key: cord-1016687-78bgchnj authors: Chalkias, Athanasios; Barreto, Erin F.; Laou, Eleni; Kolonia, Konstantina; Scheetz, Marc H.; Gourgoulianis, Konstantinos; Pantazopoulos, Ioannis; Xanthos, Theodoros title: A critical appraisal of the effects of anesthetics on immune system modulation in critically ill patients with COVID-19 date: 2021-01-09 journal: Clin Ther DOI: 10.1016/j.clinthera.2021.01.004 sha: d1a48f1c9876efbb7f2e16d1725b252e5c22cf97 doc_id: 1016687 cord_uid: 78bgchnj Purpose The aim of the present article is to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. Methods The PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies. Findings The novel coronavirus causes a wide spectrum of clinical manifestations, with large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune system modulation may vary and include both pro-inflammatory and anti-inflammatory effects. Implications Inhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in COVID-19 patients. Since February 20, 2020, the day of designation coronavirus disease by the WHO, COVID-19 has spread to include millions worldwide, with confirmed cases increasing again despite the austere applied measures. This novel coronavirus causes a wide spectrum of clinical manifestations, with large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome (ARDS) and multiple organ failure. The virus may spread through the respiratory mucosa and infect other cells, inducing a cytokine storm in the body. The infected patients have high amounts of IL-1B, IFN-γ, IP10, and MCP1, while patients with pneumonia who develop ARDS usually have significantly higher neutrophil count, lymphopenia, and more severe cytokine storm than those without ARDS [1] . Moreover, patients requiring intensive care unit (ICU) admission have higher concentrations of inflammatory mediators and cytokines than those who are not admitted to the ICU, suggesting that the cytokine storm is associated with disease severity [2] . In addition, severely ill patients have high-levels of proinflammatory cytokines, including IL-2, IL-6, IL-7, IL-10, G-CSF, IP-10, TNF-α, and procalcitonin [2, 3] . Critically ill patients with COVID-19 and acute hypoxemic respiratory insufficiency or failure will need early endotracheal intubation and mechanical ventilation. Rapid sequence induction (RSI), the recommended technique for anesthesia induction and cautious administration of general anaesthetic agents. In general, principles of airway management are like those in more controlled settings, with several drugs being recommended for RSI in COVID-19 patients [4] . Although general anesthetics may affect the immune system and may increase morbidity and mortality of patients with COVID-19, surprisingly few attempts to J o u r n a l P r e -p r o o f 3 cover this issue have been made. The aim of the present article is to briefly summarize some aspects of current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. The choices of anesthetics may differ between hospitals, cities, or countries depending on the physician preferences and availability. Until today, only two published studies report on the use of induction agents in COVID-19 [5, 6] . Propofol was used in almost all patients, usually combined with other agents, while midazolam and etomidate were used in only a small portion of patients. Neuromuscular blocking agents were used in all patients, with rocuronium being administered in 99% of patients (Table 1) . In both studies, the choice of induction agents has been usually dictated by hemodynamic considerations and not by the inflammatory status. Innate immunity is the first line of defense and refers to protective mechanisms that are present before infection and consists of the epithelial membranes, phagocytic cells, dendritic cells, natural killer (NK) cells, and several plasma proteins. The most important cellular reaction of innate immunity is inflammation, which is mediated by dendritic and NK cells. Adaptive immunity consists of mechanisms that are induced by the recognition of specific pathogen antigens and is mediated primarily by lymphocytes. However, an inflammatory immune response may also be induced by different non-infectious stimuli, anesthesia J o u r n a l P r e -p r o o f 4 itself may induce an inflammatory response in the patient. Also, endotracheal intubation does not guarantee a complication-free procedure and local inflammatory responses secondary to the presence of the tracheal tube have been described [7] . The impact of anesthetics on immune system modulation may vary and include both pro-inflammatory and anti-inflammatory effects [8] . Although these effects were first demonstrated more than 100 years ago, research so far has shown that at concentrations used clinically, different anesthetics affect the functions of the inflammatory response in a diverse manner ( Table 2) [9]. Therefore, the development of therapeutic approaches seems prudent to prevent iatrogenic harm that will lead to dysregulation of this inflammatory process and increased morbidity and mortality [77] . The effects of anesthetics on immunomodulation of inflammation are complex and the choice and use of these agents must be highly dependent on the immune status of the COVID-19 patient, especially in obese individuals, in whom the inflammationinduced synergistic conversion of tissue-resident macrophages to an M1-like phenotype and expression of cytokines and adipokines by adipocytes will aggravate the inflammatory status [78] [79] [80] . Another important contribution of anesthetics is the potent enhancement of inflammation resolution. It is known that endogenous pro-resolving bioactive mediators can terminate the inflammatory response by promoting the clearance of cellular debris and countering the release of proinflammatory cytokines/chemokines [81] . Loss of inflammation resolution mechanisms in infectious diseases sustains pathologic inflammation [79, 82] , and thus, it may be also responsible for the preservation of dysregulated inflammation and associated mortality in COVID-19 [83] [84] [85] . The resolution of inflammation is also stimulated by another pathway involving the arachidonic acid-derived epoxyeicosatrienoic acids (EETs). These J o u r n a l P r e -p r o o f mediators modulate ion transport and gene expression, producing vasorelaxation, promote clearance of cellular debris, and activate anti-inflammatory programs to inhibit several key pro-inflammatory cytokines [82] . Various anesthetics agents can modify these processes. It is known that leukotrienes are metabolites of arachidonic acid derived from the action of 5-lipoxygenase (5-LO) [86] . Propofol may inhibit 5-LO and decrease the production of leukotrienes in dendritic cells and probably other types of immune and non-immune cells [24] . Also, dexmedetomidine has been shown to upregulate netrin-1, an orchestrator of inflammation-resolution, resulting in upregulation of pro-resolving (lipoxin) and downregulation of proinflammatory (leukotriene-B4) humoral mediators [60] . The shift of arachidonic acid metabolism to favor inflammation resolution enhances the production of EETs from arachidonic acid by cytochrome P450 epoxygenases [87, 88] . This is very important for patients with low-grade or chronic inflammation, in whom mitigation of disease severity should be a priority. This mitigation can be further enhanced by the propofol-induced suppression of COX enzyme activity [89] . However, ETTs are pulmonary vasoconstrictors and are rapidly metabolized to less vasoactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH) [82, 88, [90] [91] [92] . Therefore, administration of propofol may be more effective in the early stages of inflammation, while in advanced respiratory failure with cytokine storm, propofol may be better administered in combination with an sEH inhibitor (e.g. urea, carbamate, or amide derivatives) and a pulmonary vasodilator (e.g. i.v. epoprostenol or inhaled iloprost) to decrease lung inflammation and improve lung function [93]. However, these combinations must be further evaluated in well-conducted trials. Interestingly, EETs appear to affect other organs as well. In the renal cortex, EETs selectively oppose V1-receptor-mediated vasoconstriction, contributing to the J o u r n a l P r e -p r o o f 6 relative insensitivity of medullary blood flow to V1-receptor activation. The vasculature of the injured kidney has an impaired vasodilatory response in critically ill patients and loses its autoregulatory behavior [94] . Consequently, EETs may have renoprotective effects, which is of great importance considering the increased incidence of acute kidney injury in patients with COVID-19 [95] . Several EETs have also been shown to improve the recovery of contractile function in isolated perfused mouse hearts [96] subjected to global ischemia and reperfusion and reduce the infarct size in intact canine, rat, and mouse hearts [97] . Of note, the cardioprotective effects of various EETs are the result of activation of the δopioid receptor by the release of the δ-active peptide Met-enkephalin [98] . Also, in hypoxic and hemodynamically unstable patients, the increased hypoxia-inducible factor-1α levels may play a role in cardioprotection mediated by EET-B in reperfusion [99, 100] . There is also evidence that the k-opioid receptor may mediate part of the EET effect [101] , while EETs and opioids are acting on similar signaling pathways comes from the preconditioning and postconditioning field. All these indicate that the role of opioid receptors in patients with COVID-19 is multifaceted and must be further investigated [98] . Inhibition of the development of severe inflammation and the enhancement of inflammation resolution by anesthetics may be a promising alternative approach to limit severe organ damage and improve outcomes in COVID-19 patients [102]. Based on current evidence, midazolam, propofol, ketamine, dexmedetomidine, opioids, rocuronium, cisatracurium, and succinylcholine may have favorable immunomodulatory effects when used in induction or maintenance of anesthesia. However, etomidate may be harmful, and its use may be questionable. J o u r n a l P r e -p r o o f Etomidate is a short-acting intravenous anaesthetic agent used for emergency anesthesia and for years it is one of the drugs of choice for RSI and endotracheal intubation [103] . Etomidate is a carboxylated imidazole (C 14 H 16 N 2 O 2 ) that binds at a distinct binding site associated with a Clionopore at the GABA A receptor. This increases the duration of time for which the Clionopore is open and prolongs the post-synaptic inhibitory effect of GABA in the thalamus. It is believed that etomidate does not compromise sympathetic tone or myocardial function and produces minimal hemodynamic changes after induction [104] . Nevertheless, the advantage of its hemodynamic stability and the disadvantage of its adrenocortical inhibition are not well-proven due to the lack of adequately powered randomized controlled trials. Until now, most of the evidence is based on systematic reviews and retrospective studies. In 2008, the results of the CORTICUS multicenter, randomized, double-blind, placebo-controlled trial suggested that etomidate may slow time to reversal of shock or reduce the number of patients who reverse shock, raising serious concerns about the use of etomidate in cases of septic shock [105] . Another study reported that etomidate treatment is associated with an increased incidence of non-responsiveness to corticotropin in septic shock patients, with hydrocortisone administration having no effect on outcome in these patients [39] . [41] . Despite the existence of possible bias, their meta-analysis found a statistically significant association between a single dose of etomidate for RSI and mortality, which persisted even after a second sensitivity analysis. Nevertheless, another systematic review and meta-analysis published in 2015 reported that there was no significant correlation between etomidate and mortality in patient with sepsis [46] . The same year, however, a Cochrane database systematic review reported that although there is no conclusive evidence that etomidate increases mortality or healthcare resource utilization in critically ill patients, it does seem to increase the risk of adrenal gland dysfunction and multi-organ system dysfunction [42] . In clinical practice, while etomidate may have fallen from favor over the last five to ten years, because of its effects on adrenal hormone levels affecting adrenoceptor function, it remains an important tool for RSI. In 2009, Warner et al. analyzed the data of a clinical trial investigating prehospital hypertonic saline administration in severely ill trauma patients and reported that a single-dose of etomidate for RSI was associated with increased ARDS and multiple organ dysfunction syndrome (MODS) partly due to an effect of etomidate on the inflammatory response (i.e. inhibition of 11β-hydroxylase) [48] . However, apart from the decrease in adrenocortical function and cortisol levels for up to 12-72 hours after a single dose [49] , the use of etomidate may be associated with other more insidious unintended effects. The first evidence on the association of etomidate with 'late death' was reported by a study of trauma patients conducted in 1983 [52] . Twenty years later a J o u r n a l P r e -p r o o f retrospective analysis reported that etomidate use was associated with an increase in the development of inflammatory organ injury, with patients with APACHE score >20 exerting the higher risk for adrenal suppression, ARDS, or MODS [48] . This finding was further supported by the results of a sub-study of the HYPOLYTE multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone in trauma patients, reporting that etomidate is an independent risk factor for hospital-acquired pneumonia on day 28 [50] . In an investigation of the association of etomidate with mortality in critically ill patients, the authors reported that etomidate administration was associated with a trend toward a relative increase in mortality [51] . However, the small increase in relative risk reported in the literature until 2013 may be underestimated because most of the previous trials have been underpowered to detect it. In 2014, Hinkewich and Green reported an absolute increase in 28-day mortality of 9.2% in trauma patients who received etomidate [106] . Although the difference in mortality was not significant after adjustment for covariates, they stated that their data showed a trend towards increased mortality, advocating that etomidate should be used ICU days, and mortality were unaffected (p=0.33, p=0 . 07, and p=0.70, respectively). The researchers concluded that the use of etomidate in the acute setting of trauma patients is associated with increased inflammatory response and worsening of respiratory function. The evidence is alarming and may be extremely important for the management of critically ill patients with COVID-19, in whom the equilibrium of the inflammatory response appears to be a major determinant of survival. Moreover, etomidate has been reported to increase pro-inflammatory cytokine production ex vivo in whole blood cell cultures challenged with lipopolysaccharide and could therefore prolong the systemic inflammatory response syndrome in COVID-19 patients [43] , increasing the possibility of secondary infections and corticosteroid dysfunction [44, 45, 107, 108] . On the other hand, the etomidate-mediated decrease of cortisol concentration may decrease monocyte and neutrophil activity and the homing of dendritic cells [109] . Furthermore, the decreased cortisol levels increase in the risk for inflammationrelated complications, such as ARDS and MODS, by impairing the maintenance of vascular tone and endothelial integrity, enhancing the production of phospholipases A2, and impairing leukocyte apoptosis [110] . Also, low cortisol increases L-selectin and CD 11b expression on neutrophils and monocytes, which promote chemotaxis, migration of white blood cells, and tissue destruction [48] . May 2020 reported that most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones [112] . Also, the recommendation in the recent Surviving Sepsis Campaign Guidelines is to use low dose corticosteroid therapy ("shock reversal"), over no corticosteroid therapy, in mechanically ventilated adults with COVID-19 and ARDS (weak recommendation, low quality evidence) [113] . Understandably, there is a conflict due to the limited evidence, but the medical community may err toward enthusiasm with steroids given the profound inflammation. Based on the aforementioned, etomidate administration may increase the use of other corticosteroids than the currently recommended dexamethasone, and safe alternatives should be used for RSI, alone or in combination, in patients with COVID-19 [111, 114, 115] . Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease Clinical features of patients infected with 2019 novel coronavirus in Wuhan HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression Intubation and Ventilation amid the COVID-19 Outbreak: Wuhan's Experience Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling The effect of midazolam and propofol on interleukin-8 from human polymorphonuclear leukocytes Tumor necrosis factor-a modulates the selective interference of hypnotics and sedatives to suppress Nformyl-methionyl-leucyl-phenylalanine-induced oxidative burst formation in neutrophils Propofol attenuated TNF-α-modulated occludin expression by inhibiting Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway in hCMEC/D3 cells Effects of general anaesthesia on inflammation Propofol decreases random and chemotactic stimulated locomotion of human neutrophils in vitro Propofol inhibits human neutrophil functions Mechanisms of intralipid effect on polymorphonuclear leukocytes Propofol emulsion reduces proliferative responses of lymphocytes from intensive care patients Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production Effects of intravenous anesthetics on bacterial elimination in human blood in vitro Do etomidate and propofol influence oxygen radical production of neutrophils? Low-dose ketamine affects immune responses in humans during the early postoperative period Stereoselective suppression of neutrophil function by ketamine? Immunopharm Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro Effects of etomidate on free intracellular amino acid concentrations in polymorphonuclear leucocytes in vitro The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis* Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood Persistent systemic inflammatory response syndrome is predictive of nosocomial infection in trauma Serum cytokines and critical illness-related corticosteroid insufficiency Single-dose etomidate does not increase mortality in patients with sepsis: a systematic review and metaanalysis of randomized controlled trials and observational studies Duration of adrenal inhibition following a single dose of etomidate in critically ill patients Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury Stress free: to be or not to be? Etomidate increases susceptibility to pneumonia in trauma patients Etomidate, adrenal function, and mortality in critically ill patients Mortality amongst multiple trauma patients admitted to an intensive therapy unit Etomidate in Trauma Patients is Associated with Inflammation and Pulmonary Dysfunction Anesthetics, immune cells, and immune responses Effects of short-term propofol and dexmedetomidine on pulmonary morphofunction and biological markers in experimental mild acute lung injury Dexmedetomidine Suppressed the Biological Behavior of HK-2 Cells Treated with LPS by Down-Regulating ALKBH5 Dexmedetomidine Preconditioning Protects Cardiomyocytes Against Hypoxia/Reoxygenation-Induced Necroptosis by Inhibiting HMGB1-Mediated Inflammation Dexmedetomidine protects against high mobility group box 1-induced cellular injury by inhibiting pyroptosis Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice Opioids and the immune system Editor's choice: Opioids and immune modulation: more questions than answers Immunosuppression by morphine is mediated by central pathways Opioid mediated effects on the immune system: sympathetic nervous system involvement Effects of fentanyl on cellular immune functions in man Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and mu(3) opiate receptor-dependent mechanism Effect of the opioid remifentanil on cellular immune response in the rat Rocuronium Bromide Inhibits Inflammation and Pain by Suppressing Nitric Oxide Production and Enhancing Prostaglandin E2 Synthesis in Endothelial Cells Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1 Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome Neuromuscular blockers in early acute respiratory distress syndrome Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials Effects of cisatracurium in combination with ventilation on inflammatory factors and immune variations in sepsis rats Early administration of cisatracurium attenuates sepsis-induced diaphragm dysfunction in rats Modification of mediators of immune reaction after general anaesthesia Proteomic changes induced by anaesthesia and muscle relaxant treatment prior to electroconvulsive therapy Treatment of tetanus; severe bone-marrow depression after prolonged nitrous-oxide anaesthesia he impact of obesity on severe disease and mortality in people with SARS-CoV-2: A systematic review and meta-analysis Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Sagittal abdominal diameter may effectively predict future complications and increased mortality in intensive care unit patients with severe sepsis Pro-resolving lipid mediators are leads for resolution physiology Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Soluble Urokinase Plasminogen Activator Receptor: A Biomarker for Predicting Complications and Critical Care Admission of COVID-19 Patients Nasal High Flow Use in COPD Patients with Hypercapnic Respiratory Failure: Treatment Algorithm & Review of the Literature Intraoperative initiation of a modified ARDSNet protocol increases survival of septic patients with severe acute respiratory distress syndrome Biosynthesis and metabolism of leukotrienes Soluble epoxide hydrolase is a therapeutic target for acute inflammation Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function Intravenous anesthetic propofol suppresses prostaglandin E2 and cysteinyl leukotriene production and reduces edema formation in arachidonic acid-induced ear inflammation Soluble epoxide hydrolase deficiency or inhibition enhances murine hypoxic pulmonary vasoconstriction after lipopolysaccharide challenge International Study of Inflammation in COVID-19. Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo Evidence for a role of opioids in epoxyeicosatrienoic acid-induced cardioprotection in rat hearts Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3 Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells Opioid-induced implications for vasopressor-free resuscitation Etomidate for procedural sedation in emergency medicine Etomidate as an Induction Agent in Sepsis Hydrocortisone therapy for patients with septic shock The impact of etomidate on mortality in trauma patients Initial Immune Response in Escherichia coli, Staphylococcus aureus, and Candida albicans Bacteremia Cardiopulmonary Arrest and Resuscitation in Severe Sepsis and Septic Shock: A Research Model Neuroendocrine regulation of immunity Assessment of Post-Resuscitation Intestinal Injury and Timing of Bacterial Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis Binds to peripheral receptors on macrophages and modulates their metabolic oxidative responsiveness • Inhibits human neutrophil function and the activation of mast cells induced by TNF-α • Suppresses expression of IL-6 mRNA in human blood mononuclear cells • Suppresses monocyte chemotaxis Suppresses the respiratory burst of reactive oxygen species, inhibits NF-κB activation via suppression of IκB-α degradation, and inhibits p38 activation in lipopolysaccharide -stimulated macrophages Suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling • Reduces extracellular IL-8 accumulation by diminishing its secretion from polymorphonuclear leukocytes, despite constantly high intracellular levels and mRNA expression of IL-8 Propofol • Suppress oxidative burst formation in TNF-a-primed neutrophils • Attenuates TNF-α-modulated occludin expression by inhibiting Hif-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells • Impairs several monocyte and neutrophil functions of the innate immune system • Its inhibitory properties on human neutrophils and complement activation may be related to its lipid carrier vehicle At least partly inhibits human neutrophil chemotaxis by suppressing the p44/42 mitogen-activated protein kinase (MAPK) pathway • Has proliferative-suppressing effects in polymorphonuclear leukocytes of critically ill patients who are primarily immunosuppressed • Reduces extracellular IL-8 accumulation by diminishing its secretion from polymorphonuclear leukocytes, despite constantly high intracellular levels and mRNA expression of IL-8 • Binds to 5-lipoxygenase and attenuates leukotriene B 4 production • Produces only cell-mediated immunomodulatory effects on innate immunity that might be generated by its lipid solvent • Drug-specifically suppress neutrophil function and reduces their phagocytic capacity • Reduces the phagocytotic capacity of alveolar macrophages and increases their gene expression of pro-inflammatory cytokines (IL-1b, IL-8, interferon-gamma, and TNF-α • Long chain triglycerides-diluted propofol inhibits neutrophil superoxide production, reduces the burst activity of neutrophils, and inhibits phagocytosis • Long/medium chain triglycerides-diluted propofol raises the burst activity of neutrophils • Reduces the intracellular calcium concentration in neutrophils • Chemically resembles the chain-breaking antioxidant a-tocopherol due to its phenolic hydroxyl group Ketamine • Inhibition of transcription factor activator protein-1 and nuclear factor kappa B (NF-κB) • Decreases the production of CRP, TNF-α, and IL-6 • Attenuates lipopolysaccharide -induced liver injury by reducing cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and NF-κB-binding activity Exerts suppressive effects on the adhesion-molecule expression and oxygen-radical production of human neutrophils Etomidate • The preparation with long/medium chain triglycerides increases the respiratory burst activity of polymorphonuclears • Mediates its suppressive effects on polymorphonuclear function by changing cellular amino acid turnover • Increases the incidence of non-responsiveness to corticotropin in septic shock patients Suppresses adrenal function, even as a single dose, and increases the possibility of pro-inflammatory cytokine production and secondary infections • A single-dose of etomidate is associated with increased acute respiratory distress syndrome and multiple organ dysfunction syndrome partly due to an effect of etomidate on the inflammatory response (i.e. inhibition of 11β-hydroxylase • Increases the development of inflammatory organ injury in trauma patients • Is associated with increased inflammatory response and worsening of respiratory function Dexmedetomidine • Reduces proinflammatory cytokine levels in septic and critically ill patients Significantly decreases leukocyte count, CRP, IL-6, IL-8, and TNF-α levels Suppresses the biological behavior of HK-2 cells treated with lipopolysaccharide by down-regulating ALKBH5 Dexmedetomidine preconditioning protects cardiomyocytes against hypoxia/reoxygenation-induced necroptosis by inhibiting high-mobility group box-1-mediated inflammation Protects against high mobility group box 1-induced cellular injury by inhibiting proptosis • Preemptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release through α7nAChR-dependent mechanism Opioids • Different opioids affect immune function differently depending on drug factors, host factors, and the duration of exposure • Morphine, fentanyl, remifentanil, methadone and codeine present strong immunomodulatory effects hydrocodone, oxycodone, and buprenorphine present much weaker or no immune-modulating capacity • Opioids that cross the blood brain barrier exert more immunomodulatory effects than opioids that do not cross it • Can cause direct sympathetic nervous activation, which may suppress the proliferation and function of some immune cell populations and primary and secondary lymphoid tissues Acute administration of opioids results in either a reduction or no change in adrenocorticotropic hormone or glucocorticoids Attenuate the circadian rhythm of adrenocorticotropic hormone and cortisol, leading to consistent increments in circulating levels of these hormones, which might be sufficient to produce immune suppression • Impair monocyte and neutrophil function, NK cell-mediated cytotoxicity, lymphocyte and macrophage proliferation, and cytokine release Promote apoptosis by direct activation of the enzymes involved in cell apoptosis (mainly morphine Inhibit leukocyte function by increasing intracellular concentrations of nitric oxide and cyclic adenosine monophosphate, and by inhibiting nuclear NF-κB via nitric oxide-dependent mechanisms • Enhance NK-cell cytotoxicity and increase NK and cytotoxic (CD8+) cell counts (mainly fentanyl • Produce inhibitory effects on leukocyte migration, NK-cell activity, and mitogen-induced lymphocyte proliferation (mainly sufentanil and alfentanil Rocuronium • Modulates cytokine production by macrophages/monocytes during the stress response • Exerts central sympatholytic effects, including stimulation of cholinergic anti-inflammatory pathways • Has antinociceptive action involving interactions between pain and immune factors (proinflammatory cytokines • Inhibits inflammation and pain by suppressing nitric oxide production and enhancing prostaglandin E2 synthesis in endothelial cells Cisatracurium • Decreases the plasma levels of TNF-α and IL-6 by inhibition of nicotinic acetylcholine receptor-α1 in lung injury • Decreases the pulmonary concentrations of IL-1β, IL-6, and IL-8 and the serum concentrations of IL-1β and IL-6 in acute respiratory distress syndrome Decreases the expression of high-mobility group box-1 in lung tissues and the cluster of differentiation (CD) 4+ and CD8+ in T-lymphocyte subsets Decreases the expression of TNF-α, IL-6, and high-mobility group box-1 in serum, as well as an alleviation of highmobility group box-1 protein expression in the diaphragm in early stages of sepsis Succinylcholine • Decrease the number of total lymphocytes, total IgE, and CD4/CD8 fractions • Increases fatty acid-binding protein, insulin, IL-1b, prolactin, S100, calcium-binding protein B, and TNF-α when administered with methohexital Acknowledgments: Nothing to acknowledge.