Signa Vitae. 2024; 20(9): 1-15. doi: 10.22514/sv.2024.105
Review

Effects of anesthesia and other perioperative factors on immune function: a narrative review

Yining Chen1,†, Junwei Kang1,†, Yulang Wang2, Xiongxiong Pan1,*,

1Department of Anesthesiology and Perioperative Medicine, the First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China

2Department of Anesthesiology, the Affiliated Hospital of Xuzhou Medical University, 221002 Xuzhou, Jiangsu, China

*Corresponding Author(s):xiongxiong@njmu.edu.cn (Xiongxiong Pan)

† These authors contributed equally.

History Submitted: 01 January 2024 | Accepted: 08 May 2024 | Published: 08 September 2024
Copyright:  ©2024  The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

This study investigates the impact of perioperative factors on patients’ immune functions including physiological condition, surgical strategy, anesthesia methodology, intraoperative usage of anesthetics, blood transfusion, intraoperative body temperature, and inspired oxygen concentration. Results demonstrate that the individual perioperative factors have varying degree of impact, while their combined effect may cause changes in patients’ immune function. The study outcomes suggest that patient’s immune function must be assessed prior to the surgery based on individual characteristics. The surgical and anesthetic methods are accordingly selected. During the surgery, prudent usage and monitoring of factors like anesthesia techniques, anesthetics, inhaled oxygen concentration, blood transfusion, and patient’s body temperature are vital for minimizing the immune system disruptions. These findings practically guide regarding the optimization of perioperative care strategies and mitigation of immunosuppression risks.

Keywords:Immune function;Perioperative factors;Anesthesia
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Cite this article

Yining Chen, Junwei Kang, Yulang Wang, Xiongxiong Pan. Effects of anesthesia and other perioperative factors on immune function: a narrative review. Signa Vitae. 2024; 20(9): 1-15. doi: 10.22514/sv.2024.105

1. Introduction

Multiple perioperative factors alter the patient’s immune function. They subsequently have an impact on perioperative infections and surgical outcomes.

The immune system is divided into innate and adaptive immunity. Innate immunity involves the evolutionarily conserved host defense systems which rapidly respond to the pathogens without specific antigenic stimuli. Contrarily, adaptive immunity recognizes antigens and maintains antigen-specific immune “memory” to protect the host from forthcoming attacks by the same pathogen.

Several factors may influence innate and adaptive immunity prior to and during surgery. Sometimes, relationship between the two types of immunity is also affected. However, the changes in immune function are not completely understood because of the immune system’s complexity, patient’s pathophysiological state, and impacts of surgery and anesthesia on organ systems. The impact of perioperative factors on patient’s immune function cannot thus be described by terms like “immunosuppression” or “immune activation”.

The perioperative management and patients’ prognosis can be improved by understanding the influence of perioperative factors on immune function of surgical patients.

In this review, the common perioperative factors affecting the immune function of patients are summarized.

2. Characteristics related to the patient

2.1 Age

World is facing an exacerbation in population aging. Body’s immune function declines with the age, known as immune aging. It increases the susceptibility to infectious diseases, cancers, autoimmune disorders, and other chronic illnesses [1].

Immune aging in innate immunity is depicted through changes in skin and mucosal barriers, macrophages, neutrophils, dendritic cells (DCs), and natural killer (NK) cells. With the age, turnover of skin cells decreases, sweat and sebum secretions diminish, and structural changes occur to damage the skin and mucosal barriers. Macrophages function is affected by the aging which include phagocytic activity, secretions of cytokines and chemokines, antimicrobial defense, infiltration, wound healing, and antigen presentation [2]. An animal model study has revealed that the expression of Toll-like receptors (TLRs) on macrophages decreases with the age [3]. TLRs have role in recognizing pathogen-specific molecular patterns, activating innate immune responses, and consequently regulating the adaptive immunity. The number, adhesion, and migration functions of neutrophils are unaffected by aging [4], however, their potential regarding phagocytosis, reactive oxygen species (ROS) production, and intracellular killing decreases [5, 6]. DCs’ overall number is not affected by aging, yet the specific subpopulations (such as Langerhans cells in skin [7], and plasmacytoid DCs [8]) decrease in number. Furthermore, aging affects the functionality of pattern recognition receptors, phagocytosis and migration [9, 10]. The number of NK cells increases in elderly individuals possibly because of mature cells accumulation, however, there is decrease in target cell cytotoxicity and cytokine secretion [11]. Mouse models [12] study has shown that aging affects NK cells migration. The cytokine secretion function declines [11], and proliferation response to Interleukin-2 (IL-2) stimulation decreases [13].

Adaptive immune response is affected more by the age-related changes in immune system [14]. Aging affects T and B cells number. T cells absolute values decrease during aging [15]. The activity and proliferative capacity also decline, which reduce the function of immune response [16]. Animal model and human studies have found that T cell function declines with age [17, 18]. It is discovered in mouse models that aging leads to functional defects in T cells because of changes in quantity or function of T cell surface glycoproteins. This may hinder T cell signal transduction and function [19]. Aging reduces B cell repertoire diversity as characterized by the decrease in naive B cells, increase in memory B cells [20], and reduction in clonal expansion capacity of memory B cells [21], which ultimately decrease the antibody production by B cells.

Older patients compared to younger ones are thus more prone to immune dysfunction during the perioperative period. This increases the challenges of postoperative recovery (Fig. 1).

The aging impact on innate and adaptive immunity. TLRs: Toll-Like Receptors; ROS: Reactive Oxygen Species; DCs: Dendritic Cells; PRRs: Pattern Recognition Receptors; IL-2: Interleukin-2; IFN-γ: Interferon-γ; TNF-α: Tumor Necrosis Factor; CSR: Class-switch recombination; SHM: Somatic Hypermutation.

Fig. 1.The aging impact on innate and adaptive immunity. TLRs: Toll-Like Receptors; ROS: Reactive Oxygen Species; DCs: Dendritic Cells; PRRs: Pattern Recognition Receptors; IL-2: Interleukin-2; IFN-γ: Interferon-γ; TNF-α: Tumor Necrosis Factor; CSR: Class-switch recombination; SHM: Somatic Hypermutation.

2.2 Alcohol

Excessive alcohol consumption is linked to immunosuppression [22], which affects the innate and adaptive immune cells regarding quantity, phenotype and function.

The impact of alcohol on innate immune function depends on exposure pattern. Production of inflammation mediators decreases with acute drinking and enhances with chronic drinking [23]. Alcohol misuse may deplete NK cells, impair its cytotoxicity [22], and affect antigen presentation of Kupffer cells [24]. Alcohol misuse affects the activation, recruitment, phagocytosis, and killing functions of neutrophils [25].

Alcohol also impacts adaptive immune function. Acute alcohol exposure may reduce inflammation and increase number of peripheral blood B and T cells [26]. On the contrary, chronic alcohol consumption suppresses T cells proliferation and induces apoptosis [27], which decreases the number of Cluster of Differentiation 4+ T (CD4+ T) and CD8+ T cells, and inhibits T cell activation and function [26]. It also reduces B cell count [26] and differentiation [28], and decreases protective antibodies production [29].

Alcohol-induced immune dysfunction and suppression may be caused by the inhibition of thymus and spleen growth, which damages intestinal barriers [30]. Resultantly, nutrients are difficult to absorb and cause nutritional immunosuppression [31]. It also harms the bone marrow by affecting granulocytes function [32]. Liver damage by alcohol consumption can compromise the immune function [33]. Alcohol misuse disrupts hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, which cause higher baseline cortisol levels [34] to further impair the immune function via neuroendocrine system.

2.3 Diabetes

Diabetes mellitus type 2 (T2DM) is a low-grade chronic inflammatory condition affecting the entire body. These inflammatory responses are linked to the activation of innate immunity. Immune function dysregulation in diabetic individuals is interlinked with metabolic disruptions to create cause-and-effect relationship. Immune dysfunction worsens the metabolic disturbances, and consequently metabolic byproducts adversely affect the immune system. Immune dysfunction contributes toward the complications of heart, brain, kidney, etc. and the infections in diabetic patients [35].

Neutrophils and monocytes in diabetics show reduced phagocytic and chemotactic functions, which decrease the antigen presentation [36]. DCs create a link between innate and adaptive immune responses, and this link is reduced in diabetic people [37].

The humoral and cellular immune functions are compromised in diabetic patients. Elevated blood glucose can modify the structure and thus functions of immunoglobulins to weaken the humoral immunity. Glycation lowers the antibody affinity for antigens, and increases the dissociation rates of antigen-antibody complex [38]. The susceptibility to infections is thus increased. Several studies have demonstrated the elevated levels of activated CD4+ CD278+ T helper cells, cytotoxic T cells, and Th17 cells [39, 40], while the decreased levels of CD4+ T-cells [40], naive T-cells [41], and Tregs [42]. Cytokine production like that of IL-2 is crucial for antibody production and lymphocyte function, and its imbalance further inhibits the humoral immune function.

Several factors during perioperative period such as the stress, anxiety, surgical trauma, pain, and anesthesia can trigger body’s stress response which increase the synthesis and release of stress hormones through HPA axis. This causes metabolic changes including the increased glucose levels, decreased insulin production, and reduced sensitivity to insulin. Resultantly, stress-induced hyper-glycemia occurs during the perioperative period. Intraoperative elevated blood glucose is an independent risk factor for postoperative complications and mortality in patients [43]. Controlling blood glucose during surgery can thus protect the body’s immune function, reduce complications, and improve prognosis.

Insulin therapy can control the blood glucose and thus alleviate its inhibitory impact on immune function. Insulin is also an immune-regulating hormone which modulates the differentiation and effector functions of immune cells. It induces T cells to differentiate into Th2 subtype, regulate neutrophil migration, and enhance prostaglandin E2 production. Consequently, immune function is protected directly and indirectly to reduce the risk of associated complications and mortality [44]. However, recent studies have demonstrated that severe hypoglycemic events are increased during the insulin-intensive therapy [45, 46, 47]. A study compared the impact of IIT (intensive insulin therapy; maintaining blood glucose between 4.4 and 6.1 mmol/L) and CIT (conventional insulin therapy; blood glucose <11.1 mmol/L) on postoperative immune function of diabetic patients undergoing radical gastrectomy. It was found that IIT group had higher human leukocyte antigen (HLA)-DR expression on postoperative days 3 and 5. Moreover, low HLA-DR expression was associated with the impairment of monocytic functions. IIT thus improved the postoperative immune-suppressed condition and enhanced monocytic function [48]. In a study on patients undergoing coronary artery bypass grafting, moderate blood glucose control reduced the hypoglycemic events, complications, and mortality compared to the strict blood glucose control [49]. Hypoglycemia is a complication of strict blood glucose control and its relationship with immune function and clinical relevance is unclear.

2.4 Obesity

Obese patients have chronic inflammation throughout the bodies. Their immune function is impaired which exacerbate immune dysfunction in perioperative period. Clinical studies demonstrate that increased body mass index (BMI) may disrupt the immune function during perioperative period in patients of hip and knee replacement surgeries, which causes delayed wound healing [50].

Obesity triggers chronic inflammation in adipose tissue. It is marked by the infiltration and activation of immune cells and leads to cytokines and chemokines production. Obesity also disrupts the functions of innate and adaptive immune cells [51, 52, 53]. The innate immune cells are reprogrammed in obese individuals, especially the mononuclear phagocytes to cause inflammation [54]. A shift toward pro-inflammatory phenotype is indicated by the increase of pro-inflammatory T cells (Th1 and Th17), and decrease of anti-inflammatory T cells (Treg and Th2) in adipose tissue and circulation [53, 55]. B cells also adopt the pro-inflammatory phenotype [56]. T cells and B cells differentiation, function and survival are affected in obese individuals [53, 57, 58].

Obesity leads to abnormal release of pro-inflammatory cytokines and adipokines (such as leptin) from adipose tissue to cause local and systemic inflammation [59, 60]. This disrupts immune cells’ function, and promotes transition of T and B cells toward pro-inflammatory cell subtypes [55]. It also triggers immune cells’ proliferation and enhances cytokine secretion [61]. Circulating lipids like the free fatty acids activate pro-inflammatory pathways in immune cells [62]. Obesity increases fat deposition in immune tissues, disrupts tissue integrity, and impairs the production and maturation of white blood cells to negatively impact the immunity.

3. Intraoperative factors

3.1 Blood transfusion

Studies have revealed that perioperative blood transfusion suppresses patient’s immune function, known as transfusion-related immunomodulation (TRIM) [63, 64]. TRIM mechanisms include the inhibition of NK cells, monocytes and macrophage activity, release of immunosuppressive prostaglandins, inhibition of IL-2 production, increase in number of inhibitory T cells, and activity enhancement. Reduced recipient immune function increases postoperative infections and tumor recurrence, and affects the patient prognosis [63, 65].

Blood transfusion methods (allogeneic and autologous) have different effects on recipient immune function and outcomes. Perioperative allogeneic blood transfusion decreases T cell subpopulations and NK cells in malignant tumor patients, increases inhibitory cytokine secretion, and decreases stimulatory cytokine secretion. They all lead to Th1/Th2 imbalance and transient decrease in plasma immunoglobulin levels. On the contrary, autologous blood transfusion has less inhibitory impact on immune function in malignant tumor patients and may improve postoperative immune function [66]. A study compared the effects of two blood transfusion methods on immune function of patients receiving total hip replacement. It was found that autologous blood transfusion had minor impact on postoperative immune function compared to that of allogeneic [67]. It even improved the immune function and recurrence survival of liver cancer patients [68].

The storage time of suspended red blood cells (RBCs) also affects patient’s immune function. The storage time impact of transfused suspended RBCs on immune function of gastrointestinal cancer patients was studied. It was depicted that storage of suspended RBCs for less than two weeks resulted in higher levels of CD4+ T cells and CD4/CD8 ratio in patients after transfusion as compared to those stored for more than 2 weeks. Shorter storage period had lower adverse reactions [69]. In another study, effects of RBCs transfusion on immune function in critically ill children were investigated [70]. Longer storage times of RBCs were associated with congenital immunosuppression. They sustained systemic inflammation, which was not the case in fresh RBCs transfusions.

The volume of transfused suspended RBCs also affects patient’s immune function. Aguilar-Nascimento JE suggested that the low survival rate related to TRIM in colorectal cancer might be because of the increase in quantity of allogeneic blood transfusions and/or prolonged blood storage time [71]. The impact of perioperative blood transfusion on immune function and prognosis in colorectal cancer patients was studied. It was exhibited that the mortality rate was higher in patients receiving ≥3 Units of blood compared to those with <3 Units. The survival rate was negatively correlated to transfusion volume [72].

Does reducing the white blood cell (WBC) count mitigate TRIM? Decreasing WBCs can be beneficial for specific patients. The effect of leukodepleted RBCs transfusion on immune function in bladder cancer patients was evaluated [73]. It was revealed that perioperative RBCs transfusion reduced immune function, and decreased T cell subpopulations, NK cells, and immunosuppressive acidic protein (IAP) levels. In contrast, leukodepleted RBCs transfusion improved the immune function.

Studies on pancreatic [74], ovarian (cytoreductive surgery) [75], and colon cancers have found associations between perioperative allogeneic blood transfusion and the cancer recurrence risk, however, this relationship is controversial. A definitive conclusion is yet not reached despite several mechanistic studies to elucidate this relationship.

3.2 Hypothermia

Intraoperative hypothermia is caused by large volume of rapid fluid infusion, blood transfusion, abdominal lavage fluid, excessive surgical exposure, and the anesthesia state. Anesthetic drugs inhibit the regulation of body temperature by affecting central and peripheral nervous systems. Some anesthetic drugs cause vasodilation which increases heat dissipation. Muscle relaxants reduce muscle activity to decrease heat production [76]. Intraoperative hypothermia is caused after the spinal-epidural anesthesia in cesarean delivery [77]. It results from core-to-peripheral redistribution of body heat [78]. Perioperative hypothermia prolongs anesthesia recovery time and affects patient coagulation function to cause cardiovascular abnormalities. It also suppresses immune function, increases postoperative infections, and affects patient prognosis.

It was found in animal models that hypothermia exposure suppressed innate immunity of freshwater drum and led to oxidative stress and immunosuppression [79]. An in vitro human study found that hypothermia reduced the HLA-DR expression, delayed Tumor Necrosis Factor-α (TNF-α) clearance, and increased IL-10 release compared to control. Perioperative hypothermia thus reduced the cell-mediated immunity [80]. Recent clinical trials demonstrated that Tregs had strong immunosuppressive potential and anti-inflammatory phenotype. Another study found that mild hypothermia of 33 °C preserved Tregs stability and function, and accelerated their proliferation to suppress the deleterious immune response [81].

Hypothermia’s inhibition regarding body immune function may be related to following factors. Low temperatures trigger stress response in the body, activate HPA axis, and increase cortisol and catecholamine concentrations in circulation. These factors inhibit T cells activity and synthesis of Th1-type cytokines, IL-2 and Interferon- γ (IFN- γ). Furthermore, low body temperatures lead to increased intraoperative blood loss and the need for blood transfusion, which increases immunosuppression risk.

3.3 Oxygen inhalation concentration

Most patients receive routine oxygen supplements during anesthesia and surgery. These oxygen inhalation concentrations range from 30% to 100%. There is no consensus on the optimal oxygen concentration. Prolonged exposure to high oxygen concentrations leads to cough, tachypnea, reduced lung capacity, and increased alveolar-capillary permeability, which result in pulmonary edema and fibrosis [82]. These timeframes are beyond the duration of oxygen inhalation during surgery. A meta-analysis of 17 randomized controlled trials found no evidence that oxygen inhalation concentration of 80% is associated with increased risk of perioperative harm compared to 30% to 35%. Oxygen inhalation concentration of 80% had no safety issues in adult surgical patients receiving general anesthesia [83]. High oxygen concentrations like 80% are beneficial to the patients without associated risks. The World Health Organization’s evidence-based guidelines recommend high-concentration (80%) oxygen inhalation to reduce surgical site infections in adult patients undergoing tracheal intubation for general anesthesia [84].

Studies show that perioperative high-concentration oxygen supplementation improves inflammation and immune function. Studies on laparoscopic Nissen fundoplication surgery [85] and laparoscopic cholecystectomy surgery [86] exhibited that low-concentration (Fraction of Inspired Oxygen (FIO2) 30%) oxygen supplementation decreased the expression of monocyte HLA-DR and increased the plasma elastase concentrations after surgery. On the contrary, no significant differences were observed in patients receiving high-concentration (FIO2 80%) oxygen supplement. Monocyte HLA-DR expression is an indicator for innate immunity and its expression is clinically significant in postoperative patient assessments. Patients with persistently low HLA-DR expression are in immunosuppressed state. High-concentration oxygen supplementation (FIO2 80%) reduces postoperative increase in pro-inflammatory cytokines, i.e., IL-1, IL-6, C-Reactive Protein (CRP). The perioperative high-concentration oxygen thus reduces postoperative inflammatory responses and prevents immunosuppression. However, studies are limited on whether immune function differences affect the clinical outcomes. Further research is required to determine the correlation between clinical outcomes and immunological changes.

3.4 Surgical approach

Surgical trauma and stress suppress body’s immune function. The suppression extent is related to surgical trauma level. Studies show that laparoscopic surgery has less stress and immunosuppression compared to open surgery, which helps in postoperative recovery [87, 88]. Moreover, laparoscopic surgery allows higher levels of B cells and NK cells [89], and shorter immunosuppression duration.

Nevertheless, research has found that pneumoperitoneum during the laparoscopic surgery has dual effect on peritoneal defense system which involves changes in peritoneal morphology and metabolism [90]. Peritoneal changes are influenced by the gas type, pressure applied, and pneumoperitoneum duration. Regarding the local peritoneal immune function, CO2 pneumoperitoneum in laparoscopic surgery induces more immunosuppression compared to open surgery. CO2 pneumoperitoneum leads to local peritoneal hypoxia, and decreased intraperitoneal pH to result in peritoneal acidosis. CO2 absorption through peritoneum affects systemic acid-base balance. These factors alter the cytokine production and phagocytic function of peritoneal macrophages [91]. Animal studies indicate that Secretory Immunoglobulin A (sIgA) levels in pneumoperitoneum group are increased compared to the open surgery group. This may be because of CO2 pneumoperitoneum which reduces visceral and portal blood flow and leads to intestinal ischemia. This temporarily impairs mucosal barrier function and causes mucosal damage [92]. Pneumoperitoneum pressure also affects patient recovery and innate immune homeostasis. Low-pressure pneumoperitoneum improves postoperative recovery, maintains innate immune homeostasis, and reduces postoperative inflammation markers and damage-associated molecular patterns linked to tissue ischemia [93]. Reducing pneumoperitoneum pressure to 6–8 mmHg during laparoscopic surgery decreases postoperative inflammation and prevents postoperative immunosuppression [94].

3.5 Anesthesia techniques

Volatile anesthetics and opioid drugs in the perioperative period are associated with immunosuppression. Regional anesthesia like the epidural anesthesia provides effective pain relief in perioperative period. Combining epidural anesthesia with general anesthesia reduces the extent of postoperative immune suppression caused by surgery and pain and improves body’s immune function during perioperative period [95]. An animal study demonstrated that propofol general anesthesia combined with lidocaine epidural anesthesia increased the number and percentage of cells and monocytes postoperatively compared to propofol general anesthesia alone. Cortisol levels were also lower than those in control group to suggest that epidural anesthesia had protective effect on innate and cellular immunity [96]. Clinical studies have also shown that epidural anesthesia combined with general anesthesia can alleviate immunosuppression after the surgeries pertaining to gastric cancer [97], esophageal cancer [98, 99], and orthopedic [100]. Tumor recurrence is reduced after the surgery.

The immune-enhancing impact of epidural anesthesia after surgery can be attributed to three mechanisms: reducing opioid drugs and general anesthetics usage during general anesthesia; combined epidural anesthesia blocking the harmful signaling from surgical area; and blocking surgical stimulation from being transmitted to central nervous system. Both incoming and outgoing harmful pathways are thus blocked. The general anesthesia drugs have inhibitory effect on patient’s cerebral cortex system. They cannot block the HPA axis activation, and synthesis and release of catecholamines caused by surgical stimulation. They possess direct immunosuppressive effect [101]. Combined epidural anesthesia provides effective pain relief as the pain itself causes immunosuppression. Epidural anesthesia also acts as the postoperative epidural analgesia, which is more effective than patient-controlled intravenous analgesia. Epidural analgesia combined with general anesthesia prevents surgery-induced hyperglycemia by reducing endogenous glucose production [102]. Excluding contraindications related to epidural anesthesia and employing epidural anesthesia combined with general anesthesia provides more effective perioperative pain relief and alleviates postoperative immunosuppression.

3.6 Anesthetics

3.6.1 Opioid drugs

Opioid drugs are among the most effective analgesics in treating severe pain. Studies suggest that opioids may indirectly influence the immune system by affecting pain pathways. Pain itself can lead to immunosuppression. Opioids relieve pain and alleviate this immunosuppression. However, most in vitro and in vivo studies suggest that opioids suppress the body immune function [103]. It is manifested via the decreased cytotoxic activity of NK cells [104], reduced T cells and B cells response to mitogens, inhibition of in vivo and in vitro antibody formation, suppression of neutrophil and macrophage phagocytic activity and cytokine production [105], promotion of macrophage apoptosis, and reduced macrophage TLR4 expression [106, 107].

The immunosuppressive impact of opioid drugs on immune system includes direct and indirect actions. Previous views have focused on opioids activating the HPA axis, which leads to increased stress hormones release, and results in immunosuppression. However, it is discovered that opioid receptors are distributed outside the central nervous system in tissues and organ systems (such as immune system cells). More studies suggest that opioid drugs interact with innate and adaptive immune systems and impact the opioid receptors on immune cells. The μ-opioid receptor is specifically involved in opioid-induced immunosuppression [108]. Opioid drugs induce apoptosis of immune-active cells expressed with opioid receptors. However, the same immune-suppressive effects are not induced by all opioid drugs. Different opioid drugs show varying effects on immune system including immunosuppression, immune stimulation, or dual actions [109].

Morphine suppresses NK cells activity and lymphocyte differentiation, promotes lymphocyte apoptosis, lowers TLR4 expression on macrophages [110, 111], and mediates neutrophil infiltration [112]. It hampers dendritic cells maturation, diminishes antigen-presenting potential, and restrains antigen-specific CD8+ T cells activation [113]. Th1/Th2 ratio is decreased after administering morphine via Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT) pathway [114]. Both morphine and fentanyl reduce humoral response because of reduced phagocytosis by macrophages [115].

Fentanyl and sufentanil also reduce NK cells activity, however they increase regulatory T cells count [116, 117]. Cataldo analyzed fentanyl effect on splenic cellular immune response in mouse. It was found that 24 h of fentanyl administration reduced lymphoproliferation, and natural killer cell activity [115].

Remifentanil inhibits NK cells activity [104] and lymphocyte proliferation [118]. In a rat study, it reduced the activation and cytokine secretion from bronchoalveolar neutrophils and macrophages in Lipopolysaccharide (LPS)-induced lung injury [119]. Low-dose remifentanil infusion in healthy volunteers did not alter the number or NK cells cytotoxicity after 8-h infusion [120].

Oxycodone did not affect the monocyte and neutrophil phagocytosis or NK activity, however it decreased IL-6 production by T cells [121]. Oxycodone compared to morphine slightly suppressed the effector phase of cell-mediated immune response both in mice and clinical study [122, 123].

Tramadol is an atypical opioid analgesic. It was compared with morphine regarding the postoperative immune response and pain in uterine cancer patients. It was suggested that tramadol attenuated the postoperative immunosuppression and enhanced NK cells activity compared to morphine [124, 125]. Furthermore, in a study on gastric cancer surgery patients, tramadol reduced T cell subpopulations and NK cells to improve perioperative cellular immune function [126].

Evaluating the extent of immunosuppression by opioid drugs is thus essential for selecting appropriate analgesics.

Opioid receptor antagonists reverse the respiratory depression caused by opioid drugs. Studies indicated that low-dose opioid receptor antagonists improved the immune function. Postoperative infusion of low-dose naloxone increased NK cells and CD4/CD8 T cells in sufentanil-controlled analgesia patients undergoing thoracoscopic surgery. The immunosuppression caused by opioid drugs was mitigated [127]. Low-dose naltrexone (LDN) also increased M1-type macrophages to inhibit colorectal cancer progression [128]. The surgery-induced natural killer cell cytotoxicity, B and T cell proliferation, and IFN- γ production were reduced in animal experiments. They were alleviated by naltrexone [129], along with the increase in Th1 and decrease in Th2 cytokine production [130]. LDN might thus be an immunomodulatory agent in therapies for cancer and immune-related diseases [131].

3.6.2 Volatile anesthetics

Some volatile anesthetics induce apoptosis of immune cells (T cells and NK cells) and inhibit lymphocytes proliferation and function to reduce adaptive immune responses. An animal study found that isoflurane decreased T cell and monocyte infiltration in murine model [132]. Isoflurane and sevoflurane triggered apoptosis in human T cells and B cells [133, 134], while desflurane did not induce apoptosis [134]. A clinical trial on 40 breast cancer surgery cases showed that desflurane maintained the Th1/Th2 and IL2/IL4 ratios [135]. Isoflurane and sevoflurane decreased Th1/Th2 ratio in patients [133, 134]. Moreover, isoflurane, sevoflurane and desflurane caused B cell damage due to endoplasmic reticulum calcium release [136].

Volatile anesthetics also inhibit the body innate immune function. Sevoflurane and isoflurane increase oxidative stress (OS), and lead to M1 macrophage polarization [137], attenuates recruitment and phagocytosis of neutrophils [138], weakens macrophage phagocytosis [139], reduces number of circulating NK cell, and suppresses cytotoxicity [104].

Volatile anesthetics indirectly affect the immune system via hormone levels. Volatile anesthesia patients have enhanced stress responses, pronounced surgical-induced inflammatory reactions, and altered cell-mediated immunity compared to the total intravenous anesthesia [140]. Volatile anesthetics also affect immune function by influencing blood glucose levels. Patients undergoing anesthesia with sevoflurane in combination with fentanyl have higher blood glucose compared to those with propofol in combination with fentanyl [141]. Possible mechanisms include volatile anesthetics promoting the opening of Adenosine Triphosphate (ATP)-sensitive potassium channels in pancreatic β cells to reduce insulin secretion [142]. Propofol inhibits the opening of these channels and thus promote insulin secretion [143]. Sevoflurane and isoflurane also impair glucose-stimulated insulin secretion to cause hyperglycemia [144].

3.6.3 Propofol

Propofol is a common intravenous anesthetic and a gamma-aminobutyric acid (GABA) receptor agonist. Propofol not only enhances the activity of central GABA receptors, producing rapid hypnotic and sedative effects, but also has anti-inflammatory and antioxidant properties. It has role in immune regulation with complex impact on immune system. Propofol inhibits the neutrophil extracellular traps (NET) [145]. It also inhibits the activation and function of macrophage [146]. They all reduce pro-inflammatory cytokines release to reduce inflammatory response and tissue damage. In vitro and in vivo studies demonstrated that propofol did not impair NK cell-mediated cytotoxicity [147, 148, 149]. Propofol impact on adaptive immune function includes enhancing Cytotoxic T Lymphocyte (CTL) activity, reducing pro-inflammatory cytokines, and inhibiting Cyclooxygenase-2 (COX2) and Prostaglandin E2 (PGE2) functions [150]. It inhibits T cells proliferation without affecting Th1/Th2 ratio [151]. A mice study showed that propofol and dexmedetomidine reduced CD4+ T cells expression by increasing their apoptosis [152].

The mechanism of propofol’s impact on immune function is proposed as follows. Immune cells such as neutrophils, monocytes, macrophages, and T cells contain GABA receptors. Propofol acts on GABA receptors of immune cells, and inhibits cytokine secretion, cell proliferation, phagocytic activity, and chemotaxis [153, 154]. It also induces apoptosis. Propofol competes for binding near Intercellular Adhesion Molecule-1 (ICAM-1) contact zones to inhibit the binding of Lymphocyte Function-Associated Antigen-1 (LFA-1) to ICAM-1 on T cells, and suppress T cell proliferation and IL-2 production [155]. Mitochondrial dysfunction is the key reason for propofol-induced immunosuppression in macrophages. Clinical concentrations of propofol inhibit mitochondrial membrane potential and adenosine triphosphate (ATP) synthesis to impair the macrophage function (mitochondrial integrity is vital for macrophage chemotaxis, migration and phagocytosis) [156]. Propofol also induces the mitochondrial reactive oxygen species (ROS) production to trigger the NOD-like Receptor Family, Pyrin Domain Containing 3 (NLRP3) inflammasome activation, which in turn activates caspase-1 to cause macrophage apoptosis [157].

Compared to volatile anesthetics, propofol does not affect Th1/Th2 balance [151, 153], and reduces perioperative stress responses [158]. Propofol has protective impact on body’s immune function to promote better patient outcomes.

3.6.4 Dexmedetomidine

It is an α2 adrenergic receptor agonist with sedative and mild analgesic effects. It activates presynaptic α2 receptors on spinal cord dorsal horn neurons to reduce excitatory nerve transmission. Its action on spinal cord relates to primary nociceptive neurons. It also affects the locus coeruleus above the spinal cord to achieve analgesic effects.

Dexmedetomidine reduces the immunosuppression caused by surgery and pain. In cancer patients undergoing surgery, it maintains CD3 cells proportion, number of NK cells, CD4/CD8 ratio, and Th1/Th2 balance, while decreasing pro-inflammatory cytokines levels like those of IL-6 and TNF-α [159]. Dexmedetomidine regulates immune system through its direct impact on immune cells and indirectly by acting on α2 adrenergic receptors to inhibit norepinephrine release in periphery, which indirectly affects immune cells. Dexmedetomidine reduces IL-6 and TNF-α levels in rat splenocytes and lymphocytes as stimulated by LPS. This effect is blocked by α2 adrenergic receptor antagonist (yohimbine) to indicate that dexmedetomidine inhibits inflammatory responses by acting on α2 adrenergic receptors. This experiment also shows that dexmedetomidine does not affect the immune cells activity in spleen and lymph nodes [160].

Dexmedetomidine directly affects the function of monocytes and macrophages. Li et al. [161] reported that dexmedetomidine reduced Nuclear Factor kappa B (NF-κB)-p65 phosphorylation to minimize TNF-α production in mouse BV-2 microglial cells and RAW264.7 macrophages as stimulated by LPS. It led to the decreased levels of pro-inflammatory cytokines. Dexmedetomidine increased F4/80+Ly6G+ macrophages in Dex-treated mice. It enhanced Transforming Growth Factor Beta 1 (TGF-β1) production secreted by macrophage, and led to attenuated cytokine storm and accelerated inflammation resolving [152]. Dexmedetomidine also regulated sympathetic nervous system (SNS) and HPA axis to reduce Adrenocorticotropic Hormone (ACTH) secretion and cortisol levels. Consequently, it alleviated the inflammation induced by surgical stress and immunosuppression [162].

Analgesic effects of dexmedetomidine protect immune function during perioperative period. Pain activates the SNS through neuroendocrine pathways to promote the plasma catecholamines and immune responses, induce redistribution of immune cells (e.g., neutrophils, monocytes and T cells), enhance NK cell cytotoxic activity, lymphocytes proliferation, and cytokine production [163]. Reducing pain or SNS activation by tissue damage can thus modulate the immune activity. In formalin pain mouse model, dexmedetomidine prevented pain-induced activation of NK cells, and reduced the NK cell cytotoxicity without affecting lymphocytes proliferation [164]. Furthermore, dexmedetomidine reduces early postoperative pain severity and alleviates immunosuppression by reducing opioid drugs consumption [165]. Dexmedetomidine is beneficial for the patients with compromised immune function. It does not impair lymphocytes’ function or proliferation at clinically relevant plasma concentrations [155].

3.6.5 Midazolam

It is the benzodiazepine derivative and used in clinical practice for anti-anxiety, sedation and general anesthesia. It impacts the immune regulatory properties of immune cells besides having effect on central nervous system. Previously, it was known to reduce the elevation of catecholamines induced by surgical stress for diminishing side effects of elevated cortisol on immune defense in perioperative period [166]. Recent study indicated that midazolam also affected the quantity and function of immune cells. Intraperitoneal injection of midazolam in a mouse model of liver cancer reduced the proportions of CD4+ T cells, CD8+ T cells, NK cells, monocytes, Treg cells, and M2 macrophages, while increased the DCs proportion [167]. Another similar study showed that midazolam impaired the monocyte and neutrophil function. It did not affect cytotoxic T-lymphocyte (CTL) activity [168]. Midazolam also induced phenotypic changes in DCs, reduced the expressions of CD80, CD68 and major histocompatibility complex II (MHC II) in mouse DCs, and inhibited the DC antigen presentation capacity (DCs are the antigen-presenting cells that present antigens to naive T cells for differentiating into T helper 1 and other effector molecules). It thus suppressed the immune response induced by mouse DCs [169].

Midazolam also inhibits the macrophages immune activation [170]. It inhibits immune response of macrophages stimulated by LPS through the translocator protein (TSPO) signaling pathway [171]. It suppresses NF-κB activation in macrophages and reduces release of pro-inflammatory factors like Inducible Nitric Oxide Synthase (iNOS) and COX2 [172]. COX2 induces immune evasion and suppresses immune responses. Kang et al.[167] suggested that midazolam also reduced Programmed Death-Ligand 1 (PD-L1) expression in hepatocellular carcinoma to weaken the PD-L1 inhibitory effect on T cell immune activity and reduce CD8 T cells exhaustion in liver cancer. These factors have made the midazolam a potential anti-tumor drug for cancer immunotherapy.

3.6.6 Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are the first-line conventional drugs in treating pain of all levels. They are recommended for acute perioperative pain management when there are no contraindications. Adding NSAIDs to multimodal analgesia has improved perioperative pain management, reduced adverse effects associated with opioid drugs, and decreased the perioperative complications.

Unlike opioid drugs acting on central nervous system, NSAIDs alleviate pain by reducing inflammation caused by tissue damage and preventing peripheral and central sensitization. NSAIDs possess antipyretic, analgesic, and anti-inflammatory effects. Studies have shown that excessive prostaglandin (PG) release leads to postoperative immunosuppression. PGE2 is a major metabolite produced from arachidonic acid as catalyzed by cyclooxygenase (COX). It is among the most biologically active and widely studied prostaglandins. It inhibits cell-mediated immune response, upregulates immune suppressive cytokines such as IL-10 and TGF, and suppresses normal T cell proliferation response [173]. PGE2 also reduces NK cells cytotoxicity and cytokines production [174]. It impairs proliferation and activation of effector T cell and increases Tregs infiltration [175, 176]. On the contrary, NSAIDs inhibit PG synthesis by blocking COX, reducing PGE2 levels, and improving immunosuppression. NSAIDs enhance NK cell-mediated cytotoxicity and promote proliferation and function of CD4+ and CD8+ T cells to enhance anti-tumor immunity and reduce tumor metastasis risk [177, 178]. However, a previous study reported that these drugs inhibit humoral immunity [179].

A clinical study, on liver cancer patients undergoing hepatectomy, made comparisons of using fentanyl alone or in combination for the pain relief. Patients in perioperative fentanyl combined with parecoxib sodium group had faster recovery of NK cell percentages compared to preoperative levels along with the higher levels of CD3+ T cells. This indicated that parecoxib sodium alleviated immunosuppression caused by surgery and opioid drugs [180]. It was also found in a study of laparoscopic surgery for cervical cancer patients that parecoxib sodium could balance cytokines levels produced by Th1/Th2, Th17 and Treg, reduce postoperative elevation of IL-2, IFN-γ and IL-17 levels, and inhibit excessive production of IL-4, IL-10 and TGF-β to alleviate the surgery-induced immunosuppression [181]. Parecoxib sodium also inhibits the increase in neutrophil-to-lymphocyte ratio (NLR) after the modified radical mastectomy, suppresses inflammatory response in breast cancer patients, and enhances patient immune function [182].

3.6.7 Lidocaine

Lidocaine modulates the immune cells activity. Clinical studies indicate that lidocaine alleviates postoperative immune suppression and inhibits inflammatory cytokines expressions [183, 184]. Clinical doses of lidocaine enhance NK cells cytotoxicity [185]. Lidocaine reduces lung injury and neutrophil infiltration in acute pulmonary edema mice [186]. Moreover, it decreases circulating NET [187]. In vitro study has shown that lidocaine reduces inflammatory cytokines release from dendritic cells and macrophages to exert anti-inflammatory and anti-tumor effects [188, 189]. Lidocaine enhances cellular and humoral immunity in the patients. Animal experiments demonstrate that lidocaine injection increases immunoglobulins levels in dogs [96]. Perioperative administration of lidocaine in breast cancer patients undergoing surgery, increases the percentages of NK cells, CD3+ cells, CD4+ cells and CD4+/CD8+ ratio to enhance the cellular immunity [190]. Immunomodulatory effects of lidocaine can be attributed to its anti-inflammatory characteristics, direct action on immune cells, or modulation via the sympathetic nervous system/hypothalamic-pituitary-adrenal (HPA) axis. Lidocaine injection in non-small cell lung cancer patients decreases serum cortisol levels [191].

The effects of mentioned drugs on innate and adaptive immune functions are summarized in Table 1.

Table 1.Effects of volatile anesthetic agents, intravenous anesthetic agents, and perioperative adjuvant agents on innate and adaptive immunity.
Innate immunityAdaptive immunity
MacrophageNeutrophilNatural killer cellT cellB cell
MorphineTLR4↓ [104] Phagocytosis↓ [115]Infiltration↑ [112]Cytotoxicity↓ [104]CD8+ T↓ [113] Th1/Th2↓ [110, 114]Humoral immunity↓ [115]
FentanylFunction↓ Phagocytosis↓/Activity↓ [115, 116]Treg cell↑ [116] Proliferation↓ [115]Humoral immunity↓ [115]
RemifentanilActivity↓ [119]Activity↓ [119]Activity↓ [104]Proliferation↓ [118]Proliferation↓ [118]
OxycodonePhagocytosis— [121]Phagocytosis— [121]Activity— [121]IL-6 production↓ [121] Effector phase↓ [122, 123]/
Tramadol//Activity↑ [124, 125]Function↑ [126]/
NaltrexoneM1-type↑ [128]/Count↑ [127] Cytotoxicity↑ [129]CD4/CD8 T↑ [129] Proliferation↑ [129] Th1/Th2↑ [130]Proliferation↑ [129]
SevofluraneM1-type↑ [137] Phagocytosis [139]Recruitment and phagocytosis↓ [138]Cytotoxicity↓ [104]Apoptosis↑ [134] Function↓ Th1/Th2↓ [133, 134]Apoptosis↑ [134] Function↓ [136]
IsofluraneM1-type↑ [137] Infiltration↓ [132] Phagocytosis [139]Cytotoxicity↓ [104]Apoptosis↑ [133] Count↓ [132] Th1/Th2↓ [133, 134]Apoptosis↑ [133] Function↓ [136]
Desflurane///Apoptosis— [134] Th1/Th2, IL2/IL4— [135]Apoptosis— [134] Function↓ [136]
PropofolActivation and function↓ [146]NET↓ [145]Cytotoxicity— [147, 148, 149]Proliferation↓ [151] CD4+ T↓ (apoptosis↑) [152] Th1/Th2— [151, 153]/
DexmedetomidineF4/80+Ly6G+↑ [152] TGF-β1 production↑ [152]/Cytotoxicity↓ [164] Count— [159]IL-6↓, TNF-α↓ [159, 160] CD4+ T↓ (apoptosis↑) [152] Th1/Th2— [159] Proliferation— [155, 164]/
MidazolamActivation↓ [170] Function↓ [168, 171, 172] The proportion of M2↓ [167]Function↓ [168]Proportion↓ [167]CTL activity— [168] The proportions of CD4+ T cells, CD8+ T cells and Tregs↓ [167]/
NSAIDs//Cytotoxicity↑ [177, 178]Proliferation and function of CD4+ and CD8+ T cells↑ [177, 178] Cellular immunity↑ Th1/Th2↑ [177, 181]Humoral immunity↓ [179]
LidocaineInflammatory cytokines↓ [189]Infiltration↓ [186] NET↓ [187]Cytotoxicity↑ [185] Percentage↑ [190]CD3+ cells, CD4+ cells, CD4+/CD8+ ratio↑ [190]Immunoglobulins↑ [96]
Abbreviations: /: indeterminate or limited data; —: no change; ↑: increase; ↓: decrease; TLR4: Toll-Like Receptor 4; CD: Cluster of Differentiation; NET: Neutrophil Extracellular Trap; TGF-β1: Transforming Growth Factor Beta 1; IL: Interleukin; TNF-α: Tumor Necrosis Factor Alpha; CTL: Cytotoxic T Lymphocyte; NSAID: Non-Steroidal Anti-Inflammatory Drug.
The effects of perioperative factors on immune function.

Fig. 2.The effects of perioperative factors on immune function.

4. Conclusion

The perioperative factors have influence on patients’ immune function and thus cause changes in immune function among the patients (Fig. 2). The compromised immune function affects patients’ prognosis and facilitates tumor recurrence in cancer patients. Perioperative anesthesia management is thus important. It is imperative to minimize the overall systemic stress response in patients, alleviate systemic inflammatory reactions, and safeguard patient’s immune function. Preoperative assessment of patient’s immune function based on individual conditions should guide the selection of surgical procedures. A careful consideration of pros and cons is warranted in cases where blood transfusion is necessary, along with the preference for judicious blood transfusion, advocating for component transfusion, and autologous blood transfusion. Perioperative body temperatures are properly monitored and thermal conservation measures are accordingly implemented. The utilization of higher inhaled oxygen concentrations mitigates immunosuppression by reducing pro-inflammatory cytokines release. Compared to the inhalation anesthetics and opioid-class drugs, the combination of general anesthesia with regional anesthesia reduces overall dosage of general anesthetics. This concurrently mitigating immunosuppression enhances patient’s prognosis. All the mentioned factors should be designated as the standard care for all patients instead of only for immunocompromised.

Availability of data and materials

Not applicable.

Author contributions

XXP—designed the research study. YNC and JWK—performed the research and wrote the manuscript. YLW—collected and analyzed the data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021; 594: 100–105.

[Google Scholar]

De Maeyer RPH, Chambers ES. The impact of ageing on monocytes and macrophages. Immunology Letters. 2021; 230: 1–10.

[Google Scholar]

Nauseef WM. How human neutrophils kill and degrade microbes: an integrated view. Immunological Reviews. 2007; 219: 88–102.

[Google Scholar]

Van Avondt K, Strecker J, Tulotta C, Minnerup J, Schulz C, Soehnlein O. Neutrophils in aging and aging-related pathologies. Immunological Reviews. 2023; 314: 357–375.

[Google Scholar]

Fulop T, Larbi A, Douziech N, Fortin C, Guérard K, Lesur O, et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell. 2004; 3: 217–226.

[Google Scholar]

Tortorella C, Simone O, Piazzolla G, Stella I, Antonaci S. Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins. Ageing Research Reviews. 2007; 6: 81–93.

[Google Scholar]

Pilkington SM, Bulfone-Paus S, Griffiths CEM, Watson REB. Inflammaging and the skin. Journal of Investigative Dermatology. 2021; 141: 1087–1095.

[Google Scholar]

Cui Q, Li W, Wang D, Wang S, Liu A, Zhang G, et al. Immune signature and phagocytosis of circulating DC subsets in healthy adults during aging. International Immunopharmacology. 2024; 130: 111715.

[Google Scholar]

Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. The Journal of Immunology. 2010; 184: 2518–2527.

[Google Scholar]

Agrawal A, Agrawal S, Cao J, Su H, Osann K, Gupta S. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. The Journal of Immunology. 2007; 178: 6912–6922.

[Google Scholar]

Brauning A, Rae M, Zhu G, Fulton E, Admasu TD, Stolzing A, et al. Aging of the immune system: focus on natural killer cells phenotype and functions. Cells. 2022; 11: 1017.

[Google Scholar]

Beli E, Clinthorne JF, Duriancik DM, Hwang I, Kim S, Gardner EM. Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mechanisms of Ageing and Development. 2011; 132: 503–510.

[Google Scholar]

Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, et al. NK phenotypic markers and IL2 response in NK cells from elderly people. Experimental Gerontology. 1999; 34: 253–265.

[Google Scholar]

Castelo-Branco C, Soveral I. The immune system and aging: a review. Gynecological Endocrinology. 2014; 30: 16–22.

[Google Scholar]

Hirokawa K, Utsuyama M, Kasai M, Kurashima C. Aging and immunity. Acta Pathologica Japonica. 1992; 42: 537–548.

[Google Scholar]

Mahbub S, Brubaker AL, Kovacs EJ. Aging of the innate immune system: an update. Current Immunology Reviews. 2011; 7: 104–115.

[Google Scholar]

Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, et al. T cells and aging, January 2002 update. Frontiers in Bioscience. 2002; 7: d1056–d11183.

[Google Scholar]

Effros RB, Cai Z, Linton PJ. CD8 T cells and aging. Critical Reviews in Immunology. 2003; 23: 45–64.

[Google Scholar]

Sadighi Akha AA, Miller RA. Signal transduction in the aging immune system. Current Opinion in Immunology. 2005; 17: 486–491.

[Google Scholar]

Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, et al. CD27+ (memory) B cell decrease and apoptosis-resistant CD27− (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. International Immunology. 2005; 17: 383–390.

[Google Scholar]

Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D, Zheng NY, et al. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. Journal of Clinical Investigation. 2011; 121: 3109–3119.

[Google Scholar]

Ruiz-Cortes K, Villageliu DN, Samuelson DR. Innate lymphocytes: role in alcohol-induced immune dysfunction. Frontiers in Immunology. 2022; 13: 934617.

[Google Scholar]

Malherbe DC, Messaoudi I. Transcriptional and epigenetic regulation of monocyte and macrophage dysfunction by chronic alcohol consumption. Frontiers in Immunology. 2022; 13: 911951.

[Google Scholar]

Cao L, Wu D, Qin L, Tan D, Fan Q, Jia X, et al. Single-cell RNA transcriptome profiling of liver cells of short-term alcoholic liver injury in mice. International Journal of Molecular Sciences. 2023; 24: 4344.

[Google Scholar]

Malacco NLSO, Souza JAM, Martins FRB, Rachid MA, Simplicio JA, Tirapelli CR, et al. Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection. eLife. 2020; 9: e58855.

[Google Scholar]

Gacouin A, Roussel M, Le Priol J, Azzaoui I, Uhel F, Fest T, et al. Acute alcohol exposure has an independent impact on C-reactive protein levels, neutrophil CD64 expression, and subsets of circulating white blood cells differentiated by flow cytometry in nontrauma patients. Shock. 2014; 42: 192–198.

[Google Scholar]

Rehman S, Chandel N, Salhan D, Rai P, Sharma B, Singh T, et al. Ethanol and vitamin D receptor in T cell apoptosis. Journal of Neuroimmune Pharmacology. 2013; 8: 251–261.

[Google Scholar]

Wang H, Zhou H, Mahler S, Chervenak R, Wolcott M. Alcohol affects the late differentiation of progenitor B cells. Alcohol and Alcoholism. 2011; 46: 26–32.

[Google Scholar]

Verma S, Alexander CM, Carlson MJ, Tygrett LT, Waldschmidt TJ. B-cell studies in chronic ethanol mice. Methods in Molecular Biology. 2008; 447: 295–323.

[Google Scholar]

Pohl K, Moodley P, Dhanda AD. Alcohol’s impact on the gut and liver. Nutrients. 2021; 13: 3170.

[Google Scholar]

Watzl B, Watson RR. Role of alcohol abuse in nutritional immunosuppression. Journal of Nutrition. 1992; 122: 733–737.

[Google Scholar]

Shi X, DeLucia AL, Bao J, Zhang P. Alcohol abuse and disorder of granulopoiesis. Pharmacology & Therapeutics. 2019; 198: 206–219.

[Google Scholar]

Dukić M, Radonjić T, Jovanović I, Zdravković M, Todorović Z, Kraišnik N, et al. Alcohol, inflammation, and microbiota in alcoholic liver disease. International Journal of Molecular Sciences. 2023; 24: 3735.

[Google Scholar]

Georgakouli K, Manthou E, Fatouros IG, Deli CK, Koutedakis Y, Theodorakis Y, et al. HPA-axis activity and nutritional status correlation in individuals with alcohol use disorder. Nutrients. 2022; 14: 4978.

[Google Scholar]

Antar SA, Ashour NA, Sharaky M, Khattab M, Ashour NA, Zaid RT, et al. Diabetes mellitus: classification, mediators, and complications; a gate to identify potential targets for the development of new effective treatments. Biomedicine & Pharmacotherapy. 2023; 168: 115734.

[Google Scholar]

Fitas AL, Martins C, Borrego LM, Lopes L, Jörns A, Lenzen S, et al. Immune cell and cytokine patterns in children with type 1 diabetes mellitus undergoing a remission phase: a longitudinal study. Pediatric Diabetes. 2018; 19: 963–971.

[Google Scholar]

Sun Y, Zhou L, Chen W, Zhang L, Zeng H, Sun Y, et al. Immune metabolism: a bridge of dendritic cells function. International Reviews of Immunology. 2022; 41: 313–325.

[Google Scholar]

Kennedy DM, Skillen AW, Self CH. Glycation of monoclonal antibodies impairs their ability to bind antigen. Clinical and Experimental Immunology. 1994; 98: 245–251.

[Google Scholar]

Richard C, Wadowski M, Goruk S, Cameron L, Sharma AM, Field CJ. Individuals with obesity and type 2 diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy. BMJ Open Diabetes Research & Care. 2017; 5: e000379.

[Google Scholar]

Martinez PJ, Mathews C, Actor JK, Hwang SA, Brown EL, De Santiago HK, et al. Impaired CD4+ and T-helper 17 cell memory response to streptococcus pneumoniae is associated with elevated glucose and percent glycated hemoglobin A1c in Mexican Americans with type 2 diabetes mellitus. Translational Research. 2014; 163: 53–63.

[Google Scholar]

Moura J, Rodrigues J, Gonçalves M, Amaral C, Lima M, Carvalho E. Impaired T-cell differentiation in diabetic foot ulceration. Cellular & Molecular Immunology. 2017; 14: 758–769.

[Google Scholar]

Bettini M, Bettini ML. Function, failure, and the future potential of Tregs in type 1 diabetes. Diabetes. 2021; 70: 1211–1219.

[Google Scholar]

Galway U, Chahar P, Schmidt MT, Araujo-Duran JA, Shivakumar J, Turan A, et al. Perioperative challenges in management of diabetic patients undergoing non-cardiac surgery. World Journal of Diabetes. 2021; 12: 1255–1266.

[Google Scholar]

van Niekerk G, Christowitz C, Conradie D, Engelbrecht AM. Insulin as an immunomodulatory hormone. Cytokine & Growth Factor Reviews. 2020; 52: 34–44.

[Google Scholar]

Agus MS, Steil GM, Wypij D, Costello JM, Laussen PC, Langer M, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. The New England Journal of Medicine. 2012; 367: 1208–1219.

[Google Scholar]

Vellanki P, Cardona S, Galindo RJ, Urrutia MA, Pasquel FJ, Davis GM, et al. Efficacy and safety of intensive versus nonintensive supplemental insulin with a basal-bolus insulin regimen in hospitalized patients with type 2 diabetes: a randomized clinical study. Diabetes Care. 2022; 45: 2217–2223.

[Google Scholar]

Yao M, Hao Y, Wang T, Xie M, Li H, Feng J, et al. A review of stress-induced hyperglycaemia in the context of acute ischaemic stroke: definition, underlying mechanisms, and the status of insulin therapy. Frontiers in Neurology. 2023; 14: 1149671.

[Google Scholar]

Cao SG, Ren JA, Shen B, Chen D, Zhou YB, Li JS. Intensive versus conventional insulin therapy in type 2 diabetes patients undergoing D2 gastrectomy for gastric cancer: a randomized controlled trial. World Journal of Surgery. 2011; 35: 85–92.

[Google Scholar]

Bhamidipati CM, LaPar DJ, Stukenborg GJ, Morrison CC, Kern JA, Kron IL, et al. Superiority of moderate control of hyperglycemia to tight control in patients undergoing coronary artery bypass grafting. The Journal of Thoracic and Cardiovascular Surgery. 2011; 141: 543–551.

[Google Scholar]

Jasinski-Bergner S, Radetzki AL, Jahn J, Wohlrab D, Kielstein H. Impact of the body mass index on perioperative immunological disturbances in patients with hip and knee arthroplasty. Journal of Orthopaedic Surgery and Research. 2017; 12: 58.

[Google Scholar]

Vrieling F, Stienstra R. Obesity and dysregulated innate immune responses: impact of micronutrient deficiencies. Trends in Immunology. 2023; 44: 217–230.

[Google Scholar]

SantaCruz-Calvo S, Bharath L, Pugh G, SantaCruz-Calvo L, Lenin RR, Lutshumba J, et al. Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities. Nature Reviews Endocrinology. 2022; 18: 23–42.

[Google Scholar]

Schleh MW, Caslin HL, Garcia JN, Mashayekhi M, Srivastava G, Bradley AB, et al. Metaflammation in obesity and its therapeutic targeting. Science Translational Medicine. 2023; 15: eadf9382.

[Google Scholar]

Hata M, Andriessen EMMA, Hata M, Diaz-Marin R, Fournier F, Crespo-Garcia S, et al. Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation. Science. 2023; 379: 45–62.

[Google Scholar]

Green WD, Beck MA. Obesity altered T cell metabolism and the response to infection. Current Opinion in Immunology. 2017; 46: 1–7.

[Google Scholar]

Oleinika K, Slisere B, Catalán D, Rosser EC. B cell contribution to immunometabolic dysfunction and impaired immune responses in obesity. Clinical and Experimental Immunology. 2022; 210: 263–272.

[Google Scholar]

Touch S, Clément K, André S. T cell populations and functions are altered in human obesity and type 2 diabetes. Current Diabetes Reports. 2017; 17: 81.

[Google Scholar]

Frasca D, Diaz A, Romero M, Blomberg BB. Ageing and obesity similarly impair antibody responses. Clinical and Experimental Immunology. 2017; 187: 64–70.

[Google Scholar]

Huang CJ, Zourdos MC, Jo E, Ormsbee MJ. Influence of physical activity and nutrition on obesity-related immune function. The Scientific World Journal. 2013; 2013: 752071.

[Google Scholar]

Vega-Robledo GB, Rico-Rosillo MG. Adipose tissue: immune function and alterations caused by obesity. Revista Alergia Mexico. 2019; 66: 340–353. (In Spanish)

[Google Scholar]

Ait Eldjoudi D, Cordero Barreal A, Gonzalez-Rodríguez M, Ruiz-Fernández C, Farrag Y, Farrag M, et al. Leptin in osteoarthritis and rheumatoid arthritis: player or bystander? International Journal of Molecular Sciences. 2022; 23: 2859.

[Google Scholar]

Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. Journal of Biological Chemistry. 2007; 282: 35279–35292.

[Google Scholar]

Gunst MA, Minei JP. Transfusion of blood products and nosocomial infection in surgical patients. Current Opinion in Critical Care. 2007; 13: 428–432.

[Google Scholar]

Gao Y, Jin H, Tan H, Cai X, Sun Y. Erythrocyte-derived extracellular vesicles aggravate inflammation by promoting the proinflammatory macrophage phenotype through TLR4-MyD88-NF-κB-MAPK pathway. Journal of Leukocyte Biology. 2022; 112: 693–706.

[Google Scholar]

Strumper-Groves D. Perioperative blood transfusion and outcome. Current Opinion in Anesthesiology. 2006; 19: 198–206.

[Google Scholar]

Guo JR, Xu F, Jin XJ, Shen HC, Liu Y, Zhang YW, et al. Impact of allogenic and autologous transfusion on immune function in patients with tumors. Asian Pacific Journal of Cancer Prevention. 2014; 15: 467–474.

[Google Scholar]

Han ZZ, Li M, Zhang Y. The effects of allogeneic and autologous blood transfusion on immune function in patients receiving total hip replacement. American Journal of Translational Research. 2023; 15: 4709–4717.

[Google Scholar]

Gong Y, Tang Y, Xue Y, Chen L. Impact of intraoperative allogenic and autologous transfusion on immune function and prognosis in patients with hepatocellular carcinoma. Medicine. 2020; 99: e22568.

[Google Scholar]

Lan X, Chen Y, Bi Q, Xu W, Huang J. Effects of storage duration of suspended red blood cells before intraoperative infusion on coagulation indexes, routine blood examination and immune function in patients with gastrointestinal tumors. Pakistan Journal of Medical Sciences. 2023; 39: 182–187.

[Google Scholar]

Muszynski JA, Frazier E, Nofziger R, Nateri J, Hanson-Huber L, Steele L, et al; Pediatric Critical Care Blood Research Network (Blood Net) subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI). Red blood cell transfusion and immune function in critically ill children: a prospective observational study. Transfusion. 2015; 55: 766–774.

[Google Scholar]

Aguilar-Nascimento JE, Zampieri-Filho JP, Bordin JO. Implications of perioperative allogeneic red blood cell transfusion on the immune-inflammatory response. Hematology, Transfusion and Cell Therapy. 2021; 43: 58–64.

[Google Scholar]

Qiu L, Wang DR, Zhang XY, Gao S, Li XX, Sun GP, et al. Impact of perioperative blood transfusion on immune function and prognosis in colorectal cancer patients. Transfusion and Apheresis Science. 2016; 54: 235–241.

[Google Scholar]

Shi J, Gao B, Yang Y, Yang L, Li X. Influence of perioperative leukodeplated red blood cell transfusion on immune function of patients with bladder cancer. Chinese Journal of Cellular and Molecular Immunology. 2018; 34: 632–636. (In Chinese)

[Google Scholar]

Abe T, Amano H, Hanada K, Minami T, Yonehara S, Hattori M, et al. Perioperative red blood cell transfusion is associated with poor long-term survival in pancreatic adenocarcinoma. Anticancer Research. 2017; 37: 5863–5870.

[Google Scholar]

De Oliveira GS Jr, Schink JC, Buoy C, Ahmad S, Fitzgerald PC, McCarthy RJ. The association between allogeneic perioperative blood transfusion on tumour recurrence and survival in patients with advanced ovarian cancer. Transfusion Medicine. 2012; 22: 97–103.

[Google Scholar]

Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008; 109: 318–338.

[Google Scholar]

Yang C, Cheng Y, Liu S, Huang S, Yu X. Effect of preoperative oral carbohydrate loading on body temperature during combined spinal-epidural anesthesia for elective cesarean delivery. Anesthesia & Analgesia. 2021; 133: 731–738.

[Google Scholar]

Kaneko S, Hara K, Sato S, Nakashima T, Kawazoe Y, Taguchi M, et al. Association between preoperative toe perfusion index and maternal core temperature decrease during cesarean delivery under spinal anesthesia: a prospective cohort study. BMC Anesthesiology. 2021; 21: 250.

[Google Scholar]

Chen J, Li H, Xu P, Tang Y, Su S, Liu G, et al. Hypothermia-mediated apoptosis and inflammation contribute to antioxidant and immune adaption in freshwater drum, aplodinotus grunniens. Antioxidants. 2022; 11: 1657.

[Google Scholar]

Qadan M, Gardner SA, Vitale DS, Lominadze D, Joshua IG, Polk HC Jr. Hypothermia and surgery: immunologic mechanisms for current practice. Annals of Surgery. 2009; 250: 134–140.

[Google Scholar]

Marek-Trzonkowska N, Piekarska K, Filipowicz N, Piotrowski A, Gucwa M, Vogt K, et al. Mild hypothermia provides Treg stability. Scientific Reports. 2017; 7: 11915.

[Google Scholar]

Oldman AH, Martin DS, Feelisch M, Grocott MPW, Cumpstey AF. Effects of perioperative oxygen concentration on oxidative stress in adult surgical patients: a systematic review. British Journal of Anaesthesia. 2021; 126: 622–632.

[Google Scholar]

Mattishent K, Thavarajah M, Sinha A, Peel A, Egger M, Solomkin J, et al. Safety of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis. British Journal of Anaesthesia. 2019; 122: 311–324.

[Google Scholar]

Allegranzi B, Zayed B, Bischoff P, Kubilay NZ, de Jonge S, de Vries F, et al. New WHO recommendations on intraoperative and postoperative measures for surgical site infection prevention: an evidence-based global perspective. The Lancet Infectious Diseases. 2016; 16: e288–e303.

[Google Scholar]

Schietroma M, Colozzi S, Pessia B, Carlei F, Di Furia M, Amicucci G. Laparoscopic Nissen fundoplication: the effects of high-concentration supplemental perioperative oxygen on the inflammatory and immune response: a randomised controlled trial. Journal of Minimal Access Surgery. 2018; 14: 221–229.

[Google Scholar]

Schietroma M, Colozzi S, Pessia B, Carlei F, Amicucci G. The effects of high-concentration oxygen on inflammatory markers in laparoscopic cholecystectomy: a randomized controlled trial. Surgical Laparoscopy Endoscopy & Percutaneous Techniques. 2017; 27: 83–89.

[Google Scholar]

Huang C, Huang R, Jiang T, Huang K, Cao J, Qiu Z. Laparoscopic and open resection for colorectal cancer: an evaluation of cellular immunity. BMC Gastroenterology. 2010; 10: 127.

[Google Scholar]

Ypsilantis P, Lambropoulou M, Anagnostopoulos K, Kiroplastis K, Tepelopoulos G, Bangeas P, et al. Gut-barrier disruption after laparoscopic versus open major liver resection in the rat. Surgery. 2022; 171: 973–979.

[Google Scholar]

Martínez-Martínez AB, Arbonés-Mainar JM. Colorectal cancer: immune response in laparoscopic versus open colorectal surgery. Cirugia y Cirujanos. 2022; 90: 295–302.

[Google Scholar]

Yang X, Cheng Y, Cheng N, Gong J, Bai L, Zhao L, et al. Gases for establishing pneumoperitoneum during laparoscopic abdominal surgery. Cochrane Database of Systematic Reviews. 2022; 3: CD009569.

[Google Scholar]

Neuhaus SJ, Watson DI. Pneumoperitoneum and peritoneal surface changes: a review. Surgical Endoscopy. 2004; 18: 1316–1322.

[Google Scholar]

Kusano T, Etoh T, Inomata M, Shiraishi N, Kitano S. CO2 pneumoperitoneum increases secretory IgA levels in the gut compared with laparotomy in an experimental animal model. Surgical Endoscopy. 2014; 28: 1879–1885.

[Google Scholar]

Albers KI, Polat F, Helder L, Panhuizen IF, Snoeck MMJ, Polle SBW, et al. Quality of recovery and innate immune homeostasis in patients undergoing low-pressure versus standard-pressure pneumoperitoneum during laparoscopic colorectal surgery (RECOVER): a randomized controlled trial. Annals of Surgery. 2022; 276: e664–e673.

[Google Scholar]

Schietroma M, Pessia B, Stifini D, Lancione L, Carlei F, Cecilia EM, et al. Effects of low and standard intra-abdominal pressure on systemic inflammation and immune response in laparoscopic adrenalectomy: a prospective randomised study. Journal of Minimal Access Surgery. 2016; 12: 109–117.

[Google Scholar]

Konstantis G, Tsaousi G, Kitsikidou E, Zacharoulis D, Pourzitaki C. The immunomodulatory effect of various anaesthetic practices in patients undergoing gastric or colon cancer surgery: a systematic review and meta-analysis of randomized clinical trials. Journal of Clinical Medicine. 2023; 12: 6027.

[Google Scholar]

Imani Rastabi H, Khosravi M, Avizeh R, Moslemi M. Evaluation of the effect of lidocaine epidural injection on immunological indices in dogs under total intravenous anesthesia submitted to ovariohysterectomy. PLOS ONE. 2021; 16: e0253731.

[Google Scholar]

Wang L, Liang S, Chen H, Xu Y, Wang Y. The effects of epidural anaesthesia and analgesia on T lymphocytes differentiation markers and cytokines in patients after gastric cancer resection. BMC Anesthesiology. 2019; 19: 102.

[Google Scholar]

Cong X, Huang Z, Zhang L, Sun M, Chang E, Zhang W, et al. Effect of different anaesthesia methods on perioperative cellular immune function and long-term outcome in patients undergoing radical resection of esophageal cancer: a prospective cohort study. American Journal of Translational Research. 2021; 13: 11427–11438.

[Google Scholar]

Hu C, Zhang S, Chen Q, Wang R. Effects of different anesthetic and analgesic methods on cellular immune function and stress hormone levels in patients undergoing esophageal cancer surgery. Journal of Healthcare Engineering. 2022; 2022: 4752609.

[Google Scholar]

Ezhevskaia AA, Prusakova ZhB, Maksimova LP, Sholkina MN, Balmusova EA, Ovechkin AM. Effects of epidural anesthesia on stress-induced immune supression during major corrective spine surgery. Anesteziol Reanimatol. 2014; 59: 4–9. (In Russian)

[Google Scholar]

Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. Journal of Anesthesia. 2008; 22: 263–277.

[Google Scholar]

Lattermann R, Schricker T, Wachter U, Georgieff M, Goertz A. Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery. Anesthesia & Analgesia. 2001; 93: 121–127.

[Google Scholar]

Buddeberg BS, Seeberger MD. Anesthesia and oncology: friend or foe? Frontiers in Oncology. 2022; 12: 802210.

[Google Scholar]

Vrbanović Mijatović V, Gatin L, Tonković D, Bandić Pavlović D, Smuđ Orehovec S, Miklić Bublić M, et al. The effect of regional vs. general anesthesia on the immune response in breast cancer surgery: a narrative review of the literature. Acta Clinica Croatica. 2022; 61: 115–120.

[Google Scholar]

Eisenstein TK. The role of opioid receptors in immune system function. Frontiers in Immunology. 2019; 10: 2904.

[Google Scholar]

Lin M, Deng K, Li Y, Wan J. Morphine enhances LPS-induced macrophage apoptosis through a PPARgamma-dependent mechanism. Experimental and Therapeutic Medicine. 2021; 22: 714.

[Google Scholar]

Luan G, Pan F, Bu L, Wu K, Wang A, Xu X. Butorphanol promotes macrophage phenotypic transition to inhibit inflammatory lung injury via kappa receptors. Frontiers in Immunology. 2021; 12: 692286.

[Google Scholar]

Lambert DG. Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis. BJA Open. 2023; 6: 100141.

[Google Scholar]

Sun Q, Li Z, Wang Z, Wang Q, Qin F, Pan H, et al. Immunosuppression by opioids: mechanisms of action on innate and adaptive immunity. Biochemical Pharmacology. 2023; 209: 115417.

[Google Scholar]

Gao M, Sun J, Jin W, Qian Y. Morphine, but not ketamine, decreases the ratio of Th1/Th2 in CD4-positive cells through T-bet and GATA3. Inflammation. 2012; 35: 1069–1077.

[Google Scholar]

Franchi S, Moretti S, Castelli M, Lattuada D, Scavullo C, Panerai AE, et al. Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages. Brain, Behavior, and Immunity. 2012; 26: 480–488.

[Google Scholar]

Jalodia R, Kolli U, Braniff RG, Tao J, Abu YF, Chupikova I, et al. Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis. Gut Microbes. 2022; 14: 2143225.

[Google Scholar]

Plein LM, Rittner HL. Opioids and the immune system—friend or foe. British Journal of Pharmacology. 2018; 175: 2717–2725.

[Google Scholar]

Li Z, Sun Q, Liu Q, Mu X, Wang H, Zhang H, et al. Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway. Phytomedicine. 2023; 108: 154475.

[Google Scholar]

Martucci C, Panerai AE, Sacerdote P. Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses. Pain. 2004; 110: 385–392.

[Google Scholar]

Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation. 2004; 11: 255–260.

[Google Scholar]

Gong L, Qin Q, Zhou L, Ouyang W, Li Y, Wu Y, et al. Effects of fentanyl anesthesia and sufentanil anesthesia on regulatory T cells frequencies. International Journal of Clinical and Experimental Pathology. 2014; 7: 7708–7716.

[Google Scholar]

Qi Y, Yao X, Zhang B, Du X. Comparison of recovery effect for sufentanil and remifentanil anesthesia with TCI in laparoscopic radical resection during colorectal cancer. Oncology Letters. 2016; 11: 3361–3365.

[Google Scholar]

Tsuboi I, Tanaka H, Nakao M, Shichijo S, Itoh K. Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-γ and IL-2, in contrast to down-regulation of IL-6 production. Cytokine. 1995; 7: 372–379.

[Google Scholar]

Zhang Y, Du Z, Zhou Q, Wang Y, Li J. Remifentanil attenuates lipopolysaccharide-induced acute lung injury by downregulating the NF-κB signaling pathway. Inflammation. 2014; 37: 1654–1660.

[Google Scholar]

Cronin AJ, Aucutt-Walter NM, Budinetz T, Bonafide CP, DiVittore NA, Gordin V, et al. Low-dose remifentanil infusion does not impair natural killer cell function in healthy volunteers. British Journal of Anaesthesia. 2003; 91: 805–809.

[Google Scholar]

Boland JW, Foulds GA, Ahmedzai SH, Pockley AG. A preliminary evaluation of the effects of opioids on innate and adaptive human in vitro immune function. BMJ Supportive & Palliative Care. 2014; 4: 357–367.

[Google Scholar]

Filipczak-Bryniarska I, Nazimek K, Nowak B, Kozlowski M, Wąsik M, Bryniarski K. In contrast to morphine, buprenorphine enhances macrophage-induced humoral immunity and, as oxycodone, slightly suppresses the effector phase of cell-mediated immune response in mice. International Immunopharmacology. 2018; 54: 344–353.

[Google Scholar]

Saeed I, La Caze A, Hollmann MW, Shaw PN, Parat MO. New insights on tramadol and immunomodulation. Current Oncology Reports. 2021; 23: 123.

[Google Scholar]

Bradley A, Boland JW. Effects of opioids on immune and endocrine function in patients with cancer pain. Current Treatment Options in Oncology. 2023; 24: 867–879.

[Google Scholar]

Hou LW, Ding HL, Li MQ, Jin S, Wang XS, Ji LJ. Effect of tramadol on perioperative immune function in patients undergoing gastric cancer surgeries. Anesthesia Essays and Researches. 2013; 7: 54–57.

[Google Scholar]

Lin Y, Miao Z, Wu Y, Ge FF, Wen QP. Effect of low dose naloxone on the immune system function of a patient undergoing video-assisted thoracoscopic resection of lung cancer with sufentanil controlled analgesia—a randomized controlled trial. BMC Anesthesiology. 2019; 19: 236.

[Google Scholar]

Ma M, Wang X, Liu N, Shan F, Feng Y. Low-dose naltrexone inhibits colorectal cancer progression and promotes apoptosis by increasing M1-type macrophages and activating the Bax/Bcl-2/caspase-3/PARP pathway. International Immunopharmacology. 2020; 83: 106388.

[Google Scholar]

Nelson CJ, Carrigan KA, Lysle DT. Naltrexone administration attenuates surgery-induced immune alterations in rats. Journal of Surgical Research. 2000; 94: 172–177.

[Google Scholar]

Toleska M, Dimitrovski A, Dimitrovska NT. Comparation among opioid-based, low opioid and opioid free anesthesia in colorectal oncologic surgery. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2023; 44: 117–126.

[Google Scholar]

Qu N, Meng Y, Handley MK, Wang C, Shan F. Preclinical and clinical studies into the bioactivity of low-dose naltrexone (LDN) for oncotherapy. International Immunopharmacology. 2021; 96: 107714.

[Google Scholar]

Abrahams D, Ibrahim-Hashim A, Ackerman RS, Brown JS, Whelan CJ, Garfinkel MB, et al. Immunomodulatory and pro-oncologic effects of ketamine and isoflurane anesthetics in a murine model. PLOS ONE. 2023; 18: e0292492.

[Google Scholar]

Inada T, Yamanouchi Y, Jomura S, Sakamoto S, Takahashi M, Kambara T, et al. Effect of propofol and isoflurane anaesthesia on the immune response to surgery. Anaesthesia. 2004; 59: 954–959.

[Google Scholar]

Loop T, Dovi-Akue D, Frick M, Roesslein M, Egger L, Humar M, et al. Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology. 2005; 102: 1147–1157.

[Google Scholar]

Woo JH, Baik HJ, Kim CH, Chung RK, Kim DY, Lee GY, et al. Effect of propofol and desflurane on immune cell populations in breast cancer patients: a randomized trial. Journal of Korean Medical Science. 2015; 30: 1503–1508.

[Google Scholar]

Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A, Wei H. Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology. 2008; 109: 243–250.

[Google Scholar]

Odeh D, Oršolić N, Adrović E, Gaćina L, Perić P, Odeh S, et al. Effects of volatile anaesthetics and iron dextran on chronic inflammation and antioxidant defense system in rats. Antioxidants. 2022; 11: 708.

[Google Scholar]

Yuki K, Hou L, Shibamura-Fujiogi M, Koutsogiannaki S, Soriano SG. Mechanistic consideration of the effect of perioperative volatile anesthetics on phagocytes. Clinical Immunology. 2021; 222: 108635.

[Google Scholar]

Zha H, Matsunami E, Blazon-Brown N, Koutsogiannaki S, Hou L, Bu W, et al. Volatile anesthetics affect macrophage phagocytosis. PLOS ONE. 2019; 14: e0216163.

[Google Scholar]

Schneemilch CE, Ittenson A, Ansorge S, Hachenberg T, Bank U. Effect of 2 anesthetic techniques on the postoperative proinflammatory and anti-inflammatory cytokine response and cellular immune function to minor surgery. Journal of Clinical Anesthesia. 2005; 17: 517–527.

[Google Scholar]

Tylman M, Sarbinowski R, Bengtson JP, Kvarnström A, Bengtsson A. Inflammatory response in patients undergoing colorectal cancer surgery: the effect of two different anesthetic techniques. Minerva Anestesiologica. 2011; 77: 275–282.

[Google Scholar]

Kitamura T, Sato K, Kawamura G, Yamada Y. The involvement of adenosine triphosphate-sensitive potassium channels in the different effects of sevoflurane and propofol on glucose metabolism in fed rats. Anesthesia & Analgesia. 2012; 114: 110–116.

[Google Scholar]

Kusunoki M, Hayashi M, Shoji T, Uba T, Tanaka H, Sumi C, et al. Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+ channels in pancreatic beta-cells and enhances insulin secretion. PeerJ. 2019; 7: e8157.

[Google Scholar]

Suzuki K, Sato Y, Kai S, Nishi K, Adachi T, Matsuo Y, et al. Volatile anesthetics suppress glucose-stimulated insulin secretion in MIN6 cells by inhibiting glucose-induced activation of hypoxia-inducible factor 1. PeerJ. 2015; 3: e1498.

[Google Scholar]

Chen MS, Yang KS, Lin WC, Fang CL, Chen HF, Sheu SM. Lipofundin mediates major inhibition of intravenous propofol on phorbol myristate acetate and Escherichia coli-induced neutrophil extracellular traps. Molecular Biology Reports. 2022; 49: 6517–6529.

[Google Scholar]

Yi S, Tao X, Wang Y, Cao Q, Zhou Z, Wang S. Effects of propofol on macrophage activation and function in diseases. Frontiers in Pharmacology. 2022; 13: 964771.

[Google Scholar]

Chang MC, Chen YL, Chiang YC, Cheng YJ, Jen YW, Chen CA, et al. Anti-CD40 antibody and toll-like receptor 3 ligand restore dendritic cell-mediated anti-tumor immunity suppressed by morphine. American Journal of Cancer Research. 2016; 6: 157–172.

[Google Scholar]

Tazawa K, Koutsogiannaki S, Chamberlain M, Yuki K. The effect of different anesthetics on tumor cytotoxicity by natural killer cells. Toxicology Letters. 2017; 266: 23–31.

[Google Scholar]

Zhou M, Liu W, Peng J, Wang Y. Impact of propofol epidural anesthesia on immune function and inflammatory factors in patients undergoing gastric cancer surgery. American Journal of Translational Research. 2021; 13: 3064–3073.

[Google Scholar]

Kushida A, Inada T, Shingu K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacology and Immunotoxicology. 2007; 29: 477–486.

[Google Scholar]

Yu H, Chen L, Yue CJ, Xu H, Cheng J, Cornett EM, et al. Effects of propofol and sevoflurane on T-cell immune function and Th cell differentiation in children with SMPP undergoing fibreoptic bronchoscopy. Annals of Medicine. 2002; 54: 2574–2580.

[Google Scholar]

Li LC, Tian Y, Xiao J, Yang Y, Wu JN, Chen Y, et al. Dexmedetomidine promotes inflammation resolving through TGF-β1 secreted by F4/80+Ly6G+ macrophage. International Immunopharmacology. 2021; 95: 107480.

[Google Scholar]

Jin Z, Mendu SK, Birnir B. GABA is an effective immunomodulatory molecule. Amino Acids. 2013; 45: 87–94.

[Google Scholar]

Wheeler DW, Thompson AJ, Corletto F, Reckless J, Loke JC, Lapaque N, et al. Anaesthetic impairment of immune function is mediated via GABA(A) receptors. PLOS ONE. 2011; 6: e17152.

[Google Scholar]

Yuki K, Soriano SG, Shimaoka M. Sedative drug modulates T-cell and lymphocyte function-associated antigen-1 function. Anesthesia & Analgesia. 2011; 112: 830–838.

[Google Scholar]

Chen RM, Wu CH, Chang HC, Wu GJ, Lin YL, Sheu JR, et al. Propofol suppresses macrophage functions and modulates mitochondrial membrane potential and cellular adenosine triphosphate synthesis. Anesthesiology. 2003; 98: 1178–1185.

[Google Scholar]

Sun L, Ma W, Gao W, Xing Y, Chen L, Xia Z, et al. Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome. Cell Death & Disease. 2019; 10: 542.

[Google Scholar]

Senoner T, Velik-Salchner C, Luckner G, Tauber H. Anesthesia-induced oxidative stress: are there differences between intravenous and inhaled anesthetics? Oxidative Medicine and Cellular Longevity. 2021; 2021: 8782387.

[Google Scholar]

Cai Q, Liu G, Huang L, Guan Y, Wei H, Dou Z, et al. The role of dexmedetomidine in tumor-progressive factors in the perioperative period and cancer recurrence: a narrative review. Drug Design, Development and Therapy. 2022; 16: 2161–2175.

[Google Scholar]

Liu W, Yu W, Weng Y, Wang Y, Sheng M. Dexmedetomidine ameliorates the inflammatory immune response in rats with acute kidney damage. Experimental and Therapeutic Medicine. 2017; 14: 3602–3608.

[Google Scholar]

Li R, Lai IK, Pan JZ, Zhang P, Maze M. Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to prevent lipopolysaccharide-induced cognitive decline in mice. Anesthesiology. 2020; 133: 393–407.

[Google Scholar]

Umamaheswaran S, Dasari SK, Yang P, Lutgendorf SK, Sood AK. Stress, inflammation, and eicosanoids: an emerging perspective. Cancer and Metastasis Reviews. 2018; 37: 203–211.

[Google Scholar]

Sharify A, Mahmoudi M, Izad MH, Hosseini MJ, Sharify M. Effect of acute pain on splenic NK cell activity, lymphocyte proliferation and cytokine production activities. Immunopharmacology and Immunotoxicology. 2007; 29: 465–476.

[Google Scholar]

Jang Y, Yeom MY, Kang ES, Kang JW, Song HK. The antinociceptive effect of dexmedetomidine modulates spleen cell immunity in mice. International Journal of Medical Sciences. 2014; 11: 226–233.

[Google Scholar]

Cho JS, Seon K, Kim MY, Kim SW, Yoo YC. Effects of perioperative dexmedetomidine on immunomodulation in uterine cancer surgery: a randomized, controlled trial. Frontiers in Oncology. 2021; 11: 749003.

[Google Scholar]

Kamohara H, Kamohara T, Hikasa Y. A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery. American Journal of Veterinary Research. 2022; 83: 1–10.

[Google Scholar]

Kang J, Zheng Z, Li X, Huang T, Rong D, Liu X, et al. Midazolam exhibits antitumour and enhances the efficiency of Anti-PD-1 immunotherapy in hepatocellular carcinoma. Cancer Cell International. 2022; 22: 312.

[Google Scholar]

Park HJ, Piao L, Seo EH, Lee SH, Kim SH. The effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice. International Journal of Medical Sciences. 2020; 17: 428–436.

[Google Scholar]

Ohta N, Ohashi Y, Takayama C, Mashimo T, Fujino Y. Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced T helper 1-type immune response. Anesthesiology. 2011; 114: 355–362.

[Google Scholar]

Li J, Tan H, Zhou X, Zhang C, Jin H, Tian Y, et al. The protection of midazolam against immune mediated liver injury induced by lipopolysaccharide and galactosamine in mice. Frontiers in Pharmacology. 2018; 9: 1528.

[Google Scholar]

Horiguchi Y, Ohta N, Yamamoto S, Koide M, Fujino Y. Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling. International Immunopharmacology. 2019; 66: 373–382.

[Google Scholar]

Kim SN, Son SC, Lee SM, Kim CS, Yoo DG, Lee SK, et al. Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage. Anesthesiology. 2006; 105: 105–110.

[Google Scholar]

Bosch DJ, Nieuwenhuijs-Moeke GJ, van Meurs M, Abdulahad WH, Struys MMRF. Immune modulatory effects of nonsteroidal anti-inflammatory drugs in the perioperative period and their consequence on postoperative outcome. Anesthesiology. 2022; 136: 843–860.

[Google Scholar]

Tao X, Zhang R, Du R, Yu T, Yang H, Li J, et al. EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model. Journal of Experimental Medicine. 2022; 219: e20212414.

[Google Scholar]

Wu Q, Liu Z, Gao Z, Luo Y, Li F, Yang C, et al. KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+ T-cell-dependent antitumor immunity. Theranostics. 2023; 13: 1381–1400.

[Google Scholar]

Pelly VS, Moeini A, Roelofsen LM, Bonavita E, Bell CR, Hutton C, et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discovery. 2021; 11: 2602–2619.

[Google Scholar]

Rao CV. Anti-inflammatory drugs decrease the PD-L1 expression and increase the CD8+ T-cell infiltration. Cancer Prevention Research. 2022; 15: 209–211.

[Google Scholar]

Wei J, Zhang J, Wang D, Cen B, Lang JD, DuBois RN. The COX-2-PGE2 pathway promotes tumor evasion in colorectal adenomas. Cancer Prevention Research. 2022; 15: 285–296.

[Google Scholar]

Abdel Shaheed C, Beardsley J, Day RO, McLachlan AJ. Immunomodulatory effects of pharmaceutical opioids and antipyretic analgesics: mechanisms and relevance to infection. British Journal of Clinical Pharmacology. 2022; 88: 3114–3131.

[Google Scholar]

Wang RD, Zhu JY, Zhu Y, Ge YS, Xu GL, Jia WD. Perioperative analgesia with parecoxib sodium improves postoperative pain and immune function in patients undergoing hepatectomy for hepatocellular carcinoma. Journal of Evaluation in Clinical Practice. 2020; 26: 992–1000.

[Google Scholar]

Ma W, Wang K, Du J, Luan J, Lou G. Multi-dose parecoxib provides an immunoprotective effect by balancing T helper 1 (Th1), Th2, Th17 and regulatory T cytokines following laparoscopy in patients with cervical cancer. Molecular Medicine Reports. 2015; 11: 2999–3008.

[Google Scholar]

Li Y, Zhou L, Li X, Chen G, Duan K, Ding B, et al. Parecoxib suppresses the increase of neutrophil-to-lymphocyte ratio after the modified radical mastectomy. Journal of Central South University. 2017; 42: 1048–1052. (In Chinese)

[Google Scholar]

Lv X, Li X, Guo K, Li T, Yang Y, Lu W, et al. Effects of systemic lidocaine on postoperative recovery quality and immune function in patients undergoing laparoscopic radical gastrectomy. Drug Design, Development and Therapy. 2021; 15: 1861–1872.

[Google Scholar]

Lee IW, Schraag S. The use of intravenous lidocaine in perioperative medicine: anaesthetic, analgesic and immune-modulatory aspects. Journal of Clinical Medicine. 2022; 11: 3543.

[Google Scholar]

Cata JP, Ramirez MF, Velasquez JF, Di AI, Popat KU, Gottumukkala V, et al. Lidocaine stimulates the function of natural killer cells in different experimental settings. Anticancer Research. 2017; 37: 4727–4732.

[Google Scholar]

Zheng B, Yang H, Zhang J, Wang X, Sun H, Hu F, et al. Lidocaine alleviates sepsis-induced acute lung injury in mice by suppressing tissue factor and matrix metalloproteinase-2/9. Oxidative Medicine and Cellular Longevity. 2021; 2021: 3827501.

[Google Scholar]

Zhang H, Qu M, Guo K, Wang Y, Gu J, Wu H, et al. Intraoperative lidocaine infusion in patients undergoing pancreatectomy for pancreatic cancer: a mechanistic, multicentre randomised clinical trial. British Journal of Anaesthesia. 2022; 129: 244–253.

[Google Scholar]

Yin Q, Sun L, Cai X, Lou F, Sun Y, Wang B, et al. Lidocaine ameliorates psoriasis by obstructing pathogenic CGRP signaling‒mediated sensory neuron‒dendritic cell communication. Journal of Investigative Dermatology. 2022; 142: 2173–2183.e6.

[Google Scholar]

Su K, Li XT, Hong FX, Jin M, Xue FS. Lidocaine pretreatment attenuates inflammatory response and protects against sepsis-induced acute lung injury via inhibiting potassium efflux-dependent NLRP3 activation. Inflammation Research. 2023; 72: 2221–2235.

[Google Scholar]

Wei Q, Xia M, Zhang Q, Wang Z. Effect of intravenous lidocaine infusion on perioperative cellular immunity and the quality of postoperative recovery in breast cancer patients: a randomized controlled trial. Gland Surgery. 2022; 11: 599–610.

[Google Scholar]

Hou YH, Shi WC, Cai S, Liu H, Zheng Z, Qi FW, et al. Effect of intravenous lidocaine on serum interleukin-17 after video-assisted thoracic surgery for non-small-cell lung cancer: a randomized, double-blind, placebo-controlled trial. Drug Design, Development and Therapy. 2021; 15: 3379–3390.

[Google Scholar]