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Published in final edited form as: Int Immunopharmacol. 2021 Apr 29;97:107709. doi: 10.1016/j.intimp.2021.107709

The immunomodulatory mechanism of dexmedetomidine

Koichi Yuki 1
PMCID: PMC8324520  NIHMSID: NIHMS1699619  PMID: 33933842

Abstract

Dexmedetomidine has been increasingly introduced into the perioperative care of surgical patients. Because a subset of anesthetics/sedatives are immunomodulatory, it is critical to understand the role of dexmedetomidine in our host immune functions. Here we reviewed the role of dexmedetomidine in different immune cells. We also reviewed published clinical articles that described the role of dexmedetomidine in organ injury, cancer surgery, and infection. In animal studies, dexmedetomidine attenuated organ injury. In clinical studies, dexmedetomidine was associated with an improvement in outcomes in cardiac surgery and transplant surgery. However, there is a paucity in research examining how dexmedetomidine is associated with these outcomes. Further studies are needed to understand its clinical application from immunological standpoints.

Keywords: Dexmedetomidine, leukocyte, outcome

Introduction

Dexmedetomidine is a highly selective α2 adrenergic agonist (α2: α1 selectivity of 1,600:1) with an imidazole ring (Ma, et al. 2004). It is a dextro-enantiomer of medetomidine. Since its approval for sedation use in intensive care units in 1999, dexmedetomidine has been increasingly used in the perioperative setting. Its pharmacological action comes from its interaction with both α2 adrenergic receptors and imidazoline receptors. The α2 receptors are G-protein coupled receptors that take norepinephrine and epinephrine as ligands. The rank order of their affinity to the α2 receptors is epinephrine >= norepinephrine (Tank and Lee Wong 2015). Their binding to the ligands results in coupling with pertussis toxin-sensitive Gi/G0 proteins to attenuate adenylyl cyclase, suppress voltage-gated Ca2+ channels and activate inwardly rectifying K+ channel for cellular hyperpolarization (Limbird 1988). The α2 receptors are expressed on the central and peripheral nervous systems as well as other cells and tissues such as leukocytes and endothelial cells. Classically the α2 adrenergic receptors were identified as presynaptic autoreceptors on the sympathetic nerve terminals, inhibiting norepinephrine release (Starke 2001). However, they are also expressed post-synaptically. Imidazoline receptors consist of three subtypes: I1R is expressed in the brain nucleus and on the endothelial cells to regulate blood pressure. I2R is expressed on the adrenal gland, fat and muscle tissues to regulate glucose use in the tissue. I3R is expressed on the pancreatic cells to regulate insulin secretion (Bousquet, et al. 2020). Dexmedetomidine’s major effects include hypnotic/analgesic effect as well as cardiovascular effects. Sedation is induced by stimulating the α2 adrenergic receptor in the locus coeruleus (LC) in the pons (Khan, et al. 1999). In the central nervous system, neuromodulators are released by neurons to alter the cellular properties of target neurons and the efficacy of their synaptic transmission (Sara 2009). The main neuromodulators include serotonin, acetylcholine, dopamine and norepinephrine. The LC clusters noradrenergic neurons. The LC, composed of only 1,500 neurons in the rat, sends projections to most brain regions including the brainstem, the cerebellum, the diencephalon and the paleo- and neocortex (Jones, et al. 1977). Analgesic effect is caused by the stimulation on the α2 adrenergic receptor in the supra-spinal and spinal sites (Fig. 1). Cardiovascular effects are derived from its direct effect on the vascular α2 receptor as well as from its indirect effect on the sympathetic nerves governing the heart.

Figure 1. The effect of dexmedetomidine on HP A axis and SAM axis.

Figure 1.

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HPA, hypothalamus-pituitary-adrenal; SAM, sympathetic-adreno-medullar ;CRH, corticotrophin-releasing hormone ;ACTH, adrenocorticotrophic hormone

The immunomodulatory properties of sedatives and anesthetics have been increasingly recognized (Carbo, et al. 2013; Koutsogiannaki, et al. 2019; Koutsogiannaki, et al. 2017; Mitsui, et al. 2020; Okuno, et al. 2019; Yuki, et al. 2013; Yuki, et al. 2012; Yuki, et al. 2020). Without exception, the immunomodulatory effect of dexmedetomidine has been investigated. Here we will review the role of dexmedetomidine in perioperative immune functions.

Perioperative stress responses

Perioperative stresses lead to metabolic, endocrinological and immunological changes in surgical patients. A surgical insult triggers a central response via afferent nerves to activate both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. The HPA axis activates the pituitary gland followed by the adrenal gland, the latter of which produces cortisol. Immune responses have been shown to be modulated by the peripheral nervous system, notably by the autonomic nervous system. The autonomic nervous system can be classified into the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Among them, a sympathetic nervous system represents a major pathway involved in the crosstalk between neurons and immune system (Scanzano and Cosentino 2015). The SAM axis activates the secretion of catecholamines systemically by the adrenal gland and locally by the sympathetic nerves. The sympathetic nerves emerge from the thoracolumbar spinal cord and produce catecholamines. In contrast, the extent to which the parasympathetic neurons regulate immunity remains unresolved. The sympathetic nervous systems innervate a number of lymphoid organs and mucosa (Godinho-Silva, et al. 2019). The intensity of surgical stress depends on the severity and duration of tissue injury and may be reflected by the degree of the secretion of pituitary hormones and the activation of the sympathetic nervous system (Wang, et al. 2015).

Catecholamines and cortisol play an important role in redistributing leukocytes. Epinephrine and norepinephrine induce a redistribution of neutrophils, monocytes and T cells from the marginated pool such as spleen, lungs, lymph nodes, and bone marrows into the bloodstream and temporarily increase blood leukocyte counts (Dhabhar, et al. 2012). Then, cortisol induces the movement of monocytes and T cells out of the blood stream to the surgical site or back to their origins. In contrast, neutrophil count continues to increase as a result of emergency granulopoiesis. This is in line with our general finding in the perioperative period that neutrophil number increases and NK cell and T cell number decreases postoperatively (Bartal, et al. 2010; Gaudilliere, et al. 2014). Catecholamines and cortisol also serve to modulate cytokine profiles. Proinflammatory responses are usually dominant at the surgical site first because cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-8 are primarily secreted from resident tissue macrophages. Subsequently these cytokines activate and recruit neutrophils and monocytes to inflammatory sites by interacting with their cytokine receptors (Andersson and Tracey 2011; Stoecklein, et al. 2012). Glucocorticoid receptors are expressed in neutrophils, monocytes, macrophages, T cells and B cells and cortisol shifts them to the cells with anti-inflammatory phenotype (Elenkov 2004). Catecholamine receptors are found in monocytes, macrophages, natural killer (NK) cells, B cells and T cells, and their stimulation induces anti-inflammatory responses (Glaser and Kiecolt-Glaser 2005). Anti-inflammatory responses are induced most potently by epinephrine, followed by norepinephrine, and least by cortisol (Elenkov, et al. 2008). Anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β induce regulatory T cells, a subset of Cluster of differentiation (CD) 4+ T cells with suppressive activity, from a pool of CD4+ T cells (Brenu, et al. 2013), and these regulatory T cells also bias CD4+ T cells toward Th2 cells, which are anti-inflammatory (Marik and Flemmer 2012).

The effect of dexmedetomidine on proinflammatory and anti-inflammatory cytokine production and leukocyte number in surgical patients

A meta-analysis of patient studies by Wang et al. demonstrated that intraoperative use of dexmedetomidine infusion was associated with 1) lower plasma epinephrine, norepinephrine and cortisol levels, 2) the increased number of NK cells, B cells and CD4 cells, and the decreased number of CD8 cells, and 3) increased ratios of CD4+: CD8+ and Th1: Th2 cells, and 4) decreased TNF-α, IL-6 and increased IL-10 levels (Wang, et al. 2019).

The reduction of epinephrine and norepinephrine by dexmedetomidine is intuitive given the action of dexmedetomidine on the SAM axis as described above (Fig. 1). Regarding the HPA axis, it is known that the α2 adrenergic receptors are expressed on the pineal gland (Munoz-Hoyos, et al. 2000). This will likely lead to reduced adrenocorticotropin (ACTH) and cortisol levels under dexmedetomidine (Fig. 1).

The aforementioned NK, B, T cell number change under dexmedetomidine can be explained by the fact that the effect of catecholamine and cortisol on their mobilization was attenuated because of the less catecholamine and cortisol levels. How about neutrophil number under dexmedetomidine? So far perioperative changes of neutrophil counts under dexmedetomidine has not been reported yet. Because neutrophil number in the perioperative period is largely influenced by emergency granulopoiesis, we need to know about if dexmedetomidine affects this process.

How can we explain cytokine profiles under dexmedetomidine? Although we may expect that cytokines should be proinflammatory rather than anti-inflammatory under dexmedetomidine because anti-inflammatory prone catecholamine and cortisol levels are attenuated, dexmedetomidine administration was associated with lower TNF-α, IL-6 and increased IL-10 levels in surgical patients. This may suggest that dexmedetomidine directly affects cytokine producing cells such as monocytes/macrophages. In the followings, we will review the effect of dexmedetomidine on individual leukocytes.

The expression of α2-adrenergic receptors on immune cells

The α2 receptors consist of three subtypes; α2A, α2B and α2C. The α2A subtype is expressed widely throughout both the nervous system and peripheral tissues. The α2B subtype is expressed primarily in the periphery, with the highest amounts in the kidney. The α2c subtype is expressed primarily in the central nervous system, although small amounts are present in the kidney (Link, et al. 1996). The corresponding gene names for α2A, α2B and α2C are adra2a, adra2b and adra2c, respectively. As their mRNA expression patterns are shown (Fig. 2), they are expressed on the majority of leukocyte subtypes.

Figure 2. mRNA expression profiles of the α2 adrenergic receptor subtypes on leukocyte.

Figure 2.

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ILC, innate lymphoid cell ;DC, dendritic cell ;GN, granulocyte

Imidazoline receptors are primarily expressed on non-leukocytes. Although their association with spingosine 1-phosphate (SIP) receptors has been suggested, the role of imidazoline receptors in immunological responses is still not well determined yet (Feher, et al. 2017). Therefore, we will describe the role of dexmedetomidine in immunological responses primarily from the α2 adrenergic receptors in the followings.

Neutrophils

Neutrophils are the first-line defense immune cells against tissue injury and invading pathogens via rapid mobilization, engulfment, intracellular killing, release of antimicrobial factors and neutrophil extracellular traps. In mRNA level, human neutrophils express β3 > β2 > α1A > α1B ~ α2A ~ β1 = α2C (Scanzano, et al. 2015). Among the α2 subtypes, neutrophils express α2A on protein level (Herrera-Garcia, et al. 2014).

The effect of dexmedetomidine on neutrophils was previously studied by co-incubating neutrophils with dexmedetomidine in vitro. The study by Nishina et al. did not find any effect of dexmedetomidine at clinically relevant concentrations on neutrophil phagocytosis, chemotaxis or superoxide production (Nishina, et al. 1999). Similarly, the study by Chen et al. did not find any effect of dexmedetomidine at clinically relevant concentrations on neutrophil respiratory burst (Chen, et al. 2016). Although circulating epinephrine and norepinephrine are primarily released from the adrenal gland and the sympathetic ganglia, they have been identified within human neutrophils as well (Cosentino, et al. 1999). This may indicate that neutrophils also synthesize and release catecholamines. The contribution of neutrophil derived catecholamine in neutrophil effector functions is likely very minimal, however, even if adrenergic receptors are involved in catecholamine production.

Despite the very minimal effect of dexmedetomidine in vitro, in the murine acute inflammation model using the air pouch, α2 adrenergic agonists xylazine and UK14304 increased the resistance of neutrophil extravasation from the endothelial cells (Herrera-Garcia, et al. 2014). This was explained by the attenuation of intercellular adhesion molecule-1 (ICAM-1) expression on the endothelial cells by these α2 agonists, rather than their effects on neutrophils. Inada et al. tested the effect of dexmedetomidine in the air pouch model (Inada, et al. 2017). They found neutrophil recruitment was significantly reduced by dexmedetomidine administration at least in part due to the reduction of neutrophil chemoattractants CXCL1 and CXCL2 production. The authors speculated that CXCL1 and CXCL2 would be produced in the lining cells such as mast cells in this model. Although these murine experiments supported the in vivo effect of dexmedetomidine on neutrophil functions, these phenotypes are likely caused indirectly, which is in line with the aforementioned in vitro studies. So far, the effect of dexmedetomidine on neutrophils in vivo was primarily studied in the context of neutrophil recruitment.

Norepinephrine seems to be inhibitory for neutrophil activation. Norepinephrine was shown to suppress neutrophil chemotaxis, activation and phagocytosis (Nicholls, et al. 2018). Because dexmedetomidine administration is associated with a reduction in norepinephrine level, it is possible that dexmedetomidine administration may attenuate the reduction of neutrophil phagocytosis, which would occur in the perioperative setting. In the experimental polymicrobial abdominal sepsis model induced by cecal ligation and puncture (CLP) surgery, dexmedetomidine administration was associated with a better survival associated with decreased proinflammatory cytokine levels than non-exposure arm (Chen, et al. 2015; Wu, et al. 2020). However, bacterial loads or neutrophil effector functions were not compared in these infection models. Thus, it is important to determine in the future whether or not neutrophil effector functions against microbes are better in vivo under dexmedetomidine.

Monocytes/ Macrophages

Monocytes and macrophages are key components of innate immune cells. They can phagocytize and present antigens. Monocytes and macrophages are also major cytokine producing cells. The α2 adrenergic receptors are expressed on monocytes and macrophages (Fig. 2) (Piazza, et al. 2016).

Perioperative dexmedetomidine has been shown to be associated with less TNF-α, IL-6 and IL-8 levels immediately and one day after surgery, and with higher IL-10 level one day after surgery in a meta-analysis by Li et al (Li, et al. 2015) (Fig. 3). In line, dexmedetomidine attenuated the production of TNF-α, IL-6 and IL-8 in lipopolysaccharide (LPS) stimulated whole blood in vitro (Kawasaki, et al. 2013). Similarly norepinephrine and clonidine also attenuated the production of TNF-α, IL-6 and IL-8 in LPS stimulated whole blood in vitro (Maes, et al. 2000). Then, can the reduced TNF-α, IL-6 and IL-8 levels be explained by the direct effect of dexmedetomidine on monocytes/ macrophages?

Figure 3. The effect of dexmedetomdine on local and systemic responses.

Figure 3.

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DAMP, damage-associated molecular pattern ; PAMP, pathogen-associated molecular pattern; HMGB1, high mobility group box 1; mtDNA, mitochondorial DNA ; TLR, toll-like receptor

In monocytes and macrophages, TNF-α, IL-6 and IL-8 are produced via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling pathway. The study by Li et al. showed that dexmedetomidine (1 μM) attenuated NFκB-p65 phosphorylation, and TNF-α and IL-1β production from LPS-stimulated murine BV-2 microglial cells and RAW264.7 macrophage cells (Li, et al. 2020). The study by Sun et al. also showed that dexmedetomidine attenuated proinflammatory cytokine production in BV-2 cells (Sun, et al. 2018). The recently study by Zhou et al. also showed that dexmedetomidine treatment attenuated TNF-a and IL-6 production and enhanced IL-10 secretion from bone marrow-derived macrophages (BMDMs) stimulated by LPS (Zhou, et al. 2020). In contrast, Piazza et al. tested the effect of dexmedetomidine on proinflammatory cytokines in human primary alveolar macrophages and found that dexmedetomidine did not affect the level of proinflammatory cytokines (Piazza, et al. 2016). Thus, the effect of dexmedetomidine on proinflammatory cytokine production may be dependent on the type of cells. Further clarification is required to determine whether or not dexmedetomidine directly affects the production of proinflammatory cytokines by macrophages and monocytes. Because IL-10 suppresses TNF-α, IL-6 and IL-8 via the signaling through IL-10 receptor (de Waal Malefyt, et al. 1991; van der Poll, et al. 1994; Wang, et al. 1994), the cytokine profile on postoperative day one may be explained merely by elevated IL-10. Because IL-10 can be produced by a number of immune cells which use different promotor regions depending on the type of cells, it is also important to determine how IL-10 production was increased under dexmedetomidine in vitro and in vivo.

Dexmedetomidine affects other monocyte and macrophage functions? In the study by Zhou et al., dexmedetomidine promoted BMDMs M2 activation as evidenced by increased Arg1 and Mrc1 gene induction and decreased iNOS gene induction (Zhou, et al. 2020). Dexmedetomidine attenuated the production of reactive oxygen species (ROS) in LPS stimulated U937 monocyte cells in vitro (Chai, et al. 2020). In addition, dexmedetomidine attenuated the adhesion of U937 cells to the endothelial cells by reducing the expression of adhesion molecules lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) in vitro. Both functional alternation under dexmedetomidine was considered to be due to the reduction of connexin Cx43. The interaction between the α2 adrenergic receptor and Cx43 has not been determined yet. The effect of dexmedetomidine on in vivo monocyte function was examined about phagocytosis. Dexmedetomidine attenuated monocyte phagocytosis in LPS stimulated mice (Wu, et al. 2015). Other monocyte functions need to be examined in vivo.

NK cells

NK cells are a phenotypically distinct population of lymphocytes (CD56+/CD3−) that eradicate tumor cells or microbes using constitutively expressed lytic machinery independent of prior immunization (Vivier, et al. 2008). NK cells also express the α2 receptors (Fig. 2) (Jetschmann, et al. 1997; Xiao, et al. 2010).

Gratz et al. examined NK cell function perioperatively. NK cell cytotoxicity was attenuated following surgery using K562 tumor cells as target cells. However, dexmedetomidine administration attenuated the reduction of NK cell cytotoxicity in patients receiving general anesthesia (Gratz 1999). However, dexmedetomidine did not affect NK cell cytotoxicity against K562 cells in vitro (Tazawa, et al. 2017). NK cell function is subjected to the modulation by the central nervous system (CNS). Cortisol produced by the HPA axis attenuates NK cell cytotoxicity (Capellino, et al. 2020). Because cortisol level increases under surgical stress, a reduction in NK cell function in the perioperative period can be explained at least in part by the cortisol production. Because dexmedetomidine infusion attenuates cortisol secretion in patients and in vitro experiment did not affect NK cell cytotoxicity, the preservation of NK cell cytotoxicity by dexmedetomidine in patients is largely explained by its CNS effect.

T cells

Like other leukocytes, T cells also express the α2 adrenergic receptors (Fig. 2)(Heng, et al. 2008). The subtype of T helper cells consists of precursor helper T (Th0), T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17) and regulatory T (Treg) cells. Th1 cells produce IFN-γ and favor cell-mediated immune responses (Kurosawa and Kato 2008). Th2 cells produce IL-4 and/or IL-10 and favor humoral immunity by antibody production. Th17 cells are differentiated in an IL-23 dependent manner and produces IL-17 (Webster and Galley 2009). Treg cells are important for the induction and maintenance of peripheral tolerance, therefore preventing excessive immune responses and autoimmunity (Romano, et al. 2019). Th1/Th2 and Th17/Treg ratios can be indicated by IFN-γ/IL-4 and IL-17/IL-10 ratios, respectively. Dexmedetomidine administration was associated with IFN-γ/IL-4 and IL-17/IL-10 ratios, which indicated a shift toward Th1 and Th17 (Lee, et al. 2018). The study by Wang et al. showed that dexmedetomdine arm has higher Th1 cells and Treg cells (Wang, et al. 2021). Th17 population was not examined in the study by Wang et al.

In addition, dexmedetomidine was associated with the expression of programmed cell death-1 (PD-1) and its ligand (PD-L1) on T cells (Wang, et al. 2021). Because stress responses can lead to immunosuppressive T cell phenotype with PD-1 expression (Qiao, et al. 2018), this can be likely explained by the attenuation of stress responses by dexmedetomidine. Dexmedetomidine did not attenuate IL-2 production from T cells or proliferation in vitro (Yuki, et al. 2011). However, the experiment using splenocytes explanted from mice receiving dexmedetomidine showed that dexmedetomidine attenuated T cell proliferation (Wu, et al. 2015). It is unclear if in vivo exposure of dexmedetomidine altered T cell phenotype. Overall the effect of dexmedetomidine on T cell function remains to be studied further. The effect of dexmedetomidine on B cells was limitedly studies, and we will not discuss here.

Dexmedetomidine and immunological outcomes

Overall dexmedetomidine administration attenuates perioperative stress responses, favoring anti-inflammatory state. Whether or not dexmedetomidine administration affects clinical immunological outcomes is an important topic. A large number of studies have been done in preclinical models but here we primarily focus on clinical studies.

Cancer outcome

The association between the choice of anesthetic regimens/ drugs and cancer outcomes is one of the most studied areas (Hiller, et al. 2018). For example, a number of studies compared the outcome of patients undergoing cancer resection surgeries either under volatile anesthetic-based general anesthesia or intravenous anesthetic-based general anesthesia (Yap, et al. 2019). The negative effect of perioperative stress on cancer outcome was also shown (Armaiz-Pena, et al. 2013; Ben-Eliyahu 2003). Dexmedetomidine can attenuate stress response and may be an advantageous drug in cancer resection surgery from this aspect. Perioperative impaired NK cell function is also associated with cancer recurrence (Freeman and Buggy 2018), but dexemedetomidine seems to preserve it (Gratz 1999). Dexmedetomidine promotes M2 macrophage polarization. M2 macrophages can facilitate angiogenesis and tumor growth (Jayasingam, et al. 2019).

Levon et al. tested the effect of dexmedetomidine in tumor growth in the rodent tumor model. In contrast to the prediction, the size of breast, lung and colon cancer was significantly larger in mice receiving dexmedetomidine (Bruzzone, et al. 2008; Lavon, et al. 2018; Szpunar, et al. 2013). In these studies, dexmedetomidine administration induced tumor growth and metastasis by directly activating the α2 adrenergic receptors on tumor cells or by activating the α2 adrenergic receptors on host stromal cells. Other explanation is by promotion of M2 macrophages.

In consistent with the animal study, the study of 1,404 patients by Cata et al. showed that intraoperative dexmedetomidine administration was associated with a decrease in the overall survival of propensity-matched patients after non-small cell lung cancer surgery (Cata, et al. 2017). However, more studies are needed to know about its clinical impact in cancer surgery.

Organ injury

A subset of invasive surgeries such as cardiac surgery and transplant surgery are known to be associated with high incidence of morbidities and mortalities. Ischemia-reperfusion involving these surgeries is one of major causes for morbidities and mortalities. Damage-associated molecular pattern (DAMP) molecules such as high mobility group box 1 (HMGB1) are released from injured cells. DAMPs activate cells via various pattern recognition receptors such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE) on various cells, which can lead them into cell death including pyroptosis, apoptosis and necrosis.

Pyroptosis is a caspase-1 dependent programmed cell death, and dexmedetomidine was shown to demonstrate cyto-protective property by attenuating pyroptosis (Ji, et al. 2019) (Fig. 3).

The study of a total of 1,134 patients undergoing coronary artery bypass (CABG) surgeries and CABG plus valvular surgeries by Li et al. showed that perioperative dexmedetomidine use was associated with a decrease in postoperative mortality up to one year and decreased incidence of postoperative complications (Ji, et al. 2013). Another study of 724 patients undergoing CABG surgeries by the same group also showed that perioperative dexmedetomidine use was associated with better in-hospital, 30-day and 1-year survival rates (Ji, et al. 2014). The similar result was shown by Cheng et al (Cheng, et al. 2016). In infant cardiac surgery, neurological complications post cardiopulmonary bypass as well as perioperative sedation are one of serious comorbidities (Whiting, et al. 2015). Dexmedetomidine has shown to be neuroprotective in animal models (Rajakumaraswamy, et al. 2006; Sifringer, et al. 2015), and the role of dexmedetomidine in infant cardiac surgery has been under evaluation currently (Zuppa, et al. 2019).

In the study of 780 patients undergoing kidney transplantation by Chen et al., dexmedetomidine administration was associated with a decrease in delayed graft failure, risk of acute rejection, infection and overall complications in the early post-transplantation phase (Chen, et al. 2020). Furthermore, in a meta-analysis of 20 studies by Biccard et al., dexmedetomidine use was associated with a trend towards improved all-cause mortality, non-fatal myocardial infarction and myocardial ischemia (Biccard, et al. 2008). The results from these clinical studies are in line with the cyto-protective property of dexmedetomidine.

Infection

Although dexmedetomidine administration favored CLP sepsis as described above, it is unclear if the outcome result could be explained by the attenuation of proinflammatory cytokine production by dexmedetomidine or due to other reasons. In LPS model, dexmedetomidine attenuated neurological damage (Sun, et al. 2019). Pathogen-associated molecular pattern (PAMP) molecules such as LPS activate inflammatory cells and can induce cell death. Dying cells can release DAMPs. Sun et al. showed that dexmedetomidine not only decreased cell death (pyroptosis) by LPS but also decreased the release of DAMPs (Fig. 3), suggesting that it could potentially serve to attenuate organ injury in the setting of infection.

In the clinical study of sepsis, dexmedetomidine administration was not significantly associated with any improvement of mortality or ventilator-free days (Kawazoe, et al. 2017). Although the data regarding surgical infections has been shown by other sedatives/ anesthetics (Shibamura-Fujiogi, et al. 2020), the effect of dexmedetomidine on surgical site infections remains to be determined.

Summary

Dexmedetomidine attenuates surgical stress responses and poses anti-inflammatory shift in our immunological responses. In animal models, dexmedetomidine showed cyto-protective property to attenuate organ damage. However, it increased tumor size. In clinical studies, dexmedetomidine administration was associated with an improvement of outcomes in cardiac surgery and transplant surgery. However, it was associated with a decrease in survival in tumor surgery, indicating that its clinical benefit may be depending on the clinical context. However, there is a paucity in research examining how dexmedetomidine is associated with these outcomes. Further studies are needed to understand its clinical application from immunological standpoints.

Highlights.

  • Dexmedetomidine is a highly specific α2 adrenergic agonist with increasing use in the perioperative medicine.

  • A number of immune cells express the α2 adrenergic receptors.

  • Preclinical and clinical studies demonstrated both benefit and disadvantage of dexmedetomidine use depending on clinical context.

Acknowledgments

Finance:

This work is in part supported by NIH GM118277/ GM127600 (K.Y.)

Footnotes

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Conflict of Interest:

None

Competing interests:

Author declared no conflict of interest.

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