Effect GA
Effect GA
Effect GA
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
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.
1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
494 C. E. Schneemilch et al
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
messenger RNA
Protein Expression
BIOLOGICAL RESPONSE
Barbiturates
IL, interleukin.
Effects of general anaesthesia on inflammation 497
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.
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.
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
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
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