Combined Dexamethasone and Dexmedetomidine as Adjuncts to Popliteal and Saphenous Nerve Blocks in Patients Undergoing Surgery of the Foot or Ankle: A Randomized, Blinded, Placebo-controlled Clinical Trial.

BACKGROUND: Both dexamethasone and dexmedetomidine increase the duration of analgesia of peripheral nerve blocks. The authors hypothesized that combined intravenous dexamethasone and intravenous dexmedetomidine would result in a greater duration of analgesia when compared with intravenous dexamethasone alone and placebo. METHODS: The authors randomly allocated participants undergoing surgery of the foot or ankle under general anesthesia and with a combined popliteal (sciatic) and saphenous nerve block to a combination of 12 mg dexamethasone and 1 µg/kg dexmedetomidine, 12 mg dexamethasone, or placebo (saline). The primary outcome was the duration of analgesia measured as the time from block performance until the first sensation of pain in the surgical area as reported by the participant. The authors predefined a 33% difference in the duration of analgesia as clinically relevant. RESULTS: A total of 120 participants from two centers were randomized and 119 analyzed for the primary outcome. The median [interquartile range] duration of analgesia was 1,572 min [1,259 to 1,715] with combined dexamethasone and dexmedetomidine, 1,400 min [1,133 to 1,750] with dexamethasone alone, and 870 min [748 to 1,138] with placebo. Compared with placebo, the duration was greater with combined dexamethasone and dexmedetomidine (difference, 564 min; 98.33% CI, 301 to 794; P < 0.001) and with dexamethasone (difference, 489 min; 98.33% CI, 265 to 706; P < 0.001). The prolongations exceeded the authors' predefined clinically relevant difference. The duration was similar when combined dexamethasone and dexmedetomidine was compared with dexamethasone alone (difference, 61 min; 98.33% CI, -222 to 331; P = 0.614). CONCLUSIONS: Dexamethasone with or without dexmedetomidine increased the duration of analgesia in patients undergoing surgery of the foot or ankle with a popliteal (sciatic) and saphenous nerve block. Combined dexamethasone and dexmedetomidine did not increase the duration of analgesia when compared with dexamethasone.

Validation of PRE-DELIRIC and E-PRE-DELIRIC in a Danish population of intensive care unit patients-A prospective observational multicenter study.

BACKGROUND: Delirium is a clinical condition characterized by an acute change in brain function and is frequently observed in critically ill patients. The condition has been associated with negative outcomes, making it crucial to identify patients who are at risk. Two recent prediction models have been developed to estimate the risk of delirium in intensive care unit (ICU) patients; the prediction model for delirium (PRE-DELIRIC) and the early prediction model for delirium (E-PRE-DELIRIC). We aimed to perform an external validation of these models in a Danish cohort of critically ill patients. METHODS: We conducted a prospective, observational multicenter study to validate the PRE-DELIRIC and E-PRE-DELIRIC models in a population of patients admitted to four general ICUs in the Zealand Region of Denmark. From January 2022 to January 2023 all adult patients acutely admitted to the participating ICUs were assessed for eligibility. Patients had to be admitted to the ICU for >24 h to be included in the study. Included patients were screened with E-PRE-DELIRIC upon ICU admission and PRE-DELIRIC after 24 h of admission and followed throughout their ICU stay with CAM-ICU delirium assessments. Our primary outcomes were the prognostic accuracy measured by Area Under the Receiver Operating Characteristics (AUROC) and the calibration plot for the E-PRE-DELIRIC and PRE-DELIRIC prediction models. RESULTS: We included 660 patients, of whom 660 were assessed with E-PRE-DELIRIC, and 622 were assessed with PRE-DELIRIC. PRE-DELIRIC showed acceptable discrimination with AUROC of 0.70 (95% CI 0.66 to 0.74) and good calibration. E-PRE-DELIRIC had inadequate discrimination AUROC of 0.63 (95% CI 0.58 to 0.67) and poor calibration. CONCLUSION: In a Danish cohort, we found that the PRE-DELIRIC model demonstrated acceptable performance and E-PRE-DELIRIC demonstrated poor performance. In critically ill adult patients PRE-DELIRIC may be useful in identifying patients at high risk of delirium.

Primary outcomes and anticipated effect sizes in randomised clinical trials assessing adjuncts to peripheral nerve blocks: A scoping review.

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.

Real-world causal evidence for planned predictive enrichment in critical care trials: A scoping review.

BACKGROUND: Randomised clinical trials in critical care are prone to inconclusiveness due, in part, to undue optimism about effect sizes and suboptimal accounting for heterogeneous treatment effects. Although causal evidence from rich real-world critical care can help overcome these challenges by informing predictive enrichment, no overview exists. METHODS: We conducted a scoping review, systematically searching 10 general and speciality journals for reports published on or after 1 January 2018, of randomised clinical trials enrolling adult critically ill patients. We collected trial metadata on 22 variables including recruitment period, intervention type and early stopping (including reasons) as well as data on the use of causal evidence from secondary data for planned predictive enrichment. RESULTS: We screened 9020 records and included 316 unique RCTs with a total of 268,563 randomised participants. One hundred seventy-three (55%) trials tested drug interventions, 101 (32%) management strategies and 42 (13%) devices. The median duration of enrolment was 2.2 (IQR: 1.3-3.4) years, and 83% of trials randomised less than 1000 participants. Thirty-six trials (11%) were restricted to COVID-19 patients. Of the 55 (17%) trials that stopped early, 23 (42%) used predefined rules; futility, slow enrolment and safety concerns were the commonest stopping reasons. None of the included RCTs had used causal evidence from secondary data for planned predictive enrichment. CONCLUSION: Work is needed to harness the rich multiverse of critical care data and establish its utility in critical care RCTs. Such work will likely need to leverage methodology from interventional and analytical epidemiology as well as data science.

Mixing short- and long-acting local anaesthetics in peripheral nerve blocks: Protocol for a systematic review and meta-analysis.

INTRODUCTION: This protocol describes a systematic review and meta-analysis to evaluate the clinical effects of mixing short- and long-acting local anaesthetics in peripheral nerve blocks. Clinicians often combine short- and long-acting local anaesthetics to achieve a briefer onset time. However, this may come with a prize, namely a shorter total duration of the block, which is of clinical importance. OBJECTIVE: This systematic review aims to strengthen the knowledge of the clinical effects associated with this practice. The primary outcome is the duration of block analgesia. Secondary outcomes are block onset time, sensory and motor block duration. Exploratory outcomes are postoperative pain scores, cumulative 24-h opioid consumption and the prevalence of serious adverse events. METHODS: We will conduct a meta-analysis of the extracted data, and the risk of bias for each study will be evaluated. We will perform a Trial Sequential Analysis, subgroup, and sensitivity analyses and assess the overall risk of publication bias. Finally, we will evaluate the review using the GRADE principles.

Peripheral nerve blocks for closed reduction of distal radius fractures-A protocol for a systematic review.

BACKGROUND: Current methods of anaesthesia used for closed reduction of distal radial fractures may be insufficient for pain relief and muscle relaxation, potentially compromising reduction quality and patient satisfaction. Peripheral nerve blocks have already been implemented for surgery of wrist fractures and may provide optimal conditions for closed reduction due to complete motor and sensory blockade of the involved nerves. However, existing literature on peripheral nerve blocks for closed reduction is sparse, and no updated systematic review or meta-analysis exists. AIMS: This protocol is developed according to the PRISMA-P statement. The systematic review and meta-analysis aim to consolidate the literature regarding the effect and harm of peripheral nerve blocks compared with other anaesthesia modalities for closed reduction of distal radius fractures in adults. METHODS: The two primary outcomes are the proportion of participants needing surgery after closed reduction and pain during closed reduction. We will only include randomised clinical trials. Two review authors will each independently screen literature, extract data, and assess risk of bias with Risk of Bias 2 Tool. Meta-analysis will be carried out with Rstudio. We will also perform a Trial Sequential Analysis. The certainty of evidence will be judged using GRADE guidelines. DISCUSSION: We will use up-to-date methodology when conducting the systematic review outlined in this protocol. The results may guide clinicians in their decision-making regarding the use of anaesthesia for closed reduction of distal radius fractures in adults.

Risks of serious adverse events with non-steroidal anti-inflammatory drugs in gastrointestinal surgery: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly recommended for perioperative opioid-sparing multimodal analgesic treatments. Concerns regarding the potential for serious adverse events (SAEs) associated with perioperative NSAID treatment are especially relevant following gastrointestinal surgery. We assessed the risks of SAEs with perioperative NSAID treatment in patients undergoing gastrointestinal surgery. METHODS: We conducted a systematic review of randomised clinical trials assessing the harmful effects of NSAIDs versus placebo, usual care or no intervention in patients undergoing gastrointestinal surgery. The primary outcome was an incidence of SAEs. We systematically searched for eligible trials in five major databases up to January 2024. We performed risk of bias assessments to account for systematic errors, trial sequential analysis (TSA) to account for the risks of random errors, performed meta-analyses using R and used the Grading of Recommendations Assessment, Development and Evaluation framework to describe the certainty of evidence. RESULTS: We included 22 trials enrolling 1622 patients for our primary analyses. Most trials were at high risk of bias. Meta-analyses (risk ratio 0.78; 95% confidence interval [CI] 0.51-1.19; I2 = 4%; p = .24; very low certainty of evidence) and TSA indicated a lack of information on the effects of NSAIDs compared to placebo on the risks of SAEs. Post-hoc beta-binomial regression sensitivity analyses including trials with zero events showed a reduction in SAEs with NSAIDs versus placebo (odds ratio 0.73; CI 0.54-0.99; p = .042). CONCLUSION: In adult patients undergoing gastrointestinal surgery, there was insufficient information to draw firm conclusions on the effects of NSAIDs on SAEs. The certainty of the evidence was very low.

Peripheral nerve blocks for closed reduction of distal radius fractures-A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Peripheral nerve blocks may provide better conditions for closed reduction of distal radius fractures as compared to other more frequently used modalities. In this systematic review, we evaluate existing evidence on the effect and harm of peripheral nerve blocks for closed reduction of distal radius fractures in adults. METHODS: We performed a systematic review with meta-analysis and trial sequential analysis including trials investigating the use of peripheral nerve blocks for closed reduction of distal radius fractures. Co-primary outcomes were (1) the quality of the closed reduction measured as the proportion of participants needing surgery afterwards and (2) pain during closed reduction. RESULTS: Six trials (n = 312) met the inclusion criteria. One trial reported on the need for surgery with 4 of 25 participants receiving nerve block compared to 7 of 25 receiving haematoma block needing surgery (RR 0.57, 96.7% CI [0.19; 1.71], p = .50). Four trials reported pain during closed reduction. In a meta-analysis, pain was not statistically significantly reduced with a nerve block (-2.1 Numeric Rating Scale (NRS) points (0-10), 96.7% CI [-4.4; 0.2], p = .07, tau2 = 5.4, I2 = 97%, TSA-adj. 95% CI [-11.5; 7.3]). No trial sequential boundaries were crossed, and the required information size was not met. Pre-planned subgroup analysis on trials evaluating ultrasound guided peripheral nerve blocks (patients = 110) showed a significant decrease in 'pain during reduction' (-4.1 NRS, 96.7% CI [-5.5; -2.6], p < .01, tau2 = 0.9, I2 = 80%). All trial results were at high risk of bias and the certainty of the evidence was very low. CONCLUSION: The certainty of evidence on the effect of peripheral nerve blocks for closed reduction of distal radius fractures is currently very low. Peripheral nerve blocks performed with ultrasound guidance may potentially reduce pain during closed reduction. High-quality clinical trials are warranted.

The efficacy and safety of ankle blocks for foot and ankle surgery: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Peripheral nerve blocks may be essential elements in a multimodal pain management regime following foot and ankle surgery. We assessed the effects of ankle blocks compared with no intervention/sham block or a sciatic nerve block in patients undergoing surgery of the foot or ankle. METHODS: We searched CENTRAL, Medline, and Embase for randomised clinical trials comparing ankle block with no intervention/sham block or a sciatic nerve block for patients undergoing surgery of the foot or ankle. Our primary outcomes were duration of analgesia and cumulative 24-hour opioid consumption. We followed the recommendations of the Cochrane Handbook, and performed meta-analysis, Trial Sequential Analysis (TSA), and assessed the risk of bias and certainty of the evidence using the GRADE approach. RESULTS: We included five trials (362 participants) comparing ankle block with no intervention/sham block and three trials (247 participants) comparing ankle block with a sciatic nerve block. Ankle block may increase the duration of analgesia when compared with no intervention/sham block (MD 431 min; 96.7% CI 208 to 654), but the evidence was very uncertain. Duration was decreased when compared with a sciatic nerve block (MD -410 min; 96.7% CI -462 to -358). The ankle block duration was probably important in both comparisons. The effects on cumulative 24-hour opioid consumption were very uncertain in both comparisons. CONCLUSIONS: Ankle block may increase the duration of analgesia when compared with no intervention/sham block, but the evidence was very uncertain, and decrease the duration of analgesia when compared with a sciatic nerve block. The ankle block duration was probably clinically important in both comparisons. The effects on cumulative 24-hour opioid consumption were very uncertain.

Perineural and Systemic Dexamethasone and Ulnar Nerve Block Duration: A Randomized, Blinded, Placebo-controlled Trial in Healthy Volunteers.

BACKGROUND: The authors hypothesized that both perineural and systemic dexamethasone as adjuncts to bupivacaine increase the duration of an ulnar nerve block compared with bupivacaine alone, and that systemic dexamethasone is noninferior to perineural dexamethasone. METHODS: The authors performed bilateral ulnar nerve blocks with 3 ml bupivacaine 5 mg/ml in 16 healthy volunteers on two trial days. According to randomization, subjects received adjunct treatment with 1 ml dexamethasone 4 mg/ml + 1 ml of saline (perineural condition) in one arm and 2 ml saline in the other arm (systemic condition, through absorption and redistribution of the contralaterally administered perineural dexamethasone) on one trial day; and 2 ml saline in one arm (placebo condition) and 2 ml of lidocaine in the other arm (lidocaine condition) on the other trial day. The primary outcome was the duration of the sensory nerve block assessed by temperature discrimination. RESULTS: Mean sensory block duration was 706 ± 94 min for the perineural condition, 677 ± 112 min for the systemic condition, and 640 ± 121 min for the placebo condition. The duration of the sensory nerve block was greater with perineural dexamethasone versus placebo (mean difference 66 min (95% CI, 23 to 108). Block duration was similar between systemic dexamethasone and placebo (mean difference 36 min; 95% CI, -30 to 103). CONCLUSIONS: Perineural dexamethasone as an adjunct to bupivacaine in healthy volunteers resulted in a greater duration of an ulnar nerve block when compared with placebo. Systemic dexamethasone resulted in a similar duration as placebo.

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. METHODS: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. RESULTS: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. CONCLUSIONS: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. TRIAL REGISTRATION: CRD42017081133, date of registration 28 November 2017.

Ketamine for postoperative pain treatment in spinal surgery: Systematic review with meta-analysis and trial sequential analysis.

AIM: We aimed to assess the beneficial and harmful effects of perioperative pain treatment with ketamine in patients undergoing spinal surgery. METHODS: We searched Medline, Embase, and CENTRAL from inception until 15 February 2023 for randomised clinical trials comparing ketamine with placebo or no intervention in patients undergoing spinal surgery. The primary outcomes were cumulative opioid consumption at 24 h postoperatively and serious adverse events. We adhered to recommendations of the Cochrane Collaboration and performed meta-analysis, Trial Sequential Analysis (TSA) to assess the risks of random errors, risk of bias assessment to evaluate the risks of systematic errors, and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included a total of 28 randomised clinical trials enrolling 2110 participants providing data for our pre-defined outcomes. Twenty-three trials enrolled adult participants and 5 trials enrolled paediatric participants. Three trials were at low risk of bias. Meta-analysis and TSA of trials including adults showed that ketamine versus placebo or no intervention seemed to reduce the cumulative 24-h opioid consumption (mean difference -17.57 mg; TSA-adjusted 95% confidence interval, -24.22 to -10.92; p < .01; low certainty of evidence), and there was no evidence of a difference of ketamine versus placebo or no intervention on the risk of serious adverse events (risk ratio 2.16; 96.7% confidence interval, 0.35 to 13.17; p = .36; very low certainty of evidence). CONCLUSION: In adults undergoing spinal surgery, ketamine may reduce cumulative 24-h opioid consumption. Ketamine may increase the occurrence of serious adverse events, but the evidence was very uncertain.

Glucocorticoids added to paracetamol and NSAIDs for post-operative pain: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as the basic pain treatment regimen for most surgeries. Glucocorticoids have well-known anti-inflammatory and anti-emetic properties and may also demonstrate analgesic effects. We assessed benefit and harm of adding glucocorticoids to a combination of paracetamol and NSAIDs for post-operative pain management. METHODS: We searched Embase, Medline and CENTRAL for randomised clinical trials investigating the addition of glucocorticoids versus placebo/no intervention to paracetamol and an NSAID in adults undergoing any type of surgery. We assessed three primary outcomes: cumulative opioid consumption at 24 h postoperatively, serious adverse events and pain at rest at 24 h postoperatively. We performed meta-analysis and trial sequential analysis (TSA), assessed risk of bias using the Risk of Bias 2 tool and used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the certainty of the evidence. RESULTS: We identified 12 relevant trials of which nine trials randomising 804 participants were included in quantitative analysis. When added to paracetamol and NSAIDs, we found no evidence of a difference of glucocorticoids versus placebo/no intervention in cumulative opioid consumption at 24 h postoperatively (mean difference [MD] -0.28, TSA-adjusted 95% confidence interval [CI] -1.90 to 1.33, p = .68, moderate certainty of evidence), serious adverse events (risk ratio (RR) 0.99, TSA-adjusted 95% CI 0.27-3.63, p = .93, very low certainty of evidence) or pain on the Numeric Rating Scale at 24 h postoperatively (MD -0.39, TSA-adjusted 95% CI -0.84 to 0.17, p = .10, moderate certainty of evidence). All outcomes were assessed to be at high risk of bias and TSA showed that we had insufficient information for most outcomes. CONCLUSION: Glucocorticoids added to a baseline therapy of paracetamol and an NSAID likely result in little to no difference in cumulative opioid consumption and pain at rest at 24 h postoperatively. In addition, the evidence is very uncertain about the effect on serious adverse events. For most outcomes we did not have sufficient information to draw firm conclusions and the certainty of the evidence varied from moderate to very low. EDITORIAL COMMENT: Multimodal approaches for post-operative analgesia are favoured, including paracetamol and nonsteroidal anti-inflammatory drugs. In this meta-analysis, pooled results from clinical trials are assessed to describe possible benefit of addition of glucocorticoid treatment for analgesia. The findings did not identify additional benefit, though the certainty of the evidence was not high.

Remimazolam for sedation: A protocol for a systematic review with meta-analysis, trial sequential analysis, and GRADE approach.

BACKGROUND: Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into consideration when choosing the ideal sedative. Midazolam and propofol are frequently employed. However, they are associated with respiratory depression with increasing dosage. Also, midazolam has a potentially unpredictable pharmacodynamic response and propofol may cause hypotension and injection site pain. Remimazolam may provide a superior alternative due to its rapid pharmacodynamic profile and insignificant circulatory effects. METHODS: This protocol employs the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The review aims to assess the beneficial and harmful clinical effects of remimazolam versus placebo or other sedatives in adult patients requiring sedation in relation to a diagnostic or therapeutic procedure, or due to other circumstances. Three primary outcomes are identified: Sedation success rate, respiratory complications, and hemodynamic complications. Six secondary outcomes are identified: among these are quality of recovery and serious adverse events. All randomized trials are included. The search strategy includes six major biomedical databases. Literature screening and data extraction will be performed independently by two authors. Risk of systemic error will be assessed with Risk of Bias 2 Tool. Risk of random error will be assessed with trial sequential analysis. Heterogeneity will be evaluated by appropriate statistical tests. The certainty of the evidence will be judged using Grading of Recommendations Assessment, Development, and Evaluation. Meta-analysis will be carried out with Rstudio. A "Summary of Findings" table will be presented with our primary and secondary outcome results. DISCUSSION: The systematic review with up-to-date methodology outlined in this protocol investigates the clinical effects of remimazolam in relation to procedural sedation. The results may guide clinicians in the clinical use of remimazolam.

Dexmedetomidine for the prevention of delirium in adults admitted to the intensive care unit or post-operative care unit: A systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess any benefit or harm, we conducted a systematic review of randomised clinical trials (RCTs) allocating adults to dexmedetomidine versus placebo/no intervention for the prevention of delirium in intensive care or post-operative care units. DATA SOURCES: We searched Medline, Embase, CENTRAL and other databases. The last search was 9 April 2022. DATA EXTRACTION: Literature screening, data extraction and risk of bias volume 2 assessments were performed independently and in duplicate. Primary outcomes were occurrences of serious adverse events (SAEs), delirium and all-cause mortality. We used meta-analysis, Trial Sequential Analysis, and GRADE (Grading Recommendations Assessment, Development and Evaluation). DATA SYNTHESIS: Eighty-one RCTs (15,745 patients) provided data for our primary outcomes. Results from trials at low risk of bias showed that dexmedetomidine may reduce the occurrence of the most frequently reported SAEs (relative risk [RR] 0.69; 95% CI 0.43-1.09), cumulated SAEs (RR 0.70; 95% CI 0.52-0.95) and the occurrence of delirium (RR 0.62; 95% CI 0.43-0.89). The certainty of evidence was very low for delirium. Mortality was very low in trials at low risk of bias (0.4% in the dexmedetomidine groups and 1.0% in the control groups) and meta-analysis did not provide conclusive evidence that dexmedetomidine may result in lower or higher all-cause mortality (RR 0.47; 95% CI 0.18-1.21). There was a lack of information from trial results at low risk of bias for all primary outcomes. CONCLUSIONS: Trial results at low risk of bias showed that dexmedetomidine might reduce occurrences of SAEs and delirium, while no conclusive evidence was found for effects on all-cause mortality. The certainty of evidence ranged from very low for occurrence of delirium to low for the remaining outcomes.

Collaboration for Evidence-based Practice and Research in Anaesthesia (CEPRA): A consortium initiative for perioperative research.

Evidence in perioperative care is insufficient. There is an urgent need for large perioperative research programmes, including pragmatic randomised trials, testing daily clinical treatments and unanswered question, thereby providing solid evidence for effects of interventions given to a large and growing number of patients undergoing surgery and anaesthesia. This may be achieved through large collaborations. Collaboration for Evidence-based Practice and Research in Anaesthesia (CEPRA) is a novel collaborative research network founded to pursue evidence-based answers to major clinical questions in perioperative medicine. The aims of CEPRA are to (1) improve clinical treatment and outcomes and optimise the use of resources for patients undergoing anaesthesia and perioperative care, and (2) disseminate results and inform caretakers, patients and relatives, and policymakers of evidence-based treatments in anaesthesia and perioperative medicine. CEPRA is inclusive in its concept. We aim to extend our collaboration with all relevant clinical collaborators and patient associations and representatives. Although initiated in Denmark, CEPRA seeks to develop an international network infrastructure, for example, with other Nordic countries. The work of CEPRA will follow the highest methodological standards. The organisation aims to structure and optimise any element of the research collaboration to reduce economic costs and harness benefits from well-functioning research infrastructure. This includes successive continuation of trials, harmonisation of outcomes, and alignment of data management systems. This paper presents the initiation and visions of the CEPRA network. CEPRA aims to be inclusive, patient-focused, methodologically sound, and to optimise all aspects of research logistics. This will translate into faster research conduct, reliable results, and accelerated clinical implementation of results, thereby benefiting millions of patients whilst being cost and labour-saving.

Effects of adding exercise to usual care in patients with either hypertension, type 2 diabetes or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: To assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. DESIGN: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. DATA SOURCES: The CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science and BIOSIS searched from inception to July 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included all randomised clinical trials adding any form of trialist defined exercise to usual care versus usual care in participants with either hypertension, type 2 diabetes or cardiovascular disease irrespective of setting, publication status, year and language. OUTCOME AND MEASURES: The primary outcomes were all-cause mortality, serious adverse events and quality of life. DATA EXTRACTION AND SYNTHESIS: Five independent reviewers extracted data and assessed risk of bias in pairs. Our methodology was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Grading of Recommendations Assessment, Development and Evaluation and Cochrane Risk of Bias-version 1. RESULTS: We included 950 trials, of which 248 trials randomising 21 633 participants reported on our predefined outcomes. All included trials were at high risk of bias. The major types of exercise reported were dynamic aerobic exercise (126/248 trials), dynamic resistance exercise (25/248 trials), and combined aerobic and resistance exercise (58/248 trials). The study participants were included due to cardiovascular diseases (189/248 trials), type 2 diabetes (41/248 trials) or hypertension (16/248 trials). The median intervention period was 3 months (IQR: 2-4 months) and the median follow-up period was 6 months (IQR: 3-8 months) after randomisation. Meta-analyses and trial sequential analyses showed evidence of a beneficial effect of adding exercise to usual care when assessing all-cause mortality (risk ratio (RR) 0.82; 95% CI 0.73 to 0.93; I2=0%, moderate certainty of evidence) and serious adverse events (RR 0.79; 95% CI 0.71 to 0.88; I2=0%, moderate certainty of evidence). We did not find evidence of a difference between trials from different economic regions, type of participants, type of exercise or duration of follow-up. Quality of life was assessed using several different tools, but the results generally showed that exercise improved quality of life, but the effect sizes were below our predefined minimal important difference. CONCLUSIONS: A short duration of any type of exercise seems to reduce the risk of all-cause mortality and serious adverse events in patients with either hypertension, type 2 diabetes or cardiovascular diseases. Exercise seems to have statistically significant effects on quality of life, but the effect sizes seem minimal. PROSPERO REGISTRATION NUMBER: CRD42019142313.

Patient-Important Outcomes Other Than Mortality in Contemporary ICU Trials: A Scoping Review.

OBJECTIVES: Randomized clinical trials (RCTs) conducted in adult ICU patients increasingly include patient-important outcomes other than mortality. This comes with challenges regarding outcome choices/definitions, handling of deceased patients and missing data in analyses, and choices of effect measures and statistical methods due to complex distributions. This scoping review aimed to characterize how these challenges are handled in relevant contemporary RCTs. DATA SOURCES: We systematically searched 10 selected journals for RCTs conducted primarily in adult ICU patients published between 1 January 2018 and 5 May 2022 reporting at least one patient-important outcome other than mortality, including "days alive without"…-type outcomes, functional/cognitive/neurologic outcomes, health-related quality of life (HRQoL) outcomes, and ordinal/other outcomes. STUDY SELECTION: Abstracts and full-texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined and pilot-tested extraction forms and subsequently categorized to facilitate analysis. DATA SYNTHESIS: We included 687 outcomes from 167 RCTs, with 32% of RCTs using a patient-important outcome other than mortality as a (co-)primary outcome, most frequently "days alive without"…-type outcomes. Many different functional/cognitive/neurologic (103) and HRQoL (29) outcomes were reported. Handling of deceased patients varied, with analyses frequently restricted to survivors only for functional/cognitive/neurologic (62%) and HRQoL (89%) outcomes. Follow-up was generally longer and missing data proportions higher for functional/cognitive/neurologic and HRQoL outcomes. Most outcomes were analyzed using nonparametric tests (31%), linear regression/ t tests (27%), chi-square-like tests (12%), and proportional odds logistic regression (9%), often without presentation of actual treatment effects estimates (38%). CONCLUSIONS: In this sample of RCTs, substantial variation in practice and suboptimal methodological choices were observed. This calls for increased focus on standardizing outcome choices and definitions, adequate handling of missing data and deceased patients in analyses, and use of statistical methods quantifying effect sizes.

Perioperative prevention of persistent pain after total hip and knee arthroplasty-Protocol for two systematic reviews.

BACKGROUND: Between 9% and 20% of patients experience moderate to severe persistent postoperative pain after total hip or knee arthroplasty. Severe immediate postoperative pain limits rehabilitation and is associated with the development of persistent postoperative pain. Therefore, perioperative analgesic and physiotherapeutic interventions are of interest to reduce persistent pain. In two systematic reviews with identical methodology, we aim to investigate the effects of (a) perioperative analgesic interventions and (b) physiotherapeutic interventions in reducing persistent pain after total hip and knee arthroplasty. METHODS: We will include randomised and cluster-randomised controlled trials on perioperative analgesic and physiotherapeutic interventions for patients undergoing elective total hip or knee arthroplasty for osteoarthritis. After contact with the authors, trials without pain data 3-24 months postoperatively will be excluded. Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and reference lists will be searched for eligible trials. Two authors will independently screen, extract data and assess the risk of bias. The primary outcome is pain scores 3-24 months postoperatively. Meta-analyses will be performed for interventions with two or more trials. We will conduct trial sequential analyses and assign Grading of Recommendations, Assessment, Development and Evaluation (GRADE) ratings. CONCLUSION: No previous review on reduction of persistent postoperative pain has included non-pharmacological or invasive analgesic techniques. These two reviews with identical methodology will summarise the evidence of analgesic and physiotherapeutic perioperative interventions to prevent persistent pain. PROSPERO REGISTRATION: CRD42021284175.

Risk of serious adverse events associated with non-steroidal anti-inflammatory drugs in orthopaedic surgery. A protocol for a systematic review.

BACKGROUND: Postoperative pain is a common condition following orthopaedic surgeries and causes prolonged hospitalisation, delayed rehabilitation and hamper the quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and anti-inflammatory mediators in the treatment of postoperative pain. The association of NSAIDs with serious adverse events may however keep some clinicians and clinical decision makers from using NSAIDs perioperatively. The evidence regarding the risks of serious adverse events following perioperative use of NSAIDs in orthopaedic surgery is sparse and needs to be assessed in a systematic review. This is a protocol for a systematic review that aims to identify the risks of serious adverse events from perioperative use of NSAIDs in orthopaedic patients. METHODS: Our methodology is based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and the eight-step assessment procedure suggested by Jakobsen and colleagues. We wish to assess if NSAIDs versus placebo, usual care or no intervention, will influence the risks of serious adverse events in patients undergoing orthopaedic surgery. We will include all randomised trials assessing the use of NSAIDs perioperatively. To identify trials we will search the Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cochrane Central Register, Science Citation Index Expanded on Web of Science and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess trials. Extracted data will be analysed using RStudio and Trial Sequential Analysis. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes. We will assess the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: This systematic review can potentially aid clinicians and clinical decision makers in the use of NSAIDs for treatment of postoperative pain following orthopaedic surgeries.