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Background Prolonging effects of adjuncts to local anaesthetics in peripheral nerve blocks have been demonstrated in randomised clinical trials. The chosen primary outcome and anticipated effect size have major impact on the clinical relevance of results in these trials. This scoping review aims to provide an overview of frequently used outcomes and anticipated effect sizes in randomised trials on peripheral nerve block adjuncts. Methods For our scoping review, we searched MEDLINE, Embase and CENTRAL for trials assessing effects of adjuncts for peripheral nerve blocks published in 10 major anaesthesia journals. We included randomised clinical trials assessing adjuncts for single-shot ultrasound-guided peripheral nerve blocks, regardless of the type of interventional adjunct and control group, local anaesthetic used and anatomical localization. Our primary outcome was the choice of primary outcomes and corresponding anticipated effect size used for sample size estimation. Secondary outcomes were assessor of primary outcomes, the reporting of sample size calculations and statistically significant and non-significant results related to the anticipated effect sizes. Results Of 11,854 screened trials, we included 59. The most frequent primary outcome was duration of analgesia (35/59 trials, 59%) with absolute and relative median (interquartile range) anticipated effect sizes for adjunct versus placebo/no adjunct: 240 min (180–318) and 30% (25–40) and for adjunct versus active comparator: 210 min (180–308) and 17% (15–28). Adequate sample size calculations were reported in 78% of trials. Statistically significant results were reported for primary outcomes in 45/59 trials (76%), of which 22% did not reach the anticipated effect size. Conclusion The reported outcomes and associated anticipated effect sizes can be used in future trials on adjuncts for peripheral nerve blocks to increase methodological homogeneity., Background: Prolonging effects of adjuncts to local anaesthetics in peripheral nerve blocks have been demonstrated in randomised clinical trials. The chosen primary outcome and anticipated effect size have major impact on the clinical relevance of results in these trials. This scoping review aims to provide an overview of frequently used outcomes and anticipated effect sizes in randomised trials on peripheral nerve block adjuncts. Methods: For our scoping review, we searched MEDLINE, Embase and CENTRAL for trials assessing effects of adjuncts for peripheral nerve blocks published in 10 major anaesthesia journals. We included randomised clinical trials assessing adjuncts for single-shot ultrasound-guided peripheral nerve blocks, regardless of the type of interventional adjunct and control group, local anaesthetic used and anatomical localization. Our primary outcome was the choice of primary outcomes and corresponding anticipated effect size used for sample size estimation. Secondary outcomes were assessor of primary outcomes, the reporting of sample size calculations and statistically significant and non-significant results related to the anticipated effect sizes. Results: Of 11,854 screened trials, we included 59. The most frequent primary outcome was duration of analgesia (35/59 trials, 59%) with absolute and relative median (interquartile range) anticipated effect sizes for adjunct versus placebo/no adjunct: 240 min (180–318) and 30% (25–40) and for adjunct versus active comparator: 210 min (180–308) and 17% (15–28). Adequate sample size calculations were reported in 78% of trials. Statistically significant results were reported for primary outcomes in 45/59 trials (76%), of which 22% did not reach the anticipated effect size. Conclusion: The reported outcomes and associated anticipated effect sizes can be used in future trials on adjuncts for peripheral nerve blocks to increase methodological homogeneity.

Background: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment. Methods: Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant). Conclusion: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care.

BACKGROUND: Managing postoperative pain while minimizing opioid-related adverse drug events (ORADEs) remains a significant challenge. The OPI•AID Zone Tool is proposed as a novel clinical decision support tool that - both graphically and in a scoring-system - represents the relationship between pain management and the occurrence of ORADEs, aiming to enhance patient outcomes in postoperative care. The OPI•AID Zone Tool places pain score on the x-axis and an ORADE score on the y-axis, and stratifies patients into five zones to reflect the composite impact of pain severity and ORADEs on the quality of postoperative patient care. The study will have two key aims: (1) to explore whether the OPI•AID Zone Tool can function as a composite outcome measure for postoperative pain and ORADEs, and (2) to evaluate the use of the OPI•AID Zone Tool in visual presentations and for evaluation of patients' postoperative pain management quality.METHODS: This prospective observational cohort study will include 200 adults undergoing various surgical procedures in general anesthesia with a subsequent stay in the post-anesthesia care unit (PACU) at Bispebjerg Hospital, Denmark. Substudy 1 primary outcome: To assess whether a zone score in the OPI•AID Zone Tool is associated with patient-perceived health (EQ VAS), quality of recovery (QoR-PACU), and time to discharge readiness in PACU, and if the zone score has a stronger association than pain and ORADE score in themselves. Substudy 2 primary outcome: To assess how the use of intraoperative non-opioid analgesics impact where patients are placed in the OPI•AID Zone Tool's XY scatterplot right after surgery. To assess if patients who receive more comprehensive non-opioid analgesic basic regimens, generally fall into lower zones.CONCLUSION: The OPI•AID Zone Tool could potentially be a valuable clinical decision-making tool for optimizing postoperative care by simultaneously addressing pain management and the risk of ORADEs. By

Background Morphine-sparing effects are often used to evaluate non-opioid analgesic interventions. The exact effect that would warrant the implementation of these interventions in clinical practice (a minimally important difference) remains unclear. We aimed to determine this with anchor-based methods. Methods This was a post hoc analysis of three studies investigating pain management after hip or knee arthroplasty (PANSAID [NCT02571361], DEX-2-TKA [NCT03506789] and Pain Map [NCT02340052]). The overall population was median aged 70, median ASA 2, 54% female. We examined the correlation between 0 and 24 h postoperative iv morphine equivalent consumption and the severity of nausea, vomiting, sedation and dizziness. The anchor was different severity degrees of these opioid-related adverse events. The primary outcome was the difference in morphine consumption between patients experiencing no versus only mild events. Secondary outcomes included the difference in morphine consumption between patients with mild versus moderate and moderate versus severe events. We used Hodges–Lehmann median differences, exact Wilcoxon–Mann–Whitney tests and quantile regression. Results The difference in iv morphine consumption was 6 mg (95% confidence interval: 4–8) between patients with no versus only mild events, 5 mg (2–8) between patients with mild versus moderate events and 0 mg (−4 to 4) between patients with moderate versus severe events. Conclusions In populations comparable to this post-hoc analysis (orthopaedic surgery, median age 70 and ASA 2), we suggest a minimally important difference of 5 mg for 0–24 h postoperative iv morphine consumption., BACKGROUND: Morphine-sparing effects are often used to evaluate non-opioid analgesic interventions. The exact effect that would warrant the implementation of these interventions in clinical practice (a minimally important difference) remains unclear. We aimed to determine this with anchor-based methods.METHODS: This was a post hoc analysis of three studies investigating pain management after hip or knee arthroplasty (PANSAID [NCT02571361], DEX-2-TKA [NCT03506789] and Pain Map [NCT02340052]). The overall population was median aged 70, median ASA 2, 54% female. We examined the correlation between 0 and 24 h postoperative iv morphine equivalent consumption and the severity of nausea, vomiting, sedation and dizziness. The anchor was different severity degrees of these opioid-related adverse events. The primary outcome was the difference in morphine consumption between patients experiencing no versus only mild events. Secondary outcomes included the difference in morphine consumption between patients with mild versus moderate and moderate versus severe events. We used Hodges-Lehmann median differences, exact Wilcoxon-Mann-Whitney tests and quantile regression.RESULTS: The difference in iv morphine consumption was 6 mg (95% confidence interval: 4-8) between patients with no versus only mild events, 5 mg (2-8) between patients with mild versus moderate events and 0 mg (-4 to 4) between patients with moderate versus severe events.CONCLUSIONS: In populations comparable to this post-hoc analysis (orthopaedic surgery, median age 70 and ASA 2), we suggest a minimally important difference of 5 mg for 0-24 h postoperative iv morphine consumption.

Background: The leading principle in peri-operative pain management is multimodal analgesia, which reduces opioid requirements and associated adverse effects. Pragmatic pain trials should optimally test interventions in addition to multimodal non-opioid analgesics and interventions to ensure clinical relevance and baseline levels of opioid consumption that reflect clinical settings. We aimed to investigate opioid consumption and use of non-opioid analgesics administered adjunct to interventions in post-operative pain trials after total hip and knee arthroplasty. Methods: A systematic literature search was conducted 7 January 2020 in The Cochrane Library's CENTRAL, PubMed, and EMBASE. Trials investigating analgesic interventions for post-operative pain in adults undergoing total hip or knee arthroplasty were included. The primary outcome was the aggregated median 0–24 h post-operative opioid consumption. Further, we assessed the use of paracetamol, non-steroidal anti-inflammatory drugs, gabapentinoids, high-dose glucocorticoids, local infiltration analgesia and nerve blocks administered as co-interventions equally to all participants. We assessed trends over time for all outcomes. Results: Of 14,200 records, 570 trials were included. Median 0–24 h opioid consumption was 21 and 22 mg iv morphine equivalents in hip and knee arthroplasty trials, respectively. Meta-regression showed no overall linear correlation between opioid consumption and publication year. The use of multimodal non-opioid analgesia increased over time, though only 48% of trials published from 2010 to 2020 administered two or more non-opioid analgesics. Applying more non-opioid analgesics was associated with lower opioid consumption in intervention groups. Conclusion: Post-operative 0–24 h morphine consumption was median 21–22 mg. The demonstrated differences in non-opioid multimodal analgesic regimens between research and clinical settings, can potentially diminish the demonstrated opioid-sparing

Background: The patient-relevant minimal important difference for opioid consumption remains undetermined, despite its frequent use as primary outcome in trials on postoperative pain management. A minimal important difference is necessary to evaluate whether significant trial results are clinically relevant. Further, it can be used as effect size to ensure that trials are powered to find clinically relevant effects. By exploring the dose–response relationship between postoperative opioid consumption and opioid-related adverse effects, we aim to approximate the minimal important difference in opioid consumption anchored to opioid-related adverse effects. Methods: This is a post-hoc analysis of aggregated data from two clinical trials (PANSAID NCT02571361 and DEX2TKA NCT03506789) and one observational cohort study (Pain Map NCT02340052) on pain management after total hip and knee arthroplasty. The primary outcome is the Hodges–Lehmann median difference in opioid consumption between patients with no opioid-related adverse effects and patients experiencing the mildest degree of one or more opioid-related adverse effects (i.e., mild nausea, sedation and/or dizziness or vomiting). Secondary outcomes include the Hodges–Lehmann median difference in opioid consumption that corresponds to one point on a cumulated opioid-related adverse event 0–10 scale. Further, we will explore the proportion of patients that experience opioid-related adverse effects for consecutive opioid dose intervals of 2 mg iv morphine equivalents. Quantile regression will be used to assess any significant interactions with patient baseline characteristics. Conclusions: This study will hopefully bring us one step closer to determining relevant opioid reductions and thereby improve our understanding of intervention effects and planning of future trials.

Background: New-onset atrial fibrillation (NOAF) is common in hospitalised patients with critical illness and associated with worse outcomes. Several interventions are available in the management of NOAF, but the overall effectiveness and safety of these interventions compared with placebo or no treatment are unknown. Methods: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials (RCT) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses, the Cochrane Collaboration, and Grading of Recommendations Assessment, Development and Evaluation statements. We searched RCTs assessing any pharmacological and non-pharmacological treatment compared with placebo or no treatment in critically ill hospitalised patients with NOAF. The primary outcomes were all-cause mortality, adverse events, and health-related quality of life. Results: We included 16 trials (n = 1891) evaluating seven interventions. All trials were adjudicated ‘some concerns’ or ‘high risk’ of bias. The evidence is very uncertain for mortality (RR 0.53, 95% CI 0.03–8.30), adverse events (RR 1.28, 95% CI 0.85–1.92), and treatment efficacy i.e. rhythm control (RR 1.54, 95% CI 1.20–1.97; TSA-adjusted CI 0.56–4.53) between pharmacological treatment and placebo/no treatment (very low certainty evidence). There were no data for health-related quality of life or most of our secondary outcomes. Conclusions: The existing data are insufficient to firmly conclude on effects of any intervention against NOAF on any outcome in hospitalised patients with critical illness. Randomised trials of the most frequently used interventions against NOAF are warranted in these patients.

A man in his mid-30s was admitted with a thunderclap headache. He was conscious and hypertensive. A decade earlier, severe hypertension had been diagnosed and extensively investigated without revealing an underlying cause. Brain imaging showed subarachnoid haemorrhage caused by a ruptured pericallosal aneurysm. Endovascular occlusion was attempted, but as the sheath could not pass the aortic arch, it was converted to surgical aneurismal clipping. Intraoperative blood pressure measurement revealed a peak-to-peak gradient of 100 mm Hg across the aortic arch and an ankle/brachial index of 0.46 (normal range 0.9-1.2). Aortic coarctation was suspected, and angiographic imaging and echocardiography confirmed the diagnosis. Subacute direct stenting was performed, which normalised the peak-to-peak gradient and ankle/brachial index. To minimise the risk of severe complications, early diagnosis of aortic coarctation is important and can be facilitated by ankle/brachial index and echocardiography in the suprasternal view.

Background: The Consolidated Standards of Reporting Trials (CONSORT) statement aims to improve transparent reporting of randomised clinical trials. It comprises a participant flow diagram with the reporting of essential numbers for enrolment, allocation and analyses. We aimed to quantify the use of participant flow diagrams in randomised clinical trials on postoperative pain management after total hip and knee arthroplasty. Methods: We searched PubMed, Embase and CENTRAL up till January 2020. The primary outcome was the proportion of trials with adequate reporting of participant flow diagrams, defined as reporting of number of participants screened for eligibility, randomised and included in the primary analysis. Secondary outcomes were recruitment (randomised:screened) and retention (analysed:randomised) rates, reporting of a statistical strategy, reasons for exclusion from the primary analysis and handling of missing outcome data. Trends over time were assessed with statistical process control. Results: Of the 570 included trials, we found adequate reporting in 240 (42%). Reporting with participant flow diagram increased significantly over time. Median recruitment was 73% (IQR 44–91%), and retention was 97% (IQR 93–100%). These rates did not change over time. Trials with adequate reporting of participant flow were more likely to report a statistical strategy (41% vs 8%), reasons for post-randomisation exclusions (100% vs 55%) and handling of missing outcome data (14% vs 6%). Conclusions: Adherence to participant flow diagrams for RCTs has increased significantly over time. Still, there is room for improvement of adequate reporting of flow diagrams, to increase transparency of trials details.

Background: Sample size determination is essential for reliable hypothesis testing in clinical trials and should rely on adequate sample size calculations with alpha, beta, variance, and an effect size being the minimal clinically important difference (MCID). This facilitates interpretation of the clinical relevance of statistically significant results. No gold standard for MCIDs exists in postoperative pain research. Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for English language articles on randomised trials investigating analgesic interventions after total hip or knee arthroplasty. Primary outcomes were the reported MCIDs for pain score and cumulated rescue opioid consumption. Secondary outcomes included reported sample size calculations and propensity to report statistical significance without reaching MCID. Trend analyses were conducted using statistical process control. Results: We included 570 trials. Median MCID for 0-24 h opioid consumption was 10 mg i.v. morphine equivalents for absolute reductions (interquartile range [IQR]: 6.8-14.5) and relative 40% (IQR: 30–50%). Median MCIDs for pain scores were absolute 15 mm at rest (IQR: 10–20) and 18 mm during movement (IQR: 10–20) on a 0–100 mm VAS and relative 30% (IQR: 20–30%). No trends were demonstrated for MCIDs. Adequate sample size calculations were reported in 34% of trials. In 46% of trials with statistically significant primary outcomes, the differences did not reach the predetermined MCID. Conclusions: We provide clinician-perceived MCID estimates for rescue opioid consumption and pain scores that can be used for sample size calculations until reliable evidence-based patient-rated MCIDs emerge. Nearly half of the trials with significant findings did not reach the predetermined MCID.

Background The external validity of randomized controlled trials (RCTs) is critical for the relevance of trial results in a clinical setting. We aimed to assess the external validity of RCTs investigating postoperative pain treatment after total hip and knee arthroplasty (THA and TKA) by comparing patient characteristics in these trials with a clinical cohort. Further, we assessed the use of exclusion criteria of the included RCTs. Methods We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant RCTs up to June 2019. Data on patient characteristics from this research population were compared with an unselected clinical cohort from the Danish Hip and Knee Arthroplasty Registries in the period 2005-2019. Trends in patient characteristics and the use of exclusion criteria were assessed with control charts. Results In total, 550 RCTs with 48 962 participants were included in the research cohort. The clinical cohort included 101 439 THA patients and 90 505 TKA patients. Patient characteristics (age, body mass index (BMI), American Society of Anesthesiologists (ASA) score and sex distribution) in the research cohort resembled those of the clinical cohort. Age, BMI and ASA scores did not change over time in the research cohort. In the clinical cohort, age increased among both THA and TKA patients, and BMI and ASA scores increased among TKA patients. Most commonly used exclusion criteria in the RCTs were high ASA score (62%), older age (45%), obesity (32%) and chronic opioid use (41%). Exclusion of chronic opioid users and individuals with obesity increased over time. Conclusion Patient characteristics in research trials investigating postoperative pain management after THA and TKA currently resemble those of a clinical cohort. However, individuals in the clinical cohort are getting older, and TKA patients more obese with increasing ASA scores. Concomitantly, RCTs increase the tendency to exclude patients with older age, obesity, chroni

INTRODUCTION: The aim of this systematic review was to document efficacy, safety and quality of evidence of analgesic interventions after total knee arthroplasty (TKA).METHODS: This PRISMA-compliant and PROSPERO-registered review includes all-language randomized controlled trials of medication-based analgesic interventions after TKA. Bias was evaluated according to Cochrane methodology. Outcomes were opioid consumption (primary), pain scores at rest and during mobilization, adverse events, and length of stay. Interventions investigated in three or more trials were meta-analysed. Outcomes were evaluated using forest plots, Grading of Recommendations Assessment, Development and Evaluation (GRADE), L'Abbe Plots and trial sequential analysis.RESULTS: The included 113 trials, investigating 37 different analgesic interventions, were characterized by unclear/high risk of bias, low assay sensitivity and considerable differences in pain assessment tools, basic analgesic regimens, and reporting of adverse events. In meta-analyses single and continuous femoral nerve block (FNB), intrathecal morphine, local infiltration analgesia, intraarticular injection of local anaesthetics, non-steroidal anti-inflammatory drugs, and gabapentinoids demonstrated significant analgesic effects. The 24-hour morphine-sparing effects ranged from 4.2 mg (CI: 1.3, 7.2; intraarticular local anaesthetics), to 16.6 mg (CI: 11.2, 22; single FNB). Pain relieving effects at rest at 6 hours ranged from 4 mm (CI: -10, 2; gabapentinoids), to 19 mm (CI: 8, 31; single FNB), and at 24 hours from 3 mm (CI: -2, 8; gabapentinoids), to 16 mm (CI: 8, 23; continuous FNB). GRADE-rated quality of evidence was generally low.CONCLUSION: A low quality of evidence, small sample sizes and heterogeneity of trial designs prohibit designation of an optimal procedure-specific analgesic regimen after TKA.