REVIEW

CURRENT
OPINION Anesthesia-induced immune modulation
Jan Rossaint and Alexander Zarbock

Purpose of review
Surgery, invasive procedures and anesthesia itself may induce an inflammatory response in the patient.
This represents an evolutionary inherited and conserved response of the host to environmental stimuli and
may lead to both beneficial and potentially harmful effects. This review highlights the mechanisms of
anesthesia-induced and perioperative immune modulation.
Recent findings
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The innate and adaptive immune system serve the host in protection against invading pathogens. Yet, an
inflammatory immune response may also be induced by different noninfectious stimuli, for example invasive
perioperative procedures and the surgical trauma itself. These stimuli may lead to the activation of the
immune system with the consequence of perturbation of cell, tissue of even organ functions in cases of an
overshooting immune response. Several perioperative factors have been identified that modulate the
immune response, for example different anesthetic drugs and surgical tissue injury, but their impact on
immune system modulation may also vary with respect to the procedural context and include both pro-
inflammatory and anti-inflammatory effects.
Summary
The current review will highlight the current knowledge on the perioperative anesthesia-induced and
surgery-induced modulation of the immune response and also address possible intervention strategies for
the development of future therapeutic approaches.
Keywords
anesthesia, immune response, inflammation, perioperative, surgery

INTRODUCTION HOST IMMUNE RESPONSE TO SURGICAL

Surgical procedures induce a modulation of the
immune system and in some cases even a dysregu-
lated immune response of the host. While the inev-
itable tissue damage in association with the surgery
contributes in large parts to the immune modula-
tion, evidence from preclinical studies and clinical
trials demonstrate that general anesthesia, but also
regional anesthetic procedures, and the administra-
tion of dedicated anesthetic drugs also substantially
alter the immune function. In addition, also further
periprocedural interventions, for example the
administration of blood products, the mechanical
ventilation of the patient during anesthesia and
eventually the use of extracorporeal circulatory sup-
port systems during cardiac surgery may signifi-
cantly modulate the immune system. These
effects may be directly mediated by the drugs itself,
for example following the use of hypnotic agents
such as propofol, volatile anesthetics and opioids
[1]. This review highlights the latest research results
how anesthesia during surgical procedures modu-
lates immune function, and thus may have an
impact on the patient’s outcome.
TISSUE TRAUMA
Surgical procedures automatically cause tissue
injury, which is associated with the release of certain
intracellular molecules and signaling mediators
called alarmins, also termed ‘damage-associated
molecular pattern’ molecules [2]. These molecules
may bind to evolutionary highly conserved pattern
recognition receptors (PRR), for example Toll-like
receptors (TLRs) on the cell surface of a whole range
of cell types, including leukocytes [3,4]. This
response is generally beneficial and aids in transfer-
ring danger signals to intact host tissue and leads to
cell priming and preparation for upcoming cell
Department of Anesthesiology, Intensive Care and Pain Medicine, Uni-
versity Hospital M€
unster, M€
unster, Germany
Correspondence to Alexander Zarbock, Department of Anesthesiology,
Intensive Care and Pain Medicine, University Hospital M€
unster, Albert-
Schweitzer-Campus 1, Building A1, 48149 M€ unster, Germany.
Tel: +49 251 83 47252; fax: +49 251 88704;
e-mail: zarbock@uni-muenster.de
Curr Opin Anesthesiol 2019, 32:799–805
DOI:10.1097/ACO.0000000000000790

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Technology, education and safety
KEY POINTS
 Both anesthesia-related and surgery-related
perioperative measures may modulate the patient’s
immune response and lead to the activation of different
components of the immune system.
 Anesthesia-induced activation, in particular of the
adaptive immune system, may also induce persistent,
postoperative immunosuppression.
 If the effects of anesthesia-induced immune modulation
are relevant for the patient’s outcome still requires
further studies in most cases.
stress in an attempt to preserve and restore host
tissue integrity and homeostasis [3,5]. However,
an overshooting alarmin release may also induce a
strong immune activation and dysregulation which
carries the imminent risk of excessive host tissue
damage and organ dysfunction and cause postoper-
ative infections due to prolonged exhaustion of the
immune system and following immune system sup-
pression, deterioration of lung function, transient
cognitive impairment, and kidney injury [6–9].
Mechanistically, the binding of alarmins to PRRs
causes the activation of different signaling mole-
cules within the cells. One common consequence
is the activation of transcription factors, for example
the prototypic proinflammatory element NF-kB
(nuclear factor kappa-light-chain-enhancer of acti-
vated B cells). Following activation, NF-kB trans-
locates from the cytosol into the cellular nucleus
and initiates the transcription of various genes, for
example chemokines, cytokines and other inflam-
matory mediators (Fig. 1). These mediators are pre-
sented by the cell or released into the extracellular
space and serve to activate sentinel cells of both the
innate and adaptive immune system residing in the
tissue, for example dendritic cells, monocytes and
macrophages [10]. Of note, different alarmins may
evoke a distinct immune response based on their
affinity to different PRRs expressed on different cell
types and tissues [11]. Apart from the detour over
PRR-expressing tissue cells and immune sentinels,
several alarmins, for example S100 proteins, are also
capable of directly activating leukocytes [12,13]. Yet
the most prominent way by which alarmins (e.g.
serum amyloid A, IL-33, IL-16 and HMGB-1)
released under different inflammatory conditions
evoke an immune response is by activation of senti-
nel cells and vascular endothelial cell. In response to
activation, these cells transform into an inflamed
phenotype with the expression of inflammatory
mediators and adhesion molecules on their cell
surface [14,15].
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NEUTROPHILS AND THE PERIOPERATIVE
MODULATION OF THE IMMUNE
RESPONSE
Neutrophils are among the most abundant leuko-
cyte subpopulations and resemble the main cellular
component of the innate immune defense to com-
bat invading pathogens, for example bacteria [16].
Neutrophils possess various cell-specific features
that enable them to fulfill their task. In particular,
neutrophils may produce and release highly reactive
oxygen species (ROS) and specialized proteolytic
enzymes that both serve to attack the cellular integ-
rity of pathogenic organisms. Furthermore, neutro-
phils are also capable of cellular uptake and internal
digestion of pathogens during phagocytosis. In
2004, in was discovered that neutrophils are also
able to produce and release neutrophil extracellular
traps (NETs) [17]. NETs are generated by active
decondensation of nuclear DNA, which is then dec-
orated with granular neutrophilic proteins and cast
into the extracellular space as a web-like structure.
NETs have been shown to physically entangle and
eliminate circulating bacteria [17]. However, exces-
sive activation and recruitment of neutrophils dur-
ing inflammatory processes also carries the risk of
severe cell and tissue damage that may lead to organ
dysfunction [18]. Importantly, surgical trauma and
the consecutive inflammatory response may lead to
increased oxidative stress and significant activation
and recruitment of neutrophils into peripheral
organs [19]. This is especially important during
cardiac surgery procedures with help of the extra-
corporeal circulation. Neutrophils in particular react
to exposure toward foreign surfaces, and the contact
to the cardiopulmonary bypass system may induce a
profound inflammatory response, systemic inflam-
mation, endothelial dysfunction with increased vas-
cular permeability, and organ injury [20]. In the
postoperative phase, these patients often switch to
a state of immune system exhaustion and immuno-
suppression with impaired immune cell function
[21]. Vascular endothelial cells are important for
the maintenance of circulatory hemostasis. These
cells are lined on their luminal surface by the gly-
cocalyx composed of glycoproteins proteoglycans
substituted with highly branched sugar chains [22].
This layer prevents the direct access of circulating
immune cells in the blood stream to surface adhe-
sion molecules on the surface of endothelial cells
[23]. Yet, degrading enzymes which shed and
destroy the glycocalyx (e.g. hyaluronidase and hep-
arinase) are released during vascular inflammation,
but also under states of vascular hypovolemia and
hypoperfusion [24,25]. In the presence of alarmins
the endothelial cells are activated and switch from a
resting state to an inflammatory phenotype by
Volume 32  Number 6  December 2019
 Perioperative inflammation Rossaint and Zarbock

Exogenous Sterile cell

infecons stress or injury

Insult

PAMP/DAMP
release

PRRs
PRRs
Recognion
M⏀ Epithelial cells
APCs

NF-kB
Iniaon
Inflammatory
Acvaon and chemokine release
nuclear translocaon

O-
O- O-
Response O-
-
O- O
Leukocyte ROS and protease
Recruitment release Tissue injury

FIGURE 1. Initiation of an immune response by infectious and sterile insults. APC, antigen-presenting cell; DAMP, damage-
associated molecular patterns; Mf, macrophage; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PAMP,
pathogen-associated molecular patterns; PRR, pattern recognition receptor; ROS, reactive oxygen species.

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Technology, education and safety
expression of proinflammatory cell surface mole-
cules, for example chemokines and adhesion mol-
ecules for leukocytes. The surface expression of
adhesion molecules and chemokines presented on
glycosaminoglycans on the luminal surface leads to
the recruitment of leukocytes from the blood stream
into the perivascular tissue [18]. The glycocalyx and
the vascular endothelial cells are also vulnerable to
NET-associated cytotoxicity, which may cause gly-
cocalyx deterioration, endothelial cell dysfunction
and perturbation of vascular integrity with
increased edema formation [26]. This is of particular
importance as perioperative stress and surgical tis-
sue trauma are known to cause increased NET pro-
duction and release [27].
EFFECTS OF ANESTHESIA MEDICATION
ON IMMUNE CELL FUNCTIONS
Current research over the last years has demon-
strated that the application of drugs frequently used
to induce and maintain anesthesia are associated
with significant effects on the immune system.
However, as these drugs are almost never applied
isolated without any concomitant surgical proce-
dure or intervention, it appears difficult to delineate
the isolated effect of anesthetic drugs on the
immune system in the clinical context. Thus, the
majority of studies investigating the immune-mod-
ulatory properties of anesthetic agents are derived
from laboratory investigations. The findings from
these studies demonstrate that almost all anesthetic
drugs modulate the function of the immune system,
either directly or indirectly [28,29]. The underlying
molecular mechanisms are manifold, including leu-
kocyte apoptosis and inhibition of leukocyte cell-
intrinsic functions (e.g. the phagocytosis of patho-
gen and cellular debris) [30].
OPIOIDS
Opioids are frequently used for analgesia during
balanced general anesthesia, but also for neuraxial
anesthesia (spinal and epidural anesthesia). How-
ever, opioids are also known for their widespread
modulation of the adaptive and innate immune
system function of the host [31]. Almost all leuko-
cyte subsets express the m-receptor for opioids, and
opioids strongly bind to these receptors, which
induced several effects. On macrophages, m-receptor
ligation leads to sustained desensitization of several
chemokine receptors, for example the receptors
CXCR1/2 and CCR1/2 [32]. Furthermore, it has been
shown that the activation of the m-receptor leads to
reduced activation of the proinflammatory tran-
scription factor NF-kB. As a result, the chemokine
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production and liberation from leukocytes is
altered, which is also reflected by significant
changes in the chemokine micromilieu, for example
with respect to local release of the proinflammatory
chemokine CXCL2 [32]. The opioid m-receptor may
also affect the cell-intrinsic functionality of granu-
locytes by perturbation of ROS production and
decreasing phagocytosis [33,34]. Beyond cell func-
tionality, opioids also modulate cell apoptosis. In
particular, high concentrations of morphine have
been demonstrated to cause apoptosis in macro-
phages, presumably through TLR9 and p38 [35].
Opioids also affect the adaptive immune system,
for example by binding to m-receptors on antigen-
presenting cells and B cells causing the downregu-
lation of MHC (major histocompatibility complex)
class II molecules which translates in diminished
cell proliferation and activation [36]. Furthermore,
the opioid activation of m-receptors forces T-cell
differentiation into T helper cells (TH2 phenotype)
[36]. This effect is mainly held responsible for the
opioid-induced T-cell agony in the perioperative
and early postoperative phase [37]. The clinical
implications of the m-receptor-mediated modula-
tion of the perioperative immune response may
be important due to the wide-spread perioperative
use of opioids and the modulation of the immune
response. Although inhibitory effects of opioids
particularly on the adaptive immune system imply
and an increase in patient susceptibility to postop-
erative infections and worse patient outcome, it
remains hard to finally judge the effects on patient
outcome and the immune response to different
stimuli in the perioperative and postoperative
period at this point and further research is needed.
INTRAVENOUS HYPNOTIC DRUGS
Intravenously administered hypnotic drugs, for
example propofol, thiopental and midazolam, are
an important part of modern perioperative anesthe-
sia regiments and frequently used in clinical rou-
tine. Previous studies have investigated the
immune-modulatory effects of these medications.
Propofol has been shown to increase the tissue
infiltration of natural killer (NK) T cells and T-helper
cells while it did not affect T-cell counts or leukocyte
& &&
cell apoptosis [38,39 ,40 ]. Furthermore, propofol
has also been shown to increase NK cell cytotoxicity
&&
[41 ] and the expression of tumor-killing effector
&&
molecules [42 ]. In particular, propofol also coun-
teracts the stress-induced inhibition of NK cell acti-
vation by sympathetic catecholamine release [43].
Current research indicates that NK cell activation
and cytotoxicity is an important determinant that
affects metastatic distribution during tumor surgery
Volume 32  Number 6  December 2019

[44]. Here, propofol could have potentially benefi-
cial effects, although clearly more mechanistic
investigations are necessary to finally judge whether
an anesthetic regimen using propofol may be favor-
able in these cases. Propofol has also been shown to
modulate the function of the innate immune sys-
&&
tem [45 ]. Here, propofol appears to decrease NET
formation by activated neutrophils through inhibi-
&&
tion of hypochlorus acid production and Erk [46 ].
Propofol also affects macrophage polarization by
inhibition of macrophage differentiation towards
the pro-inflammatory M1 phenotype and increased
expression of genes indicative for the anti-inflam-
&&
matory M2 phenotype [47 ]. In addition to T cells,
neutrophils and macrophages, propofol also modu-
lates the function of mast cells. It has been shown
that propofol limits mast cell degranulation and this
effect also translated into reduced cardiac ischemia-
&&
reperfusion injury ex vivo [48 ]. Thus, propofol
appears to modulate the function of several immune
cell subsets under different physiological and path-
ological circumstances. The GABAA (gamma-amino-
butyric acid) receptor has been proposed to be the
side of action by which propofol and sodium thio-
pental, another frequently used intravenous hyp-
notic drug, modulate leukocyte function [49].
These receptors are expressed on various leukocyte
subpopulations, for example monocytes, and it has
been shown that propofol and also sodium thiopen-
tal impair monocyte function via GABAA receptor
activation [49]. This finding may hold important
value also for the development of therapeutic strate-
gies to counteract anesthesia-induced immunosup-
pression. The benzodiazepine midazolam is
frequently used for perioperative anxiolysis and pro-
cedural sedation. Current research indicated that
midazolam may modulate the immune response
by inhibition of the lipopolysaccharide-evoked,
&
proinflammatory response in macrophages [50 ].
This prolonged phenomenon may contribute to
the development of an immunosuppression in the
&
postoperative phase [50 ]. In conclusion, research has
demonstrated different aspects by which intravenous
anesthetic drugs may modulate immune function,
but if these findings may also be outcome-relevant,
for example by translating into a greater susceptibil-
ity to infections in human patients, is still unclear
and requires further clinical trials.
VOLATILE ANESTHETICS
The volatile anesthetic gases sevoflurane and des-
flurane are important components for the perioper-
ative maintenance of modern, balanced anesthesia
concepts, but may also modulate the immune
response. Sevoflurane has been shown to induce
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Perioperative inflammation Rossaint and Zarbock
apoptosis in T-lymphocytes and B-lymphocytes
and change the Th1/Th2 ratio of lymphocytes,
whereas desflurane does not [51]. Furthermore, sev-
oflurane and desflurane decrease the blood count of
lymphocytes and NK cells while increasing neutro-
phil counts [52], while the definite effect of volatile
anesthetics on leukocyte cell-intrinsic functions is
still controversial. In animal experiments exposure
to sevoflurane led to the induction of an inflamma-
tory response in the lung and increased proinflam-
matory gene expression in lung-resident alveolar
macrophages [53]. In contrast, desflurane adminis-
tration ameliorated the deleterious, inflammatory
effects in a rat model of ventilator-induced lung
injury (VILI) by inhibiting NF-kB activation and
&
release of proinflammatory mediators [54 ]. Signifi-
cantly, a recent experimental study could show
similar protective effects for sevoflurane posttreat-
ment in a murine VILI model, which is controversial
&
to previous publications [55 ]. Most of the studies
investigating the effect of volatile anesthetics on the
immune function were performed in models of
acute inflammation, yet the experimental, and even
more important, clinical data on the role of immune
modulation by volatile anesthetics in the perioper-
ative setting remain scarce and to date do not allow
for substantial conclusion which volatile anesthetic
might be preferable in a given perioperative situa-
tion or should be avoided.
REGIONAL ANESTHESIA
The use of regional anesthetic procedures, either as a
stand-alone procedure or as part of a combined
anesthetic regime, is nowadays standard practice.
In combination with general anesthesia, neuraxial
procedures and peripheral nerve blocks may sub-
stantially contribute to reduce vegetative stress and
decrease the impact of the surgery and anesthesia on
the patient. In particular, serum levels of the proto-
typic stress hormone cortisol have been proven to be
lower during surgical procedures conducted under
regional anesthesia when compared with anesthetic
regimes including general anesthesia [56]. Further-
more, it could be demonstrated that orthopedic
knee surgery conducted with the aid of neuraxial
anesthesia led to a significant lower postoperative
incidence of infections compared with general anes-
thesia. This could be attributable to a less anesth
esia-induced perturbances of the immune system
response during regional anesthesia [57]. This view
is also supported by studies reporting a reduced
duration of T-cell anergy and disturbances in T
lymphocyte subsets (e.g. Th1, Th2 and regulatory
T cells) in association with anesthetic regimes
utilizing regional anesthesia techniques [58,59].
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Technology, education and safety
However, clearly more research is necessary to
finally judge the effect and molecular mechanisms
of regional anesthesia compared with general anes-
thesia with respect to immune system modulation.
CONCLUSION
Current research has broadened our view on peri-
operative, anesthesia-induced and surgery-induced
modulation of the immune function and shaped
our perception of the associated effect on the
patients’ outcome after surgical procedures. Yet,
to develop and safely apply clinical strategies and
therapeutic approaches to limit the negative effects
of perioperative immune modulation clearly more
research is necessary to understand the underlying
molecular mechanisms. In particular, the beneficial
aspects of the immune system and the perioperative
immune response need to the retained to assure the
host self-defense and maintain homeostasis while
limiting the negative aspects of inadequate
immune system activation or persisting postopera-
tive immunosuppression on the other side. Further-
more, the development of novel diagnostic tool sets
helping the physician to judge the perioperative
modulation of the immune system on site are nec-
essary and would improve perioperative patient
care in the future.
Acknowledgements
None.
Financial support and sponsorship
The current work was supported by the Deutsche For-
schungsgemeinschaft (grant no. RO 4537/4-1, RO 4537/
5-1 to J.R. and KFO342/1 to A.Z.).
Conflicts of interest
There are no conflicts of interest.
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45. Meier A, Chien J, Hobohm L, et al. Inhibition of human neutrophil extracellular
&& trap (NET) production by propofol and lipid emulsion. Front Pharmacol 2019;
10:323.
Clinical implications of neutrophil extracellular trap (NET) formation, especially with
respect to anesthesia in the perioperative setting, are scarce. This study adds an
important aspect to the field as the authors reporst inhibition of neutrophil NET
production by propofol, with potential implications of the perioperative modulation
of the immune response.
46. Chen MS, Lin WC, Yeh HT, et al. Propofol specifically reduces PMA-induced
&& neutrophil extracellular trap formation through inhibition of p-ERK and HOCl.
Life Sci 2019; 221:178–186.
In addition to the work by Meier et al., this study provides more molecular
mechanistic insights regarding the putative inhibitory effect of propofol on NET
formation by neutrophils.
47. Kochiyama T, Li X, Nakayama H, et al. Effect of propofol on the production of
&& inflammatory cytokines by human polarized macrophages. Mediators Inflamm
2019; 2019:1919538.
Polarization of macrophages either towards the anti-inflammatory M1 or proin-
flammatory M2 phenotype is important for the fate of many inflammatory conditions.
Kochiyama et al. report that propofol is capable of modulating macrophage
polarization in vitro.
0952-7907 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Perioperative inflammation Rossaint and Zarbock
48. Yu X, Sun X, Zhao M, et al. Propofol attenuates myocardial ischemia
&& reperfusion injury partly through inhibition of resident cardiac mast cell
activation. Int Immunopharmacol 2018; 54:267–274.
The study is of particular interest as it demonstrated the protective therapeutic
potential of propofol for ischemia-induced inflammatory insults.
49. Wheeler DW, Thompson AJ, Corletto F, et al. Anaesthetic impairment of
immune function is mediated via GABA(A) receptors. PLoS One 2011;
6:e17152.
50. Horiguchi Y, Ohta N, Yamamoto S, et al. Midazolam suppresses the lipopo-
& lysaccharide-stimulated immune responses of human macrophages via trans-
locator protein signaling. Int Immunopharmacol 2019; 66:373–382.
One of the few available studies demonstrating the modulation of the immune
response by benzodiazepines.
51. Loop T, Dovi-Akue D, Frick M, et al. Volatile anesthetics induce caspase-
dependent, mitochondria-mediated apoptosis in human T lymphocytes in
vitro. Anesthesiology 2005; 102:1147–1157.
52. Pirbudak Cocelli L, Ugur MG, Karadasli H. Comparison of effects of low-flow
sevoflurane and desflurane anesthesia on neutrophil and T-cell populations.
Curr Ther Res Clin Exp 2012; 73:41–51.
53. Kotani N, Takahashi S, Sessler DI, et al. Volatile anesthetics augment
expression of proinflammatory cytokines in rat alveolar macrophages during
mechanical ventilation. Anesthesiology 1999; 91:187–197.
54. Lin X, Ju YN, Gao W, et al. Desflurane attenuates ventilator-induced lung injury
& in rats with acute respiratory distress syndrome. BioMed Res Int 2018;
2018:7507314.
Interesting study that stands in contrast to the results presented by Wagner et al.
55. Wagner J, Strosing KM, Spassov SG, et al. Sevoflurane posttreatment
& prevents oxidative and inflammatory injury in ventilator-induced lung injury.
PLoS One 2018; 13:e0192896.
Interesting study that stands in contrast to the results presented by Lin et al.
56. Milosavljevic SB, Pavlovic AP, Trpkovic SV, et al. Influence of spinal and
general anesthesia on the metabolic, hormonal, and hemodynamic response
in elective surgical patients. Med Sci Monit 2014; 20:1833–1840.
57. Liu J, Ma C, Elkassabany N, et al. Neuraxial anesthesia decreases post-
operative systemic infection risk compared with general anesthesia in knee
arthroplasty. Anesth Analg 2013; 117:1010–1016.
58. Chen WK, Ren L, Wei Y, et al. General anesthesia combined with epidural
anesthesia ameliorates the effect of fast-track surgery by mitigating immuno-
suppression and facilitating intestinal functional recovery in colon cancer
patients. Int J Colorectal Dis 2015; 30:475–481.
59. Cheng YC, Cheng XB, Li XJ, et al. Combined general and regional anesthesia
and effects on immune function in patients with benign ovarian tumors treated
by laparoscopic therapy. Int J Clin Exp Med 2013; 6:716–719.
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