[Hemodynamic, immunologic and systemic stress response during surgery under total intravenous anesthesia with midazolam-ketamine-fentanyl or remifentanil-midazolam: a randomized clinical trial]. / Estudio comparativo de anestesia total intravenosa con midazolam- ketamina-fentanilo y remifentanilo-midazolam: evaluación de la respuesta hemodinámica, leucocitaria y de los marcadores sistémicos de estrés.

OBJECTIVE: To assess the effect of stress from surgery on hemodynamics, white cell count, and systemic markers during cholecystectomies performed under 2 intravenous anesthetic techniques. PATIENTS AND METHOD: Randomized clinical trial in patients classified ASA 1 or 2. The patients received 0.15 mg x kg(-1) of midazolam, 1 mg x kg(-1) x h(-1) of ketamine, and 2 microg x kg(-1) of fentanyl (MKF group) or 1 microg x kg(-1) x min of remifentanil and 0.15 mg x kg(-1) of midazolam (RM group). Hemodynamic parameters, white cell counts in circulating blood, and serum levels of cortisol, prolactin, and interleukin-6 were recorded before surgery, after intubation, and at the end of surgery. RESULTS: Thirty-two patients were enrolled. Hemodynamic stability was good in both groups. After intubation, mean (SD) heart rate (75 [14] beats x min(-1)) and systolic (96 [14] mm Hg) and diastolic (60 [7] mm Hg) blood pressures were lower in the RM group than in the MKF group (99 [17] beats x min(-1); 121 [29] mm Hg; and 79 [14] mm Hg, respectively, P<0.01). After surgery whi- te cell (10528 [6480] microL(-1)) and neutrophil (8155 [5657] microL(-1)) counts and cortisol concentration (225 [257] ng x mL(-1)) were significantly lower in the RM patients than in the MKF patients (white cell count, 14,002 [5927] cells x micromL(-1); neutrophil count, 11530 [5657] cells x microL(-1), and 788.8 [146] ng x mL(-1); P<0.01). CONCLUSIONS: The 2 intravenous anesthesia regimens compared differ slightly with regard to their effects on surgical stress. Anesthesia with remifentanil and midazolam contributes to reducing the inflammatory response through modulation of the neurohumoral response to stress.

Effects of sevoflurane general anesthesia: immunological studies in mice.

Based on the immunomodulatory effects of anesthesia and surgery, a study was undertaken to assess the effect of sevoflurane anesthesia on the immune system in a murine model without surgery. Adult male mice were anesthetized with 3% sevoflurane (1.2 minimal alveolar concentration, MAC) in oxygen for 40 min, whereas nontreated animals served as controls. After sevoflurane anesthesia, peripheral blood leukocyte counts, the splenic composition and in vitro macrophage phagocytic activity and lymphoproliferative response were assessed. The in vivo specific immune response to sheep red blood cells (SRBC), a conventional T-dependent antigen was determined. In addition, liver, spleen, thymus and kidney histopathology and also hepatic and renal functions after anesthesia were studied. Sevoflurane diminished the number of peripheral blood lymphocytes and splenic B-cell counts, enhancing CD4+ lymphocytes in spleen. The in vitro functionality of macrophages and the mitogen-induced lymphoproliferative response were preserved, while the in vivo immune response to SRBC was enhanced in treated animals. Microscopic studies revealed conserved architecture of the spleen, thymus, lymph node, liver and kidney, and there were no differences in serum parameters of hepatic and renal functions between treated and control groups. Our results suggest that 3 days after the anesthetic exposure, animals treated with sevoflurane modulated their peripheral blood leukocyte counts, splenic lymphoid composition and the characteristics of the specific response to SRBC, while there was no evidence of hepatic or renal toxicity.

Effects of halothane reexposure in female mice and their offspring.

Female CBi mice subjected to multiple exposures to halothane inhalation anesthesia before mating were investigated for the potential effects of such intervention on a specific antibody response mounted by them and their offspring. An assessment of the toxicologic and reproductive performance of female mice undergoing anesthesia was also performed. Adult female mice received three episodes of halothane anesthesia at weekly intervals. Seventy-two hours after the last dose, mice were subjected to the following procedures: 1) study of the specific humoral immune response to sheep red blood cells (SRBC); 2) hematologic, hepatologic, and histopathologic studies; and 3) mating with syngeneic sires. Halothane-treated females had increased amounts of specific antibody secreting B cells, with liver studies showing evidence of microscopic fatty changes and decreased lipid peroxidation. Anesthesia did not alter reproductive performance but lowered offspring survival. Offspring displayed depressed antibody response after challenge with SRBC at weaning and at 60 d of age. The anti-SRBC antibody response that was found to be enhanced in halothane anesthetized females, seemed to be conversely impaired when studied in the offspring.

Effects of repetitive sevoflurane anaesthesia on immune response, select biochemical parameters and organ histology in mice.

Animal and technical models often require repeated anaesthetic administrations for surgical procedures. As there is evidence for immunomodulatory effects of anaesthesia, the effects of repeated exposure to sevoflurane anaesthesia on the immune response in mice were studied. Sevoflurane was administered in vivo under conditions that simulate those in clinical procedures. Adult male mice were anaesthetized with 3% sevoflurane in oxygen for 40 min weekly for 3 weeks. Untreated animals served as controls. After sevoflurane anaesthesia, peripheral blood leukocyte counts, the composition and in vitro function of spleen cells (lymphocytes and macrophages) and the in vivo immune response to a conventional T-dependent antigen were assessed. In addition, liver, spleen and kidney histopathology and also hepatic and renal function were studied. Three days after the latest anaesthetic procedure, the absolute number of both leukocyte and lymphocyte counts were reduced in peripheral blood. Splenic cell composition (LB, LTCD3(+), LTCD4(+) and LTCD8(+)), macrophage function and the mitogen-induced lymphoprolipherative response were preserved. Yet, the in vivo humoral response to a conventional antigen was augmented following the antigenic challenge. Assessment at day 9 after the last anaesthetic procedure revealed the persistence of the humoral response alteration. Nevertheless, sevoflurane-treated animals showed no evidence of histological changes or alteration in hepatic or renal function.

[Effects of sevoflurane anesthesia on the immune response and biochemical parameters in mice. Comparison between single exposure and repeated anesthesia]. / Efectos de la anestesia con sevoflurano sobre la respuesta inmunitaria y parámetros bioquímicos en ratones. Comparación entre exposición única y anestesia reiterada.

OBJECTIVE: Given that anesthesia and surgery are known by their immunomodulatory effects, we aimed to compare the immune response after 1 or 3 anesthetic exposures to sevoflurane in a murine model without surgery. MATERIAL AND METHODS: Young adult male mice, non-controlled for body conformation, were exposed 1 (group S1) or 3 times (group S3) to 3% sevoflurane in oxygen (1.2 maximum alveolar concentration) for 40 minutes. Untreated animals were used as controls. Three days after in vivo exposure to sevoflurane, the cellular composition of peripheral blood and of the spleen were studied. We also studied the in vivo response to exogenous (sheep red blood cells: SRBC) and endogenous antigens (heat shock proteins: HSP 65 and HSP 70) as well as biomarkers of toxicity. RESULTS: The number of leukocytes in peripheral blood decreased in S3 animals, and the number of lymphocytes decreased in both groups. B cells in spleen decreased only in the S1 group, but an increased in vivo response to SRBC was seen in both S1 and S3 mice in comparison with the control animals. Re-exposure to sevoflurane led to a decrease in immunoglobulin G response only to HSP 70. Plasma markers of liver and kidney function did not change after anesthetic exposure. CONCLUSION: Changes in leukocyte populations in peripheral blood and in antibody-producing capacity occur after either a single exposure or repeated exposures to sevoflurane. However no changes occur in biomarkers of toxicity.

Halothane-associated enhancement of the secondary immune response to sheep erythrocytes in mice: cell transfer studies.

The effect of halothane anesthesia on the humoral immune response to sheep red blood cells was studied in mice immunized twice, with a 15-day interval. On both occasions, mice were exposed to 1.5% halothane for 40 min immediately after sensitization. Halothane reexposure resulted in increased numbers of IgG-secreting cells (IgG-SC) as well as circulating 7S-serum agglutinins. To examine further whether this effect could be obtained in syngeneic recipients, adoptive transfer experiments employing spleen cells were performed. While mice receiving cells from unimmunized and anesthetized donors displayed significantly higher levels of IgG-SC, recipients of cells from normal, immunized and immunized-anesthetized donors showed a depressed response when compared to control counterparts. Besides the possibility of an enhancing effect of halothane reexposure on the humoral response, this procedure may counteract normal physiological immunoregulatory processes during the generation of the immune response.

Oxygen tension-associated changes on secondary immune response in halothane or isoflurane anesthetized mice.

The impact that reexposure to anesthetics delivered in 100% oxygen or in synthetic air (21% oxygen/79% nitrogen) has on the secondary humoral immune response to sheep red blood cells was studied. Mice were immunized twice with a 15-day interval and anesthetized immediately after each antigenic challenge with 1.5% halothane or 1.5% isoflurane for 40 min. Halothane in oxygen resulted in increased numbers of IgG-secreting cells (IgG-SC), while halothane in air depressed the response when compared to control mice. In contrast, isoflurane vaporized in oxygen did not affect IgG-SC numbers, while isoflurane given in air lowered the response. Furthermore, neither 100% oxygen, nor the stress of being in an anesthesia chamber breathing synthetic air for 40 min had any immunological effect in non-anesthetized mice. The inspired oxygen concentration during halothane or isoflurane anesthesia has an effect on the secondary immune response. The effect is different between halothane and isoflurane, possibly due to differences in the extent of their metabolic and pharmacodynamic properties.

Inhalatory anesthetic (halothane) associated changes in the immune response in mice.

The extent of surgery, the patient's age, health status and other factors may contribute to alteration of the immune system during anesthesia and surgery. In addition, inhalatory anesthetics may cause acute and chronic toxicity because of the production of intermediate and end metabolic compounds. The present work was undertaken to evaluate, both in vivo and in vitro, if repeated doses of halothane were able to affect the immune response in a murine model developed at our laboratory. Weekly doses of halothane were administered to mice subjected to no surgery and three days after the last anesthetic-exposure, several immunologic parameters were assessed. Results on the in vivo response to sheep red blood cells showed that halothane treatment increased the amount of specific antibody secreting B-cells, without affecting the delayed type hypersensitivity reaction to the same antigen. In vitro studies on spleen cell composition showed that halothane re-exposure diminished the number of CD4+, CD8+ and B-cells. Such changes were not translated into alterations on the mitogen-driven lymphoproliferation, as well as macrophage phagocytic and lytic functions. Our results indicate that halothane re-exposure is able to modulate the immune response affecting both the number of antibody secreting cells involved in a specific in vivo response, and the splenic lymphoid cell composition. Since such halothane-induced immune alterations might bias the results of a wide range of physiological research, even those involving other systems, a careful selection of the anesthetic agent and methods by which the compound is administered is advisable.