Local Anesthetics and the Inflammatory Response

LOCAL anesthetics (LA) are known for their ability to block Na+channels. However, they have significant effects in several settings other than local and regional anesthesia or antiarrhythmic treatment, the areas in which they are used traditionally. These effects result from LAs interacting with other cellular systems as well. Interestingly, some of these effects occur at concentrations much lower than those required for Na+channel blockade. For example, whereas the half-maximal inhibitory concentration (IC50) of lidocaine at the neuronal Na+channel is approximately 50–100 μm (depending on the specific channel subtype and study preparation), 1the compound inhibits signaling through m1 muscarinic receptors (expressed recombinantly in Xenopus laevis oocytes) with an IC50of 20 nm, that is, 1,000- to 5,000-fold lower. 2This sensitivity of other targets has two important consequences. First, we assume that LAs, at concentrations that result in significant Na+channel blockade, also affect a number of other systems. Second, relatively low LA concentrations (such as attained in blood during epidural anesthesia or analgesia or during intravenous LA infusion) that block neuronal Na+channels to a limited extent only still can have significant pharmacologic effects. We suggest that some of these “alternative actions” may be beneficial in the clinical setting, and others may be responsible for some adverse effects of LAs. Although Butterworth and Strichartz 3a decade ago urged investigation of such actions and their mechanisms, much remains to be discovered. To demonstrate the variety of LA effects, table 1provides an overview of various LA actions reported in the literature. This review focuses on an area in which alternative actions of LAs show much promise for clinical application: their effects on the inflammatory response and especially on inflammatory cells (mainly polymorphonuclear granulocytes PMNs but also macrophages and monocytes). PMNs do not express Na channels, 4and LA effects on these cells therefore are not caused by Na channel blockade. LA effects on these cells are not affected by Na channel blockers such as tetrodotoxin or veratridine. 5Overactive inflammatory responses that destroy rather than protect are critical in the development of a number of perioperative disease states, such as postoperative pain, 6–8adult respiratory distress syndrome (ARDS), 9–11systemic inflammatory response syndrome, and multiorgan failure. 12–15Perioperative modulation of such responses is therefore relevant to the practice of anesthesiology, and LAs may play significant roles in this regard.In general terms, inflammation can be described as a reaction of the host against injurious events such as tissue trauma or presence of pathogens. Release of vasoactive mediators from tissue mast cells (histamine, leukotrienes), as well as from platelets and plasma components (bradykinin), causes vasodilation and increased vascular permeability, leading to the classic inflammatory signs of redness (rubor ) and heat (calor ). The resulting edema causes swelling (tumor ), and interactions of inflammatory mediators with the sensory systems induce pain (dolor ). Significant local inflammation causes a systemic response, termed the acute phase reaction . This response is manifested by increases in acute phase proteins (C-reactive protein, complement factor C3, fibrinogen, and serum albumin), followed by activation of several systems of mediators (kinin system, complement system, lipid mediators, and cytokines). Cytokines, in particular, are important for regulation of the inflammatory response. The local release of cytokines (interleukin-1 IL-1, IL-8, tumor necrosis factor TNF) coordinates the inflammatory response at the site of injury and induces neutrophil chemotaxis to the site of inflammation. Some cytokines (IL-1, IL-6, TNF) released from inflammatory sites mediate the systemic response. They induce fever and the acute phase reaction, mobilize neutrophils from the bone marrow, and promote lymphocyte proliferation.The inflammatory response induces cells (primarily PMNs and monocytes) to migrate into the affected area, in which they destroy pathogens, largely by phagocytosis. This process can be divided into several stages (fig. 1):The inflammatory response is essential for structural and functional repair of injured tissue. It is, however, a double-edged sword. Excessive generation of proinflammatory signals, as occurs in several disease states, can aggravate tissue damage because of products derived from inflammatory cells. This suggests that modulation of the inflammatory response (e.g. , by LAs) might prevent such tissue damage.This section describes some actions of LAs on inflammatory processes. We focus on three specific disease states relevant to anesthesiologists: inflammatory lung injury, increased microvascular permeability, and myocardial ischemia–reperfusion injury. In addition, we discuss briefly the use of LAs to treat inflammatory bowel disease, an area of active clinical investigation. Finally, we refer to an issue of considerable importance: the possibility that LAs, because of their antiinflammatory properties, might increase the risk of infection in certain settings.High LA concentrations have been used in some studies, and, in order to judge the clinical relevance of the various reports, it is important to consider the concentrations of LAs used in clinical practice. These concentrations differ widely, depending on the method of application. In order to achieve systemic effects after intravenous administration of LAs, plasma levels in the low micromolar range are required (for lidocaine, approximately 0.5–5.0 μg/ml, corresponding to 2–20 μm);16For example, intravenous administration of lidocaine at 2–4 mg/min leads to plasma concentrations of 1–3 μg/ml (4–12 μm) after 150 min. 17After 15 min a 2 mg/kg intravenous bolus of lidocaine results in peak plasma levels of 1.5–1.9 μg/ml (6–8 μm). 18Similar plasma concentrations are obtained after epidural administration 19or topical application of LAs (1 mg/cm2) in partial-thickness burns 20; LAs applied topically on intact skin are likely to achieve substantially lower plasma concentrations. Plasma concentrations of lidocaine above 10 μg/ml tend to produce adverse effects. 21In contrast, after local application or tissue infiltration of these drugs, LA tissue concentrations are typically in the millimolar range. Similar concentrations are present around the spinal nerves after epidural or spinal administration of LAs. 22LA concentrations at specific sites vary widely, depending on the method of administration. In vivo , LAs are largely protein-bound, lowering the concentrations available for interactions with signaling systems.Most studies have used lidocaine as a prototypical compound. Although other LAs appear to exhibit largely similar actions, there is clearly a lack of comparative studies with LAs from various classes, and very few structure–function studies have been performed. Data obtained with lidocaine cannot necessarily be extrapolated to other LAs.Polymorphonuclear granulocytes, macrophages, and cytokines play crucial roles in the pathogenesis of inflammatory lung injury. Cytokines increase the expression of adhesion molecules, thereby increasing margination of PMN accumulated in the lung. The attachment of PMN affects endothelial cells and microvascular permeability.Nishina et al. 23reported that pre- or early posttreatment with lidocaine (bolus 2 mg/kg + 2 mg · kg−1· h−1continuous infusion, yielding plasma concentrations of 1.2–2.5 μg/ml 5–10 μm) attenuates the late phase of acid installation–induced lung injury in rabbits. Lidocaine decreased PMN accumulation in the lung. Superoxide anion production by PMNs obtained from the pulmonary artery was inhibited, indicating reduced free radical generation. In turn, this endothelial damage and therefore might pulmonary The increase in pulmonary and was in and levels in used for concentrations of LA in clinical concentrations of LA have been to affect the of macrophages The in cytokines was likely a result from of the inflammatory response, rather than of production by macrophages or and Plasma levels of and IL-8, and concentrations in in The antiinflammatory effects of lidocaine lung after by of and of decreased and increased The effects likely a result of of and activation of of PMNs with endothelial cells also may be important in the pathogenesis of by margination of PMN in response to an inflammatory to endothelial LAs with the of inflammation in , a of these in lung injury might be et al. in a of with lidocaine concentration μg/ml μm]) increases in PMN PMN activation and to the inflammatory and PMN as by an of free radical The of lidocaine was not a result of in of PMN to endothelial PMN and of release by lidocaine may the of microvascular in Similar results obtained by et that with lidocaine of 2 mg/kg followed by of 2 mg · kg−1· attenuates lung injury in by the accumulation and the of by to concentrations inflammatory PMN activation and in the may be in the pathogenesis of this This is by the that protect the lung in such the effects of LAs on inflammatory it be that their antiinflammatory prevent lung injury. et al. a of LAs on inflammatory responses and pulmonary in a of lung injury. Lidocaine to relevant plasma concentrations μg/ml μm]) decreased in and in PMN accumulation than in rabbits. PMN from a in indicating reduced free radical release and therefore of endothelial The lung as by a in and of the lung. Lidocaine was with of lung have been to be in various of and the to be their antiinflammatory microvascular is in inflammatory relevant to and studies have effects of LAs on this an in vivo of in lidocaine, or the the inflammatory reaction, as by of and of in the the with in the release of mediators such as vasoactive may have to the of lidocaine, this not lidocaine of the of the reduced the inflammatory reaction in the bowel with several of the inflammation may be a likely for the in this results obtained by et al. the effects on of topical pre- and posttreatment of the with lidocaine and anesthetics a of microvascular Although to the on lidocaine a inhibitory et al. by μm) of plasma indicating that the is not specific to injury the complement and other inflammatory resulting in plasma with and a for inflammatory mediators in the pathogenesis of in the of LAs protect microvascular increasing infection skin burns in et al. that topical application or systemic administration of LAs, in resulting in plasma concentrations plasma in with This be by several of the known effects of LAs. of PMN to the site of of generation of and production increased local reduced PMN and to injured may to the reduced plasma These not however, by et al. , not that LAs affect and of sensory with in release of to be important for edema development after injury, et al. that the was the concentration of lidocaine was increased from 10 to · kg−1· for this is activation or block of at the lidocaine similar and is the of LAs on vascular in and in vivo concentrations (for lidocaine corresponding to induce concentrations induce It is that edema and vasodilation the inflammatory response increase the of but et al. that lidocaine applied to the skin of with partial-thickness burns in concentrations to was with pain plasma concentrations or and These studies suggest that may be obtained from topical with LAs, in with to the development of several bowel and are caused by and inflammatory In a effects, clinical studies have that LAs can be against the inflammation of these et al. that with with mg peak plasma concentrations μg/ml μm]) decreased inflammation and reduced clinical after only 2 of of the inflammatory and as well as of nerves also may play a in these as for the LA release of proinflammatory products with other acid and also may to this beneficial of however, to release by in at concentrations than concentration μm) the of bowel in radical in a significant of LAs mg bolus + mg/min intravenous infusion, or 2 mg/kg also the of postoperative in is with release of inflammatory mediators such as and of resulting in of after is likely to be a result of inflammatory in the area LAs affect the release of inflammatory beneficial effects on bowel may result at in from antiinflammatory effects. This is by the that antiinflammatory are also antiinflammatory of LAs is and after serum levels have might on bowel after was these show significant promise for the use of LAs in the of inflammatory bowel disease, as well as in the of postoperative myocardial is not an inflammatory disease, but and ischemia–reperfusion injury, is by a significant inflammatory response. interactions during myocardial and are to play a crucial and are important in myocardial injury with of the PMN can induce structural in the through the of free and acid et al. that that PMN may studies have that and are important of the inflammatory response in myocardial is as a of tissue injury in this expression of PMN and adhesion and their increases in the acute phase of myocardial is not that of adhesion molecules, PMN accumulation in the significant effects on myocardial ischemia–reperfusion injury in administration of against reduced myocardial injury in an after with which decreased levels and reduced adhesion of PMN to injured leading to PMN accumulation and against injury. also significant in myocardial endothelial injury can be by PMN during in a of myocardial have that lidocaine, or in a of the and reduced after in reduced by release of contrast, et al. in their lidocaine concentration μm) reduced myocardial PMN accumulation These might be caused by the the of is used for antiarrhythmic after myocardial It is that of the antiarrhythmic in this is a result of antiinflammatory effects of lidocaine in areas of myocardial Although lidocaine administration to be in in several studies in and decreased caused by free on important of the antiinflammatory of LAs is a increase in to of the PMN response may the ability to however, that the PMN is to the et al. that the of PMNs from lidocaine was only Although et al. , that lidocaine has beneficial effects on bowel in radical that lidocaine might be in in LA or in with of In a to the of et al. , to a study by et al. , which of with lidocaine mg/kg intravenous bolus + mg · kg−1· from but of that with but not with lidocaine only a et al. increased infection risk of local was applied to that LAs are likely to be beneficial in settings of in which the inflammatory response is a In contrast, LAs might be in settings of in which an inflammatory response is required to the in millimolar in in vivo . inhibits of and but has on or lidocaine inhibits of these and a number of pathogens, similar of and this are suggest that the to be rather than et al. that and against in the skin was to of than or actions, however, are obtained only at concentrations. et al. that low concentrations of at limited and not of They that LAs are to for example, epidural concentrations of or to have of LAs in the epidural are in the millimolar range. to studies it might be that the of epidural LAs to of epidural LAs from epidural might result in a infection concentrations of LAs also an in in to study the of LAs against et al. that anesthetics with such as can by to but only with than and applied in with also inhibited, but the was reduced was with It is likely that the inhibitory is against the and not with by with the of cellular LAs can in a This is by other such as and presence of a especially a is the and effects of LAs are only at antiinflammatory actions of these at systemic levels in can increase the risk of This has not been relevant in the in vivo studies reported to in settings of of the of the described is that these can inflammatory responses significant of host The section describes the cellular actions this inflammatory play an important in the early phase of inflammation. of release is therefore a for in inflammatory cells such as PMNs and is a of PMN It induces margination at endothelial and generation and with vascular It has a for PMNs , it is a in and in vivo . release of this an antiinflammatory because PMNs are to the inflammatory LAs block In of PMNs or with concentrations of lidocaine or lidocaine and may some of the antiinflammatory effects of the in with induces edema of by LAs may in the beneficial effects of LAs on edema is inflammatory on on respiratory and release of cytokines such as therefore also to an antiinflammatory of LAs. In , LAs, such as lidocaine and μm) release in blood cells. also inhibits release from and mast cells in at concentrations in the micromolar range. therefore that LAs can the release of several critical inflammatory in to effects on PMNs and this may be of the by which they their antiinflammatory of PMNs to may induce endothelial injury, which is by several adhesion of the important for adhesion of PMN to and is a of the is on the of but expression increases after inflammatory of PMN to endothelial cells by increases levels in the endothelial in which can have effects. against protect in against endothelial injury. studies have a of of expression on PMN after or lidocaine This may to the beneficial in vivo effects of on tissue concentrations μm) obtained after LA factor in interactions by PMN and expression on PMNs of cellular adhesion molecules, such as Lidocaine to PMNs during with the of and expression of The was and decreased PMN in . increases in play a in PMN of is also by lidocaine of increases in be responsible for this to PMNs the for cells. of PMNs endothelial and prevent PMNs from and therefore from to is by of and of processes. of production and are with and of processes. PMNs are to LAs in or these also followed by of and therefore PMN to sites of inflammation. with these effects. also occurs after of or to the tetrodotoxin not affect the LA to Na+channel and that macrophages in and with lidocaine or with and of processes. In , lidocaine induces a of significant effects are obtained with concentrations In vivo , bolus of mg/kg lidocaine in caused a in of min 15 min after lidocaine mg · kg−1· after bolus this inhibitory for the of Similar results obtained in a bolus of lidocaine for of is by a increase in PMN and into the In lidocaine mg/kg followed by mg · kg−1· of and of after of and of lidocaine this lidocaine caused a than of inflammation than to of the at and 1–3 after the was In the μm) inhibits PMN adhesion in and This may be caused by an on PMN or of PMN may result in from in blood and in from effects on anesthetics the ability of PMNs to to a a significant on PMN accumulation at the site of of PMNs is a during the inflammatory response. inhibitory on PMN has been reported by several in and in vivo et al. in that lidocaine inhibits PMN and with of PMNs in the presence of 20 et al. in , to μm lidocaine inhibits of the functional of with cellular with in and of the may to the of the compound. that a number of PMNs migrate to an injured of local administration of LAs on are of because these are into tissue for pain after on this however, Some in vivo have effects, LA et al. the effects of lidocaine on PMN accumulation in a an in vivo was by of a to the of the with 10 mg lidocaine reduced the accumulation of PMN in the area with in the lidocaine was reduced indicating of of et al. that in PMN accumulation during is by lidocaine mg/kg bolus followed by of mg · kg−1· the of the et al. that lidocaine, at micromolar accumulation and of PMNs in an in vivo These may be by of PMN therefore of a inhibitory on and of addition, it is that LAs release by that LAs the ability of PMNs to migrate to the site of inflammation by with the critical of adhesion and The result is decreased PMN process can be described as a response of PMNs after to such as IL-8, or is a of PMN and to play a in the of inflammatory which induces tissue damage rather than protect the the process is but are as overview of the and of PMN was in by et al. effects of LAs on PMN have not been in We have in that lidocaine of PMNs by acid in a μm). to other LA actions on these signaling the LAs at an the lidocaine effects similar to those of It is that of to the antiinflammatory actions of LAs, and in the effects of the response of inflammatory cells to a This might LAs can tissue damage PMN required for host and are likely to be in the In other of and have been described for several LAs that the might be to affect of LAs on and to have not been of LAs with PMN PMNs which can be as an of that is, free radical generation. Although some have the of this for investigation of PMN because the of is is a to production by In , lidocaine and for lidocaine and for depending on the of of effects of lower concentrations have been Some have reported or only a of by LAs in et al. in of PMN free radical generation by LAs in a and 10 The inhibitory with the for that is, the LAs of free radical and for their to affect free radical generation by of these inhibitory effects, the of LA is to be blockade. et al. in effects of lidocaine, and on and production of in LAs μm) caused a but significant in response. inhibitory on release was by an This this because free radical release may tissue and increased on in the effects of LAs on free radical release in vivo . inhibitory of LAs on PMN affects not only the production of also the generation of and et al. in that LAs at concentrations of release of such as and LAs do not the but rather the ability of PMNs to produce results in from release of by et al. in the effects of lidocaine on and release and these effects with the ability of PMN to . Lidocaine release of and reduced the of from to These in for lidocaine and at roles in the inflammatory in vivo the number of PMNs to endothelial cells of production has an antiinflammatory attenuates tissue injury during and in vivo . contrast, of by the in macrophages or neutrophils has been in the pathogenesis of or tissue injury against the host leading to failure. of by The attenuates acute lung injury in vivo . vivo of and PMN chemotaxis and and attenuates acute lung inflammation by and of lower effects of LAs on has not been described in In , LAs or generation in may to the effects of LAs, it to be a are in the inflammatory response. the against injurious they significant of cytokines and other inflammatory In an in study of macrophages, and lidocaine of and free radical This was with and at LA concentrations as present in during et al. in that LAs by macrophages, in a and the and the by in also is by in concentrations μm) into inhibits and of PMNs in . such as respiratory and are to by and the LAs to lidocaine inhibits in PMNs in . also and respiratory in macrophages in , or of the of the may to effects of LAs on These the that the of lidocaine on and other might result in from to an inhibitory on variety of actions of LAs on inflammatory cells have been of which suggest that LAs might the inflammatory response in various disease in studies concentrations of LAs above the relevant vivo studies of the or similar demonstrate effects at concentrations. The for this are The issue is because that free LA concentrations be available in in as with in vivo It may be that the targets of LAs interactions in vivo that cannot be attained in a in the to LAs during in vivo may play a We in Xenopus sensitivity of acid signaling to lidocaine and increased than from 10 min to is known the specific in these effects. In Na+channel can be because in Na+channels are not in the cells study because in vivo LAs induce effects at concentrations much lower than those required for Na+channel blockade. have been (fig. but only a few targets have been described in LA interactions with receptors are an area of active because mediators in the inflammatory process through receptors of this We have that LAs signaling of several receptors inflammatory responses acid well as m1 muscarinic acid and factor in Xenopus in on several signaling is the of LA sensitivity of acid of have that the signaling of the is not in the LA effects of the on are described of LA with signaling have been very specific is This area clearly in as well as in vivo , for antiinflammatory of LAs. on PMN and free radical as well as to the site of appear The these effects are relevance is the in concentrations required to achieve effects on inflammatory cells in much lower in vivo concentrations. use of for the of the inflammatory response may be of with topical is It that some of the beneficial effects of epidural administration of LAs leads to blood levels to those attained after intravenous infusion) may be caused by antiinflammatory effects of LAs. on pain and are In those not or to or postoperative epidural intravenous of LAs be in order to postoperative inflammatory In the of however, there is an increased risk of be in two First, we to a of the of of LAs on the inflammatory studies are because they can to the development of Second, clinical studies be to the effects of LAs in cells and in also can be applied to clinical for and of of of for the