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

Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase C-epsilon-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 mu M) 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 PKC epsilon translocation inhibitor peptide. Changes in PKC epsilon Ser(729) 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 PKC epsilon translocation inhibitor peptide. OA increases via PLD and propofol decreases PKC epsilon Ser(729) phosphorylation, a crucial step in the activation of PKC epsilon. 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/PKC epsilon-mediated pathway, and PKC epsilon maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge

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.Funding Agencies|ALF funding Region Orebro County [OLL-880951]; Regional Research Council, Central Sweden [RFR-298211]; research committee of Region Orebro County [OLL-784751]</p

(A): Time-lapse imaging reveals the dynamics of neurite retraction after addition of propofol.

<p>Upper panel: Cortical cell cultures were treated with CCM for 5 min (-5 to 0 min), exposed to 2 µM propofol and observed for 10 min. Images shown were taken -1 and 10 min following addition of propofol. The arrows indicate the tip of the neurites, with the neurite extending towards the upper left corner show a trailing remnant (very thin treadlike structure). Lower panel: The same cell identified with DIC microscopy (right) after fixation with 4% PFA/PBS for 30 min, followed by immunostaining of β₃ tubulin to identify neuronal cells (left). The neurite with the trailing remnant is out of focus in the fluorescent picture. Cell orientation is different, as the cell is examined in different microscopes for the upper and lower panels. (B): Propofol-induced neurite retraction is dependent on Rho Kinase. Graph of time-dependent response of cortical cell cultures in CCM that were pretreated with the HA-1077 0.08-80 µM for 40 min, observed for 5 min in CCM-HA1077 and then exposed to 2 µM propofol (P2) for 10 min. Propofol addition is shown by an arrow. Values are expressed as percentage of neurite length (100%) 1 min before propofol addition and represent mean ± SEM. Data were based on at least 5 neurites in each HA-1077/propofol group and n = 9 cells, 10 neurites in the propofol group. Propofol induced a neurite retraction to 74.4±5.6% of initial length. Pretreatment of the cells with the RhoA-kinase inhibitor HA-1077 (0.08 – 80 µM) for 40 min blocked the propofol-induced neurite retraction to (95.5±2.5%, n = 6) for 0.08 µM after 10 min, with the same blocking effect for 0.08 – 80 µM HA-1077, (n = 5 each). All concentations tested were significantly different from propofol after 5 min and onwards (p<0.001, 2-way ANOVA with Bonferroni post-hoc test). No retraction was seen by 80 µM HA-1077 alone (99.1±1.8%, n = 5).</p

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

BACKGROUNDComputer-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.OBJECTIVEThe 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.DESIGNThis was an observational cohort study.SETTINGUniversity Hospital Linkoping, University Hospital orebro, Finspang Hospital and Kalmar Hospital, Sweden from October 2011 to April 2013.PATIENTSA total of 35 ASA I patients aged 18 to 49 years were recruited.INTERVENTIONSThe 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 30min after LOC.MAIN OUTCOME MEASURESThe primary outcome was measurement of BIS, EEG and clinical LOC.RESULTSThe 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 20min.CONCLUSIONThere 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 REGISTRYThis trial was not registered because registration was not mandatory at the time of the trial.Funding Agencies|Medical Research Council of Southeast Sweden; Swedish Research Council; County Council in Ostergotland</p

Proposed pathway for Orexin A inhibition of propofol-induced neurite retraction.

<p>A proposed schematic view of how propofol and OA interfere with neurite retraction. Propofol binds to GABA_AR and causes neurite retraction through the RhoA/ROK pathway by activating the acto-myosin complex (blue box), where phosphorylation of myosin via myosin light chain kinase (MLCK)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097129#pone.0097129-Turina1" target="_blank">[3]</a> causes contraction of the neurite. When myosin is de-phosphorylated via myosin light chain phosphatase (MLCP) the neurite extends. OA binds to OXR and activates PLD, increasing DAG, which activates PKCε by increasing the phosphorylation of PKCε Ser⁷²⁹. The activated PKCε translocates from the cytosol to the cell membrane. The now activated PKCε then interfere with a membrane effector, possibly the GABA_AR<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097129#pone.0097129-Chou1" target="_blank">[43]</a>, which might cause a decrease in the amount of GABA_AR at the cell surface. PKCε also have an actin binding motif, that could directly interfere with the cytoskeletal actin involved in the contractile response causing neurite retraction. PKCε stabilizes F-actin<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097129#pone.0097129-Newton1" target="_blank">[28]</a> when bound, and then retraction could not take place. Propofol reduces the phosphorylation of PKCε Ser⁷²⁹ below the amount in unstimulated cells, suggesting that propofol counter-balances the normal activity of cellular PKCε; the signalling pathway of propofol might include PLD as inhibition of PLD restore PKCε Ser⁷²⁹ phosphorylation. The exact pathway used, is yet to be determined.</p

(A): Orexin A inhibits propofol-induced neurite retraction by activation of phospholipase D.

<p>Graph of time-dependent response of cortical cell cultures in CCM pretreated with the PLD inhibitor FIPI (100 nM) for 60 min, observed for 5 min in CCM-FIPI and exposed to 2 µM propofol (P2, arrow) for 15 min. OA (10 nM) was added 1 min before propofol exposure. Values are expressed as percentage of neurite length (100%) 1 min before OA addition and represent mean ± SEM. The propofol-induced retraction was blocked with OA (101.1±2.2%, n = 6). FIPI prevented the inhibitory effect of OA on propofol-induced neurite retraction already after 5 min and caused retraction to (54.7±8.6%, n = 6), after 15 min. No retraction was seen by FIPI alone (100.4±0.5%, n = 6). Propofol retraction is not inhibited by FIPI (59.1± 16.1%, n = 3) at 15 min. The retraction response for FIPI/P2 and FIPI/OA/P2 was significant from 5 min (p<0.001, 2-way ANOVA followed by Bonferroni post-hoc test). (B) The inhibitory effect of Orexin A on propofol-induced neurite retraction is protein kinase C-dependent. Graph of time-dependent response of cortical cell cultures first observed for 5 min in CCM, and thereafter pretreated with the PKC inhibitor staurosporine (3 nM) for 5 min and exposed to 2 µM propofol (P2) for 10 min. OA (10 nM) or the OA solvent acetic acid (AE, 0.001%) was added 1 min before propofol exposure. Values are expressed as percentage of neurite length (100%) 1 min before OA/AE addition and represent mean ± SEM. OA block the propofol-induced retraction (98.6±3.4%, n = 6). No retraction was seen by staurosporine alone (97.8±0.9, n = 6). Staurosporine prevented the inhibitory effect of OA on propofol-induced neurite retraction (78.3±9.9%, n = 7), 10 min after propofol addition, p<0.001 compared with OA/P2 (2-way ANOVA, followed by Bonferroni post-hoc test). Staurosporine did not affect the response of AE/P2 after 10 min (neurite retraction (86.1±3.3%, n = 7, p<0.05 compared with OA/P2). Pretreatment with the PKC activator PMA (100 nM) for 3 min abolished the propofol-induced neurite retraction after 15 min (97.9±5.2 %, n = 6). The colour-coded arrow indicates propofol addition for each experiment. (C) The orexin effect is due to translocation of protein kinase Cε. Graph of time-dependent neurite retraction on cortical cell cultures pre-incubated for 45 min with the PKCε translocation inhibitor peptide (PKCεI, 5 µM), stimulated with OA (10 nM) or the OA solvent acetic acid (AE, 0.001%) 1 min (thick arrow) before propofol (2 µM (P2), thin arrow) exposure for 11 min, the PKCεI alone or AE/P2. PKCεI alone did not change neurite length (102.8 ±2.3%, n = 5). AE/P2 retracted the neurite to (64.7±7.2%, n = 4), non significant compared with PKCεI/AE/propofol (63.3±10.0%, n = 7, 2-way ANOVA, followed by Bonferroni post-hoc test). When PKCε cannot translocate from the cytosol to the membrane, OA could not prevent retraction (51.6±8.6%, n = 10) at 10 min after propofol addition. All propofol treatments were significantly different from PKCεI (p<0.001). (D) Orexin A activates PKCε via a PLD dependent phosphorylation of PKCε Ser⁷²⁹ whereas propofol reduces PKCε Ser⁷²⁹ phosphorylation. Western blot analysis of PKCε Ser⁷²⁹ phosphorylation on cortical cell cultures treated with CCM, P2 (2 µM, 10 min), or OA (10 nM, 11 min), with or without FIPI (100 nM). CCM and P2 cells were treated with acetic acid (0.001%) for 11 min (CCM) or 1 min before addition of propofol (P2). FIPI was preincubated for 1 h, and supplemented throughout the experiment. Blots were visualized with an anti-PKCε Ser⁷²⁹ phosphorylation antibody (1∶1000)/horseradish peroxidase linked anti-rabbit antibody (1∶5000). OA increases the PKCε Ser⁷²⁹ phosphorylation compared to CCM, and this is reduced when PLD is blocked by FIPI, whereas propofol-treated cells showed a decrease in PKCε Ser⁷²⁹ phosphorylation that increased after FIPI treatment (n = 5). The lanes shown are from the same blot, but rearranged into rows.</p

To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial

Background: Major adverse cardiac events (MACEs) are a common cause of deathafter non-cardiac surgery. Despite evidence for the benefitof aspirin for secondary prevention, it is often discontinuedin the perioperative period due to the risk of bleeding. Methods: We conducted a randomized, double-blind, placebo-controlledtrial in order to compare the effect of low-dose aspirin withthat of placebo on myocardial damage, cardiovascular, and bleedingcomplications in high-risk patients undergoing non-cardiac surgery.Aspirin (75 mg) or placebo was given 7 days before surgery andcontinued until the third postoperative day. Patients were followedup for 30 days after surgery. Results: A total of 220 patients were enrolled, 109 patients receivedaspirin and 111 received placebo. Four patients (3.7%) in theaspirin group and 10 patients (9.0%) in the placebo group hadelevated troponin T levels in the postoperative period (P=0.10).Twelve patients (5.4%) had an MACE during the first 30 postoperativedays. Two of these patients (1.8%) were in the aspirin groupand 10 patients (9.0%) were in the placebo group (P=0.02). Treatmentwith aspirin resulted in a 7.2% absolute risk reduction [95%confidence interval (CI), 1.3–13%] for postoperative MACE.The relative risk reduction was 80% (95% CI, 9.2–95%).Numbers needed to treat were 14 (95% CI, 7.6–78). No significantdifferences in bleeding complications were seen between thetwo groups. Conclusions: In high-risk patients undergoing non-cardiac surgery, perioperativeaspirin reduced the risk of MACE without increasing bleedingcomplications. However, the study was not powered to evaluatebleeding complications.  This is a pre-copy-editing, author-produced PDF of an article accepted for publication in British Journal of Anaesthesia following peer review. The definitive publisher-authenticated version:Anna Oscarsson Tibblin, Anil Gupta, Mats Fredrikson, Johannes Järhult, Matti Nyström, Eva Pettersson, Bijan Darvish, Helena Krook, Eva Swahn and Christina Eintrei, To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial, 2010, British Journal of Anaesthesia, (104), 3, 305-312.is available online at: http://dx.doi.org/doi:10.1093/bja/aeq003Copyright: Oxford University Presshttp://www.oxfordjournals.org