Early perioperative immunological effects of anaesthesia and analgesia in patients undergoing prostate cancer surgery: A randomised pilot study
A number of retrospective studies published in the last decade have found controversial results for the association between regional analgesia and cancer recurrence following surgery.1,2 It is believed that morphine and inhaled anaesthetics may impair function of important immune cells such as T-lymphocytes and natural killer (NK) cells.3,4 Although preclinical data support this hypothesis, retrospective studies in humans show mixed results. Therefore, we were interested in assessing immunological function in patients undergoing open radical prostatectomy to assess whether the clinical data can be explained in immunological terms. In this prospective, randomised pilot study, our hypothesis was that thoracic epidural analgesia in contrast to patient-controlled analgesia with morphine preserves the innate (monocytes and NK cells) as well as the adaptive (T-cell mediated) immune responses.
Following regional ethics committee approval (Uppsala, Sweden; Dnr 2009/235, 30 September 2009) and enrolment in Clinicaltrials.gov (NCT01367418), informed verbal and written consent were obtained from 26 patients (American Society of Anesthesiologists status 1 to 2) in the age group 50 to 75 years between February 2010 and April 2011.
Patients’ randomisation and concealed allocation to Group P (general anaesthesia and analgesia with postoperative patient-controlled analgesia) or Group E (combined, general and epidural anaesthesia with patient-controlled thoracic epidural analgesia postoperatively) was done by using cards inserted into opaque, sealed envelopes by an independent person not involved in the study. The study was only blinded to laboratory personnel involved in biochemical assays. In addition, eight healthy men serving as the control group (Group C) were recruited to measure the natural variation in NK-cell cytotoxicity. Perioperative analyses included sub-populations of leucocytes, cell-mediated immune response after mitogen stimulation, NK-cell cytotoxicity, vascular endothelial growth factor (VEGF) and IFN-g/IL-10 ratio. Blood samples were obtained from patients enrolled in a previous study investigating the neurohormonal and the acute inflammatory response after radical retropubic prostatectomy.5
Immunological analysis of leucocyte populations was determined by flow cytometry after immunostaining. Flow cytometric assay of specific cell-mediated immune response in activated whole blood and flow cytometric assay of NK cells immune response in activated whole blood were used to measure the degree of proliferation of lymphocytes and monocytes after stimulation with mitogens, as well as NK-cell cytotoxicity preoperatively, and at 24 and 72 h after the first blood sampling.
Continuous data or interval scaled data were summarised with mean and SD and analysed with unpaired t test. Ordinal scale data were summarised with median and range and analysed using the Mann–Whitney U test and corrected for repeated measurements with Bonferroni–Holm correction. The immunological data were analysed by analysis of variances for repeated measurements as a general linear model. Log transformation was used if needed because of skewed distributions. All analyses used SPSS version 17.0 (SPSS Inc., Chicago, Illinois, USA). A P value of less than 0.05 was considered to be statistically significant.
We found no statistically significant differences in NK-cell cytotoxicity expressed in percentage between Groups P and E over time (P = 0.54 at 24 h and P = 0.41 at 72 h). The variation of NK-cell cytotoxicity in Group C (unoperated) was 1.6 (0 to 37.7), 6.5 (0.70 to 16.91) and 8.2 (2.15 to 32.7) preoperatively and at 24 and 72 h, respectively, postoperatively. The reactivity of T-lymphocytes sub-populations did not show statistically significant differences between Groups P and E at any time point (T-helper CD4+, P = 0.54; T-cytotoxic CD8+, P = 0.72). The CD4+/CD8+ ratio remained constant between the groups over time (P = 0.99). We observed a better preserved cytotoxic T-lymphocyte population in Group E and T-helper lymphocytes in Group P, postoperatively. After mitogen stimulation with phytohaemoagglutinin, neither the cytotoxic lymphocytes nor the T-helper sub-population differed significantly between the groups at any measured times (Table 1).