Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Minimal important difference in postoperative morphine consumption after hip and knee arthroplasty using nausea, vomiting, sedation and dizziness as anchors.

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.

Associations of dexamethasone's effect on morphine consumption after total knee arthroplasty-Subgroup analyses.

The DEXamethasone twice for pain treatment after Total Knee Arthroplasty (DEX-2-TKA) trial showed that adding one and two doses of 24 mg intravenous dexamethasone to paracetamol, ibuprofen and local infiltration analgesia, reduced morphine consumption (primary outcome) within 48 h after TKA. We aimed to explore the differences in the effect of dexamethasone on morphine consumption in different subgroups. Quantile regression adjusted for site was used to test for significant interaction between the predefined dichotomised subgroups and treatment group. The subgroups were defined based on baseline data: sex (male/female), age (≤65 years/>65 years), American Society of Anaesthesiologists (ASA)-score (ASA I + II/III), visual analogue score of preoperative pain at rest (≤30 mm/>30 mm), pain during mobilisation (≤30 mm/>30 mm), type of anaesthesia (spinal anaesthesia/general anaesthesia and spinal converted to general anaesthesia), and prior daily use of analgesics (either paracetamol and/or NSAID/neither). These analyses were supplemented with post hoc multivariate linear regression analyses. Test of interaction comparing sex in the pairwise comparison between DX2 (dexamethasone [24 mg] + dexamethasone [24 mg]) versus placebo (p = .02), showed a larger effect of dexamethasone on morphine consumption in male patients compared to females. Test of interaction comparing age in the pairwise comparison between DX1 (dexamethasone [24 mg] + placebo) versus placebo (p = .04), showed a larger effect of dexamethasone on morphine consumption in younger patients (≤65 years) compared to older. All remaining subgroup analyses showed no evidence of a difference. The supplemental multivariate analyses did not support any significant interaction for sex (p = .256) or age (p = .730) but supported a significant interaction with the type of anaesthesia (p < .001). Our results from the quantile regression analyses indicate that the male sex and younger age (≤65 years) may be associated with a larger analgesic effect of dexamethasone than the effects in other types of patients. However, this is not supported by post-hoc multivariate linear regression analyses. The two types of analyses both supported a possible interaction with the type of anaesthesia.

Prolonged effects of dexamethasone following total knee arthroplasty: A pre-planned sub-study of the DEX-2-TKA trial.

OBJECTIVES: The DEX-2-TKA trial demonstrated that one and two doses of 24 mg intravenous dexamethasone reduced opioid consumption and pain after total knee arthroplasty (TKA). We aimed to investigate the prolonged effects of dexamethasone after the 48-h intervention period. DESIGN: This was a prospective, pre-planned questionnaire follow-up on postoperative days 3-7 of patients in the DEX-2-TKA trial that randomly received: DX1 (dexamethasone 24 mg + placebo), DX2 (dexamethasone 24 mg + dexamethasone 24 mg), and placebo (placebo + placebo) perioperatively and 24 h later. SETTING: A multicenter trial performed at five Danish hospitals. PARTICIPANTS: We analyzed 434 of 485 adult participants enrolled in the DEX-2-TKA trial. OUTCOME MEASURES: Primary outcome was difference between groups in average of all numerical rating scale (NRS) pain scores reported in the morning, at bedtime, and the daily average pain on postoperative days 3-7. Secondary outcomes were sleep quality and patient satisfaction. RESULTS: The median (interquartile range) pain intensity levels for postoperative days 3-7 were: DX2 3.2 (2.1-4.3); DX1 3.3 (2.3-4.1); and placebo 3.3 (2.5-4.7). Hodges-Lehmann median differences between groups were: 0 (95% confidence interval - 0.54 to 0.2), P = 0.38 between DX1 and placebo; 0.1 (-0.47 to 0.33), p = .87 between DX1 and DX2; and 0.1 (-0.6 to 0.13), p = .20 between DX2 and placebo. We found no relevant differences between groups on sleep quality on postoperative days 3-7 nor for patient satisfaction with the analgesic treatment. CONCLUSIONS: We found that neither one nor two doses of 24 mg intravenous dexamethasone demonstrated prolonged effects on overall pain or sleep quality on postoperative days 3-7 after total knee arthroplasty. We also found that dexamethasone had no effect on patient satisfaction. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03506789 (main result trial).

Association between using a prehospital assessment unit and hospital admission and mortality: a matched cohort study.

OBJECTIVES: This study aimed to compare hospital admission and 30-day mortality between patients assessed by the prehospital assessment unit (PAU) and patients not assessed by the PAU. DESIGN: This was a matched cohort study. SETTING: This study was conducted between November 2021 and October 2022 in Region Zealand, Denmark. PARTICIPANTS: 989 patients aged >18, assessed by the PAU, were identified, and 9860 patients not assessed by the PAU were selected from the emergency calls using exposure density sampling. EXPOSURE: Patients assessed by the PAU. The PAU is operated by paramedics with access to point-of-care test facilities. The PAU is an alternative response vehicle without the capability of transporting patients. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was hospital admission within 48 hours after the initial call. The key secondary outcomes were admission within 7 days, 30-day mortality and admission within 6 hours. Descriptive statistical analyses were conducted, and logistic regression models were used to estimate adjusted OR (aOR) and 95% CI. RESULTS: Among the PAU assessed, 44.1% were admitted within 48 hours, compared with 72.9% of the non-PAU assessed, p<0.001. The multivariable analysis showed a lower risk of admission within 48 hours and 7 days among the PAU patients, aOR 0.31 (95% CI 0.26 to 0.38) and aOR 0.50 (95% CI 0.38 to 0.64), respectively. The 30-day mortality rate was 3.8% in the PAU-assessed patients vs 5.5% in the non-PAU-assessed patients, p=0.03. In the multivariable analysis, no significant difference was found in mortality aOR 0.99 (95% CI 0.71 to 1.42). No deaths were observed in PAU-assessed patients without subsequent follow-up. CONCLUSION: The recently introduced PAU aims for patient-centred emergency care. The PAU-assessed patients had reduced admissions within 48 hours and 7 days after the initial call. Study findings indicate that the PAU is safe since we identified no significant differences in 30-day mortality. TRIAL REGISTRATION NUMBER: NCT05654909.

Chronic Pain and Functional Outcome 3 years After Total Knee Arthroplasty and Perioperative Dexamethasone: A Follow-Up of the Randomized, Clinical DEX-2-TKA Trial.

BACKGROUND: Perioperative dexamethasone as an adjunct to multimodal analgesia, has an opioid-sparing and pain alleviating effect after total knee arthroplasty (TKA), however, the 3-year effects are unknown. We aimed to investigate the 3-year effect of 1 (DX1) or 2 (DX2) intravenous doses of 24 mg dexamethasone or placebo on pain, physical function, and health-related quality of life after TKA. METHODS: Patients who participated in the Dexamethasone Twice for Pain Treatment after TKA (DEX-2-TKA) were invited to physical tests and questionnaires (self-reported characteristics, Oxford Knee Score, EuroQol-5Dimensions-5Levels (EQ5D5L), and PainDetect). The tests were 40-meter Fast Paced Walk (40FPW) test, Timed Up and Go (TUG), 30 Second Chair Stand test (30CST), Stair Climb Test (SCT), bilateral knee Range of Motion, and knee extension torque. For each test the peak pain intensity was registered on a 0 to 100 mm Visual Analogue Scale. Primary outcome was average peak pain intensity during the 40FPW, TUG, 30CST and SCT. Secondary outcomes were the tests and questionnaires. Out of 252 eligible patients, 133 (52.8%) underwent the tests and 160 (63.5%) answered the questionnaires. Mean follow-up time was 33 months (range, 23 to 40). RESULTS: Median (interquartile range) peak pain intensity was 0 (0 to 65) for the DX2 group, 0 (0 to 51) for DX1 group and 0 (0 to 70) for the placebo group (P = .72). No differences in secondary outcomes were identified. CONCLUSION: One or 2 intravenous doses of 24 mg dexamethasone did not impact chronic pain development or physical function 3 years after TKA.

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.

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

BACKGROUND: The RECIPE trial systematically investigates the effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimise risk of bias and to prevent data-driven analysis, we present this detailed statistical analysis plan. METHODS: The RECIPE trial is a randomised, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 h postoperatively. Primary outcome is total opioid consumption 0-24 h after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6 = 0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. DISCUSSION: The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.

Minimal important difference in opioid consumption based on adverse event reduction-A study protocol.

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.

Effect of Dexamethasone on Myocardial Injury After Total Knee Arthroplasty: A Substudy of the Randomized Clinical DEX-2-TKA Trial.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) carries a high postoperative mortality. In this preplanned, subgroup analysis of the randomized DEX-2-TKA Trial, we investigated the effect of dexamethasone versus placebo on the concentration of cardiac troponin I and T (TnI and TnT) on the first postoperative morning after total knee arthroplasty. In addition, frequency of MINS, myocardial infarction, and major adverse cardiovascular events where evaluated. METHODS: We included 290 patients who received either 24 mg of dexamethasone intravenously (given perioperatively) or placebo. Blood samples were analyzed as either TnI or T depending on trial site. RESULTS: A total of 236 samples were eligible for analysis of TnI and 38 samples for TnT on the first postoperative morning. The median (IQR) TnI concentration was 4.6 ng/L (0-7.2 ng/L) in the dexamethasone group and 4.5ng/l (0-7.0 ng/L) in the placebo group (P = .96) on the first postoperative morning. The median TnT was 9 ng/L (6-11 ng/L) in the dexamethasone group and 8 ng/L (5-10 ng/L) in the placebo group (P = .68). The frequencies of MINS, myocardial infarction, and major adverse cardiovascular events were similar in the compared groups, but these analyses were underpowered. CONCLUSION: We found no effect of dexamethasone on postoperative concentration of troponin I or T on the first postoperative morning after total knee arthroplasty.

Systemic glucocorticoids as an adjunct to treatment of postoperative pain after total hip and knee arthroplasty: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Postoperative analgesic effects of systemic glucocorticoids given as an adjunct to treatment are largely undetermined in alloplastic procedures. OBJECTIVES: To investigate the beneficial and harmful effects of peri-operative systemic glucocorticoid treatment for pain after total hip arthroplasty (THA) or total knee arthroplasty (TKA). DESIGN: A systematic review of randomised clinical trials (RCTs) with meta-analyses, trial sequential analyses and GRADE. Primary outcome was 24 h intravenous (i.v.) morphine (or equivalent) consumption with a predefined minimal important difference (MID) of 5 mg. Secondary outcomes included pain at rest and during mobilisation (MID, VAS 10 mm), adverse and serious adverse events (SAEs). DATA SOURCES: We searched EMBASE, Cochrane CENTRAL, PubMed and Google Scholar up to October 2021. ELIGIBILITY CRITERIA: RCTs investigating peri-operative systemic glucocorticoid versus placebo or no intervention, for analgesic pain management of patients at least 18 years undergoing planned THA or TKA, irrespective of publication date and language. RESULTS: We included 32 RCTs with 3521 patients. Nine trials were at a low risk of bias. Meta-analyses showed evidence of a reduction in 24 h cumulative morphine consumption with glucocorticoids by 5.0 mg (95% CI 2.2 to 7.7; P  = 0.0004). Pain at rest was reduced at 6 h by 7.8 mm (95% CI 5.5 to 10.2; P  < 0.00001), and at 24 h by 6.3 mm (95% CI 3.8 to 8.8; P  < 0.00001). Pain during mobilisation was reduced at 6 h by 9.8 mm (95% CI 6.9 to 12.8; P  < 0.00001), and at 24 h by 9.0 mm (95% CI 5.5 to 12.4, P  < 0.00001). Incidence of adverse events was generally lower in the glucocorticoid treatment group. SAEs were rarely reported. The GRADE rated quality of evidence was low to very low. CONCLUSION: Peri-operative systemic glucocorticoid treatment reduced postoperative morphine consumption to an individually relevant level following hip and knee arthroplasty. Pain levels were reduced but were below the predefined MID. The quality of evidence was generally low. REGISTRATION: PROSPERO ID: CRD42019135034.

Paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty: protocol for the randomised, placebo-controlled, parallel 4-group, blinded, multicentre RECIPE trial.

INTRODUCTION: Multimodal analgesia with paracetamol, non-steroidal anti-inflammatory drug and glucocorticoid is recommended for hip arthroplasty, but with uncertain effects of the different combinations. We aim to investigate benefit and harm of different combinations of paracetamol, ibuprofen and dexamethasone following total hip arthroplasty. METHODS AND ANALYSIS: RECIPE is a randomised, placebo-controlled, parallel 4-group, blinded trial with 90-day and 1-year follow-up performed at nine Danish hospitals. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Eligible participants undergoing total hip arthroplasty are randomised to:group A: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous placebo; group B: oral paracetamol 1000 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group C: oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group D: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg.Primary outcome is cumulative opioid consumption at 0-24 hours. Secondary outcomes are pain at rest, during mobilisation and during a 5 m walk and adverse events. Follow-up includes serious adverse events and patient reported outcome measures at 90 days and 1 year. A total of 1060 participants are needed to demonstrate a difference of 8 mg in 24-hour morphine consumption assuming an SD of 24.5 mg, a risk of type I errors of 0.0083 and a risk of type 2 errors of 0.2. Primary analysis will be a modified intention-to-treat analysis.With this trial we aim to verify recommendations for pain treatment after total hip arthroplasty, and investigate the role of dexamethasone as an analgesic adjuvant to paracetamol and ibuprofen. ETHICS AND DISSEMINATION: This trial is approved by the Region Zealand Committee on Health Research Ethics (SJ-799). Plans for dissemination include publication in peer-reviewed journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT04123873.

Effect of dexamethasone on intraoperative remifentanil dose in total knee arthroplasty surgery under general anaesthesia.

BACKGROUND: The effects of glucocorticoids may include both genomic and rapid nongenomic effects. The potential rapid analgesic effect during surgery has not previously been investigated. We aimed to explore the effect of dexamethasone on intraoperative infusion rate of remifentanil in patients undergoing total knee arthroplasty (TKA) surgery under general anaesthesia. METHODS: In this post hoc subgroup analysis, we included patients randomised in the DEX-2-TKA trial, who were operated under total intravenous anaesthesia with remifentanil and propofol. Trial medication, intravenous dexamethasone 24 mg or placebo, was administered immediately after anaesthesia onset. The primary outcome was the median weight-corrected infusion rate of remifentanil during surgery. Secondary outcomes included median weight-corrected infusion rate of propofol, median intraoperative bispectral index and time spent in the post-anaesthesia care unit. RESULTS: Eighty-seven patients were included in the analysis of the primary outcome. A significantly higher remifentanil infusion rate was observed in the dexamethasone group compared with the placebo group, p = .02. None of the secondary outcomes resulted in statistically significant differences between groups. CONCLUSION: This explorative post hoc analysis of the randomised DEX-2-TKA trail showed that patients undergoing TKA surgery under general anaesthesia and who received dexamethasone seemed to have a higher remifentanil infusion rate compared with patients who received placebo. The clinical implications of the potentially increased remifentanil infusion rate need to be validated and explored further. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05002361 (12 August 2021).

Improving neuromuscular monitoring and reducing residual neuromuscular blockade via e-learning: A multicentre interrupted time-series study (INVERT study).

BACKGROUND: Neuromuscular monitoring should be applied routinely to avoid residual neuromuscular block. However, anaesthetists often refrain from applying it, even when the equipment is available. We aimed to increase neuromuscular monitoring in six Danish anaesthesia departments via e-learning. METHODS: Interrupted time series study, with baseline data from a previous study and prospective data collection after implementation of the module, which was available for 2 weeks from 21 November 2016. We included all patients receiving general anaesthesia with muscle relaxants until 30 April 2017. Main outcome was application of acceleromyography, grouped as succinylcholine only and non-depolarising relaxants. Secondary outcomes were last recorded train-of-four ratio (non-depolarising) relaxants and score on a ten-question pre- and post-course multiple-choice test. RESULTS: The post-intervention data consisted of 6525 cases (3099 (48%) succinylcholine only, 3426 (52%) non-depolarising relaxants). Analysing all departments, we found a positive pre-intervention trend in application of acceleromyography for both groups, of estimated 7.5% and 4.8% per year, respectively (p < .001). The monitoring rate increased significantly for succinylcholine in two departments post-intervention (p = .045 and .010), and for non-depolarising relaxants in one department (p = .041), but followed by a negative trend of -37.0% per year (p = .041). The rate was already close to 90% at the time of the intervention and the mean last recorded train-of-four ratio was 0.97 (SD 0.21), also without a significant change. The median score on the post-course test increased from 7 (IQR 5-8) to 9 (IQR 8-10) (p < .001, Wilcoxon Signed-Ranks Test). CONCLUSION: We found no overall effect of the e-learning module on application of neuromuscular monitoring, although the post-course test indicated an effect on anaesthetists' knowledge in this field. TRIAL REGISTRATION: Trial registration: Clinicaltrials.gov identifier: NCT02925143. https://clinicaltrials.gov/ct2/show/NCT02925143.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Participants with mild, moderate, or severe pain following total hip arthroplasty. A sub-study of the PANSAID trial on paracetamol and ibuprofen for postoperative pain treatment.

OBJECTIVES: In this sub-study of the 'Paracetamol and Ibuprofen in Combination' (PANSAID) trial, in which participants were randomised to one of four different non-opioids analgesic regimen consisting of paracetamol, ibuprofen, or a combination of the two after planned primary total hip arthroplasty, our aims were to investigate the distribution of participants' pain (mild, moderate or severe), integrate opioid use and pain to a single score (Silverman Integrated Approach (SIA)-score), and identify preoperative risk factors for severe pain. METHODS: We calculated the proportions of participants with mild (VAS 0-30 mm), moderate (VAS 31-60 mm) or severe (VAS 61-100 mm) pain and the SIA-scores (a sum of rank-based percentage differences from the mean rank in pain scores and opioid use, ranging from -200 to 200%). Using logistic regression with backwards elimination, we investigated the association between severe pain and easily obtainable preoperative patient characteristics. RESULTS: Among 556 participants from the modified intention-to-treat population, 33% (95% CI: 26-42) (Group Paracetamol + Ibuprofen (PCM + IBU)), 28% (95% CI: 21-37) (Group Paracetamol (PCM)), 23% (95% CI: 17-31) (Group Ibuprofen (IBU)), and 19% (95% CI: 13-27) (Group Half Strength-Paracetamol + Ibuprofen (HS-PCM + IBU)) experienced mild pain 6 h postoperatively during mobilisation. Median SIA-scores during mobilisation were: Group PCM + IBU: -48% (IQR: -112 to 31), Group PCM: 40% (IQR: -31 to 97), Group IBU: -5% (IQR: -57 to 67), and Group HS-PCM + IBU: 6% (IQR: -70 to 74) (overall difference: p=0.0001). Use of analgesics before surgery was the only covariate associated with severe pain (non-opioid: OR 0.50, 95% CI: 0.29-0.82, weak opioid 0.56, 95% CI: 0.28-1.16, reference no analgesics before surgery, p=0.02). CONCLUSIONS: Only one third of participants using paracetamol and ibuprofen experienced mild pain after total hip arthroplasty and even fewer experienced mild pain using each drug alone as basic non-opioid analgesic treatment. We were not able, in any clinically relevant way, to predict severe postoperative pain. A more extensive postoperative pain regimen than paracetamol, ibuprofen and opioids may be needed for a large proportion of patients having total hip arthroplasty. SIA-scores integrate pain scores and opioid use for the individual patient and may add valuable information in acute pain research.

Waking Up in Pain: a prospective unselected cohort study of pain in 3702 patients immediately after surgery in the Danish Realm.

BACKGROUND: Acute and persistent pain after surgery is well described. However, no large-scale studies on immediate postoperative pain in the operating room (OR) exist, hindering potential areas of research to improve clinical outcomes. Thus, we aimed to describe the occurrence and severity of immediate postoperative pain in a large, unselected cohort. METHODS: This was a prospective cohort study, encompassing all procedures in 31 public hospitals in the Danish Realm, during a 5-day period including the weekend. Data on procedures and anesthesia were collected and the main outcome was occurrence of moderate or severe pain in the OR. Secondary outcomes included pain, sedation and nausea in the OR or during the first 15 min in the postanesthesia care unit (PACU) including relevant risk factors. Descriptive and logistic regression statistics were used. RESULTS: A total of 3675 procedures were included for analysis (87% inclusion rate). Moderate or severe pain occurred in 7.4% (95% CI 6.5% to 8.3%) of cases in the OR immediately after awakening, rising to 20.2% in the OR and/or PACU. Large intraprocedure and interprocedure variations occurred (0.0%-37.5%), and in 20% of cases with epidural-general anesthesia patients experienced moderate or severe pain. Independent risk factors were female sex, younger age, preoperative pain, daily opioid use and major surgical procedures. CONCLUSION: Moderate or severe pain in the immediate postoperative phase occurred in 20% of all cases with procedure and anesthesiological technique variations, suggesting a need for identification of relevant procedure-specific risk factors and development of preventive treatments. TRIAL REGISTRATION NUMBER: RoPR ID 43191.

The PANSAID randomized clinical trial: A pre-planned 1-year follow-up regarding harm.

BACKGROUND: Limiting harm from postoperative pain treatment is important. However, long-term follow-up from acute pain trials are rare. The aim of the study was to provide long-term follow-up data regarding harm from the "Paracetamol and Ibuprofen in Combination" (PANSAID) trial. METHODS: In this preplanned long-term follow-up study from the PANSAID trial, we used data from Danish national health registries (the Danish National Patient Registry and the Danish Civil Registration System) in addition to the 90-day follow-up in the original trial. The primary outcome was 1-year proportion of patients with one or more serious adverse events. RESULTS: One-year follow-up was complete for 551 patients (99%). We found three additional patients with one or more serious adverse events in the 1-year follow-up compared with the 90-day follow-up. The relative risk of having one or more serious adverse event when randomized to ibuprofen compared with paracetamol was 1.40 (95% CI: 0.84-2.33, P = .20). CONCLUSION: We found no statistically significant difference in 1-year serious adverse events between patients randomized to ibuprofen compared with paracetamol in patients having planned primary total hip arthroplasty. There were few additional events from the 90-day follow-up to the 1-year follow-up.

DEX-2-TKA - DEXamethasone twice for pain treatment after Total Knee Arthroplasty: Detailed statistical analysis plan for a randomized, blinded, three-group multicentre clinical trial.

BACKGROUND: Optimization of post-operative pain treatment is of upmost importance. Multimodal analgesia is the main post-operative pain treatment principle, but the evidence on optimal analgesic combinations is unclear. With the "DEXamethasone twice for pain treatment after TKA" trial, we aim to investigate the role of one or two doses of glucocorticoid for post-operative pain treatment after total knee arthroplasty. To ensure transparency and minimization of bias, we present this article with a detailed statistical analysis plan, to be published before the last participant is enrolled. METHODS: "DEXamethasone twice for pain treatment after TKA" (DEX-2-TKA) is a randomized, blinded, three-group multicentre clinical trial. Participants will be randomized to one of three intervention groups: single dose of iv dexamethasone 24 mg, two consecutive doses of iv dexamethasone 24 mg or matching iv placebo. All three intervention groups will receive paracetamol, NSAID (ibuprofen) and local infiltration analgesia. Participants, treatment providers, outcome assessors, data managers, statisticians and conclusion drawers will be blinded to the allocated intervention. The primary outcome is total opioid consumption (iv morphine milligram equivalents) 0-48 hours post-operatively. Secondary outcomes are (1) visual analogue scale pain levels: (a) during active 45 degrees flexion of the knee at 24 and 48 hours post-operatively, (b) at rest at 24 and 48 hours post-operatively, and (c) during 0-24 hours (highest score) and 24-48 hours post-operatively (highest score); and (2) the proportion of participants with one or more adverse events within 48 hours post-operatively. DISCUSSION: The DEX-2-TKA trial will provide high quality data regarding benefits and harms of adding one or two high-doses of dexamethasone to a multimodal analgesic regimen. TRIAL REGISTRATION: EudraCT: 2018-001099-39 (08/06-18); ClinicalTrials.gov: NCT03506789 (24/04-2019).

DEX-2-TKA-DEXamethasone twice for pain treatment after Total Knee Arthroplasty: A protocol for a randomized, blinded, three-group multicentre clinical trial.

BACKGROUND: Multimodal analgesia is considered the leading principle for post-operative pain treatment, but no gold standard after total knee arthroplasty (TKA) exists. AIM: To investigate the beneficial and harmful effects of one or two doses of 24 mg intravenous dexamethasone (DXM) as part of a multimodal analgesic regimen (paracetamol, NSAID and perioperative local infiltration analgesia) after TKA. We hypothesize that addition of DXM will reduce post-operative opioid consumption. METHODS: DEXamethasone twice for pain treatment after TKA is a randomized, blinded, three-group multicentre clinical trial. Participants will be randomized to one of three groups: placebo, single dose of DXM or two consecutive doses of DXM. Participants, treatment providers and investigators will be blinded to the allocated intervention. The primary outcome is total opioid consumption (units of morphine equivalents) 0-48 hours post-operatively. INCLUSION CRITERIA: unilateral, primary TKA; age ≥18 years; American Society of Anesthesiologists-Score 1-3; Body Mass Index ≥18 and ≤40; for women-not pregnant; and written informed consent. EXCLUSION CRITERIA: allergy or contraindications against trial medication; daily use of high dose opioid and/or use of methadone/transdermal opioids; daily use of systemic glucocorticoids; dysregulated diabetes; and patients suffering from alcohol and/or drug abuse. Four-hundred-and-eighty-six eligible participants are needed to detect or discard a difference of 10 mg morphine equivalents 0-48 hours post-operatively maintaining a familywise error rate of 0.05 and a power of 90% for the three possible pairwise comparisons. DISCUSSION: Recruiting is planned to commence September 2018 and expected to finish March 2020. TRIAL REGISTRATION: EudraCT: 2018-001099-39 (08/06-18); ClinicalTrials.gov: NCT03506789 (24/04-2019). Editorial Comment This is the protocol for the largest randomized clinical trial investigating the effect of one or two doses of dexamethasones on pain treatment after total knee arthroplasty. Due to the pragmatic and rigerous design this study will deliver results of high quality and external validity.