Effects of analgesic and surgical modality on immune response in colorectal cancer surgery.

BACKGROUND AND OBJECTIVE: Different surgical methods, anesthesia, and analgesia are known to modify the surgical stress response, especially in patients with malignancy. We compared the impact of patient-controlled intravenous (PCA) versus epidural analgesia (EDA) on tumor-related mucosal immune response in patients undergoing open or laparoscopic surgery for colorectal cancer. METHODS: In a University Hospital subgroup (n = 43) of a larger cohort (n = 235) of patients undergoing open or laparoscopic surgery for colorectal carcinoma randomized to PCA or EDA, colorectal tissues were stained for interleukin-10 (IL-10), tumor necrosis factor (TNF), and mast cell tryptase and then examined by immunofluorescence microscopy. RESULTS: More IL-10+-cells were found in patients undergoing open compared to laparoscopic surgery in the PCA (P < 0.05) and EDA group (P < 0.0005), respectively, and numbers of TNF+-cells were higher in the open surgery group who received PCA (P < 0.05). No differences in IL-10 or TNF expressions were detected between EDA/PCA within the open or laparoscopic surgery groups, respectively. Fewer mast cells were observed in patients undergoing laparoscopic compared to open surgery combined with PCA (P < 0.05). Within the open surgery group, EDA resulted in fewer mucosal mast cells compared to the PCA group (P < 0.05). CONCLUSIONS: The surgical method, rather than type of analgesia, may have higher impact on peri-operative inflammation. Laparoscopic surgery when combined with EDA for colorectal cancer caused a decrease in the TNF and IL-10 expression and mast cells. EDA seems to have an anti-inflammatory effect on cancer-related inflammation during open surgery.

Comparison between epidural and intravenous analgesia effects on disease-free survival after colorectal cancer surgery: a randomised multicentre controlled trial.

BACKGROUND: Thoracic epidural analgesia (TEA) has been suggested to improve survival after curative surgery for colorectal cancer compared with systemic opioid analgesia. The evidence, exclusively based on retrospective studies, is contradictory. METHODS: In this prospective, multicentre study, patients scheduled for elective colorectal cancer surgery between June 2011 and May 2017 were randomised to TEA or patient-controlled i.v. analgesia (PCA) with morphine. The primary endpoint was disease-free survival at 5 yr after surgery. Secondary outcomes were postoperative pain, complications, length of stay (LOS) at the hospital, and first return to intended oncologic therapy (RIOT). RESULTS: We enrolled 221 (110 TEA and 111 PCA) patients in the study, and 180 (89 TEA and 91 PCA) were included in the primary outcome. Disease-free survival at 5 yr was 76% in the TEA group and 69% in the PCA group; unadjusted hazard ratio (HR): 1.31 (95% confidence interval [CI]: 0.74-2.32), P=0.35; adjusted HR: 1.19 (95% CI: 0.61-2.31), P=0.61. Patients in the TEA group had significantly better pain relief during the first 24 h, but not thereafter, in open and minimally invasive procedures. There were no differences in postoperative complications, LOS, or RIOT between the groups. CONCLUSIONS: There was no significant difference between the TEA and PCA groups in disease-free survival at 5 yr in patients undergoing surgery for colorectal cancer. Other than a reduction in postoperative pain during the first 24 h after surgery, no other differences were found between TEA compared with i.v. PCA with morphine.

How Anesthetic, Analgesic and Other Non-Surgical Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A Summary of Current State of Evidence.

The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.

Is there a relationship between anaesthesia and dementia?

BACKGROUND: Long-term cognitive problems are common among elderly patients after surgery, and it has been suggested that inhalation anaesthetics play a role in the development of dementia. This study aims to investigate the hypothesis that patients with dementia have been more exposed to surgery and inhalational anaesthetics than individuals without dementia. METHODS: Using 457 cases from a dementia-registry and 420 dementia-free controls, we performed a retrospective case-control study. The medical records were reviewed to determine exposure to anaesthesia occurring within a 20-year timeframe before the diagnosis or inclusion in the study. Data were analysed using multivariate logistic regression and propensity score analysis. RESULTS: Advanced age (70 years and older, with the highest risk in ages 80-84 years) and previous head trauma were risk factors for dementia. History of exposure to surgery with anaesthesia was a risk factor for dementia (OR = 2.23, 95% CI 1.66-3.00, P < 0.01). Exposure to inhalational anaesthetics with halogenated anaesthetics was associated with an increased risk of dementia, compared to no exposure to anaesthesia (OR = 2.47, 95% CI 1.17-5.22, P = 0.02). Exposure to regional anaesthesia was not significantly associated with increased risk of dementia (P = 0.13). CONCLUSION: In this 20-year retrospective case-control study, we found a potential association between dementia and prior anaesthesia. Exposure to general anaesthetics with halogenated anaesthetic gases was associated with an increased risk of dementia.

Determination of loss of consciousness: a comparison of clinical assessment, bispectral index and electroencephalogram: An observational study.

BACKGROUND: Computer-processed algorithms of encephalographic signals are widely used to assess the depth of anaesthesia. However, data indicate that the bispectral index (BIS), a processed electroencephalography monitoring system, may not be reliable for assessing the depth of anaesthesia. OBJECTIVE: The aim of this study was to evaluate the ability of the BIS monitoring system to assess changes in the level of unconsciousness, specifically during the transition from consciousness to unconsciousness, in patients undergoing total intravenous anaesthesia with propofol. We compared BIS with the electroencephalogram (EEG), and clinical loss of consciousness (LOC) defined as loss of verbal commands and eyelash reflex. DESIGN: This was an observational cohort study. SETTING: University Hospital Linköping, University Hospital Örebro, Finspång Hospital and Kalmar Hospital, Sweden from October 2011 to April 2013. PATIENTS: A total of 35 ASA I patients aged 18 to 49 years were recruited. INTERVENTIONS: The patients underwent total intravenous anaesthesia with propofol and remifentanil for elective day-case surgery. Changes in clinical levels of consciousness were assessed by BIS and compared with assessment of stage 3 neurophysiological activity using the EEG. The plasma concentrations of propofol were measured at clinical LOC and 20 and 30 min after LOC. MAIN OUTCOME MEASURES: The primary outcome was measurement of BIS, EEG and clinical LOC. RESULTS: The median BIS value at clinical LOC was 38 (IQR 30 to 43), and the BIS values varied greatly between patients. There was no correlation between BIS values and EEG stages at clinical LOC (r = -0.1, P = 0.064). Propofol concentration reached a steady state within 20 min. CONCLUSION: There was no statistically significant correlation between BIS and EEG at clinical LOC. BIS monitoring may not be a reliable method for determining LOC. CLINICAL TRIALS REGISTRY: This trial was not registered because registration was not mandatory at the time of the trial.

Orexin a phosphorylates the γ-Aminobutyric acid type A receptor ß2 subunit on a serine residue and changes the surface expression of the receptor in SH-SY5Y cells exposed to propofol.

Propofol activates the γ-aminobutyric acid type A receptor (GABAA R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase Cɛ (PKCɛ). The human SH-SY5Y cells express both GABAA Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAA R. The effects of OA are studied with flow cytometry and immunoblotting. This study shows that OA stimulates phosphorylation on the serine residues of the GABAA R ß2 subunit and that the phosphorylation is caused by the activation of PLD and PKCɛ. OA administration followed by propofol reduces the cell surface expression of the GABAA R, whereas propofol stimulation before OA increases the surface expression. The GABAA R ß2 subunit is important for receptor recirculation, and the effect of OA on propofol-stimulated cells may be due to a disturbed recirculation of the GABAA R.

Pharmacogenetics, plasma concentrations, clinical signs and EEG during propofol treatment.

A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high-performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9-promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (subdelta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9-331C/T had a higher propofol clearance than those without (p = 0.03) and required a higher induction dose (p = 0.03). The patients with UGT1A9-1818T/C required a longer time to LOC (p = 0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p = 0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern.

Orexin A inhibits propofol-induced neurite retraction by a phospholipase D/protein kinase Cε-dependent mechanism in neurons.

BACKGROUND: The intravenous anaesthetic propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons. Orexin A (OA) is an endogenous neuropeptide regulating wakefulness and may counterbalance anaesthesia. We aim to investigate if OA interacts with anaesthetics by inhibition of the propofol-induced neurite retraction. METHODS: In primary cortical cell cultures from newborn rats' brains, live cell light microscopy was used to measure neurite retraction after propofol (2 µM) treatment with or without OA (10 nM) application. The intracellular signalling involved was tested using a protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (PMA)] and inhibitors of Rho-kinase (HA-1077), phospholipase D (PLD) [5-fluoro-2-indolyl des-chlorohalopemide (FIPI)], PKC (staurosporine), and a PKCε translocation inhibitor peptide. Changes in PKCε Ser729 phosphorylation were detected with Western blot. RESULTS: The neurite retraction induced by propofol is blocked by Rho-kinase and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, staurosporine and PKCε translocation inhibitor peptide. OA increases via PLD and propofol decreases PKCε Ser729 phosphorylation, a crucial step in the activation of PKCε. CONCLUSIONS: Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC inhibits neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKCε-mediated pathway, and PKCε maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge.

Platelet function assessed by whole-blood aggregometry in patients undergoing non-cardiac surgery.

BACKGROUND: The risk/benefit of continuing low-dose acetylsalicylic acid (aspirin) for secondary prevention in the perioperative period is still debated. The primary aim of this study was to determine the effect of acetylsalicylic acid compared with placebo on platelet function in the perioperative period. METHODS: This is a subgroup analysis of a randomised, double-blind, placebo-controlled multicentre study. High-risk patients undergoing major non-cardiac surgery were randomised to 75 mg acetylsalicylic acid or placebo 7 days preoperatively, until the third postoperative day. In 36 patients, platelet function in response to arachidonic acid was assessed by whole-blood impedance aggregometry using a multiplate analyser 1 h before surgery, directly after surgery and 48 h postoperatively. RESULTS: The platelet function was significantly reduced in patients treated with acetylsalicylic acid compared with placebo in the preoperative period [200 aggregation units (AU) min (interquartile range [IQR] 133-261 AU min⁻¹) vs. 860 AU min (IQR 800-1010 AU min), P < 0.001] as well as postoperatively [198 AU min (IQR 138-270 AU min) vs. 605 AU min (IQR 434-836 AU min), P < 0.001]. The platelet response was significantly reduced postoperatively compared with preoperatively in patients receiving placebo [860 AU min (IQR 800-1010 AU min) vs. 605 AU min (IQR 434-861 AU min), P = 0.0009]. No significant differences were found between pre- and postoperative platelet function in patients on acetylsalicylic acid [200 AU min (IQR 133-261 AU min) vs. 198 AU min (133-270 AU min), P = 0.21]. CONCLUSION: Multiplate whole-blood impedance aggregometry demonstrates acetylsalicylic affect in preoperative as well as postoperative samples derived from patients undergoing non-cardiac surgery.

Stress factors affecting academic physicians at a university hospital.

Research is limited regarding occupational stress in academic physicians; professionals whose work situation includes the three areas of clinical practice, research, and teaching. The aim of this study was to gain knowledge of factors experienced as stressful by academic physicians employed by a university hospital. A questionnaire assessing the frequency and intensity of 36 potentially stressful factors was sent to all 157 academic physicians who were employed at the Linköping University Hospital, Sweden. The response rate was 77%. Both a high frequency and intensity of stress was experienced by 66% of the academic physicians in relation to "time pressure" and by almost 50% in connection with both "find time for research" and having "conflict of interest between different work assignments". Moreover, physicians in the higher age group and those who had attained a higher academic position experienced less stress. The female participants experienced more stress than the males due to gender-related problems and to variables associated with relationships at work. More knowledge is needed to determine the consequences of this finding and to identify coping strategies used for handling such stress.

[Renewed medical education in Linkoping. Problem-based learning, basic science and public health intensified]. / Läkarutbildningen i linköping förnyas. Problembaserat lärande, basvetenskap och folkhälsa förstärks.

A complete undergraduate medical programme in Linköping started 1986. The curriculum was innovative applying problem-based learning, community-orientation, and multi-professional training. After almost 20 years, a revision is implemented to vitalise the original educational principles. A curriculum committee coordinates seven multi-disciplinary theme-groups, mainly based on organ systems, responsible for planning and implementation of their parts during the whole curriculum. Critical appraisal, professional development, and population health are strengthened. Problem based learning is improved by using web-based scenarios and information technology. Phase I (2 semesters) focuses on basic concepts in basic science in relevant contexts, and Phase II (3 semesters) on normal structure, pathophysiology, diagnostic methods, and treatment. Phase III starts with a semester for a student research project and an elective period. The following five semesters deal with clinical medicine in hospitals and health centres with clerkships in four week periods changing with two week theoretical blocks related to the themes.