Best Practice & Research Clinical Anaesthesiology

Vol. 18, No. 3, pp. 493–507, 2004

doi:10.1016/j.bpa.2004.01.002
available online at http://www.sciencedirect.com

Effects of general anaesthesia on inflammation

Christine E. Schneemilch* MD

Thomas Schilling MD
Department of Anaesthesiology and Intensive Care Medicine, Otto-von-Guericke-University, Leipziger Str. 44 D-39120
Magdeburg, Germany

Ute Bank PhD

Institute of Medical Technology Leipziger Str. 44 D-39120 Magdeburg, Germany

General anaesthesia accompanied by surgical stress may influence the inflammatory responses
that are essential for maintaining the homeostatic state during the postoperative course. Severe
dysregulation of the inflammatory process may provoke or aggravate postoperative
complications, e.g. increased susceptibility to infections, inadequate stress reactions and
hypercatabolism. Anaesthetics have been suspected of impairing various functions of the immune
system either directly, by disturbing the functions of immune-competent cells, or indirectly by
modulating the stress response. In the past, conflicting data on the possible immunological side
effects of anaesthetics have been published. Potential reasons for these controversial findings
include heterogeneous patient study groups with diverse pre-existing diseases, lack of
standardisation of surgical procedures, major differences in the length and severity of surgical
tissue injury and a small number of randomised studies. Although the immunological effects are of
minor consequence in subjects with normal immune functions, the suppression of cellular and
humoral immunity following surgery and general anaesthesia may be relevant in patients with pre-
existing immune disorders.

Key words: general anaesthesia; inflammatory response; immune function; cytokines.

Accidental and surgical injury to tissues initiates an inflammatory response, which is

essential for tissue reconstitution. Dysregulation of this inflammatory process may
provoke postoperative complications, e.g. wound healing disturbances or infections
leading to sepsis followed by multiple organ failure and death. In cancer patients, the
immunosuppression may accelerate the growth and metastasis of residual cancer cells.
The perioperative balance between immunostimulatory and immunosuppressive
mechanisms is affected by multiple factors. Anaesthetic agents and anaesthesia

* Corresponding author. Tel.: þ49-391-6713500; Fax: þ 49-391-6713501.

E-mail address: christine.schneemilch@medizin.uni-magdeburg.de (C.E. Schneemilch).

1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
494 C. E. Schneemilch et al

management are suspected of impairing various aspects of the inflammatory response

process, either directly by disturbing the functions of immune cells or indirectly by
modulation of the stress response.1 – 5
Over 100 years ago, Chadbourne6 and Snell7 observed amplified effects of
anaesthetics on postoperative immune dysregulation. Expanding scientific research in
the past three decades has promoted investigations and improved our knowledge of
the inflammatory responses to specific and non-specific attacks. However, the clinical
implications of these findings have not been satisfactorily defined. Despite major
studies, this topic remains a matter for controversial discussion.8,9 Most investigational
data have been confined to in vitro studies and are therefore separated from the
homeostatic regulation network. Many in vivo studies have suggested that the
immunomodulatory effects of anaesthesia are negligible in comparison to the processes
triggered by tissue injuries. Nevertheless, in patients with pre-existing immune
dysfunctions with sepsis and multiple organ failure, as well as in high risk surgical
patients, anaesthetics and the preferences of anaesthesia management may have clinical
implications. Last, but not least, the increased number of elderly risk patients in major
surgery makes it necessary to consider the various aspects of the immunomodulatory
properties of anaesthetics.
This review describes the effects of several anaesthetics used in general anaesthesia
on various aspects of the inflammatory response and will discuss the possible
implications in clinical practice.

EFFECTS OF SEVERAL ANAESTHETICS USED IN GENERAL

ANAESTHESIA— IN VITRO STUDIES

With regard to the various potential effects related to surgical stress and/or other
variables influencing the immunomodulatory properties of anaesthetics in vivo, many
investigators have assayed these effects in a controlled in vitro research environment.
The increasing knowledge of recent years is strongly related to the development in
basic sciences and to the improvement in laboratory techniques, e.g. in cell separation
and cell culture methods. It has been demonstrated that anaesthetics at the
concentrations used clinically, depress the functions of the inflammatory response
differently.
Recent studies have been mainly performed to examine the effects of
anaesthetics on various functions (chemotaxis, phagocytosis) of local-acting immune
competent cells such as monocytes, macrophages, neutrophils, endothelial cells and
natural killer (NK) cells. Mostly, changes in cell-mediated immunity were
investigated using mitogen/antigen induced lymphocyte proliferation, expression of
cell surface receptors and cellular cytokine release. Cytokines are so-called
biological response modifiers and regulate the activity, differentiation and growth of
many cell types involved in the inflammatory/immune system. They are active by
binding to specific cell surface receptors resulting in a changed pattern of mRNA
and protein synthesis (Figure 1). Contradictory reports in this field of investigation
may be explained by the use of different methodological techniques for cell
separation or for cell culture.
In the most important in vitro effects of various anaesthetic agents are described
and possible molecular mechanisms are discussed (Table 1).
 Effects of general anaesthesia on inflammation 495

Agents

Surface receptors
Second messengers

Gene transcription factors

messenger RNA

Protein Expression

BIOLOGICAL RESPONSE

Figure 1. Possible targets of anaesthetics used in general anaesthesia.

Barbiturates

Short- and intermediate-acting barbiturates administered over prolonged periods may

induce iatrogenic immunosuppression. A higher incidence of infections has been
496 C. E. Schneemilch et al

Table 1. In vitro effects of anaesthetic agents used in general anaesthesia.

Agent In vitro effects References

Thiopental Inhibits bactericidal functions of leuko- Krumholz et al12

cytes
Inhibits neutrophil functions (chemotaxis, O’Donnell et al;13 Skoutelis et al;14
adherence, phagocytosis, respiratory Hulse et al;15
burst) Heine et al;16 Nishina et al;17
Krumholz et al;18
Inhibits monocyte functions (phago- Heller et al;19 Davidson et al;20
cytosis, respiratory burst)
Inhibits lymphocyte proliferation Devlin et al;21 Chanimov et al;22
Reduces CD14 þ expression Rossano et al;23 Larsen et al;24
Takaono et al;25
Inhibits IL-1ra release; increases IL-10
release
Depresses antigen induced IL-2 release Correa-Sales et al26
Inhibits transcription factors Ichiyama et al;27 Loop et al29
Decreases activity of nitric oxidase Galley et al31
synthase
Propofol Impairs neutrophil function O’Donnell et al;13 Skoutelis et al;14
Galley and Webster41
Inhibits monocyte functions (oxidative Jensen et al;33 Murphy et al;34
burst, phagocytosis) Fröhlich et al35
Inhibits protein kinase effects generated Mikawa et al36
by lipid solvent
Nagata et al39
Cleary and Pickering;37 Kelbel et al;38
Ohmizo et al40
Lymphocyte proliferation not impaired Pirttikangas et al;43 Salo et al45
Cytokine release not impaired Larsen et al;24 Hoff et al46
Sufentanil/ Reduces migration of transendothelial Hofbauer et al64
alfentanil leukocytes
Inhibits lymphocyte proliferation Sacerdote et al65
Fentanyl No effect on polymorphonuclear cells Jaeger et al62
No effects on spontaneous and endo- Larsen et al24
toxin-stimulated cytokine response
Enhances natural killer cell cytotoxicity Yeager et al60
Numbers of T- and B- lymphocytes Jacobs et al61
unchanged
Volatile anaes- Dose and time-dependent
thetics
Inhibitory effects on neutrophil functions Welch;66 Nakagawara et al;67 Fröhlich et al68
Depresses lymphocyte proliferation Ferrero et al;69 Hamra and Yaksh70
Suppressive effects on cytokine release Stevenson et al;71 Mitsuhata et al72
Depresses cytokine in alveolar cells Giraud et al73
Increases pro-inflammatory cytokines Kotani et al74

IL, interleukin.
 Effects of general anaesthesia on inflammation 497

described in head injured patients with increased intracranial pressure receiving

prolonged infusions of thiopental.10,11
Thiopental is one of the most investigated anaesthetic agents and is widely used for
the induction of general anaesthesia. Its inhibitory effects on the non-specific immune
system have been well documented in several studies. Thiopental in clinically used
concentrations has been shown to inhibit the bactericidal functions of leukocytes12 as
well as inhibiting polarization, chemotaxis, adherence, phagocytosis and the respiratory
burst of neutrophils and chemotaxis of monocytes.13,18 In high concentrations,
thiopental affects neutrophil and monocyte phagocytosis.19,20
In addition, thiopental is known to depress mitogen/antigen induced lymphocyte
proliferation in different culture mediums.21,22 It decreases the quantity of cytokines
released in response to mitogens or endotoxins.23 – 26 Recent studies have suggested
different molecular mechanisms for some effects associated with thiopental. It has been
shown that thiopental inhibits the activation of nuclear factorkappaB (NF-kB), a
transcription factor involved in the expression of many genes.27 – 30 Activation of NF-kB
results in the binding of specific promoter elements and the expression of mRNA from
proinflammatory cytokine genes. These findings suggest that the NF-kB pathway is a
target for the immunosuppressive effect of thiopental.
In a small number of studies the inhibitory aspects of thiopental on nitric oxide
(NO), an important biological mediator of the inflammatory response, which is
produced in a variety of cells as a reaction to receptor stimulation by NO synthetase31,
has been investigated. NO is thought to function as a neurotransmitter involved in
excitatory amino acid-mediated (NMDA) neurotoxicity32 and it plays a role possibly by
interaction with NMDA receptors.
In summary, the described inhibitory effects of thiopental indicate direct cell
mediated inhibition of the immune response and a strong anti-inflammatory effect.

Propofol

Most in vitro studies are based on investigations into the function of the non-specific
immune response. Propofol has been shown to impair several monocyte and
neutrophil functions of the non-specific immune system, including polarization13,
chemotaxis14,15,33, oxidative burst34,35 and phagocytosis.36 While some authors have
supposed that the observed inhibition properties of propofol are related to its lipid
carrier vehicle37,38 other investigators have suggested that protein kinases involved in
signalling pathways are responsible for the effects of propofol.39 In a study carried out to
estimate the effect of propofol on complement activation, evidence has been given that
propofol’s actions were generated by the lipid solvents.40 Propofol, in clinically relevant
concentrations, inhibits the production of a chemotactic agent in human neutrophils.41,
42
Proliferative suppressing effects of propofol were only observed in polymorphnuclear
cells obtained from critically ill patients who were primarily immunosuppressed.43 The
lymphocyte proliferation44,45 and cytokine release in response to endotoxin were not
found to be impaired in whole blood culture medium obtained from healthy
volunteers.24,46 In an animal model, a study of the effect of propofol on the
inflammatory response to endotoxin reported that propofol had anti-inflammatory
effects during endotoxemia.47 The molecular mechanisms have not been established in
detail yet; however, propofol is not known to inhibit the activation of NF-kB.29
In conclusion, recent data suggest that propofol produces only cell-mediated
immunomodulatory effects on non-specific immunity and these may be more probably
generated by the lipid solvent.
498 C. E. Schneemilch et al

Opioids

Synthetic opioids have been considered to affect the cellular and humoral components
of the immune response in a different manner. Modulation of the immune response is
mediated by opioid receptors48,49 that are expressed on immunocompetent cells and
by the participation of both the central nervous system and the hypothalamic –
pituitary –adrenal (HPA) axis.50,51
There are well-documented, dose-dependent, immunosuppressive effects of
morphine, which is known to impair both monocyte and neutrophil function, NK
cell-mediated cytotoxicity, lymphocyte proliferation and cytokine release. Morphine
promotes apoptosis in lymphocytes and macrophages by the activation of the enzymes
involved in apoptotic cell death. Furthermore, the drug affects NO release and inhibits
cell adhesion. In addition, morphine treatment exerts inhibitory effects on the
immune system by an increased secretion of stress-related hormones.52 – 56 Some
studies have reported inhibitory effects of opioids resulting in a decrease in
the intracellular concentrations of cyclic AMP57,58 or in a nuclear binding inhibition
of NF-kB by NO- dependent mechanisms.59
Recent studies estimating the effects of the synthetic opioids used in general
anaesthesia showed no more than transient immunomodulatory changes. Fentanyl is
known to enhance NK-cell cytotoxicity and to increase the relative number of NK
(CD16/56þ) and cytotoxic (CD8þ) cells in healthy volunteers.60 Fentanyl is also able to
increase the NK cell count; however, the production of superoxide by polymorph-
nuclear cells and the number of circulating B- and T-lymphocytes remained
unchanged.61 These effects of fentanyl on NK cells seem to be more centrally mediated
since fentanyl did not affect the NK cell activity. Fentanyl does not impair the function of
polymorphnuclear cells.62 This can be explained by a reduced interaction of synthetic
opioids with specific leukocyte opioid receptors.63
In two studies, sufentanil and alfentanil were observed to produce inhibitory effects
on leukocyte migration64, NK cell activity and mitogen-induced lymphocyte
proliferation.65
The immunosuppressive effects of opioids have been known for more than 100 years;
however, the precise molecular mechanisms are largely unidentified. In summary, there is
no evidence that synthetic opioids, such as fentanyl, sufentanil or alfentanil, modulate or
attenuate the direct cell immune response by means of specific opioid receptors.

Volatile anaesthetic agents

Volatile anaesthetics were originally investigated in order to elucidate potential

immunomodulatory effects. Whilst several studies have observed dose and time-
dependent inhibitory effects, these could not be confirmed by others. The reasons for
these inconsistent investigational reports may be related to differences in the
methodology and laboratory techniques used.1,8
Various studies have shown inhibitory effects on neutrophil function66 – 68, decreased
lymphocyte proliferation69,70 and suppressive effects on cytokine release in peripheral
blood mononuclear cells.71,72 Halogenated anaesthetics are known to suppress
inflammatory cytokines in rat alveolar cells;73 in contrast, exposure to volatile
anaesthetics and mechanical ventilation induced an increased gene expression of pro-
inflammatory cytokines.74 Volatile anaesthetics have been shown to affect the
expression of inducible NO synthetase by the reversible inhibition of voltage-
dependent calcium channels and decreased intracellular calcium concentrations.73
 Effects of general anaesthesia on inflammation 499

Thus, the in vitro effects of volatile anaesthetics are predominantly the inhibition of
immunological products but effects are generally transient, as well as being dose and
time-dependent.

GENERAL ANAESTHESIA AND INFLAMMATION—IN VIVO STUDIES

In contrast to the well-documented immunomodulatory effects of the different

anaesthetic agents used in general anaesthesia, in vitro reports based on in vivo studies
have suggested only transient direct effects on the immune response (Table 2).
The anaesthetics used in general anaesthesia may modulate the inflammatory
response by either acting on immune cells or, in association with preferred
anaesthesiology techniques, by affecting the stress response.
Inflammation incorporates a complex of proceedings for inactivating and eliminating
aggressive agents, initiating the reparative healing of wounds and maintaining the
homeostatic balance. Surgical interventions initiate inflammatory responses that are
influenced by multiple factors, such as preoperative health status, biological variation,
the extent and duration of surgery, drug treatment, anxiety, pain and, not least, the
anaesthetic technique selected. In this field, the conflicting data in preceding reports
make it difficult to evaluate the clinical significance. Possible reasons for controversial
findings include heterogeneous patient groups with different pre-existing disorders,
poor standardisation of surgical procedures, major differences in the duration and
severity of tissue injuries and the small number of randomised studies. Therefore, some
recent studies were performed in patients undergoing minor surgical procedures that
aimed to minimise surgical effects.
In investigations of peripheral blood cell counts and the effects on mitogen/antigen
induced lymphocyte proliferation in patients undergoing different types of surgery
under different techniques of anaesthesia, the authors related the observed changes to
the extent of tissue trauma and stress response.75,76 In all reports, corresponding
evidence regarding the increased number of neutrophils after surgery and
anaesthesia was found.77 As in cases of minor surgery when no or similar changes in
mitogen-induced lymphocyte proliferation were observed for different techniques of
general anaesthesia78 – 80, different effects were seen within the lymphocyte subsets.79,80
Comparable studies found an increase in T- and B-cell numbers as well as a decreased
percentage of NK-cells during anaesthesia before surgery. Balanced inhalational
anaesthesia with isoflurane increased the cytotoxic CD8þ cell count, whereas
intravenous anaesthesia with propofol/fentanyl increased the percentage of CD4þ
cells.81,82 Contradictory data were available from other studies, in which an increased
number of NK-cells and an enhanced NK-cell cytotoxicity were observed60,81 – 86
independent of the type of anaesthesia.
In recent years, further studies have been performed to investigate the changes in
the cytokine response and their possible correlation to the endocrine stress response.
The observed changes in the production and release of cytokines were based on in
vitro studies, suggesting that different anaesthetic techniques had an effect on
the balance of pro- and anti-inflammatory cytokines. Pro-inflammatory cytokine
response is related to surgical stress and is known to be influenced by the anaesthetic
techniques used.88 – 90
Significantly lower concentrations of the pro-inflammatory cytokine interleukin-6
(IL-6) in the response to surgery were found using intravenous anaesthesia.90 – 92 Some
authors have attributed this observation to the effects of alfentanil on opioid
500 C. E. Schneemilch et al

Table 2. In vivo effects of different general anaesthetic techniques on inflammation.

Studies Patients Type of surgery Main results References

ðnÞ

different types of 77 different types of depressed lymphocyte Cullen and VanBelle75

anaesthesia surgery proliferation and changes
(balanced volatile, in leukocyte counts
ketamine, regional related to surgery stress
anaesthesia)
Neurolepta- 12 hip replacement no changes after anaes- Salo76
naesthesia thesia before surgery
General vs. epi- 20 hip replacement general depressed lym- Hole und Unsgaard77
durale (thio/fent phocyte proliferation
vs. bupivacaine
volatile vs. NLA 40 ophthalmic vs. volatile anaesthesia þ Koenig et al78
(halothane vs. gynaecological major surgery depressed
DHB þ Fentanyl) lymphocyteproliferation
similar changes in minor
surgery
intravenous anaes- 27 minor breast sur- decrease of NK-cells Pirttigangas et al79
thesia (propofol gery similar propofol increased
vs. thiopental) T-helper cells no changes
in lymphocyte prolifer-
ation
volatile vs. intra- 20 hysterectomy intravenous diminished Crozier et al92
venous (isoflurane IL-6 concentration in
vs. propofol/alfen- response to surgery
tanil)
volatile vs. intra- 30 hysterectomy lymphocyte proliferation Pirttigangas et al80
venous (thio/iso- similar changes in lym-
flurane vs. phocyte and subsets simi-
propofol/fentanyl) lar increased IL-6
concentration similar
volatile vs. intra- 20 hysterectomy propofol promote anti- Gilliland et al97
venous (isoflurane inflammatory cytokine
vs. propofol) response Opioid suppress
pro-inflammatory cyto-
kine response No changes
before surgery
balanced anaes- 30 orthopedic sur- decreased NK-cells, Brand et al81
thesia (thiopental, gery before sur- increased B-cells
fentanyl isoflur- gery increased CD8 þ -cells
ane) increased IFNg, TNFa
increased sIL-2R
thiopental 32 minor surgery antigen induced lympho- Correa-Sales et al26
cyteproliferation and IL-2
production depressed
high dose vs. low 16 cardiac surgery no differences in cytokine Brix-Christensen et
dose fentanyl production al94
sevoflurane per se 59 after anaesthesia neutrophils decreased Morisaki et al83
before surgery lymphocyte increased

(continued on next page)

 Effects of general anaesthesia on inflammation 501

Table 2 (continued)
Studies Patients Type of surgery Main results References
ðnÞ

volatile vs. intra- 46 open vs laparo- similar changes in pro- Delogu et al87
venous (isoflurane scopic cholecys- inflammatory cytokines
vs. propofol) tectomy (IL-6, TNFa)
intravenous (pro- 40 laparoscopic vs. no effects on IL-1ß. IL-4, Helmy et al95
pofol/sufentanil) open cholecys- IL-6, TNF and IFN similar
tectomy decrease of IL-2
volatile vs. intra- 40 non-thoracic non- isoflurane increased gene Kotani et al74
venous (isoflurane abdominell expression of pro-inflam-
vs. propofol) matory cytokines in
alveolar mocrophages
volatile vs. local 23 cataract surgery similar changes in neutro- Goto et al84
(sevoflurane vs. phils and neutrophile
local) apoptosis similar changes
in cytokine concen-
trations
balanced vs. intra- 32 lumbar discect- intravenous decreased Schneemilch et al91
venous (thio/fen- omy IL-6 in response to sur-
t/isoflurane vs. gery similar changes
propofol/sufenta- before surgery
nil)
propofol vs. iso- 30 neuroradiological propofol decreased res- Heine et al86
flurane diagnostics piratory burst in neutro-
phils phagocytic capacity
similar
general (thio/iso- 19 absence of surgery antibody responses to Procopio et al85
flurane) vs. epi- healthy volunteers antigen similar antibody-
durale dependent cell cytotoxi-
city increased in epidurale
increase of NK-cell cyto-
toxicity similar no changes
in phagocytosis
volatile vs. intra- 30 cardiac surgery sevoflurane increased IL-6 El Azab et al90
venous (sevoflur- (CABG) before similar changes in TNF,
ane vs. propofol or bypass-starting IL-8 correlation between
midazolam/alfenta- IL-6 and clamping time
nil)
intravenous with 30 minor elective increased T-helper Brand et al82
propofol/fentanyl orthopedic sur- (CD4 þ ) cells increased
gery before sur- B-cells decreased
gery NK-cells enhanced
TNFa-, IFNg, IL-1b
release decreased IL-10
release

NK, natural killer; IL, interleukin; TIVA; IFN, interferon; TNF, tumour necrosis factor; vs., versus.
502 C. E. Schneemilch et al

CENTRAL
NERVOUS SYSTEM
neurotransmitters

neurotransmitters
hormones
cytokines

Anaesthetic
management

hormones
NEURO
IMMUNE ENDOKRINE
SYSTEM SYSTEM
cytokines

Figure 2. Communications between central-, immune and neuro-endocrine system and possible modulation
by anaesthesiological management.

receptors92, others, however, could not support this hypothesis.93 While numerous
reports87,94,95,97 have demonstrated similar changes under both intravenous and
inhalational anaesthesia even before surgery, other studies have observed both
increases90,96 or decreases99 in pro-inflammatory cytokines using different inhalational
agents.
Differences in both study design and the definition of different time-points make the
comparison and interpretation of these data difficult.
Alterations to the cytokine balance by different types of anaesthesia have been
suggested as effects of the preferred anaesthetic procedure on the modulation of the
stress response. Cytokines, peptide hormones and neurotransmitters are affected by
the endocrine, immune and nervous systems and by interaction with universally used
receptors.98 Emerging evidence indicates that the disturbed balance between the pro-
and the anti-inflammatory response is mediated by the modulatory effects of the
different anaesthetic techniques on cytokine release.
Therefore, it is possible to conclude that the choice of anaesthesiological
management may affect the inflammatory response to surgery by means of centrally
mediated mechanisms (Figure 2).

SUMMARY

Surgical interventions and general anaesthesia initiate inflammatory responses that

are essential for maintaining homeostatic regulation. Severe dysregulation of
 Effects of general anaesthesia on inflammation 503

the inflammatory process may induce postoperative complications. The assessment of

the potential effects of different anaesthetics is difficult, since different factors may
affect the perioperative balance between the pro- and anti-inflammatory mechanisms.
Conflicting data have been published on anaesthetics. The various explanations put
forward to explain controversial findings include: heterogeneous patient groups with
different pre-existing disorders, poor standardisation of surgical procedures, major
differences in duration and severity of tissue injury and the small number of
randomised studies. Anaesthetics have been suspected of impairing various aspects
of the immune system function either directly by affecting the functioning of
immunocompetent cells or indirectly by modulation of the stress response. All
anaesthetic agents have the in vitro capability of affecting the functions involved in
the inflammatory response; the extent depends on the concentrations used, the
methodological techniques used for cell separation and/or cell culture and the study
design. The published data suggest some evidence that the choice of anaesthesio-
logical management technique will modulate the stress-induced immune response.
Although these effects are transient and may be of minor importance in subjects with
normal immune systems, in patients with immune system dysfunctions or multiple
organ failure and in high risk patients the influence of anaesthetics and the choice of
anaesthesiological management technique on the perioperative inflammation may have
clinical implications.

Practice points
† all anaesthetic agents have the capacity to influence the functions involved in the
inflammatory response; the extent depends on the concentrations, the
methodological techniques and the study design used
† the inhibitory effects of thiopental indicate direct cell-mediated inhibition of the
immune response and a strong anti-inflammatory effect
† the inhibitory effects of volatile anaesthetics are usually transient, dose and time
dependent
† synthetic opioids are not known to inhibit the inflammatory response
† general anaesthesia has transient and insignificant effects in the healthy patient
† management of anaesthesia and timing of elective surgical interventions is more
important in immune compromised patients

Research agenda
† prospective, randomised clinical trials are needed to evaluate the effects of
anaesthetics on the inflammatory response even before surgery
† the exact determination of immunologically relevant time points is needed
† the impaired inflammatory response caused by general anaesthesia should be
investigated in high-risk or critically ill patients
† in vitro studies need to be designed to investigate the largely unknown
molecular mechanisms
† using more complex in vitro models to reflect the in vivo situation may produce
further useful information
504 C. E. Schneemilch et al

REFERENCES

1. Thomson DA. Anesthesia and the immune system. Journal of Burn Care Rehabilitation 1987; 8: 483–487.
* 2. Salo M. Effects of anaesthesia and surgery on the immune response. Acta Anaesthesiologica Scandinavica
1992; 36: 201 –220.
3. Kress HG & Eberlein T. Effect of anaesthesia and operation on essential immune functions.
Anaesthesiologie Intensivmedizin Notfallmedizin und Schmerztherapie 1992; 27: 393 –402.
* 4. McBride WT, Armstrong MA & McBride SJ. Immunomodulation: an important concept in modern
anaesthesia. Anaesthesia 1996; 51: 465–473.
5. Laffey JG, Boylan JF & Cheng DCH. The systemic inflammatory response to cardiac surgery.
Anesthesiology 2002; 97: 215–252.
6. Chadbourne TL. Ether leucosis. Philadelphia Medical Journal 1899; 3: 390–395.
7. Snell JJ. Immunität und Narkose. Berliner Klinische Wochenschrift 1903; 40: 212 –214.
8. Stevenson GW, Hall SC, Rudnick S et al. The effect of anesthetic agents on the human immune response.
Anesthesiology 1990; 72: 542–552.
9. Galley HF, DiMatteo MA & Webster NR. Immunomodulation by anaesthetics, sedative and analgesic
agents: Does it matter? Intensive Care Medicine 2000; 26: 267–274.
10. Eberhardt KE, Thimm BM, Spring A & Maskos WR. Dose-dependent rate of nosocomial pulmonary
infection in mechanically ventilated patients with brain oedema receiving barbiturates: a prospective case
study. Infection 1992; 20: 12–18.
11. Stover JF & Stocker R. Barbiturate coma may promote reversible bone marrow suppression in patients
with severe isolated traumatic brain injury. European Journal of Clinical Pharmacology 1998; 54: 529–534.
12. Krumholz W, Demel C, Jung S et al. The effects of thiopentone, etomidate, ketamine and midazolam on
several bactericidal functions of polymorphonuclear leucocytes in vitro. European Journal of Anaesthesia
1995; 12: 141– 146.
13. O’Donnell NG, McSharry CP, Wilkinson PC & Asbury AJ. Comparison of the inhibitory effect of
propofol, thiopentone and midazolam on neutrophil polarization in vitro in the presence or absence of
human serum albumin. British Journal of Anaesthesia 1992; 69: 70–74.
14. Skoutelis A, Lianou P, Papageorgiou E et al. Effects of propofol and thiopentone on polymorphonuclear
leukocyte functions in vitro. Acta Anaesthesiologica Scandinavica 1994; 38: 858– 862.
15. Hulse D, Kusel JR, O’Donnell NG & Wilkinson PC. Effects of anaesthetics on membrane motility and
locomotor responses of human neutrophils. Immunology and Medical Microbiol 1994; 8: 241–248.
16. Heine J, Leuwer M, Scheinichen D et al. Flow cytometry evaluation of the in vitro influence of four i.v.
anaesthetics on respiratory burst of neutrophils. British Journal of Anaesthesia 1996; 77: 387 –392.
17. Nishina K, Akamatsu H, Mikawa K et al. The inhibitory effects of thiopental, midazolam, and ketamine on
human neutrophil function. Anesthesia and Analgesia 1998; 86: 159–165.
18. Krumholz W, Reussner D & Hempelmann G. The influence of several intravenous anaesthetics on the
chemotaxis of human monocytes in vitro. European Journal of Anaesthesiology 1999; 16: 547 –549.
19. Heller A, Heller S, Blecken S, Urbaschek R & Koch T. Effects of intravenous anesthetics on bacterial
elimination in human whole blood in vitro. Acta Anaesthesiologica Scandinavica 1998; 42: 518– 526.
20. Davidson JA, Boom SJ, Pearsall FJ, Zang P & Ramsay G. Comparison of the effects of four i.v. anaesthetic
agents on polymorphonuclear leukocyte function. British Journal of Anaesthesia 1995; 74: 315–318.
21. Devlin EG, Clarke RSJ, Mirakhur RK & McNeil TA. Effects of four i.v. induction agents on T-lymphocyte
proliferations to PHA in vitro. British Journal of Anaesthesia 1994; 73: 315–317.
22. Chanimov M, Berman S, Weissgarten J et al. Substances used for local and general anaesthesia in major
surgery suppress proliferative responsiveness of normal rat peripheral blood mononuclear cells in
culture. European Journal of Anaesthesiology 2000; 17: 248 –255.
23. Rossano F, Tufano R, Cipollaro de L’Ero G et al. Anaesthetic agents induce human mononuclear
leukocytes to release cytokines. Immunopharmacology and Immunotoxicology 1992; 14: 439–450.
* 24. Larsen B, Hoff G, Wilhelm W et al. Effect of intravenous anesthetics on spontaneous and endotoxin
stimulated cytokine response in cultured human whole blood. Anesthesiology 1998; 89: 1218–1227.
25. Takaono M, Yogosawa T, Okawa-Takatsuji M & Aotsuka S. Effects of intravenous anaesthetics on
interleukin (IL)-6 and IL-10 production by lipopolysaccharide-stimulated mononuclear cells from healthy
volunteers. Acta Anaesthesiologica Scandinavica 2002; 46: 176–179.
26. Correa-Sales C, Tosta CE & Rizzo LV. The effects of anesthesia with thiopental on T lymphocyte
responses to antigen and mitogens in vivo and in vitro. International Journal of Immunopharmacology 1997;
19: 117–128.
27. Ichiyama T, Nishikawa M, Lipton JM et al. Thiopental inhibits NF-kappaB activation in human glioma cells
and experimental brain inflammation. Brain Research 2001; 17: 56 –61.
28. Fröhlich D, Wittmann S, Rothe G, Schmitz G & Taeger K. Thiopental impairs neutrophil oxidative
response by inhibition of intracellular signalling. European Journal of Anaesthesiology 2002; 19: 474–482.
 Effects of general anaesthesia on inflammation 505

* 29. Loop T, Liu Z, Humar M et al. Thiopental inhibits the activation of nuclear factor kappaB. Anesthesiology
2002; 96: 1202–1213.
30. Pahl HL. Activators and target genes of Rel/NF-kB transcription factors. Oncogene 1999; 18:
6853–6856.
31. Galley HF, Nelson LR & Webster NR. Anaesthetic agents decrease the activity of nitric oxidase synthase
from human polymorphonuclear leukocytes. British Journal of Anaesthesia 1995; 75: 326 –329.
32. Hanbauer I. The role of nitric oxide in neurotransmitter release. In: Moncade S, Nistico G & Higgs EA
(eds). Nitric Oxide: Brain and Immune System, London: Portland Press Proceedings, 1993, pp 135–141.
33. Jensen AG, Dahlgren C & Eintrei C. Propofol decreases random and chemotactic stimulated locomotion
of human neutrophils in vitro. British Journal of Anaesthesia 1993; 70: 99–100.
34. Murphy PG, Ogilvy AJ & Whiteley SM. The effect of propofol on the neutrophil respiratory burst.
European Journal of Anaesthesiology 1996; 13: 471– 473.
35. Frohlich D, Rothe G, Schwall B et al. Thiopentone and propofol, but not methohexitone nor midazolam,
inhibit neutrophil oxidative responses to the bacterial peptide FMLP. European Journal of Anaesthesiology
1996; 13: 582 –588.
36. Mikawa K, Akamatsu H, Nishina K et al. Propofol inhibits human neutrophil functions. Anesthesia and
Analgesia 1998; 87: 695 –700.
37. Cleary TG & Pickering LK. Mechanisms of intralipid effect on polymorphonuclear leukocytes. Journal of
Clinical and Laboratory Immunology 1983; 11: 21 –26.
38. Kelbel I, Koch T, Weber A et al. Alterations of bacterial clearance induced by propofol. Acta
Anaesthesiologica Scandinavica 1999; 43: 71–76.
39. Nagata T, Kansha M, Irita K & Takahashi S. Propofol inhibits FMLP-stimulated phosphorylation of p42
mitogen-activated protein kinase and chemotaxis in human neutrophils. British Journal of Anaesthesia
2000; 86: 853 –858.
40. Ohmizo H, Iwama H & Sugita T. Compliment activation by propofol and its effect during propofol
anaesthesia. Anaesthesiology and Intensive Care 1999; 27: 623–627.
41. Galley HF & Webster NR. Effects of propofol and thiopentone on the immune response. Anaesthesia
1994; 52: 921 –923.
42. Galley HF, Dubbels AM & Webster NR. The effect of midazolam and propofol on interleukin-8 from
human polymorphonuclear leukocytes. Anesthesia and Analgesia 1998; 86: 1289– 1293.
43. Pirttinkangas CO, Perttila J & Salo M. Propofol emulsion reduces proliferative responses of lymphocytes
from intensive care patients. Intensive Care Medicine 1993; 19: 299–302.
44. Pirttikangas CO, Salo M, Riutta A et al. Effects of propofol and intralipid on immune response and
prostaglandin E2 production. Anaesthesia 1995; 50: 317–321.
45. Salo M, Pirttikangas CO & Pulkki K. Effects of propofol emulsion and thiopentone on T helper cell type-
1/type-2 balance in vitro. Anaesthesia 1997; 52: 341–344.
46. Hoff G, Bauer I, Larsen B & Bauer M. Modulation of endotoxin-stimulated TNF-alpha gene expression by
ketamine and propofol in cultured human whole blood. Der Anaesthesist 2001; 50: 494–499.
47. Taniguchi T, Yamamoto K, Ohmoto N et al. Effects of propofol on hemodynamic and inflammatory
responses to endotoxemia in rats. Critical Care Medicine 2000; 28: 1101–1106.
* 48. Bidlack JM. Detection and function of opioid receptors on cells from the immune system. Clinical and
Diagnostic Laboratory Immunology 2000; 7: 719–723.
49. Rittner HL, Brack A, Machelska H et al. Opioid peptide-expressing leukocytes: identification,
recruitment, and simultaneously increasing inhibition of inflammatory pain. Anesthesiology 2001; 95:
500– 508.
50. Stefano GB, Scharrer B, Smith EM et al. Opioid and opiate immunoregulatory processes. Critical Review of
Immunology 1996; 16: 109– 114.
51. Hernandez MC, Flores LR & Bayer BM. Immunosuppression by morphine is mediated by central
pathways. Journal of Pharmacology and Experimental Therapeutics 1993; 267: 1336–1341.
* 52. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK & Rogers TJ. Opioids, opioid receptors, and the immune
response. Drug and Alcohol Dependence 2001; 62: 111– 123.
53. Welters I. Opioids and immunesuppression. Clinical relevance. Der Anaesthesist 2003; 52: 442–452.
54. Sacerdote P, Manfredi B, Mantegazza P & Panerai AE. Antinociceptive and immunosuppressive effects of
opiate drugs: a structure-related activity study. British Journal of Pharmacology 1997; 121: 834–840.
55. Manfreda SE, Dunzendorfer S, Schratzenberger P et al. The chemotaxis of human peripheral B
lymphocytes by 223 beta-endorphin is reversible by naloxone. Anesthesia and Analgesia 1998; 86:
670– 672.
56. Yeager MP, Yu CT, Campbell AS et al. Effect of morphine and beta-endorphin on human Fc receptor-
dependent and natural killer cell functions. Clinical Immunology and Immunopathology 1992; 62: 336– 343.
57. Kavelaars A, Ballieux RE & Heijnen CJ. Differential effects of beta-endorphin on cAMP levels in human
peripheral blood mononuclear cells. Brain, Behavior and Immunity 1990; 4: 171–179.
506 C. E. Schneemilch et al

58. Zhang Y, Lin JX & Vilcek J. Synthesis of interleukine-6 in human fibroblast is triggered by an increase of
intracellular cyclic AMP. Journal of Biology and Chemistry 1988; 263: 6177–6182.
59. Welters ID, Menzebach A, Goumon Y et al. Morphine inhibits NF-kB nuclear binding in human
neutrophils and monocytes by a nitric oxide dependent mechanism. Anesthesiology 2000; 92:
1677– 1684.
60. Yeager MP, Procopio MA, DeLeo JA et al. Intravenous fentanyl increases natural killer cell cytotoxicity
and circulating CD 16(þ) lymphocytes in humans. Anesthesia and Analgesia 2002; 94: 94–99.
61. Jacobs R, Karst M, Scheinichen D et al. Effects of fentanyl on cellular immune functions in man.
International Journal of Immunopharmacology 1999; 21: 445 –454.
62. Jaeger K, Scheinichen D, Heine J et al. Remifentanil, fentanyl, and alfentanil have no influence on the
respiratory burst of human neutrophils in vitro. Acta Anaesthesiologica Scandinavica 1998; 42:
1110– 1113.
63. Bilfinger TV, Fimiani C & Stefano GB. Morphines immunoregulatory actions are not shared by fentanyl.
International Journal of Cardiology 1998; 64: 61 –66.
64. Hofbauer R, Moser D, Salfinger H, Frass M & Kapiotis S. Sufentanil inhibits migration of human
leukocytes through human endothelial cell monolayers. Anesthesia and Analgesia 1998; 87: 1181–1185.
65. Sacerdote P, Gaspani L, Rossoni G et al. Effect of the opioid remifentanil on cellular immune response in
the rat. International Journal of Immunopharmacology 2001; 1: 713– 719.
66. Welch WD. Halothane reversibly inhibits human neutrophil bacterial killing. Anesthesiology 1981; 55:
650–654.
67. Nakagawara M, Takeshige K, Takamutsu J et al. Inhibition of superoxide production and Ca
2 þ mobilization in human neutrophils by halothane, enflurane, and isoflurane. Anesthesiology 1986;
64: 4–12.
68. Fröhlich D, Rothe G, Schwall B et al. Effects of volatile anaesthetics on human neutrophil oxidative
response to the bacterial peptide FMLP. British Journal of Anaesthesia 1997; 78: 718–723.
69. Ferrero E, Ferrero ME, Marni A et al. In vitro effects of halothane on lymphocytes. European Journal of
Anaesthesiology 1986; 3: 321–330.
70. Hamra JG & Yaksh TL. Halothane inhibits T cell proliferation and interleukin-2 receptor expression in
rats. Immunopharmacology and Immunotoxicology 1996; 18: 323 –336.
71. Stevenson GW, Hall S, Miller PJ et al. The effect of anaesthetic agents on human immune system function.
I. Design of a system to deliver inhalational anesthetic agents to leukocyte cultures in vitro. Journal of
Immunological Methods 1986; 88: 277 –283.
* 72. Mitsuhata H, Shimizu R & Yokoyama MM. Suppressive effects of volatile anaesthetics on cytokine release
in human peripheral blood mononuclear cells. International Journal of Immunopharmacology 1995; 17:
529 –534.
73. Giraud O, Molliex S, Rolland C et al. Halogenated anesthetics reduce interleukin-1b-
induced cytokine secretion by rat alveolar type II cells in primary culture. Anesthesiology 2003;
98: 74– 81.
74. Kotani N, Takahashi S, Sessler DI et al. Volatile anaesthetics augment expression of pro-inflammatory
cytokines in rat alveolar macrophages during mechanical ventilation. Anesthesiology 1999; 91: 187–197.
75. Cullen BF & VanBelle G. Lymphocyte transformation and changes in leukocyte count: effects of
anesthesia and operation. Anesthesiology 1975; 43: 563–569.
76. Salo M. The effect of anaesthesia and total hip replacement on the phytohaemagglutinin and concanavalin
A responses of lymphocytes. Annales of Chirurgiae et Gynaecologiae 1977; 66: 299 –303.
77. Hole A & Unsgaard G. The effect of epidural and general anaesthesia on lymphocyte functions during and
after major orthopaedic surgery. Acta Anaesthesiologica Scandinavica 1983; 27: 135–141.
78. Koenig A, Koenig DU, Heicappel R & Stoeckel H. Differences in lymphocyte mitogenic stimulation
pattern depending on anaesthesia and operative trauma: I. Halothane –nitrous oxide anaesthesia.
European Journal of Anaesthesiology 1987; 4: 17–24.
79. Pirttikangas CO, Perttila J, Salo M et al. Propofol infusion anaesthesia and immune response in minor
surgery. Anaesthesia 1994; 49: 13–16.
80. Pirttikangas CO, Salo M, Mansikka M et al. The influence of anaesthetic technique upon the immune
response to hysterectomy. Anaesthesia 1995; 50: 1056–1061.
81. Brand JM, Kirchner H, Poppe C & Schmucker P. The effects of general anaesthesia on human peripheral
immune cell distribution and cytokine production. Clinical Immunology and Immunopathology 1997; 83:
190–194.
* 82. Brand JM, Frohn C, Luhm J et al. Early alterations in the number of circulating lymphocyte
subpopulations and enhanced proinflammtory immune response during opioid-based general
anesthesia. Shock 2003; 20: 213–217.
83. Morisaki H, Aoyama Y, Shimada M, Ochiai R & Takeda J. Leucocyte distribution during sevoflurane
anaesthesia. British Journal of Anaesthesia 1998; 80: 502 –503.
 Effects of general anaesthesia on inflammation 507

84. Goto Y, Ho SL, McADoo J et al. General versus regional anaesthesia for cataract surgery: effects of
neutrophil apoptosis and the postoperative pro-inflammatory state. European Journal of Anaesthesiology
2000; 17: 474 –480.
85. Procopio MA, Rassias AJ, DeLeo JA et al. The in vivo effects of general and epidural anesthesia on human
immune function. Anesthesia and Analgesia 2001; 93: 460 –465.
86. Heine J, Jaeger K, Osthaus A et al. Anaesthesia with propofol decreases FMLP-induced neutrophil
respiratory burst but not phagocytosis compared with isoflurane. British Journal of Anaesthesia 2000; 85:
424– 430.
87. Delugo G, Famularo G, Luzzi S et al. General anesthesia mode does not influence endocrine or
immunologic profile after open or laparoscopic cholecystectomy. Surgical Laparoscopy Endoscopy and
Percutaneous Techniques 1999; 9: 326–332.
88. Klava A, Windsor AC, Farmery SM et al. Interleukin-10. A role in the development of postoperative
immunosuppression. Archiv Surgery 1997; 132: 425–429.
* 89. Sheeran P & Hall GM. Cytokines in anaesthesia. British Journal of Anaesthesia 1997; 78: 201– 219.
90. El Azab SR, Rossel PM, DeLange JJ et al. Effect of VIMA with sevoflurane versus TIVA with propofol or
midazolam-sufentanil on the cytokine response during CABG surgery. European Journal of Anaesthesiology
2002; 9: 276–282.
91. Schneemilch CE & Bank U. Release of pro- and anti-inflammatory cytokines during different anesthesia
procedures. Anaesthesiologie and Reanimation 2001; 26: 4 –10.
92. Crozier TA, Muller JA, Quittkat D et al. Effect of anaestheia on cytokine responses to abdominal surgery.
British Journal of Anaesthesia 1994; 72: 280–285.
93. McBride WT, Armstrong MA, Crockard AD et al. Selective reduction in leukocyte antigen expression
following high dose fentanyl administration at cardiac surgery. British Journal of Anaesthesia 1994; 73:
717– 718.
94. Brix-Christensen V, Tonnesen E, Sorensen IJ et al. Effects of anaesthesia based on high versus low doses
of opioids on the cytokine and acute-phase protein responses in patients undergoing cardiac surgery.
Acta Anaesthesiologica Scandinavica 1998; 42: 63– 70.
95. Helmy SA, Wahby MA & El-Nawaway M. The effect of anaesthesia and surgery on plasma cytokine
production. Anaesthesia 1999; 54: 733–738.
96. Lahat N, Zlotnick AY, Shtiller R et al. Serum levels of IL-1, IL-6 and TNF in patients undergoing
coronary artery bypass grafts or cholecystectomy. Clinical and Experimental Immunology 1992; 89:
255– 260.
97. Gilliland HE, Armstrong MA, Carabine U & McMurray TJ. The choice of anaesthetic maintenance
technique influences the anti-inflammatory cytokine response to abdominal surgery. Anesthesia and
Analgesia 1997; 85: 1394–1398.
* 98. Haddad JJ, Saade NE & Safieh-Garabedian B. Cytokines and neuro –immune–endocrine interactions: a
role for the hypothalamic–pituitary–adrenal revolving axis. Journal of Neuroimmunology 2002; 133:
1 –19.
99. Helmy SA, Al-Attiyah RJ. The effect of halothane and isoflurane on plasma cytokine levels. Anaesthesia
2000; 55: 904 –910.