Perioperative dexmedetomidine for the prevention of postoperative delirium after cardiac surgery: a systematic review, Bayesian meta-analysis, and Bayesian re-analysis of the DECADE trial.

Perioperative dexmedetomidine for the prevention of postoperative delirium after cardiac surgery: a systematic review, Bayesian meta-analysis, and Bayesian re-analysis of the DECADE trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Br J Anaesth . 2025 Apr 30;134(6):1671–1682. doi: 10.1016/j.bja.2025.02.031 Perioperative dexmedetomidine for the prevention of postoperative delirium after cardiac surgery: a systematic review, Bayesian meta-analysis, and Bayesian re-analysis of the DECADE trial Tessa Hunt 1, 2, † , Thomas Payne 1, 2, 3, ⁎, † , James M Brophy 4, 5, 6 , Joanne Irons 2 , Andy Y Wang 2 , Charles Cartwright 2 , Benjamin Moran 7, 8, 9 , John A Loadsman 1, 2 , Robert D Sanders 1, 2, 10, 11 Author information Article notes Copyright and License information 1 Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia 2 Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW, Australia 3 Royal Melbourne Hospital, Melbourne Health, Parkville, VIC, Australia 4 Department of Medicine, McGill University, Montreal, QC, Canada 5 Department of Epidemiology, McGill University, Montreal, QC, Canada 6 Department of Biostatistics, McGill University, Montreal, QC, Canada 7 Department of Intensive Care, Gosford Hospital, Gosford, Australia 8 Department of Anaesthesia and Pain Medicine, Gosford Hospital, Gosford, Australia 9 School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia 10 Institute of Academic Surgery, Royal Prince Alfred Hospital, Sydney Local Health District, New South Wales, Australia 11 NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW, Australia ⁎ Corresponding author. tompayne302@gmail.com † Co-first authors. Received 2024 Nov 20; Accepted 2025 Feb 25; Issue date 2025 Jun. © 2025 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies. PMC Copyright notice PMCID: PMC12106890  PMID: 40312168 Abstract Background Dexmedetomidine is seen as a promising agent for the prevention of postoperative delirium after cardiac surgery, but the largest study (DECADE) paradoxically suggested an increased risk of delirium. Methods Studies were selected using inclusion/exclusion criteria after conducting online database searches for randomised controlled trials. The primary outcome was the incidence of postoperative delirium with a minimum clinically important difference (MCID), defined as an odds ratio >1.20 or <0.84. Publication bias was quantified using Bayesian model averaging. A random-effects meta-analysis with weakly informative priors was performed. Bayesian re-analysis of DECADE using several different priors including a prior based on this meta-analysis (excluding DECADE) was also performed. Results We identified 12 eligible randomised controlled trials (3539 participants). The overall pooled effect showed a mean benefit from dexmedetomidine in delirium prevention (odds ratio 0.67 [95% credible interval 0.45, 0.92]), but any definitive evidence of benefit disappeared after accounting for publication bias (odds ratio 1.15 [95% credible interval 0.93, 2.51]). Bayesian re-analysis of the DECADE trial under a vague prior showed a 1.5% posterior probability of any benefit and only a 0.1% probability of an MCID for benefit. Combining DECADE with the unadjusted meta-analysis-derived prior increased the probability of an MCID for benefit to 17.8%, which decreased to 0.2% using the meta-analysis-derived prior adjusted for publication bias. Conclusions Pooled evidence suggests dexmedetomidine is associated with reduced incidence of postoperative delirium; however, this is highly sensitive to the possibility of publication bias. Bayesian re-analysis of the recently published DECADE trial showed the effect of dexmedetomidine differs markedly depending on the weight given to previous studies. Hence, any true benefit from the use of dexmedetomidine over standard care in this population cannot be definitively characterised at present. Systematic review protocol CRD42023401623 (PROSPERO). Keywords: Bayesian meta-analysis, Bayesian re-analysis, cardiac surgery, dexmedetomidine, postoperative delirium Editor's key points. • Ambiguity has emerged regarding the benefit of dexmedetomidine in reducing postoperative delirium in cardiac surgery patients. • Using Bayesian statistical methods, this meta-analysis quantified the role of publication bias in the field of dexmedetomidine for delirium prevention. • Bayesian re-analysis showed that the interpretation of the DECADE trial's results varies considerably depending on the weighting of other RCTs in the field. • The true effect of dexmedetomidine on postoperative delirium in adult cardiac surgery patients is yet to be definitively characterised, and additional high-quality data are required. Delirium is an acute syndrome characterised by fluctuating neurocognitive decline that presents as disordered thinking, altered consciousness, confusion, or inattention. 1 Postoperative delirium (POD) is a strong indicator for poor patient outcomes, 2 , 3 with 4–55% of cardiac surgery patients developing the condition. 4 The association between POD and cardiac surgery may be influenced by the effects of cardiopulmonary bypass 5 and patient factors (increased age, atrial fibrillation, cerebrovascular disease, and diabetes mellitus), perhaps mediated by inflammation and changes in cerebral perfusion during and after surgery. 3 , 6 Dexmedetomidine, an alpha-2 adrenoreceptor agonist with both sedative and analgesic action, has been promoted as a promising agent for delirium prevention after cardiac surgery. 7 , 8 Meta-analyses of this topic have generally observed a decrease in POD with dexmedetomidine, 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 although some studies have reported either no change 20 or no significant difference. 21 , 22 The most recent meta-analysis did not reach statistical significance when trials at high risk of bias were excluded (relative risk 0.71, 95% confidence interval [CI] 0.49–1.03; P =0.070). 23 In addition, this ambiguity is partially explained by the inclusion of the recently published and largest trial, DECADE, 24 which observed an increased risk of delirium with dexmedetomidine. These studies raise suspicion of publication bias, the presence of low-quality methodology in earlier randomised controlled trials (RCTs), or heterogeneity in trial methodology, including the quantity and timing of dexmedetomidine dosing, which may contribute to the variations in the statistical outcomes reported to date. 25 Therefore, we investigated this variability using a three-step approach. First, we performed a systematic review and Bayesian meta-analysis of the RCTs, providing quantification for the interpretation of effect size estimates and their associated uncertainties. Second, we enhanced the transparency of prior evidence by exploring the effect of publication bias on the pooled result using a Bayesian model-averaging approach. 26 Third, we used this pooled result as a prior probability for a Bayesian re-analysis of the DECADE trial to provide a more detailed evaluation of the risk of harm from dexmedetomidine that was suggested in this trial. Methods Review conduct This review was performed in accordance with the PRISMA guidelines ( Supplementary Appendix S1 ) and was prospectively registered in PROSPERO (ID: CRD42023401623). Search strategy We compared the pooled incidence of POD after cardiac surgery in RCTs comparing dexmedetomidine with control (placebo, opioid, or propofol) in adult patients aged >18 years and using a validated outcome measure for delirium diagnosis. Non-English language articles were excluded if translated text was not available. Studies with benzodiazepines as either a control agent or adjunctive therapy to one group only were also excluded, given that they may increase the rate of POD. 27 We also excluded retrospectively registered and unregistered RCTs in accordance with ICMJE guidance. 28 We included trials that were registered shortly after enrolment began but added a bias adjustment as described below. Computerised search strategies ( Supplementary Appendix S2 ) for the electronic databases Ovid Medline, Ovid Embase, and Cochrane Central were performed 17 February 17, 2023, and an updated search was conducted on February 25, 2024. Initial identification was based on titles and abstracts, with final selection based on a review of full texts. Identified studies were independently reviewed by two authors (TH and CC). Data extraction Data extraction was performed by one author (TH) in consultation with a second author (TP), before independent review by a third author (CC). Continuous outcomes were reported as mean and standard deviation, requiring some conversion from medians and interquartile ranges, as advised by the Cochrane Handbook. 29 , 30 Outcomes Postoperative delirium was our primary outcome with subgroup analysis according to the control agent and timing of dexmedetomidine dose. Prespecified secondary outcomes included the following: in-hospital and post-discharge mortality, arrhythmias, delirium duration, time to extubation, duration of ICU and hospital stay, bradycardia, and hypotension. Risk of bias The Cochrane Risk of Bias 2.0 tool was used to assess the risk of bias. The five categories evaluated were the randomisation process, deviation from intended intervention, missing outcome data, measurement of outcome, and selection of the reported result with each domain scored individually and independently (TH and CC). Any discrepancies were resolved by discussion. Final assessment can be found in Supplementary Table S1 . In addition, the REAPPRAISED checklist was used to evaluate the publication integrity of all studies ( Supplementary Appendix S3 ). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to assess the quality of evidence and summarise the findings of the primary outcome. Statistical analysis We used a Bayesian normal–normal random-effects model to pool studies on the natural log odds ratio (logOR) scale. In this hierarchal model, ‘shrinkage to the mean’ allows studies to borrow power from the other included studies, providing a ‘shrunk estimate’ of effect closer to the pooled mean. For the population effect (μ) and its standard deviation (τ), we report the median of the posterior distributions, with the 95% credible (percentile) interval (CrI) and the 95% prediction interval. 31 We exponentiated the mean effect (a logOR) to obtain the odds ratio (OR), for ease of interpretability. We interpreted the magnitude of heterogeneity (on the logOR scale) using commonly accepted cut-offs (τ≤0.1 = ‘low’; 0.1<τ≤0.5 = ‘reasonable’; 0.5<τ≤1.0 = ‘fairly high’; and τ>1.0 = ‘fairly extreme’). 31 We calculated the probability of dexmedetomidine having any benefit and the probability of that benefit exceeding the minimum clinically important difference (MCID). A Cohen's d of >0.1, equivalent to a logOR of >|0.18| (OR = 0.84 for benefit and 1.20 for harm), has been suggested as a reasonable MCID estimate, 32 with the range between these two values representing a region of practical equivalence (ROPE). To convert the MCID to the risk difference scale, we used the median control group rate as the reference level for calculation, which was 16.0%. The corresponding MCID for benefit was a 2.3% absolute risk reduction (ARR) in delirium, and the MCID for harm was a 2.5% absolute risk increase (ARI) in delirium. For our primary outcome, we used a weakly informative prior for μ, corresponding to a normal distribution with mean 0 and standard deviation 0.82 (on the logOR scale), and a weakly informative prior for τ, corresponding to a half-Cauchy distribution with a scale parameter of 0.5 (also on the logOR scale). We performed a sensitivity analysis using a vague prior (μ ∼ Normal(0, 4 2 ); τ ∼ half-Cauchy(4)). For subgroup analysis, we used a Normal(0, 0.82 2 ) prior for the regression coefficient and a Normal(0, 1 2 ) prior for the intercept. For binary secondary outcomes, we used the same priors as for our primary analysis, whereas for continuous outcomes, we used a Normal(0, 1 2 ) prior for μ. The potential bias of studies registered after beginning enrolment was modelled using a greater effect size previously observed for unregistered and retrospectively registered studies (ratio of ORs 0.81, 95% CI 0.65–1.02). 33 We multiplied 1000 random samples from the distribution of within-study effects (N(θ, σ 2 )) for each retrospectively registered trial by 1000 random samples from this ‘bias-correction’ distribution, N(0.81, 0.1 2 ), to obtain the bias-corrected within-study effects for inclusion in the meta-analysis. We assessed small study effects (including publication bias) using a Bayesian regression test for funnel plot asymmetry, with a multiplicative heterogeneity assumption. 34 This Bayesian method is an adaptation of Egger's test, which regresses the study's effect sizes on their latent (unobserved) standard errors ( SEs ) and may improve control of the false positive rate. Strongly positive β coefficients for the SE term in the regression analysis indicate funnel plot asymmetry. We also used a Bayesian model-averaging approach to account for publication bias, which averages effect estimates with their standard error (PET-PEESE) over possible selection models. 26 The output of this analysis is an inclusion Bayes factor (BF 10 ). Values >1 favour evidence of an effect, whereas those <1 favour the null hypothesis, with very large or small values implying a greater strength of evidence. The DECADE trial's published results were re-analysed using Bayesian logistic regression with various meta-analysis-derived and reference priors. Meta-analysis-derived priors were obtained from our meta-analysis, excluding the DECADE trial, and a reduced meta-analysis of studies at low risk of bias. 35 We also used a ‘publication bias-adjusted prior’, as described above, and ‘vague’, ‘neutral’, ‘sceptical’, and ‘optimistic’ reference priors, reflecting possible pre-existing beliefs towards dexmedetomidine. A wide range of reference priors has been suggested as a good quality control exercise for Bayesian analyses, 36 and these have been expressed as RCT-equivalent evidence for ease of interpretability. The size of each hypothetical RCT ( n =1000) is approximately similar to the size of the DECADE trial, meaning it should have an approximately similar influence on the posterior distribution. Descriptions of the priors are shown in Table 1 . Table 1. Description of priors used for the Bayesian re-analysis of DECADE trial. MA, meta-analysis; logOR, log odds ratio; MCID, minimum clinically important difference; RCT, randomised controlled trial. Prior Prior equivalent Description of prior Reference priors Vague Minimal information imposed on posterior estimate Does not favour one prior belief over another Sceptical Equivalent to a hypothetical n =1000 RCT showing a 31% increase in odds of delirium This effect size is 1.5 times the MCID for harm (logOR=0.27) Neutral 95% of the density lies between an odds ratio of 0.5 and 2.0 Plausible values for the effect are likely, with values closer to the null most likely Optimistic Equivalent to a hypothetical n =1000 RCT showing a 24% decrease in odds of delirium This effect size is the 1.5 times MCID for benefit (logOR= –0.27) Meta-analysis priors MA (all studies) Meta-analysis of n =2745 participants across 11 trials excluding DECADE This is similar in theory to a meta-analysis of all 12 studies; however, the analytical approach (hierarchical linear model vs . logistic regression) differs MA (low risk of bias studies only) Meta-analysis of n =787 participants across three low-risk trials excluding DECADE This attempts to attenuate the effects of various research bias parameters but using only high-quality studies MA (publication bias-adjusted estimates) Meta-analysis of n =2745 participants across 11 trials excluding DECADE, averaged across models to account for publication bias This attempts to attenuate the influence of publication bias in the literature Open in a new tab All analyses were performed in R (R Core Team, 2023. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/ ). We followed the Bayesian analysis reporting guidelines. 37 Bayesian analyses were performed using Stan via the front-end ‘brms’ package. 38 For binary outcomes, we used 4000 iterations with four chains and 2000 warm-up iterations. For continuous outcomes, we used 50 000 iterations with four chains, to optimise convergence, assessed by a Gelman–Rubin value ≤1.01 and visual inspection of trace plots ( Supplementary Fig. S1 ). The average treatment effect (ATE), used only for re-analysis of the DECADE trial, summarises the causal effect of dexmedetomidine across possible subpopulations. ATE was calculated using logistic regression followed by parametric g-computation for calculation of risk difference, 39 and delta methods for standard errors as provided by the ‘marginaleffects’ package. 40 The ‘RoBMA’ package was used for Bayesian model-averaged publication bias assessment. 26 The statistical code is publicly available at https://tompayne302.github.io/dex_cardiac_ma_2024/ , which also describes other packages used. A detailed description of the methodology can be found within the technical appendix or accessed via https://github.com/tompayne302/dex_cardiac_ma_2024 . Results Study inclusion As described in Figure 1 , of the 502 records identified by database searching, 58 full-text records were reviewed, from which a further 46 records were deemed ineligible. Authors were contacted on two instances: once for missing data, for which we received no reply, 41 and once to obtain an RCT manuscript included in previous meta-analyses, from which we could only obtain a non-English version 42 ; thus, it was excluded. Additional details about the excluded studies can be found in Supplementary Tables S2–S5 , including eight registered protocols that were complete but without available results. As summarised in Supplementary Table S3 , 22 studies included in previous meta-analyses were excluded in our study for various reasons, including the following: five with undefined or inappropriate delirium diagnostic tools, 43 , 44 , 45 , 46 , 47 four perceived to be too high risk, 48 , 49 , 50 , 51 four retrospectively registered, 52 , 53 , 54 , 55 and one retracted. 56 Of the 12 studies considered eligible, two began enrolment before obtaining registration, and we modified their effect size to account for this bias. 41 , 57 The characteristics of the included studies are outlined in Table 2 . Fig 1. Open in a new tab PRISMA flowchart. Table 2. Summary of characteristics for each of the included randomised control trials. DEX, dexmedetomidine; CABG, Coronary artery bypass graft; CAM, Confusion assessment method; CAM-S, Confusion assessment method severity; CAM-ICU, Confusion assessment method intensive care unit; RASS, Richmond agitiation sedation scale; DSM-IV, Diagnostic and statistical manual of mental disorders; ICDSC, Intensive care delirium screening checklist. ∗This outcome was reported with heterogeneity in the included studies. Best inference, calculations, or both have been used to estimate the infusion time and justified in Supplementary Table S6 . † Data not reported or cannot be deduced. ‡ Some secondary data are missing as outlined in the source manuscript. Reference Control agent Participants, n Total DEX Control Type of surgery, n (%) Intraoperative or postoperative DEX administration Total duration of DEX administration (h)∗ DEX loading dose DEX maintenance dose quantity Age, mean ( sd ) DEX control Sex, n (%) DEX Control Diagnostic tool for delirium Qu 2023 58 Normal saline or dextrose 5% in water 394 188 206 CABG only = 75 (19.0) Valve + CABG = 58 (14.7) Valve only = 178 (45.2) Other = 83 (21.1) Postoperative 0.83 No 1.0 μg kg −1 over 40 min 67.83 (7.47) 70.00 (7.47) M = 144 (76.6) F = 44 (23.4) M = 144 (69.9) F = 62 (30.1) CAM and CAM-S Momeni 2021 59 Normal saline 408 205 203 CABG only = 164 (40.2) Valve + CABG = 75 (18.4) Valve only = 126 (30.9) Other = 43 (10.5) Postoperative 10.00 No 0.4 μg kg −1 h −1 71.00 (–) † 70.00 (–) † M = 150 (73.2) F = 55 (26.8) M = 159 (78.3) F = 44 (21.7) CAM and CAM-ICU Likhvantsev 2021 60 Normal saline 169 84 85 CABG only = 95 (56.2) Valve + CABG = 16 (9.5) Valve only = 58 (34.3) Intraoperative and Postoperative 13.00 No 0.7 μg kg −1 h −1 62.60 (6.70) 62.40 (7.20) M = 62 (73.8) F = 22 (26.2) M =60 (70.6) F = 25 (29.4) CAM-ICU Turan 2020 24 Normal saline 794 ‡ 398 396 CABG = 11 (1.4) Other = 771 (98.6) Intraoperative and Postoperative 24.00 No 0.4 μg kg −1 h −1 63.00 (11.00) 62.00 (12.00) M = 266 (67.2) F = 130 (32.8) M = 287 (72.8) F = 107 (27.2) RASS and CAM-ICU Subramaniam 2019 61 Propofol 120 59 61 CABG only = 79 (65.8) Valve + CABG = 34 (28.3) Other = 7 (5.9) Postoperative <6.00 Yes 0.1–1.4 μg kg −1 h −1 67.50 (–) † 70.80 (–) † M = 51 (86.4) F = 8 (13.6) M = 50 (82.0) F = 11 (18.0) CAM and CAM-ICU Li 2017 62 Normal saline 285 142 143 CABG only = 204 (71.6) Valve + CABG = 39 (13.7) Valve only = 42 (14.7) Intraoperative and Postoperative 18.70 Yes 0.4 μg kg −1 h −1 66.40 (5.40) 67.50 (5.30) M = 95 (66.9) F = 47 (33.1) M = 102 (71.3) F = 41 (28.7) CAM and CAM-ICU Djaiani 2016 63 Propofol 183 91 92 – † Postoperative <24.00 Yes 0.2–0.7 μg kg −1 h −1 72.70 (6.40) 72.40 (6.20) M = 68 (74.7) F =23 (25.3) M = 70 (76.1) F = 22 (23.9) CAM and CAM-ICU Shehabi 2009 64 Morphine 299 152 147 CABG = 183 (61.2) Other = 116 (38.8) Postoperative 45.00 No 0.1–0.7 μg kg −1 ml −1 71.17 (7.48) 70.33 (7.49) M = 114 (75.0) F = 38 (25.0) M = 111 (75.5) F = 36 (24.5) CAM-ICU Maldonado 2009 65 Propofol 60 30 30 – † Postoperative <24.00 Yes 0.2–0.7 μg kg −1 h −1 55.00 (16.00) 58.00 (18.00) M = 26 (65.0) F = 14 (35.0) M = 22 (57.9) F = 16 (42.1) DSM-IV Wang 2023 66 Normal saline 652 326 326 Valve + CABG = 13 (2.0) Valve only = 639 (98.0) Intraoperative 4.01 Yes 0.4 μg kg −1 h −1 54.00 (11.80) 53.80 (12.60) M = 159 (48.8) F = 167 (51.2) M =166 (50.9) F = 160 (49.1) RASS and CAM-ICU Chitnis 2022 41 Propofol 67 34 33 CABG only = 44 (65.7) Valve + CABG = 13 (19.4) Valve only = 10 (14.9) Postoperative 4.40 No 0.0–1.5 μg kg −1 h −1 78.70 (–) † 78.80 (–) † M = 30 (88.2) F = 4 (11.8) M = 30 (90.9) F = 3 (9.1) ICDSC Soh 2020 57 Normal saline 108 54 54 Other = 108 (100.0) Intraoperative and Postoperative 24.00 No 0.4 μg kg −1 h −1 65.00 (–) † 65.00 (–) † M = 32 (59.2) F = 22 (40.7) M =34 (63.0) F = 20 (37.0) DSM-V Open in a new tab Primary analysis The overall forest plot summarising the association of dexmedetomidine with delirium for each of the studies included in the primary analysis with their risk of bias assessments is shown in Figure 2 a with weakly informative priors. The overall pooled mean effect for all 12 studies (bottom line in Fig. 2 a) is shown in an expanded view in Figure 2 b (OR 0.67 [95% CrI 0.45, 0.92]). There was reasonable to fairly high population-level heterogeneity (τ=0.39 [0.09, 0.75]). This high heterogeneity results in a wide prediction interval for a future study (95% CrI 0.24, 1.78) ( Fig. 2 b). Sensitivity analyses demonstrated a similar result with different priors ( Supplementary Table S7 ). The observed effect was less pronounced after removing studies at high risk of bias (OR 0.74 [95% CrI 0.52, 1.01]), and heterogeneity was marginally reduced (τ=0.34 [0.04, 0.69]) ( Supplementary Fig. S2 ). There was a 99.1% probability of dexmedetomidine having any overall beneficial effect compared with the control (area under the curve to the right of OR = 1 in Fig. 2 c = 0.9%), whereas the probability of dexmedetomidine providing an ARR of >2.3% (the MCID for benefit) was 91.0% ( Supplementary Table S8 ). Fig 2. Open in a new tab (a) Forest plot summarising the effects of dexmedetomidine on POD for each of the studies included in the primary analysis. Purple lines represent the assumed distribution of within-study effects. Blue curves represent the shrinkage distribution of each study towards the mean effect. The blue point intervals represent the median [95% CrI] for the shrinkage distribution of each study. The orange line represents the 95% prediction interval. Cochrane RoB assessments of all five domains are labelled D1–D5; ‘+’ indicates ‘low risk’, ‘?’ indicates ‘some concerns’, and ‘–’ indicates ‘high risk’. (b) Posterior distribution for the mean effect (μ) (blue line), with 66%, 80%, and 95% CrI for the mean represented by different shades of blue. The blue bar below represents the median and 95%CrI for μ. The orange bar below represents the median and 95% CrI. (c) Posterior distribution for the heterogeneity parameter (τ). The black bar represents the 95% CrI. (d) Contour-enhanced funnel plot for the outcome of POD. Plots falling on the left-hand side represent studies supporting benefits from DEX, whereas plots on the right-hand side support a harmful effect. CrI, credible interval; DEX, dexmedetomidine; POD, postoperative delirium; RoB, risk of bias. Small sample (including publication) bias Bayesian regression analysis revealed substantial evidence of funnel plot asymmetry when including all studies (β=3.86 [95% CrI 2.41, 5.50]) ( Fig. 2 d). Bayesian model averaging also showed strong evidence for publication bias (BF 10 = 214.2) that mitigated the effect of dexmedetomidine within the bias-corrected models (mean effect BF 10 = 0.58) ( Supplementary Table S9 ). Given the strong evidence for publication bias, sequential analysis for the primary outcome was not performed. Meta-regression The forest plots for subgroup analysis are presented in Supplementary Figure S3 . Studies comparing dexmedetomidine with propofol ( n =4) observed greater benefits than studies comparing dexmedetomidine with normal saline ( n =7). There was a 93% probability that the beneficial effect of dexmedetomidine on delirium was larger in studies of a propofol comparator than those of a normal saline comparator. There was an 85% chance that postoperative dose timing ( n =7) of dexmedetomidine was superior to intraoperative dose timing ( n =1) and an 83% chance that postoperative dose timing was superior to combined intraoperative and postoperative dose timing ( n =4). There was no meaningful difference between intraoperative and postoperative dose timing compared with intraoperative dosing (posterior probability of superiority = 53%) ( Supplementary Table S10 ). Dose timing was also estimated to account for 16.5% of the observed population-level heterogeneity, whereas the control agent used accounted for 30.4% ( Supplementary Table S11 ). Secondary outcomes The only secondary outcome for which the 95% CrI for the mean excluded the null was delirium duration, which was reduced by 0.43 days on average by dexmedetomidine (95% CrI –0.84, –0.02) with reasonable heterogeneity (τ=0.20 [0.01, 0.71]), based on eight studies. Other secondary outcomes are reported in Supplementary Figure S4 and Supplementary Table S12 . GRADE assessments To investigate variability across various quality indicators, we performed GRADE assessments. Overall GRADE assessments were classified as ‘low’ or ‘very low’ for all outcomes analysed. Substantial concerns were noted in four of the five categories assessed: risk of bias, imprecision, inconsistency, and publication bias ( Supplementary Table S13 ). GRADE assessment for the summary of findings is detailed in Supplementary Table S14 . DECADE re-analysis Reference priors reflect possible attitudes towards the effect of dexmedetomidine, which are expressed as RCT equivalents. Plots of the prior and posterior distributions are shown in Figure 3 . Our results show that across all reference priors for the DECADE trial's results, there remained a significant chance of increased odds of delirium from dexmedetomidine. When using a vague prior, the DECADE trial shows dexmedetomidine to have a 0.1% chance of clinically important decreased odds of delirium (blue area under the vague curve to the right of the upper limit of the grey ROPE area). Even with an optimistic prior, incorporating DECADE data results in a posterior distribution with a 3.6% chance of clinically important decreased odds of delirium. Across meta-analysis-derived priors, the overall probability that the benefit exceeds the MCID decreases when using only studies at low risk of bias to create the prior (17.8% when using all studies and 9.8% when using only studies at low risk of bias). When using the publication bias-adjusted meta-analytic estimate as the prior, the posterior probability of clinically important odds of benefit was low (0.2%). Fig 3. Open in a new tab (a) Details of the prior distributions (reference priors and meta-analysis-derived priors) used for the DECADE trial re-analysis. The ‘prior mean’ has been exponentiated from the log odds ratio scale to the odds ratio scale; however, the ‘ sd ’ remains on the log odds ratio scale. (b) Forest plot showing the prior, posterior, and likelihood distributions for each analysis. The shaded grey region denotes the ROPE. Purple curves show the likelihood from the DECADE trial (identical for each analysis). Grey curves represent the prior distribution, corresponding to the ‘prior mean +/- [ sd] ’ from (a). The black curves show the posterior distributions, teal regions suggest benefit, and red regions suggest harm. The black point interval beneath each curve represents the median and 95% credible (percentile) interval for the posterior distribution. (c) The probabilities of any harm or benefit, and the harm or benefit exceeding the MCID, are shown for each prior. (d) Median and 95% credible interval for the ATE from the DECADE trial, in the form of a risk difference (units are percentage points). ROPE, region of practical equivalence; MA, meta-analysis; MCID, minimum clinically important difference; ATE, average treatement effect. The ATE, in this case, the risk difference, was calculated from the logistic regression model using g-computation to provide interpretable effect measures. Using the sceptical and vague priors showed that there was a 95% probability that the risk difference for delirium with dexmedetomidine was >0 percentage points (pp.) (risk difference 4.2 pp. [95% CrI 0.9, 7.5] and 5.2 pp. [95% CrI 0.4, 10.0], respectively) ( Fig. 3 d and Supplementary Table S15 ). Discussion Overall, we observed a beneficial association between dexmedetomidine and reduced incidence of POD; however, this disappeared after accounting for publication bias. Re-analysis of the DECADE trial using vague priors confirmed the finding of increased delirium risk that was reported in the original DECADE manuscript. DECADE re-analysis using evidence from other RCTs as a prior reduced this chance of harm significantly; meanwhile, adjusting this prior for publication bias resulted in a high likelihood of increased delirium risk. Although our data suggest that the re-appraisal of DECADE's findings is complicated based on issues around publication bias and how prior data are weighted, it is worth emphasising that there are several issues with the DECADE trial that limit generalisability of responses, including the prolonged and rigid dosing schedule (which may be in an excess of the therapeutic dose in extubated patients), 58 limited data on additional drug exposures, haemodynamics, and lack of data on other delirium and arousal metrics. Hence, more evidence is required to clarify the effects of dexmedetomidine (if any) on delirium and identify which patient populations may benefit or be harmed. Our work contributes to a growing body of evidence supporting the uncertainty of dexmedetomidine's true effect on delirium in cardiac surgery patients. Although past meta-analyses were supportive of dexmedetomidine in this application, 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 recent work suggested studies at high risk of bias were possibly inflating the observed benefit. 23 Our finding that studies comparing dexmedetomidine with propofol showed greater benefit than studies with a normal saline comparator is likely attributable to the large influence of the DECADE trial on the pooled result (which used a normal saline comparator). The possibility of publication bias in this field has been noted in recent work, 23 but when previously investigated using conventional methods, it was not found to be a likely confounder. 11 , 20 We demonstrated how the presence of publication can significantly change the interpretation of dexmedetomidine's effect. To help clarify whether the discordance in results between DECADE and other studies arises from publication bias or heterogeneity of treatment effect, the mechanisms by which dexmedetomidine may transduce benefit, harm, or both must be scrutinised. Analysis and reporting of adverse events in RCTs is notoriously poor, 67 rendering meta-analyses of these outcomes problematic. Of the 12 RCTs included in this meta-analysis, only five reported bradycardia, whereas six reported hypotension. In contrast to our pooled analysis showing no difference in the incidence of hypotension, the DECADE trial found that patients who received dexmedetomidine were at significantly higher risk of hypotension. 24 The observed hypotension was postulated as a causal link for POD in the DECADE trial, although no significant association was observed on further testing. 24 , 68 This hypothesis is challenged by a recent RCT of ovine models, which found that dexmedetomidine did not reduce cerebral perfusion or neuroinflammation compared with the control. 69 Hence, although such mechanisms may be involved in the pathophysiology of delirium, they do not appear to be mediated by dexmedetomidine. 69 The mechanism by which dexmedetomidine may transduce benefit is also not clear. However, the sleep-promoting, neuroprotective, and anti-inflammatory properties of dexmedetomidine have been used to advocate for the possibility of its delirium-sparing effect. 7 , 8 Qu and colleagues 58 investigated the role of nighttime dosing of dexmedetomidine postoperatively. Their results suggest that sleep functions such as immune modulation may explain the observed reduction in POD. 58 Such a mechanism could be supported by our findings, which showed a favourable effect of postoperative administration of dexmedetomidine. Additional hypotheses suggest that dexmedetomidine may exert its delirium-sparing effects via reno-protective pathways, as implied by the observed reduction in acute kidney injury after dexmedetomidine administration. 18 , 57 , 70 Finally, it is also plausible that dexmedetomidine reduces delirium in some patients and increases it in others. If this were true, it would be important to identify the patient or dose administration characteristics that would signify a likelihood of response. Unfortunately, parallel-group RCTs are generally underpowered to detect subgroup–treatment interactions, 71 whereas the variability between study protocols adds further challenge. This underscores the need to continue basic scientific research into putative mechanisms of benefit and harm. A key strength in our approach was the use of a Bayesian framework, allowing for the reporting of interpretable effect size estimates and their associated uncertainties, the inclusions of prior evidence, and the ability to analyse more complex models including those accounting for possible publication bias. 39 In addition, our adherence to strict inclusion and exclusion criteria during study selection endeavours to clean up the current pool of evidence used to answer this question. This very nontrivial exercise saw the exclusion of 22 studies with a total of 12 748 subjects for fatal biases (see Supplementary Table S4 ) and the need for bias correction for two others. As has been previously observed, 72 biased studies are associated with exaggerated effect sizes, and these fatally flawed and excluded trials had a cumulative strongly positive dexmedetomidine effect (OR 0.64, 95% CI 0.50–0.82). This speaks loudly to the need for careful assessment of trial methodology and not to merely include all identified studies without critical appraisal when performing a meta-analysis. This large number of unworthy trials also underscored previous concerns about research waste. 73 This review also had some limitations. The decision to exclude studies with asymmetrical use of benzodiazepines across control and intervention groups was intended to reduce any potential confounding effect of such agents. Controversy ensues with a recent study suggesting that POD may not be increased by their use but is instead associated with dexmedetomidine. 74 Existing issues with delirium diagnosis include variability in the sensitivity of different methods in detecting hypoactive vs hyperactive presentations. An attempt to mitigate this was made during study selection with inclusion criteria for validated diagnostic tools and exclusion of studies where the diagnostic approach has not been adequately specified because of the lack of objectivity and consistency that may arise in detecting the primary outcome, including the nature, duration, or frequency of clinical features considered or personnel involved in diagnosis. Among the 12 RCTs included for primary analysis, there was considerable variability in study design, including protocols for induction and maintenance of anaesthesia. The available evidence is complicated by different control regimes and agents used here to form a common comparator to assess dexmedetomidine against available alternatives and should be considered alongside subgroup analysis. Additional variability was evident in the reporting of intervention administration between studies. As such, data for dexmedetomidine timing, duration of infusion, and time to extubation were extracted with caution using inference and assumption where necessary, as described above. In summary, this work does not summarise all available evidence but instead includes only the best methodological trials, albeit with different regimens against the nearest best comparator. Conclusions Overall pooled evidence from RCTs suggests that dexmedetomidine is associated with reduced incidence of postoperative delirium after cardiac surgery; however, this appears to be largely influenced by the presence of publication bias. We found that a significant chance of harm from dexmedetomidine remained when analysing the DECADE trial using a prior derived from other RCTs in the field and when adjusting for publication bias. Although we did not find a difference in safety outcomes across the included RCTs, this is likely complicated by limited reporting and, consequently, insufficient data. The interpretation of the DECADE trial's results varies considerably depending on the weighting attributed to other RCTs in the field. We conclude that the true effect of dexmedetomidine on postoperative delirium in adult cardiac surgery patients is yet to be definitively characterised. Funding No funding was recieved for this research. Authors' contributions Study design: RDS, TP, and TH {in consultation with JAL). Data extraction: AYW, JI, and BM. CC, TH, and TP (in discussion with RDS. TP, AYW, JMB) Data analysis: BM Drafting of manuscript: TH (with input from TP). All authors provided critical feedback on the manuscript and approved the final version. Declaration of interest RDS holds grant ( GA332267 ) from National Health and Medical Research Council (NHMRC) for the DECIDE study: Dexmedetomidine in Cardiac Surgical Intraoperative Drug Evaluation. Handling Editor: Jonathan Hardman Footnotes Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2025.02.031 . Appendix A. Supplementary data The following is the Supplementary data to this article: Multimedia component 1 mmc1.docx (1.4MB, docx) References 1. Lee J, Wong E, Marr S, Patterson C. Delirium. McMaster Textbook of Internal Medicine . Krawkow: Medycuna Praktyczna. Available from: https://empendium.com/mcmtextbook/chapter/B31.II.21.21 (accessed January 2023). 2. Evans A., Weiner M., Arora R., et al. Current approach to diagnosis and treatment of delirium after cardiac surgery. Ann Card Anaesth. 2016;19:328. doi: 10.4103/0971-9784.179634. 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