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.

Effects of avoidance versus use of neuromuscular blocking agents for facilitation of tracheal intubation in children and infants.

BACKGROUND: The European Society of Anesthesiology and Intensive Care recommends the use of neuromuscular blocking agents (NMBA) in adults, to facilitate tracheal intubation and reduce its associated complications. Children who undergo tracheal intubation may suffer some of the same complications, however, no consensus exists regarding the use of NMBA for tracheal intubation in the pediatric population. We will explore the existing evidence assessing the effects of avoidance versus the use of NMBA for the facilitation of tracheal intubation in children and infants. METHODS: This protocol follows the preferred reporting items for systematic reviews and meta-analyses protocols recommendations. We will include all randomized controlled clinical trials assessing the effects of avoidance versus the use of NMBA for facilitation of tracheal intubation (oral or nasal) using direct laryngoscopy or video laryngoscopy in pediatric participants (<18 years). Our primary outcome is incidence of difficult tracheal intubation. Secondary outcomes include incidence of serious adverse events, failed intubation, events of upper airway discomfort or injury, and difficult laryngoscopy. We will conduct a thorough database search to identify relevant trials, including CENTRAL, MEDLINE, EMBASE, BIOSIS, Web of Science, CINAHL, and trial registries. Two review authors will independently handle the screening of literature and data extraction. Each trial will be evaluated for major sources of bias with the "classic risk of bias tool" used in the Cochrane Collaboration tool from 2011. We will use Review manager (RevMan) or R with the meta package to perform the meta-analysis. We will perform a trial sequential analysis on the meta-analysis of our primary outcome, providing an estimate of statistical reliability. Two review authors will independently assess the quality of the body of evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We will use GRADEpro software to conduct the GRADE assessments and to create "Summary of the findings" tables.

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.

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.

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.

Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how.

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.

Assessing assumptions for statistical analyses in randomised clinical trials.

In order to ensure the validity of results of randomised clinical trials and under some circumstances to optimise statistical power, most statistical methods require validation of underlying statistical assumptions. The present paper describes how trialists in major medical journals report tests of underlying statistical assumptions when analysing results of randomised clinical trials. We also consider possible solutions how to improve current practice by adequate reporting of tests of underlying statistical assumptions. We conclude that there is a need to reach consensus on which underlying assumptions should be assessed, how these underlying assumptions should be assessed and what should be done if the underlying assumptions are violated.

[Dialysis catheter placement in a persistent left-sided superior vena cava].

Persistent left-sided superior vena cava (PLSVC) is a central venous anomaly in up to 0.5% of the population. It is usually asymptomatic due to drainage into the right atrium via the coronary sinus. This case report describes placement of a dialysis catheter in a 55-year-old patient with PLSVC and subsequent complications following the uncertainty of the placement. In 10%, PLSVC drains to the left atrium inducing risk of left-to-right shunt and fatal paradoxical emboli in case of catheterisation. Hence, clarification of the central venous haemodynamics by relevant imaging modalities is advised, if suspicion arises.

Preoperative airway assessment - experience gained from a multicentre cluster randomised trial and the Danish Anaesthesia Database.

Difficulties with airway management in relation to general anaesthesia have been a challenge for the anaesthesiologist since the birth of anaesthesia. Massive landmark improvements have been made and general anaesthesia is now regarded as a safe procedure. However, rare, difficult airway management still occurs and it prompts increased risk of morbidity and mortality - especially when not anticipated. Several preoperative risk factors for airway difficulties have been identified, yet none have convincing diagnostic accuracy as stand alone tests. Combining several risk factors increase the predictive value of the test and multivariable risk models have been developed. The Simplified Airway Risk Index (SARI) is a predictive model developed for anticipation of a difficult direct laryngoscopy. However, neither the diagnostic accuracy of the SARI nor of any other model has been tested prospectively and compared with existing practice for airway assessment in a randomised trial setting. The first objective of this thesis was to quantify the proportion of unanticipated difficult intubation and difficult mask ventilation in Denmark. The second objective was to design a cluster randomised trial, using state of the art methodology, in order to test the clinical impact of using the SARI for preoperative airway assessment compared with a clinical judgement based on usual practice for airway assessment. Finally, to test if implementation of the SARI would reduce the proportion of unanticipated difficult intubation compared with usual care for airway assessment. This thesis is based on data from the Danish Anaesthesia Database (DAD). Paper 1 presents an observational cohort study on 188,064 patients who underwent tracheal intubation from 2008 to 2011. Data on the anaesthesiologists' preoperative anticipations of airway difficulties was compared with actual airway management conditions, thus enabling an estimation of the proportion of unanticipated difficulties with intubation and mask ventilation. Papers 2 and 3 outline the methodology and the pre-trial calculations and considerations leading to the DIFFICAIR trial described in Paper 4. The trial was designed to randomise anaesthesia department to either thorough education in, and subsequent use of the SARI for preoperative airway assessment or to continue usual care. Registration of the SARI in DAD was made mandatory in SARI departments and impossible in usual care departments. Conditions regarding anticipation of difficulties and actual airway managements were recorded as for Paper 1. DAD data made it possible to estimate an appropriate sample size, considering the between cluster variation, and to construct a stratification variable based on 2011 baseline values of the primary outcome used in the DIFFICAIR trial. Paper 1 revealed that 1.86% of all patients who were intubated, but not planned for advanced intubation techniques (e.g. video laryngoscopy), were unanticipated difficult to intubate. However, 75 to 93% of all difficult intubations were unanticipated. Furthermore, 94% of all difficult mask ventilations were unanticipated. In Paper 4, 59,514 patients were included in the primary analyses. The proportion of unanticipated difficult intubations was 2.38% (696/29,209) in SARI departments and 2.39% (723/30,305) in usual care departments. The adjusted odds ratio was 1.03 (95% CI: 0.77-1.38), p = 0.84. No significant differences were detected in other adjusted outcome measures and neither a 58% increase in patients anticipated to have intubation difficulties nor an 84% increase in patients scheduled for advanced intubation techniques in SARI departments reached statistical significance, p = 0.29 and p = 0.06 respectively. The papers constituting this thesis demonstrate that at high proportion of airway management difficulties are unanticipated. In a cluster randomised trial it was not possible to reduce the proportion of unanticipated difficult intubation in daily clinical practice by implementing a systematic approach for airway assessment compared with usual care. However, implementation of the SARI may increase the anticipation of intubation difficulties and it may change practice towards advanced intubation techniques. This thesis underlines the continued challenge anaesthesiologists face in predicting airway management related difficulties.

Detailed statistical analysis plan for the difficult airway management (DIFFICAIR) trial.

BACKGROUND: Preoperative airway assessment in Denmark is based on a non-specific clinical assessment left to the discretion of the responsible anesthesiologist. The DIFFICAIR trial compares the effect of using a systematic and consistent airway assessment versus a non-specific clinical assessment on the frequency of unanticipated difficult airway management.To prevent outcome bias and selective reporting, we hereby present a detailed statistical analysis plan as an amendment (update) to the previously published protocol for the DIFFICAIR trial. METHOD/DESIGN: The DIFFICAIR trial is a stratified, parallel group, cluster (cluster = department) randomized multicenter trial involving 28 departments of anesthesia in Denmark randomized to airway assessment either by the Simplified Airway Risk Index (SARI) or by a usual non-specific assessment. Data from patients' preoperative airway assessment are registered in the Danish Anesthesia Database. An objective score for intubation grading the severity, that is the severity of the intubations, as well as the frequency of unanticipated difficult intubation, is measured for each group.Primary outcome measures are the fraction of unanticipated difficult and easy intubations.The database is programmed so that the registration of the SARI is mandatory for the intervention group but invisible to controls.Data recruitment was commenced in October 2012 and ended in ultimo December 2013. CONCLUSION: We intend to increase the transparency of the data analyses regarding the DIFFICAIR trial by an a priori publication of a statistical analysis plan. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01718561.

Incidence of unanticipated difficult airway using an objective airway score versus a standard clinical airway assessment: the DIFFICAIR trial - trial protocol for a cluster randomized clinical trial.

BACKGROUND: Pre-operative airway assessment in Denmark is based on a non-specific clinical assessment. Systematic, evidence-based and consistent airway assessment may reduce the incidence of unanticipated difficult airway management. By assessing multiple predictors for difficult airway management, the predictive value of the assessment increases. The Simplified Airway Risk Index (SARI) is a multivariate risk score for predicting difficult intubation.This study aims to compare the use of the SARI with a non-specified clinical airway assessment on predicting difficult intubation. Further, to compare the examination and registration of predictors for difficult mask ventilation with a non-specified clinical airway assessment on prediction of difficult mask ventilation. METHOD/DESIGN: We cluster-randomized 28 Danish departments of anaesthesia to airway assessment either by the SARI or by usual non-specific assessment. Data from patients' pre-operative airway assessment are registered in the Danish Anaesthesia Database. Objective scores for intubation and mask ventilation grade the severity of airway managements. The accuracy of predicting difficult intubation and mask ventilation is measured for each group. The primary outcome measure is the fraction of unanticipated difficult and easy intubation.The fraction of unanticipated difficult intubation in Denmark is 1.87%. With a stratified randomization, type 1 error risk of 5% and a power of 80%, 30 departments are required to detect or reject a 30% relative risk reduction equalling a number needed to treat of 180. Sample size estimation is adjusted for the study design and based on standards for randomization on cluster-level. With an average cluster size of 2,500 patients, 70,000 patients will be enrolled over a 1-year trial period. The database is programmed so that registration of the SARI and predictors for difficult mask ventilation are mandatory for the intervention group but invisible to controls. DISCUSSION: It is innovative to use a national clinical database as the basis for a randomized clinical trial. The method can serve as a precedent for implementation of evidence-based recommendations and database registration.The trial will forward understanding of how to predict and reduce unanticipated difficult airways and how to produce evidence-based recommendations for airway assessment and clinical database development. TRIAL REGISTRATION: (NCT01718561).