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Postoperative pain management in opioid users remains challenging. The perioperative administration of ketamine might lead to favourable pain outcomes in these patients. A systematic review of randomised controlled trials (RCT) with meta-analysis and assessment of the quality of evidence by GRADE was performed. Perioperative pain treatment. Adult opioid users undergoing surgery. Perioperative administration of ketamine. Primary outcomes were postoperative acute pain at rest/during movement after 24 h and number of patients with ketamine-related adverse events. Nine RCTs (802 patients with at least two weeks opioid-intake) were included. There is low-quality evidence that ketamine may slightly reduce postoperative pain during movement after 24 h (mean difference: −0.79; 95% confidence interval (CI): −1.22 to −0.36). Based on a very low-quality of evidence, we are uncertain on any effect of ketamine on pain at rest after 24 h and incidences of adverse events like hallucinations and confusion within 48 h. However, perioperative ketamine reduced cumulative mean opioid consumption by 97.3 mg (95%CI: −164.8 to −29.7) after 24 h and 186.4 mg (95%CI: −347.6 to −25.2) after 48 h. The relative risks (RR) for opioid-related adverse events were significantly different for sedation within 24 h (RR: 0.54; 95%CI 0.37 to 0.78). There is currently limited evidence for a reduced postoperative pain intensity using perioperative ketamine in preoperative opioid-consuming patients. However, a clinically relevant opioid-sparing effect was evident associated with a reduced risk for postoperative sedation and without increased harm. Therefore, ketamine might be a useful anti-hyperalgesic adjuvant in these patients. Nevertheless, with clinical heterogeneity being considerable, it's too premature to suggest any specific ketamine protocol. Furthermore, many questions (like ideal dosing, treatment duration and more favourable patient-related outcome measures including long-term effects) remain open and need to be addressed in future studies. Prospero CRD42020185497. •Perioperative ketamine might be a useful anti-hyperalgesic adjuvant in opioid users.•A decrease of morphine consumption rather than of pain intensity was observed.•Questions like ideal dosing remain open.

Background Cardiopulmonary bypass (CPB) triggers marked cytokine release often followed by a systemic inflammatory response syndrome, associated with adverse postoperative outcomes. This trial investigates the intraoperative use of haemoadsorption (HA) during cardiac surgery with CPB to assess its impact on postoperative systemic inflammatory response. Methods In this prospective randomised controlled trial (ethics approval no. 5094-14DRKS00007928), patients (> 65 years) undergoing elective on-pump cardiac surgery were randomised to intraoperative HA (CytoSorb) during CPB or standard care without HA. Primary outcome was the difference in mean interleukin (IL)-6 serum concentrations between groups on intensive care unit (ICU) admission. The secondary outcomes included various clinical and biochemical endpoints. Statistical methods included paired and unpaired t-tests, Wilcoxon, Mann–Whitney U-tests, and chi-square tests. Results Thirty-eight patients were allocated to receive either intraoperative HA (n = 19) or standard care (n = 19). The primary outcome, IL-6 levels on ICU admission, did not differ between the study group and controls (214.4 ± 328.8 vs. 155.8 ± 159.6 pg/ml, p  = 0.511). During surgery pre- versus post-adsorber IL-2, IL-6, IL-8, IL-10, heparan sulfate and myoglobin post- levels were reduced. Furthermore, IL-6 levels did not differ between the study groups on day 1 and 2 in the ICU. While sequential organ failure assessment scores, lactate levels, and C-reactive protein and procalcitonin (PCT) showed no statistically significant differences. Regarding haemodynamic stability in the treatment group the cardiac index (3.2 ± 0.7 vs. 2.47 ± 0.47 l/min/m 2 , p  = 0.012) on ICU day 2 increased, and lower fluid requirements as well as decreased fibrinogen requirement were observed. Need for renal replacement therapy did not differ though a shorter duration was observed in the treatment group. Time on ventilator, respiratory parameters, infectious complications, delirium scores, ICU and hospital lengths of stay, and mortality did not differ between groups. Conclusion HA did not reduce the IL-6 level on ICU admission or afterwards. Even though HA reduced cytokine load during cardiac surgery in the treatment group. There were no significant differences between groups in the postoperative course of other cytokine concentrations, organ dysfunction, ICU and hospital lengths of stay and mortality rates. Trial registration prospectively DRKS00007928 and published under: Baumann A, Buchwald D, Annecke T, Hellmich M, Zahn PK, Hohn A. RECCAS - REmoval of Cytokines during Cardiac Surgery: study protocol for a randomised controlled trial. Trials. 2016;17: 137. Graphical abstract

Current literature is in disagreement regarding female sex as a risk factor for pain after surgery. We hypothesized, that sex differences exist but that they are influenced by certain factors. Here, we investigated the influence of sex for different clinically relevant postoperative pain (POP) outcome parameters and evaluated the role of assumed confounders for sex differences. From 1372 screened patients undergoing orthopedic surgery at the university hospital of Muenster between March 2010 and June 2011, 890 patients were included. The validated International Pain Outcomes questionnaire was used to assess the role of sex for several aspects of POP including pain severity, physical and emotional functional interference as well as the patient's perceptions of the care they received on the first day after surgery. Assessed confounders were age, preoperative chronic pain, anesthetic technique employed and surgical procedure. All statistical analyses were performed with SPSS Statistics Software 22. Linear regression analysis demonstrated that sex was a statistically significant risk factor for \"worst pain since surgery\". Additionally, significant sex differences in \"time spent in severe pain\", \"feeling anxious due to pain\", \"feeling helpless due to pain\" and \"opioid consumption since surgery\" could be identified. An univariate general linear model showed that \"age\" and \"preoperative pain\" were significant confounders for sex differences. Further descriptive subgroup analysis revealed consistent sex differences for several POP outcome variables especially in patients older than 50 years or patients with preoperative chronic pain. However, sex differences disappeared in younger patients and in patients without preoperative pain. Our data confirmed that sex differences exist in pain intensity and frequency, pain interference with feelings and opioid consumption during the first 24 hours postoperatively. However, sex differences were significantly influenced by the factors \"age\" and \"preoperative pain\". These findings may in part explain why clinical studies get different results related to sex differences and renders specific awareness in older women and female patients with preoperative chronic pain.

[...]the REMOVE trial enrolled patients with infective endocarditis and a high inflammatory burden, whereas SIRAKI02 targeted on individuals with lower preoperative risk profiles. [...]one patient was excluded post-randomisation due to a protocol violation unrelated to HA intervention [4], without compromising the intention-to-treat (ITT) principle. The inflammatory response following cardiac surgery is multifactorial, involving ischaemia-reperfusion, inflammation, oxidative stress, haemolysis, and nephrotoxins. [...]drawing the conclusion that the trials differences in renal outcomes are primarily explained by the elimination of endotoxins may be speculative [1]. Refinement of trial methodologies, expansion of biomarker analysis, and adoption of patient-centred strategies — including optimisation of timing, dosage, duration, and patient selection algorithms—will be crucial to realise the full clinical potential of HA.

Selective-serotonin-noradrenaline-reuptake inhibitors (SSNRI) might be an interesting option for postoperative pain treatment. Objective was to investigate postoperative pain outcomes of perioperative SSNRI compared to placebo or other additives in adults undergoing surgery. Systematic review of randomised controlled trials (RCT) with meta-analysis and GRADE assessment. Acute and chronic postoperative pain treatment. Adult patients undergoing surgery. Perioperative administration of SSNRI. Primary outcomes were postoperative acute pain at rest/during movement (measured on a scale from 0 to 10), number of patients with chronic postsurgical pain (CPSP) and with SSNRI-related adverse events. Fourteen RCTs (908 patients) were included. We have high-quality evidence that duloxetine has no effect on pain at rest at 2 h (MD: −0.02; 95% confidence interval (CI) −0.51 to 0.47), but probably reduces it at 48 h (MD: −1.16; 95%CI −1.78 to −0.54). There is low- and moderate-quality evidence that duloxetine has no effects on pain during movement at 2 h (MD: −0.42; 95%CI −1.53 to 0.69) and 48 h (MD: −0.91; 95% CI −2.08 to 0.26), respectively. We have very low-quality evidence that duloxetine might reduce pain at rest (MD: −0.45; 95%CI −0.74 to −0.15) and movement (MD: −1.19; 95%CI −2.32 to −0.06) after 24 h. We have low-quality evidence that duloxetine may reduce the risk of CPSP at 6 months (RR:0.35; 95%CI 0.14 to 0.90). There is moderate-quality evidence that duloxetine increases the risk of dizziness (RR:1.72; 95%CI 1.26 to 2.34). At the expense of a higher risk for dizziness, SSNRI may be effective in reducing postoperative pain between 24 and 48 h after surgery. However, the results of the meta-analyses are mostly imprecise and duloxetine might only be used in individual cases. Protocol registration: CRD42018094699 •Perioperative duloxetine might reduce postoperative pain after 24 and 48 h, but not after 2 h.•Perioperative duloxetine may reduce the risk of CPSP 6 months after surgery.•However, duloxetine increases the risk of dizziness.

During the current debate about benefits of opioid-sparing anesthesia, any reduction of opioid-related side effects, which are associated with increased costs, length of hospital stay and even mortality,3 might be considered a relevant result that matters to our patients.2 Hussain et al reported that postoperative pain intensities at rest were significantly lower in the ESP group; this difference was clinically relevant until 6 hours after surgery, which reflects the duration of action of long-lasting local anesthetics used.1 Although we agree that this effect is short lasting, it shows in principle the efficacy of the block; we think it would have been appropriate to discuss these findings or to take it into account in the final appraisal.1 Future studies need to assess prolonged and therefore more clinically relevant efficacy with an additive/adjuvant or as catheter technique. [...]Hussain et al used a trial sequential analysis (TSA) to confirm adequacy of sample size and reliability of conclusions from the estimates of effects, but they did not consider the studies’ risk of bias.1 Nine out of 12 trials were rated as high-risk trials.1 A risk of systematic error (bias) in the included trials is a frequent cause of overestimation of benefit and underestimation of harm. [...]it is recommended that a TSA should only be performed using trials with low risk of bias.4 To conclude, the published meta-analysis of Hussain et al has distinct flaws with regard to content and methodology, as reported above. [...]its negative verdict on ESP blocks should be reconsidered.

It is known that the use of a cardiopulmonary bypass (CPB) during cardiac surgery leads to leukocyte activation and may, among other causes, induce organ dysfunction due to increased leukocyte recruitment into different organs. Leukocyte extravasation occurs in a cascade-like fashion, including capturing, rolling, adhesion, and transmigration. However, the molecular mechanisms of increased leukocyte recruitment caused by CPB are not known. This clinical study was undertaken in order to investigate which steps of the leukocyte recruitment cascade are affected by the systemic inflammation during CPB. We investigated the effects of CPB on the different steps of the leukocyte recruitment cascade in whole blood from healthy volunteers (n = 9) and patients undergoing cardiac surgery with the use of cardiopulmonary bypass (n = 7) or in off-pump coronary artery bypass-technique (OPCAB, n = 9) by using flow chamber experiments, transmigration assays, and biochemical analysis. CPB abrogated selectin-induced slow leukocyte rolling on E-selectin/ICAM-1 and P-selectin/ICAM-1. In contrast, chemokine-induced arrest and transmigration was significantly increased by CPB. Mechanistically, the abolishment of slow leukocyte rolling was due to disturbances in intracellular signaling with reduced phosphorylation of phospholipase C (PLC) γ2, Akt, and p38 MAP kinase. Furthermore, CPB induced an elevated transmigration which was caused by upregulation of Mac-1 on neutrophils. These data suggest that CPB abrogates selectin-mediated slow leukocyte rolling by disturbing intracellular signaling, but that the clinically observed increased leukocyte recruitment caused by CPB is due to increased chemokine-induced arrest and transmigration. A better understanding of the underlying molecular mechanisms causing systemic inflammation after CPB may aid in the development of new therapeutic approaches.

IntroductionEvidence synthesis of clinical trials requires consistent outcome assessment. For pain management after surgery, inconsistency of effectiveness assessment is still observed. A subproject of IMI-PainCare (Innovative Medicine Initiatives, www.imi-paincare.eu) aims for identifying core outcome domains and measurement instruments for postoperative pain in four surgical fields (sternotomy, breast cancer surgery, total knee arthroplasty, and surgery related to endometriosis) in order to harmonize outcome assessment for perioperative pain management.MethodsA multifaceted process will be performed according to existing guidelines (Core Outcome Measures in Effectiveness Trials (COMET), COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)). In a first step, outcome domains will be identified via systematic literature review and consented on during a 1-day consensus meeting by 10 stakeholder groups, including patient representatives, forming an IMI PROMPT consensus panel. In a second step, outcome measurement instruments regarding the beforehand consented core outcome domains and their psychometric properties will be searched for via systematic literature review and approved by COSMIN checklist for study quality and scale quality separately. In a three-step online survey, the IMI PROMPT consensus panel will vote for most suitable measurement instruments. The process is planned to be conducted between 11/2017 (systematic literature review on common outcome domains) and 3/2022 (final voting on core outcome measurement).

Background Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. Methods We have used a Shank2 −/− mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. Results We determined that Shank2 −/− mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2 −/− mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2 −/− mice. Limitations Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. Conclusion Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD.

Background In on-pump cardiac surgery, lungs are at high risk of periprocedural organ impairment because of atelectasis formation, ventilator-induced lung injury, and hyperinflammation due to the cardiopulmonary bypass which results in postoperative pulmonary complications in half of this patient population. The new ventilation mode flow-controlled ventilation (FCV) uniquely allows full control of ins- and expiratory airway flows. This approach reduces the mechanical power of invasive ventilation as a possible cause of ventilator-induced lung injury. The scope of FLOWVENTIN HEARTSURG is to compare perioperative individualized FCV with best clinical practice pressure-controlled ventilation (PVC) modes in patients with elective on-pump cardiac surgery procedures. We hypothesize that the postoperative inflammatory response can be reduced by the perioperative application of FCV compared to PCV. Methods FLOWVENTIN HEARTSURG is a single-center, randomized, parallel-group trial with two intervention arms: perioperative PCV modes ( n  = 70, PCV group) with an individualized positive end-expiratory pressure (PEEP) and a tidal volume of 6–8 ml/kg predicted bodyweight compared to perioperative FCV ( n  = 70, FCV group) with an individualized PEEP and driving pressure, resulting in a liberal tidal volume. As the primary study endpoint interleukin 8 plasma level is assessed 6 h after cardiopulmonary bypass as a surrogate biomarker of systemic and pulmonary inflammation. As secondary aims clinically relevant patient outcomes are analyzed, e.g., perioperative lung function regarding oxygenation indices, postoperative pulmonary and extra-pulmonary complications, SIRS-free days as well as ICU and total inpatient stays. As additional sub-studies with an exploratory approach perioperative right ventricular function parameters are assessed by echocardiography and perioperative lung aeration by electrical impedance tomography. Discussion Current paradigms regarding protective low tidal volume ventilation are consciously left in the FCV intervention group in order to reduce mechanical power as a determinant of ventilator-induced lung injury in this high-risk patient population and procedures. This approach will be compared in a randomized controlled trial with current best clinical practice PCV in FLOWVENTIN HEARTSURG. Trial registration German Clinical Trials Register DRKS00018956 . Registered on 12 June 2020 (Version 1), last update on 22 August 2022 (Version 4).