifentanil with sufentanil on pulmonary function and
showed remifentanil anaesthesia was better in improving
pulmonary function in CABG patients. Brix-Christensen et
al [27] showed that a high or low dose opioid has similar
effects on the perioperative cytokine response to cardiac
surgery.
Total intravenous anesthesia (TIVA)
The drive for cost containment in cardiac surgery was a
major impetus for development of anesthesia techniques
with short acting agents. This method utilizes induction
with propofol (0.5-1.5mg/kg followed by 25-100 mcg/kg)
and small doses of fentanyl (total doses of 5-7 mcg/kg) or
remifentanyl (1 mcg/kg bolus followed by 0.25-1
mcg/kg/min) [8].
Propofol may boost the antiinflammatory response to
surgery by several mechanisms. Propofol may maintain
hepatosplanching blood flow during CPB [28]. It not only
changes the balance between proinflammatory and
antiinflammatory cytokines, increasing production of the
antiinflammatory cytokine IL-10 and IL-1ra [29] while
decreasing neutrophil IL-8 [30] secretion, and also cleans
reactive oxygen species either [31]. And also propofol with
low doses decrease neutrophil uptake in the coronary
circulation following myocardial ischemia and reperfusion
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Inflammation & Cell Signaling 2014; 1: e75. doi: 10.14800/ics.75; © 2014 by Elif Doğan Baki, et al.
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[32]
. Propofol reduces free-radical-mediated lipid
peroxidation and systemic inflammation in patients with
impaired myocardial function undergoing CABG [33].
Several studies have investigated the effects of different
anaesthetic managements on the immune response during
and after cardiac surgery, and have suggested that propofol
may have beneficial effects on post-traumatic immune
changes [34]. In addition, it has been showed that propofol
may alleviate the cytokine response observed during septic
shock in rodents [35]. El Azab and collegues compared the
effects of three different anesthesia regimens on the
cytokine response during cardiac surgery [9]. They showed
that the cytokine response was similar after volatile
anaesthetics, propofol /sufentanil anaesthesia and
midazolam/suffentanil anesthesia [9].
A study comparing desflurane with propofol in patients
undergoing off pump CABG surgery showed that
postoperative troponin was lower and hemodynamic
function was better in patients receiving desflurane [36]. In
contrast, a small study that administered high-dose
propofol (120 mcg/kg/min), low-dose propofol (60
mcg/kg/min) while on pump or titrated isoflurane
throughout surgery improved troponin levels and gave
better hemodynamic function in the large-dose propofol
group compared to the isoflurane or low-dose propofol
group [37]. Bakı et al studied the effect of propofol versus
desflurane anesthesia on systemic immune modulation and
the central nervous system in cardiac surgery patients with
CPB. They showed that the immune reaction was less in
patients exposed to desflurane anesthesia when compared
to propofol anesthesia, as indicated by lower plasma
concentrations of IL-8 and IL-6.
Mixed intravenous/Inhalation anesthesia
Renewed interest in volatile agents came about
following studies demonstrating the protective effects of
volatile agents on ischemic myocardium and an increased
emphasis on fast track recovery of cardiac patients.
Propofol (0.5-1.5 mg/kg) or etomidate (0.1-0.3 mg/kg) is
often used for anesthesia induction. Opioids are given in
small doses together with a volatile agent with 0.5-1.5
minimum alveolar concentration (MAC) for maintenance
anesthesia. The opioid may be given in small intermittent
boluses, by continuous infusion, or both [8]. The most
commonly used volatile anesthetics are isoflurane,
sevoflurane and desflurane. Nitrous oxide is generally not
used during the time interval between cannulation and
decannulation because of its tendency to expand any
intravascular air bubbles that may form [8]. Sevoflurane,
isoflurane, and enflurane reduce IL-1β, TNF-α release by
human peripheral mononuclear cells in vitro [38]. Isoflurane
decreases alveolar macrophage phagocytosis and
microbicidal function more than propofol [39]. Halothane,
isoflurane, and enflurane minimize free radical-mediated
myocardial injury [40, 41].
Winterhalter et al compared the effects of continuous
infusion of remifentanyl with intermittent fentanyl on the
endocrine stress response and inflammatory activation
during CABG surgery [22]. They used propofol for
induction and also maintenance with sevoflurane in their
study. They showed that remifentanyl group patients were
extubated earlier than the fentanyl patients in their study.
Stress hormones (ADH, ACTH, cortisol) and interleukins
(TNF-α, IL-6, IL-8) were higher in the fentanyl group
compared to the remifentanyl group.
Other techniques
Patients with hemodynamic instability the combination
of ketamine with midazolam is a useful technique for
induction and maintenance of anesthesia.
Midazolam has little effect on host defense mechanisms
and decreases neutrophil IL-8 secretion in response to
lipopolysaccaride [30]. Midazolam decreases postischemic
uptake of neutrophils in the coronary circulation following
myocardial ischemia and reperfusion [32].
Ketamine decreases the increased levels of IL-6
concentrations during and following CPB [42] and decreases
coronary uptake of neutrophils following myocardial
ischemia and reperfusion [32]. High concentrations of
ketamine affects E.Coli clearance and neutrophil and
monocyte phagocytosis in vitro [43]. Ketamine in
subanaesthetic doses was shown to have beneficial effects
on the immune response during and after surgery [44, 45, 46].
Welters et al [10] investigated the plasma levels of
inflammatory markers with an anaesthetic regimen based
on ketamine as the sole analgesic. They showed that
anaesthesia with ketamine may have beneficial effects in
attenuating the CPB-induced systemic inflammatory
response.
Conclusions
Cardiac surgery evokes a generalized inflammatory
response in all patients, with serious clinical consequences
[2]. A better understanding of the inflammatory response to
cardiac surgery may be the key to development of
successful strategies in pharmacology, perfusion
technology, cardiovascular monitoring, and anesthetic and
surgical technique in order to minimize patient morbidity.
Conflict of interests
The authors declare that they have no conflict of
interests.
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