Propofol emulsion anaesthesia and the immune response

Infection and septic complications remain a major cause of late morbidity and mortality in surgical patients. Postoperative infections and spread of malignancy after radical surgery have been suggested as consequences of disturbed immunocompetence. Anaesthetic agents and different anaesthesia techniques can modulate the immune response to surgery. The present study was carried out on the immunological effects of propofol, the short-acting intravenous anaesthetic dissolved in a lipid emulsion. Attention was also paid to the assessment of the immunological effects of Intralipid, the solvent of propofol, and to the mechanisms of action of propofol emulsion, with special reference to immunoregulatory prostaglandin (PG) PGE2. One further aim of this study was to compare the effects of propofol anaesthesia on the immune response with those of other types of general anaesthesia in patients scheduled for surgery of different trauma grades.

The proliferative responses of lymphocytes are fundamental to mounting an effective immune response. Mitogen-induced proliferative responses of lymphocytes were assessed in an in vitro culture system after exposure of separated lymphocytes to different concentrations of propofol emulsion and Intralipid. Propofol emulsion was found to decrease pokeweed mitogen (PWM)-induced proliferative responses of lymphocytes from critically ill intensive care unit (ICU) patients (median APACHE II score 16, median TISS score 28) at clinical propofol concentrations. Intralipid emulsion was also found to have a slight reducing effect on PWM-induced proliferative responses of lymphocytes from ICU patients. Concanavalin A (Con A)-induced proliferative responses of lymphocytes from ICU patients were significantly weaker than those of lymphocytes from healthy volunteers, whereas propofol emulsion and Intralipid had no effect on phytohaemagglutinin (PHA)-and Con A-induced proliferative responses of lymphocytes from ICU patients or on mitogen-induced proliferative responses of lymphocytes from healthy volunteers. PHA and Con A stimulate T lymphocyte proliferation, whereas PWM stimulates both T and B lymphocyte proliferation. Thus, these in vitro experiments indicate that in marginally immunocompetent ICU patients propofol emulsion interferes with B lymphocyte proliferative responses or T and B lymphocyte cooperation, but not with T lymphocyte proliferative responses.

PGE2 is an important immunoregulatory prostaglandin with suppressive effects on cell-mediated immunity. PGE2 is rapidly degraded after release and only sporadically detected in blood samples. Bicyclo-PGE2 is a dehydration product of 13-14-dihydro-15-keto-PGE2, the most prominent metabolite of PGE2 in the human circulation. Bicyclo-PGE2 concentrations were measured from the plasma with an radioimmunoassay method, which realiably monitors the in vivo production of PGE2. Intravenous anaesthesia induction with propofol emulsion or thiopentone in ASA 1-2 patients stimulated in vivo production of PGE2, as reflected by increased plasma concentrations of bicyclo-PGE2 during the induction phase. In contrast, Intralipid injected into healthy volunteers at doses generally used during propofol anaesthesia induction had no effect on plasma concentrations of bicyclo-PGE2. Despite stimulation of PGE2 production during intravenous anaesthesia induction, no effects were seen on mitogen-induced lymphocyte proliferative responses in patients. Intralipid injected into volunteers had no suppressive effect on lymphocyte and their subtype counts measured with immunofluorescence technigue by flow cytometry, mitogen-induced lymphocyte proliferative responses or immunoglobulin (Ig) production measured in vitro with enzyme-linked immunosorbent assay.

The effects on the immune response of propofol infusion anaesthesia were compared with those of conventional balanced anaesthesia during surgical breast tumour biopsy (minor surgery) and with those of combined isoflurane anaesthesia during abdominal hysterectomy (major surgery) in middle-aged patients. Furthermore, the effects of propofol infusion anaesthesia on the immune response were compared with those of combined isoflurane anaesthesia during ophthalmic surgery in elderly patients. Immune responses to surgery were basically similar in the different anaesthetic groups. However, propofol infusion anaesthesia was consistently found to increase the percentages of CD4 positive (CD4+) T helper (Th) cells in the blood circulation in middle-aged and elderly patients undergoing surgery, whereas no such effect was found in patients under conventional balanced or combined isoflurane anaesthesia. CD4+ Th cell is a subset of T lymphocytes pivotal in augmenting both cell-mediated and humoral immune responses. CD4+ Th cells can further be divided into subtypes Th 1 and Th 2 according to their cytokine secretion patterns. Th 1 cells upregulate cell-mediated immunity, whereas Th 2 cells upregulate humoral immunity. Propofol infusion anaesthesia attenuated the cortisol response as a marker of the hypothalamo-pituitary-adrenal (HPA) response to surgery more than the other types of anaesthesia, explaining some of the differences in the immune response within the anaesthetic groups. The observed effects on the percentages of CD4+ Th cells can not, however, be unequivocally explained by the differences in the endocrine response to surgery. More information is needed on the proportions and functions of CD4+ Th cell subtypes during different anaesthesia techniques, as these regulatory mechanisms are considered pivotal for successful control of infections and may also be important in the immune response to tumour cells.

In conclusion, propofol emulsion had a slight suppressive effect on PWM-induced proliferative responses of lymphocytes from critically ill surgical ICU-patients at clinical concentrations in vitro. Intravenous anaesthesia induction with propofol or thiopentone stimulated in vivo production of PGE2 in ASA I-II patients, whereas Intralipid injected into volunteers had no such effect. Propofol emulsion anaesthesia in surgical patients had no suppressive effects on the immune response. The higher percentage of CD4+ Th cells after propofol infusion anaesthesia compared to conventional balanced or combined isoflurane anaesthesia is theoretically beneficial. However, its clinical importance remains to be determined.