Immunomodulatory Effects of General Anesthetics L.C. Lemaire and T. van der Poll

L.C. Lemaire and T. van der Poll

Introduction

Postoperative patients are prone to develop infectious complications, and the phe- nomenon of immunoparalysis, defined as a diminished capacity of immunocompe- tent cells to respond to infectious agents, has been implicated as a major contribut- ing factor. When inflammatory postoperative disorders are already established, intervention is difficult. However, if perioperative modulation of the inflammatory response were possible, this may influence postoperative outcome. General anesthet- ics exert a variety of effects, including sedation, amnesia, and analgesia. Current research focuses primarily on the effects of these compounds on membrane proteins in the central nervous system (CNS), to elucidate the molecular mechanism of their action. The (side-) effects of general anesthetics on other organ systems have been less extensively investigated. In this chapter, we will discuss the data available on the immunomodulatory effects of general anesthetics and the potential clinical implica- tions of these effects on the development of (postoperative) infections.

We focus on compounds widely used to maintain sedation in the intensive care unit (ICU) and anesthesia during operations. In addition, the effects of ketamine, an anesthetic often used in emergency medicine and commonly used as a general anes- thetic in second and third world countries, are described. Effects of local anesthetics on the inflammatory response are beyond the scope of this manuscript; however they have been thoroughly reviewed by Hollmann and Durieux [1].

Clinical Problem

Postoperative patients, trauma patients and patients on the ICU are prone to develop infectious complications, which substantially increase morbidity, hospital stay, and resource consumption. Infections may vary from surgical wound infection to pneumonia or severe sepsis. Even surgical wound infections, categorized as minor complications, can prolong hospitalization up to 7 days and increase the direct median cost of hospitalization by 50 % [2]. For example, in patients undergoing gas- trointestinal operations, the incidence of surgical wound infection ranges from 10 to 20 % which prolongs hospital stay by 2 to 7 days. In addition, postoperative pneu- monia or postoperative sepsis in these patients also significantly increases the length of hospital stay and costs.

Conceptually, it is thought that a balanced pro- and anti-inflammatory reaction is

necessary for appropriate tissue healing after surgery [3]. An unbalanced systemic

pro-inflammatory (‘hyperinflammatory’) reaction can result in a systemic inflam-

matory response syndrome (SIRS) or even multiple organ failure (MOF). However, a reduced pro-inflammatory reaction may cause a diminished capacity to respond to infectious agents, resulting in increased susceptibility to (postoperative) infections.

This phenomenon is termed ‘immunoparalysis’ [4]. Immunoparalysis was primarily described in response to sepsis and termed ‘LPS (lipopolysaccharide) tolerance’ [5].

When isolated peripheral blood mononuclear cells of septic patients were exposed to a second inflammatory or infectious stimulus (e.g., LPS), these cells became hypore- sponsive or ‘anergic’: Cells could not be triggered to release pro-inflammatory cyto- kines. We and others [6, 7] have shown that a comparable immune reaction is found after surgery. In these patients, the first inflammatory stimulus is provided by the surgical trauma itself. It is widely assumed that the relative incapacity of cells like monocytes, lymphocytes, and granulocytes to react to infectious stimuli (the first line of defense against bacteria) renders the host susceptible to infections [3, 4, 8].

What is Causing Immunoparalysis?

The mechanisms underlying immunoparalysis have only been partly elucidated. In septic patients, immunoparalysis is characterized by downregulation of monocytic major histocompatibility complex, HLA-DR, expression and a reduced ability of monocytes to produce LPS-induced tumor necrosis factor (TNF)- [ and interleukin (IL)-10 in vitro [9, 10]. Downregulation of HLA-DR expression resulted in dimin- ished antigen-presenting activity of monocytes. This caused reduced T-cell prolifer- ation and interferon (IFN)- * production [11]. Data also showed that IL-10 can induce immunoparalysis by downregulating TNF- [ synthesis and self-limiting IL-10 production. When peripheral blood mononuclear cells were treated for 24 h with IL- 10 (instead of LPS), washed extensively and restimulated with LPS, synthesis of IL- 10 and TNF- [ was strongly diminished, similar to the level reached by LPS desensi- tization. In addition, anti-IL-10 monoclonal antibodies prevented the LPS-mediated induction of LPS tolerance [10]. In the clinical setting it was shown that increased production of IL-10 in the first ten days post-injury correlated significantly with subsequent septic events in trauma and burn patients [12].

In patients undergoing major surgery (e.g., esophagectomy, total gastrectomy), monocytic HLA-DR expression was also decreased [7]. However, deactivation of monocytes did not occur, since TNF- [ and IL-10 cytokine production by monocytes was not inhibited. Moreover, to analyze whether the loss of HLA-DR cell surface expression would affect the antigen-presenting capacity of peripheral blood mono- cytes, unfractionated peripheral blood mononuclear cells were incubated with the bacterial superantigens, staphylococcal enterotoxin A, staphylococcal enterotoxin B, and toxic shock syndrome toxin 1, and antigen presenting capacity-dependent T-cell proliferation was determined. The capacity of monocytes to present antigens and to stimulate T-cell proliferation was not affected. In contrast, major surgery resulted in a predominant intrinsic defect in T-cell function, as revealed after direct activation of T-cells by cross-linking of CD3 and CD28 receptors. IL-2, IFN * , TNF- [ and IL-4 secretion was decreased, while IL-10 secretion was increased.

Toll-like receptors (TLR), a family of transmembrane receptor proteins, are iden-

tified as key proteins in humans and mice for the recognition of pathogens [for

review see 13]. TLR4 is necessary for LPS signaling [14]. Activation of TLR4 by LPS

triggers binding of MyD88 (myeloid differentiation factor 88) to the intracellular

portion of the receptor. MyD88 recruits IL-1 receptor-associated kinase (IRAK) 4

Table 1. Potential mechanisms of immunoparalysis

Mechanism Patients [References]

Increased IL-10 production and monocyte deactivation Sepsis [9 – 10]

Intrinsic T-cell defects Surgical patients [7]

Altered expression of Toll-like receptors

[18 – 21]

Reduced activation of MyD88, IRAK-1 or increased activity of IRAK-M Sepsis [22]

[15]. This results in the phosphorylation of IRAK-1 which in turn interacts with TNF receptor activated factor 6 (TRAF6). TRAF6 forms a complex with transforming growth factor beta-activated kinase (TAK)-1 [13]. TAK-1 acts as the common activa- tor of nuclear factor kappa B (NF-κB), as well as of the p38 (and JNK) mitogen-acti- vated protein kinase (MAPK) pathways. Activation of NF- κB results in transcription of pro-inflammatory cytokines. In parallel, the induced MAPK pathway may generate phosphorylated p38MAPK and activates another transcription factor, activator pro- tein 1 (AP-1). AP-1 also induces the transcription of pro-inflammatory genes [16]. By nature, negative regulators of the TLR signaling pathway exist which prevent strong uncontrolled inflammatory reactions (e.g. IRAK-M, SOCS1, MyD88s [13])

In studies aimed at unraveling the molecular mechanisms of immunoparalysis, downregulation of surface TLR4 expression [17] and dysregulation at different levels of the TLR4-MyD88-IRAK-NF κB signaling pathway have been found [18 – 21]. It has been shown that cells can develop immunoparalysis by degradation of IRAK (not specified whether this is IRAK-1 or IRAK-4 [18 – 20]) and phosphorylation by pro- tein kinase C (PKC) might be responsible for this [18]. In addition, rapid upregula- tion of IRAK-M expression, a cytosolic inhibitor of the TLR-pathway, was found fol- lowing a second endotoxin challenge in human monocytes and in monocytes iso- lated from septic patients [22].

In summary, the potential mechanisms of immunoparalysis, as described in the literature are depicted in Table 1. Moreover, it should be noted that the (molecular) mechanism underlying the immunoparalyzed state of a patient may be different in septic, trauma, and postoperative patients.

Do General Anesthetics Affect the Immune Response?

General anesthetics exert a variety of effects, including sedation and hypnosis.

Immunomodulation by general anesthetics has been proposed based on affected cytokine levels measured in vitro [23 – 25] and in vivo [26 – 31]. Interestingly, a study in patients undergoing transhiatal or transthoracic esophagectomy showed that the occurrence of major postoperative infectious complications was best predicted by increased duration of anesthesia, and not by surgical procedure or operation time [32]. In this section, we review data on the immunomodulatory effects of commonly used general anesthetics. We excluded those in vitro studies in which pharmacologi- cal (e.g., [34]) instead of clinically relevant concentrations [35] were used.

Propofol

Propofol (2, 6-di-isopropylphenol) is an intravenous sedative-hypnotic agent which

is administered to maintain anesthesia peroperatively or to sedate patients in the

ICU; this latter use is because treatment effect is more rapid with propofol as com-

Fig. 1. In rats, endotoxemia was

induced by a bolus injection of Esche-

derived from E. coli 0111:B4 (20 mg/

kg). Animals received either no pro- pofol (LPS only), or propofol was administered intravenously (10 mg/kg bolus followed by infusion at 10 mg/

kg/hr) 1 hour after LPS challenge (early posttreatment) or 2 hours after LPS challenge (late posttreatment).

Mortality rates were registered. The mortality rate for the early posttreat- ment group was significantly lower than for the other groups (p

0.0001).

Adapted from [31].

pared to continuous infusions of other compounds, such as midazolam or mor- phine.

Propofol inhibited IL-6 and IL-10 production by LPS-stimulated peripheral blood mononuclear cells in vitro [25]. Cytotoxicity and apoptosis of LPS-treated peripheral blood mononuclear cells were unchanged with clinically acceptable concentrations (1 – 10 µg/ml), while at pharmacological concentrations (50 mg/ml) apoptosis was increased and cytotoxicity decreased [24]. In two studies, rats were challenged with a bolus injection of Escherichia coli LPS (E. coli 0111:B4, 20 mg/kg over 2 minutes) and, thereafter, either received no propofol, or administration of propofol was started 1 hour (early posttreatment) or 2 hours (late posttreatment) after LPS-chal- lenge (10 mg/kg bolus followed by 10 mg/kg/hr during 5 hours). Posttreatment with propofol in the early stage of endotoxin-induced shock in rats profoundly reduced the mortality rate of rats and attenuated their cytokine response, while treatment at a late stage did not [30, 31]. Mortality rates 5 hours after endotoxin injection were 73 %, 9 %, and 36 % for the endotoxic, early posttreatment, and late posttreatment groups, respectively (Fig. 1). The mortality rate for the early posttreatment group was significantly lower compared to the other groups.

Volatile Anesthetics

Presently, the most commonly used inhalation anesthetics are isoflurane and sevof-

lurane. These agents have to be delivered by inhalation through an anesthetic system

which consists of various components, including an anesthesia machine, a vaporizer,

an anesthesia circuit, a ventilator and a scavenging system. Since all these compo-

nents are not present on ICU-ventilators (mainly the vaporizer and scavenging sys-

tem), use of volatile anesthetics is limited to peroperative use. In vitro studies

showed inhibitory effects of volatile anesthetics on the immune responses of differ-

ent cell types. Isoflurane inhibited IL-6 production by alveolar epithelial cells in

vitro [23]. Another study showed that LPS-induced NF- κB activation in isolated

monocytes was inhibited by clinically relevant concentrations of isoflurane. This was

associated with a decreased production of TNF- [ and IL-6 [36]. Sevoflurane-medi-

ated suppression of the transcription factor, AP-1, in primary CD3+ lymphocytes

from healthy volunteers has been reported, only, however, after 24 hrs incubation of

cells at pharmacological concentrations (8 vol%) [37].

Volatile anesthetics (halothane, isoflurane and sevoflurane) also inhibited adhe- sion of neutrophils to human umbilical vein endothelial cells (HUVECs) upon stim- ulation of these cells with 10 nM N-formyl-methionyl-leucyl-phenylalanine (fMLP).

This coincided with inhibited expression of the adhesion molecule, CD11b, on neu- trophils [38]. Comparable data were found in mice, where isoflurane administered 1 hour after LPS challenge (for 30 minutes) inhibited LPS-induced neutrophil recruit- ment into the bronchoalveolar lavage [39]. Another study revealed that isoflurane augmented the gene expression of pro-inflammatory cytokines in rat alveolar mac- rophages during mechanical ventilation [29].

In an elegant study by Fuentes and co-workers [40], mice were challenged with a lethal dose of LPS in the absence (control group) or presence of isoflurane (2 – 2.5 vol%) for 1 hour. Over the 72 hours following the LPS injection, an 85 % survival rate was observed for mice injected with LPS in the presence of isoflurane, com- pared to 23 % survival in the control group. This improved survival was associated with decreased TNF- [ , IL-6 and IL-10 plasma levels and delayed/inhibited activation of NF- κB. Moreover, the decrease in TNF- [ and IL-6 plasma-levels was dependent on the duration of anesthesia, while IL-10 plasma levels were only significantly inhibited after 1 hour of isoflurane anesthesia.

Clinical Studies Comparing Propofol and Isoflurane Anesthesia

Several patient studies have been performed in which isoflurane-anesthesia was compared to propofol-anesthesia. In patients undergoing abdominal surgery, post- operative plasma levels of the anti-inflammatory cytokine, IL-10, were higher in the group anesthetized with propofol compared to the levels in the group anesthetized with isoflurane [26]. Heine et al. showed that in patients undergoing an elective embolization of a cerebral arterio-venous malformation, neutrophil respiratory burst, but not phagocytosis, was reduced significantly more by propofol anesthesia compared to isoflurane-anesthesia [41]. Gene expression of pro-inflammatory cyto- kines in alveolar macrophages increased during anesthesia and surgery [28], and bactericidal function of these macrophages progressively decreased [27]. Moreover, gene expression of IL-8 and IFN * in alveolar macrophages was significantly higher during isoflurane anesthesia than propofol anesthesia, while expression of genes for IL-1 and TNF- [ were comparable [28].

Ketamine

Ketamine is a phencyclidine derivate with, in contrast to propofol and volatile anes- thetics, significant analgesic effects. It usually does not depress the cardiovascular and respiratory systems, but it does possess some adverse psychological effects (hal- lucinations, delirium) which have to be prevented/treated with, e.g., benzodiaze- pines. Ketamine is often used in emergency medicine (no depression of ventilation or blood pressure in unstable patients in pain) and widely used as a general anes- thetic in second and third world countries (where (anesthetic) health care facilities might be limited).

Recently, a (physiological) anti-inflammatory pathway via the parasympathetic

nervous system has been recognized. The neurotransmitter, acetylcholine, prevents

activation of the NF- κB pathway and the secretion of high mobility group box 1

(HMGB1) [42]. Consequently, the release of pro-inflammatory mediators, but not

the anti-inflammatory cytokine, IL-10, is inhibited [43]. This ‘nicotinic anti-inflam-

matory pathway’ [44] requires the activation of the [ 7-nicotinic acetylcholine recep- tors, which are present on macrophages, microvascular endothelial cells and epithe- lial cells. Ketamine inhibits the [ 7-nicotinic acetylcholine receptor in the brain [45], while propofol or isoflurane do not [46]. Although one might expect that inhibition of this receptor by ketamine would consequently lead to attenuation of the nicotinic anti-inflammatory pathway and increased levels of pro-inflammatory cytokines, this has not been found. In contrast, ketamine markedly inhibited TNF- [ , IL-6, and IL- 10 production in septic mice [47] and in cardiac surgical patients [48]. Interestingly, survival in mice was dependent on the timing of ketamine injection relative to the inoculation of the lethal dose of LPS. Ketamine (10 mg/kg) administered directly before LPS challenge, increased survival rates of mice to 86 % compared with 8 % in control mice (LPS only) after 5 days. However, when ketamine was injected 2 hours after LPS challenge survival in the ketamine group was comparable to the control group [47]. Unfortunately, this study did not measure cytokine levels in the early or late ketamine treated groups.

Potential Clinical Implications

The general anesthetics described here, volatile anesthetics, propofol and ketamine, have all been shown to affect the immune response. Of note, in animal studies, it has been revealed that the timing of the challenge with an anesthetic is of crucial impor- tance for the effect on survival. Septic animals that were immediately treated with an anesthetic (either isoflurane, propofol or ketamine) after induction of sepsis showed increased survival rates, whereas animals treated at a later stage had sur- vival rates comparable to control animals (sepsis alone). The anesthetics decreased plasma levels of pro-inflammatory cytokines and isoflurane has been shown to inhibit NF-κB. Presumably, early treatment in these studies coincided with the

‘hyperinflammatory’ phase of sepsis in which decreased pro-inflammatory cytokine levels are preferred. In contrast, in the later phase, one would favor a maintained pro-inflammatory cytokine level in order to prevent immunoparalysis.

Although inter-anesthetic differences on immune responses (and survival rates) have not been investigated in animals, differences between isoflurane-anesthesia and propofol-anesthesia have been studied in surgical patients. Propofol increased IL-10 levels postoperatively. This might indicate that propofol induces immunoparalysis.

Isoflurane increased the expression of pro-inflammatory cytokines in lung macro- phages. However, it is unknown whether this effect is limited to the lung compart- ment (isoflurane is administered through inhalation), or will also be found systemi- cally.

The mechanisms underlying the immunomodulatory effects of anesthetics are

not known precisely. Propofol can stimulate purified rat brain PKC [49]. Propofol

also possibly stimulates PKC in monocytes, downregulates IRAK, and consequently

decreases activation of NF- κB and TNF production. In mice, isoflurane has been

shown to inhibit NF-κB. In contrast, another study showed that isoflurane was able

to activate p38MAPK by itself, and to augment the LPS-induced activation of p38

MAPK [50]. This effect may enhance activation of the transcription factor, AP-1,

which could lead to increased pro-inflammatory cytokine release and prevention of

immunoparalyis.

Conclusion

General anesthetics are used extensively and for long periods to maintain anesthesia or sedate patients in the operation room or the ICU. It is well known that these patients are prone to develop infectious complications which substantially increase morbidity, hospital stay, and resource consumption. The phenomenon of immuno- paralysis, defined as a diminished capacity of immunocompetent cells to respond to infectious agents, has been implicated as a major contributing factor in this process.

We have described in vitro, animal and patient studies showing that anesthetics can affect immunocompetent cells. Interestingly, the direction of the response (produc- tion of pro-inflammatory cytokines, or not) possibly depends on the timing and on the anesthetic used. This observation may be linked to the different effects of the various agents on mechanisms involved in the development of immunoparalysis.

Therefore, the choice of anesthetic may be of importance in the occurrence of (post- operative) infections. Although more research is needed to substantiate current knowledge, if modulation of the inflammatory response by anesthetics were possi- ble, this would likely influence outcomes.

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