In vitro work suggests that IL-10 plays a pivotal role in controlling the balance of pro- and anti-inflammatory cytokines and monocyte HLA-DR expression. In 20 patients undergoing cardiac surgery, we investigated elaboration of interleukin 10 (IL-10) and its relationship to pro- and anti-inflammatory cytokines and leucocyte expression of HLA-DR and adhesion molecules. There were small increases in pro-inflammatory cytokines (IL-1, IL-8 and tumour necrosis factor (TNF) after induction, returning to baseline on induction of cardiopulmonary bypass (CPB). After CPB another transient increase in IL-8 occurred (P < 0.05). The anti-inflammatory response began with elevated IL-10 during CPB (P < 0.001), which peaked early in recovery (P < 0.001), by which time IL-1 receptor antagonist (IL-1ra) and the TNF soluble receptors (TNFsr) had also increased (P < 0.01). The next day IL-10 and IL-1ra were decreasing but TNFsr continued to increase. Induction of anaesthesia caused HLA-DR downregulation. The IL-10 peak was associated with further monocyte HLA-DR downregulation (P < 0.001) and return towards baseline of granulocyte adhesion molecule expression which transiently increased during CPB (P < 0.001). To determine which aspects of the immune response arose from the interaction of blood with the CPB apparatus, the above variables were studied within an isolated CPB circuit and the influence of fentanyl on the magnitude of any such changes determined. Five healthy volunteers donated two, 250-ml samples of blood to which was added either fentanyl 175 micrograms with heparin 1050 u. or heparin alone 1050 u. These were used to prime two identical isolated CPB circuits and circulation was conducted under identical conditions for 90 min. Of the pro-inflammatory cytokines, only IL-8 was elevated at 90 min CPB (P < 0.05). There was no increase in anti-inflammatory cytokines and TNFsr decreased (P < 0.001). Granulocyte adhesion molecules were increased during CPB. In the fentanyl group, the CD11b increase was greater and preceded CPB. The reduction in lymphocyte HLA-DR expression, observed throughout the study period (P < 0.01), was greater with fentanyl (P < 0.05). Monocyte HLA-DR expression increased (P < 0.05), but to a lesser extent with fentanyl (P > 0.05). In contrast with the in vivo response where there was a phased anti-inflammatory response beginning with IL-10, in the isolated CPB model no anti-inflammatory cytokine response occurred.

BackgroundClinical trials have not yet compared the efficacy of capsaicin 8% patch with current standard therapy in peripheral neuropathic pain (PNP).ObjectivesHead‐to‐head efficacy and safety trial comparing the capsaicin patch with pregabalin in PNP.MethodsOpen‐label, randomized, multicentre, non‐inferiority trial. Patients with PNP, aged 18–80 years, were randomly assigned to either the capsaicin 8% patch (n = 282) or an optimised dose of oral pregabalin (n = 277), and assessed for a ≥30% mean decrease in Numeric Pain Rating Scale (NPRS) score from baseline to Week 8. Secondary endpoints included optimal therapeutic effect (OTE), time‐to‐onset of pain relief and treatment satisfaction.ResultsThe capsaicin 8% patch was non‐inferior to pregabalin in achievement of a ≥30% mean decrease in NPRS score from baseline to Week 8 (55.7% vs. 54.5%, respectively; Odds ratio: 1.03 [95% CI: 0.72, 1.50]). The proportion of patients achieving OTE at Week 8 was 52.1% for the capsaicin 8% patch versus 44.8% for pregabalin (difference: 7.3%; 95% CI: −0.9%, 15.6%). The median time‐to‐onset of pain relief was significantly shorter for capsaicin 8% patch versus pregabalin (7.5 vs. 36.0 days; Hazard ratio: 1.68 [95% CI: 1.35, 2.08]; p < 0.0001). Treatment satisfaction was also significantly greater with the capsaicin 8% patch versus pregabalin. TEAEs were mild‐to‐moderate in severity, and resulted in treatment discontinuation only with pregabalin (n = 24). Systemic adverse drug reactions ranged from 0 to 1.1% with capsaicin 8% patch and 2.5 to 18.4% with pregabalin.ConclusionsThe capsaicin 8% patch provided non‐inferior pain relief to an optimized dose of pregabalin in PNP, with a faster onset of action, fewer systemic side effects and greater treatment satisfaction.

Summary ihirgrd anions such as heparin. Neutrophil actirity is generally depressed by intravenous unaesthetic induction agents, hut is enhanced by 0pioid.y. Natural killer cell activity, which is invohed in immunity against tuniour cells and iGrully infbcted cells is transientlr depressed by volatile anaesthetic agents and opioids. In contrast catecholamines enhance natural killer cell activity. Whereas drcrease in inimunoglobulin levels occur peri-operaticely, this is not thought to be us a result of drugs at clinicully used concentratiows but rather due to haemodilution. Key wordsIniniune responsc .The possible effects of anaesthesia on the immune system have been discussed from as early as 1916 [I]. This review discusses how drugs commonly used in anaesthesia and intensive care may modulate immunological parameters and looks beyond currently published work to those areas likely to be of clinical importance in the near future. Excellent guidance on basic imniunopharmacology may be found in several specialist tests, for instance Dale, Foreman and Young, Trsthook of Init~iirnopharnir~cology (Blackwell Scientific Publications) [2]. Basic structure of the immune system Innutr und adaptii~e initnunit! (Fig. I )Any immune response involves recognition of an infectious agent or other foreign material and the resulting reaction against it to remove it. The natural or innate response is rapid. non-specific for the antigen and does not improve upon repeated exposure. In contrast, the adaptive response is highly specific for a particular antigen and improves upon successive exposure to that antigen, constituting a memory mechanism which protects against future encounters with the antigen. Innate immune responses are mediated by natural killer (NK) cells and phagocytic cells such as monocytes, macrophages and polymorphonuclear neutrophils which use primitive nonspecific recognition systems to bind micro-organisms, then neutralise and destroy them. Lymphocytes are central to all adaptive immune responses, specifically recognising the antigen and initiating the response to it. B-lymphocytes release antibody which specifically recognises and binds to extracellular pathogens and their products (humoral immune response). T-lymphocytes are composed of subsets termed T-helper 1 ( T H~) , The effects of opioids on NK cell activity is controversial, and depends on the experimental system studied. It has been postulated that natural killer cells have opioid receptors and it is thought that through this mechanism 8-endorphin in vitro can augment the cytolytic activity of natural killer cells-an effect which can be blocked by naloxone [5, 61. In a rat model, stress-induced endorphins were found to have an inhibitory effect on natural killer cell activity, an effect which could be mimicked by high-dose morphine and blocked by naloxone [7]. In a preliminary report, anaesthesia in patients using a high-dose fentanyl technique led to a depression in natural killer activity lasting for 3 days. This effect could be reversed in vitro by add...

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Acute kidney injury (AKI) following cardiac surgery significantly increases morbidity and mortality risks. Improving existing clinical methods of identifying patients at risk of perioperative AKI may advance management and treatment options. This study investigated whether a combination of biomarkers and clinical factors pre and post cardiac surgery could stratify patients at risk of developing AKI. Patients (n = 401) consecutively scheduled for elective cardiac surgery were prospectively studied. Clinical data was recorded and blood samples were tested for 31 biomarkers. Areas under receiver operating characteristic (AUROCs) were generated for biomarkers pre and postoperatively to stratify patients at risk of AKI. Preoperatively sTNFR1 had the highest predictive ability to identify risk of developing AKI postoperatively (AUROC 0.748). Postoperatively a combination of H-FABP, midkine and sTNFR2 had the highest predictive ability to identify AKI risk (AUROC 0.836). Preoperative clinical risk factors included patient age, body mass index and diabetes. Perioperative factors included cardio pulmonary bypass, cross-clamp and operation times, intra-aortic balloon pump, blood products and resternotomy. Combining biomarker risk score (BRS) with clinical risk score (CRS) enabled pre and postoperative assignment of patients to AKI risk categories. Combining BRS with CRS will allow better management of cardiac patients at risk of developing AKI.