Expression Profiles of Immune Cells after Propofol or Sevoflurane Anesthesia for Colorectal Cancer Surgery: A Prospective Double-blind Randomized Trial.

BACKGROUND: The antitumor effects of natural killer cells, helper T cells, and cytotoxic T cells after cancer surgery were reported previously. This study hypothesized that propofol-based anesthesia would have fewer harmful effects on immune cells than volatile anesthetics-based anesthesia during colorectal cancer surgery. METHODS: In total, 153 patients undergoing colorectal cancer surgery were randomized and included in the analysis. The primary outcome was the fraction of circulating natural killer cells over time in the propofol and sevoflurane groups. The fractions of circulating natural killer, type 1, type 17 helper T cells, and cytotoxic T cells were investigated. The fractions of CD39 and CD73 expressions on circulating regulatory T cells were investigated, along with the proportions of circulating neutrophils, lymphocytes, and monocytes. RESULTS: The fraction of circulating natural killer cells was not significantly different between the propofol and sevoflurane groups until 24 h postoperatively (20.4 ± 13.4% vs. 20.8 ± 11.3%, 17.9 ± 12.7% vs. 20.7 ± 11.9%, and 18.6 ± 11.6% vs. 21.3 ± 10.8% before anesthesia and after 1 and 24 h after anesthesia, respectively; difference [95% CI], -0.3 [-4.3 to 3.6], -2.8 [-6.8 to 1.1], and -2.6 [-6.2 to 1.0]; P = 0.863, P = 0.136, and P = 0.151 before anesthesia and after 1 and 24 h, respectively). The fractions of circulating type 1 and type 17 helper T cells, cytotoxic T cells, and CD39+ and CD73+ circulating regulatory T cells were not significantly different between the two groups. The neutrophil to lymphocyte ratio in both groups remained within the normal range and was not different between the groups. CONCLUSIONS: Propofol-based anesthesia was not superior to sevoflurane-based anesthesia in terms of alleviating suppression of immune cells including natural killer cells and T lymphocytes during colorectal cancer surgery.

Effects of Desflurane and Sevoflurane anesthesia on regulatory T cells in patients undergoing living donor kidney transplantation: a randomized intervention trial.

BACKGROUND: Volatile anesthetic agents used during surgery have immunomodulatory effects which could affect postoperative outcomes. Recognizing that regulatory T cells (Tregs) plays crucial roles in transplant tolerance and high peripheral blood Tregs associated with stable kidney graft function, knowing which volatile anesthetic agents can induce peripheral blood Tregs increment would have clinical implications. This study aimed to compare effects of desflurane and sevoflurane anesthesia on peripheral blood Tregs induction in patients undergoing living donor kidney transplantation. METHODS: A prospective, randomized, double-blind trial in living donor kidney transplant recipients was conducted at a single center, tertiary-care, academic university hospital in Thailand during August 2015 - June 2017. Sixty-six patients were assessed for eligibility and 40 patients who fulfilled the study requirement were equally randomized and allocated to desflurane versus sevoflurane anesthesia during transplant surgery. The primary outcome included absolute changes of peripheral blood CD4+CD25+FoxP3+Tregs which measured by flow cytometry and expressed as the percentage of the total population of CD4+ T lymphocytes at pre-exposure (0-h) and post-exposure (2-h and 24-h) to anesthetic gas. P-value < 0.05 denoted statistical significance. RESULTS: Demographic data were comparable between groups. No statistical difference of peripheral blood Tregs between desflurane and sevoflurane groups observed at the baseline pre-exposure (3.6 ± 0.4% vs. 3.1 ± 0.4%; p = 0.371) and 2-h post-exposure (3.0 ± 0.3% vs. 3.5 ± 0.4%; p = 0.319). At 24-h post-exposure, peripheral blood Tregs was significantly higher in desflurane group (5.8 ± 0.5% vs. 4.1 ± 0.3%; p = 0.008). Within group analysis showed patients receiving desflurane, but not sevoflurane, had 2.7% increase in peripheral blood Treg over 24-h period (p < 0.001). CONCLUSION: This study provides the clinical trial-based evidence that desflurane induced peripheral blood Tregs increment after 24-h exposure, which could be beneficial in the context of kidney transplantation. Mechanisms of action and clinical advantages of desflurane anesthesia based on Treg immunomodulation should be investigated in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02559297 . Registered 22 September 2015 - retrospectively registered.

Relationship between Volatile Anesthetics and Tumor Progression: Unveiling the Mystery.

A series of factors can be involved in the perioperative period to cause an increase in cancer-related mortality. Unfortunately, volatile anesthesia might aggravate the deleterious effects. In this article, we review the association of diverse volatile anesthetic agents with immune system and cancer cell biology, and examine the effects on angeogenesis and postoperative metastasis or recurrence. Isoflurane, haloflurane and enflurane enhance immunosuppression and upregulate hypoxia-inducible-factor 1 and matrix metalloproteinases, leading to the cancer malignant progression, whereas roles of desflurane and sevoflurane are still unclear. As the effects of volatile anesthetics on tumor immunity have been known, it will be beneficial for using selective drugs into anesthesia and operation in cancer patients.

Immunomodulatory effects of total intravenous and balanced inhalation anesthesia in patients with bladder cancer undergoing elective radical cystectomy: preliminary results.

BACKGROUND: Although surgery and anesthesia induce immunesuppression, remains largely unknown whether various anesthetic techniques have different immunosuppressive effects on cancer patients. Therefore, the aim of this study was to investigate the influence of total intravenous anesthesia with target-controlled infusion (TIVA-TCI) and balanced inhalation anesthesia (BAL) on the peri-operative levels of inflammatory cytokines and regulatory T cells (Tregs) in patients with bladder cancer undergoing surgery. METHODS: Twenty eight consecutive patients with bladder cancer who underwent radical cystectomy were prospectively randomized into two groups to receive TIVA-TCI (n = 14) or BAL (n = 14). Before the induction of anesthesia (T0), 6-8 hours (T1) post-surgery, and 5 days post-surgery (T2), Tregs and serum levels of interleukin -1beta (IL-1ß), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin -2 (IL-2), interleukin -6 (IL-6), and interleukin -10 (IL-10) were measured. RESULTS: In the peri-operative period all cancer patients showed a marked and significant increase in IL-6. Moreover, TIVA-TCI patients also showed a higher increase in IFN-γ, whereas in BAL patients Tregs were reduced by approximately 30% during surgery. The incidence of infections, metastases, and death was similar in both groups. CONCLUSIONS: The increase in the Th1 response in the TIVA-TCI group and the reduction in Tregs in the BAL group seem to balance the immunosuppressive effect induced by IL-6. Therefore TIVA-TCI and BAL can be both used in major surgery in patients with bladder cancer without worsening the outcome.

A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse.

Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.

Hypersensitivity of laryngeal C-fibers induced by volatile anesthetics in young guinea pigs.

Inhalation induction of anesthesia with a single volatile anesthetic is commonly used in children but is sometimes associated with increased cough, secretion, and airway obstruction, which may result in part from stimulation of laryngeal C-fibers. We examined the effects of two popular volatile anesthetics, halothane and sevoflurane, on laryngeal C-fiber responsiveness in urethane-anesthetized guinea pigs (from age 4-5 weeks). After administration of halothane or sevoflurane to the functionally isolated upper airway, laryngeal C-fiber afferents recorded from the internal branch of the superior laryngeal nerve and identified by a conduction velocity of less than 2.0 m/second were tested for responsiveness to chemical and mechanical stimuli. Halothane doubled C-fiber responsiveness to capsaicin injected into the left atrium or nebulized to the larynx and to laryngeal hyperinflation, compared with sevoflurane, but it had no effect on baseline activity. The data indicate that, compared with sevoflurane, halothane more markedly enhances laryngeal C-fiber sensitivity to chemical and mechanical stimuli in young guinea pigs, which would explain the greater number of respiratory-related complications in children during induction of anesthesia with this agent.

Efecto de los anestésicos sobre el sistema inmunitario: nuestra experiencia / Effect of anesthetics on the immune system: our experience

Durante la anestesia general y el período postoperatorio, se han detectado alteraciones de diversos componentes de la respuesta inmunitaria, tanto en el número de células como en su funcionalidad, acompañados o no por cambios en la concentración de diversos factores solubles. La contribución de los anestésicos a las alteraciones perioperatorias de la respuesta inmune aún no ha sido aclarada adecuadamente. Nuestra experiencia en ratones indica que el sevoflurano es un anestésico seguro para estudios experimentales, aún en esquemas de anestesia reiterada. Si embargo, modula aspectos de la respuesta inmune, con efectos de menor intensidad que los causados por el halotano, los animales no demuestran haber recuperado sus niveles normales de respuesta. En pacientes se comparó las repercusiones de la anestesia total endovenosa (propofol, remifentanilo y vecuronio) o inhalatoria (propofol, fentanil e isoflurano) en colecistectomía por videolaparoscopía. Se verificaron diferencias entre los grupos en el intraoperatorio y en el primer día del postoperatorio, y una menor activación neuroendocrina por anestesia endovenosa. En otro grupo de experiencias, al comparar dos métodos de anestesia intravenosa total, ketamina-fentanilo-droperidol-midazolam versus remifentanilo-midazolam, se verificó que las condiciones para la intubación y la extubación fueron similares para ambas técnicas, pero este estudio sugiere que el remifentanilo proporcionó mejor estabilidad hemodinámica y neuroendocrina, así como cambios menores en los niveles de leucocitos. A partir de estas líneas experimentales podemos concluir que, si bien el trauma quirúrgico es el principal factor involucrado en los cambios neuroendocrinos relacionados con la cirugía, los diferentes procedimientos anestésicos pueden ejercer efectos inmunomodulatorios en la respuesta a la cirugía, principalmente en el período perioperatorio. En consecuencia, sugerimos que en la elección de agentes anestésicos o sedantes, ya sea para uso quirúrgico o en unidades de cuidados intensivos, se tengan en cuenta, en lo posible, sus propiedades inmunomodulatorias.

Efecto de los anestésicos sobre el sistema inmunitario: nuestra experiencia / Effect of anesthetics on the immune system: our experience

Durante la anestesia general y el período postoperatorio, se han detectado alteraciones de diversos componentes de la respuesta inmunitaria, tanto en el número de células como en su funcionalidad, acompañados o no por cambios en la concentración de diversos factores solubles. La contribución de los anestésicos a las alteraciones perioperatorias de la respuesta inmune aún no ha sido aclarada adecuadamente. Nuestra experiencia en ratones indica que el sevoflurano es un anestésico seguro para estudios experimentales, aún en esquemas de anestesia reiterada. Si embargo, modula aspectos de la respuesta inmune, con efectos de menor intensidad que los causados por el halotano, los animales no demuestran haber recuperado sus niveles normales de respuesta. En pacientes se comparó las repercusiones de la anestesia total endovenosa (propofol, remifentanilo y vecuronio) o inhalatoria (propofol, fentanil e isoflurano) en colecistectomía por videolaparoscopía. Se verificaron diferencias entre los grupos en el intraoperatorio y en el primer día del postoperatorio, y una menor activación neuroendocrina por anestesia endovenosa. En otro grupo de experiencias, al comparar dos métodos de anestesia intravenosa total, ketamina-fentanilo-droperidol-midazolam versus remifentanilo-midazolam, se verificó que las condiciones para la intubación y la extubación fueron similares para ambas técnicas, pero este estudio sugiere que el remifentanilo proporcionó mejor estabilidad hemodinámica y neuroendocrina, así como cambios menores en los niveles de leucocitos. A partir de estas líneas experimentales podemos concluir que, si bien el trauma quirúrgico es el principal factor involucrado en los cambios neuroendocrinos relacionados con la cirugía, los diferentes procedimientos anestésicos pueden ejercer efectos inmunomodulatorios en la respuesta a la cirugía, principalmente en el período perioperatorio. En consecuencia, sugerimos que en la elección de agentes anestésicos o sedantes, ya sea para uso quirúrgico o en unidades de cuidados intensivos, se tengan en cuenta, en lo posible, sus propiedades inmunomodulatorias. (AU)

Halothane effect on formalin-induced paw edema and flinching in rat.

The formalin test is a model of injury-produced inflammatory pain. Anesthetics, in clinically relevant concentrations, affect neutrophils and immune suppression. This study was to determine whether halothane reliably inhibits inflammatory reaction and formalin induced pain behavior or does not. Rats were exposed to 100% oxygen (control) or halothane, respectively for 30 min and then 24 hr later five percent formalin test was assessed. The base values of the paw's diameter were obtained earlier, and then formalin induced edema was assessed by measuring diameters of the injected paws at 5 min, 1 hr, 4 hr and 24 hr after the injection. Nociceptive behavior was quantified by counting the number of times with the paw flinched at 5 min intervals for 60 min. The diameters of edema in the halothane group lessened more than those in the oxygen group at 1 and 24 hr in each following of the injection (p<0.05). The rats pre-administered with oxygen or halothane were similar appearances in nociceptive behaviors. It suggests that halothane anesthesia might inhibit slightly the inflammatory reaction with the formalin-induced edema but might not inhibit the formalin-induced pain behavior in the event of pre-administration halothane 24 hr earlier before the formalin test of rat.

Halothane effect on formalin-induced paw edema and flinching in rat

The formalin test is a model of injury-produced inflammatory pain. Anesthetics, in clinically relevant concentrations, affect neutrophils and immune suppression. This study was to determine whether halothane reliably inhibits inflammatory reaction and formalin induced pain behavior or does not. Rats were exposed to 100% oxygen (control) or halothane, respectively for 30 min and then 24 hr later five percent formalin test was assessed. The base values of the paw's diameter were obtained earlier, and then formalin induced edema was assessed by measuring diameters of the injected paws at 5 min, 1 hr, 4 hr and 24 hr after the injection. Nociceptive behavior was quantified by counting the number of times with the paw flinched at 5 min intervals for 60 min. The diameters of edema in the halothane group lessened more than those in the oxygen group at 1 and 24 hr in each following of the injection (p<0.05). The rats pre-administered with oxygen or halothane were similar appearances in nociceptive behaviors. It suggests that halothane anesthesia might inhibit slightly the inflammatory reaction with the formalin-induced edema but might not inhibit the formalin-induced pain behavior in the event of pre-administration halothane 24 hr earlier before the formalin test of rat.

Gallstones and isoflurane hepatitis.

This report is of a case of a previously fit 65-year-old woman who developed postoperative liver dysfunction following an anaesthetic involving isoflurane. Biliary ultrasound demonstrated gallstones. However, serum antibodies to trifluoroacetylated proteins were detected, suggesting that immune sensitisation to the anaesthetic could have contributed to the impaired liver function.

Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies.

Two halogenated anesthetics, enflurane and isoflurane, have been associated with an allergic-type hepatic injury both alone and following previous exposure to halothane. Halothane hepatitis appears to involve an aberrant immune response. An antibody response to a protein-bound biotransformation product (trifluoroacetyl adduct) has been detected on halothane hepatitis patients. This study was performed to determine cross-reactivity between enflurane and isoflurane with the hypersensitivity induced by halothane. The subcellular and lobular production of hepatic neoantigens recognized by halothane-induced antibodies following enflurane and isoflurane, and the biochemical nature of these neoantigens was investigated in two animal models. Enflurane administration resulted in neoantigens detected in both the microsomal and cytosolic fraction of liver homogenates and in the centrilobular region of the liver. In the same liver, biochemical analysis detected fluorinated liver adducts that were up to 20-fold greater in guinea pigs than in rats. This supports and extends previous evidence for a mechanism by which enflurane and/or isoflurane could produce a hypersensitivity condition similar to that of halothane hepatitis either alone or subsequent to halothane administration. The guinea pig would appear to be a useful model for further investigations of the immunological response to these antigens.