Intravenous Dexmedetomidine in adult cardiac surgery: a protocol of an umbrella review

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However, recent studies and meta-analyses have been shown mixed results on its safety and effectiveness, with some studies indicating possible risks. This study seeks to assess the quality, biases, and effectiveness of all existing systematic reviews on dexmedetomidine in adult cardiac surgery to offer clearer evidence-based insights. Methods A quantitative umbrella review will assess the impact of intravenous dexmedetomidine on outcomes in adult cardiac surgery, focusing on major adverse cardiovascular events, postoperative atrial fibrillation, acute kidney injury, delirium, and ICU stay duration. Relevant literature up to August 1, 2025, will be sourced from PubMed, Embase, Cochrane Database of Systematic Reviews, and Web of Science using a comprehensive search strategy. Two independent reviewers (XTJ and MY) initially screened study titles and abstracts, resolving any disagreements with a third reviewer (GYY). Full texts of studies passing this stage were evaluated by two other reviewers (YL and SJ) using set criteria. Data extraction, methodology quality assessment, and evidence level assessment were independently completed by two people (XHB and WW). The meta-analysis was grouped according to the patients' outcomes. Data conflicts and overlaps will be used updated methods like concordance correlation analysis (CCA). Evidence synthesis involved corrected overlap analysis and meta-analysis of original studies. Discussion This umbrella review expects to systematically assess the impact of perioperative intravenous Dexmedetomidine administration on the prognosis of adult cardiac surgery. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, clarified the beneficial or adverse effects of dexmedetomidine on adult cardiac surgery. Trail registration CRD420251128632 Background Cardiac surgery is vital for treating severe heart disease, including congenital heart disease, coronary artery disease, and heart valve disease. However, it often leads to complications like postoperative major adverse cardiovascular events, arrhythmia, neurological complications, and acute kidney injury, which can negatively impact patient outcomes and increase healthcare costs [ 1 – 4 ]. Dexmedetomidine, activating α2-adrenergic receptors in the central nervous system, provides sedation, pain relief, and reduces sympathetic activity༻5.6༽. Compared to traditional drugs, it better manages cardiovascular stress during cardiac surgery by lowering plasma catecholamine levels and stabilizing heart rate and blood pressure. Its anti-inflammatory and antioxidant effects may also protect organs like the heart, brain, and kidneys, potentially decreasing postoperative complications༻7.8༽. It is widely used in the perioperative period for cardiac surgery patients. Recently, there has been an increase in the number of randomized controlled trials examining the use of dexmedetomidine in adult cardiac surgery [ 9 – 13 ], which has resulted in numerous systematic reviews and meta-analyses. The outcomes evaluated include postoperative delirium, atrial fibrillation, organ function, major adverse cardiovascular events, the duration of ICU/hospitalization, and mortality༻14–16༽. Although some reviews suggest that dexmedetomidine may reduce the incidence of postoperative delirium༻17༽,The expert consensus review on perioperative brain health emphasizes the prioritization of non-pharmacological interventions-such as early mobilization, cognitive stimulation, and effective pain management-as the primary strategy. Conversely, pharmacological interventions, including the use of dexmedetomidine for delirium prevention, require a thorough evaluation of their associated risks and benefits.༻18༽. This recommendation is due to the fact that the systematic review results of different researchers are contradictory to each other༻19.20༽. Umbrella review (also known as overview of systematic reviews),is a publication type, emerging as the result of explosive growth of systematic reviews. It allows findings of separate reviews to be compared, formulating a comprehensive but concise conclusion, providing decision-makers with the evidence they need [ 21 ]. In term of the hierarchy of evidence synthesis methods, some consider umbrella reviews to be in the highest evidence level, superseding meta-analysis, systematic reviews, and individual studies༻22༽. Methods This protocol was strictly developed in accordance with the Preferred Reporting Items for Systematic Review and Meta - Analysis Protocols (PRISMA - P) guidelines [ 23 ]. The protocol of review was registered with the International Prospective Register of systematic reviews (PROSPERO). Results of this umbrella review will be published in a peer-reviewed journal. Potential changes to the protocol will be described in the final umbrella review report. The following sections will refer to an umbrella review following Overviews of Reviews guidelines in the Cochrane Handbook for Systematic Reviews of Interventions as a “Cochrane overview” [ 24 ]. Searches, study selection, data extraction, methodology quality assessment,and strength of evidence assessment will be conducted by two reviewers independently and in duplicate, with disagreements solved through discussion with a third reviewer. Criteria for selecting This study includes all systematic review and meta-analysis of randomized controlled trials, cohort studies, and case-control studies to assess the impact of intravenous dexmedetomidine on outcomes in adult cardiac surgery. The exclusion criteria 1)encompassed studies utilizing dexmedetomidine in combination with other pharmacological agents as an intervention or exposure factor, 2)network meta-analyses, 3)non-English language studies, 4)and research involving animal models or cell cultures. The research area focuses on meta-analyses of systematic reviews concerning cardiac surgery patients who received intravenous dexmedetomidine during the perioperative period, regardless of participants' race, gender, country, or region. population The population consists of adult cardiac surgery patients. Intervention The intervention is the perioperative administration of intravenous dexmedetomidine Control the control measure involves the use of a placebo or other non-dexmedetomidine medications. Outcomes The outcomes of interest include any outcomes in the patient, such as Major Adverse Cardiovascular Events, postoperative delirium, post-surgical atrial fibrillation incidence, and acute kidney injury, as well as changes in relevant clinical indicators, including duration of mechanical ventilation, and length of hospital stay. Search strategy The search strategy used Mesh terms combining free terms, encompassing data from the inception of the databases up to August 1, 2025. The databases utilized in this process include PubMed, Embase, the Cochrane Systematic Reviews Database, and the Web of Science. The literature search will be limited to English. Citation abstracts and full text of search results will be imported to Zotero software (Detailed search strategy in each database is outlined in Additional file 1.). Data extraction Data extraction involved two reviewers independently gathering key information from each study, including: 1) First author and publication year; 2) Characteristics of the population; 3) characteristics of the Dexmedetomidine and comparator (type, dose, intensity, frequency, duration); 4) surgical type; 5) primary and secondary outcomes; 6) Number of participants; 7) number of primary studies; 8) the type of statistical analysis that was used;9) quality assessment method for reviews, pooled effect size (ES), confidence interval (CI) or standard error (SE), measurement of ES, meta-analyses method, p value of pooled ES, and heterogeneity (Cochrane Q or I 2 statistics). The following information at primary studies level will be extracted in each meta-analyses: name of the first author, year of publication, study design, exposure of interest, comparison, precalculated ES, CI or SE, measurement of ES, effect model type. Risk of Bias Assessment Conducting a rigorous risk-of-bias assessment for each included systematic review (SR) is fundamental to ensuring the quality of an umbrella review. This assessment process will adhere to the principles of dual and hierarchical evaluation to guarantee comprehensiveness and objectivity. To maintain objectivity and reproducibility, all risk-of-bias assessments will be independently conducted by two researchers. Prior to the assessment, the researchers will perform a pilot test on a small sample of literature to standardize their understanding and judgment criteria for each aspect of the assessment tool. In instances of disagreement during the assessment process, resolutions will be sought through discussion and negotiation; if consensus cannot be achieved, a third-party expert will be consulted to make the final decision. 1.Selection and Hierarchical Implementation of Assessment Instruments The risk-of-bias evaluation in the umbrella review will conducted at two distinct levels. The first level involves assessing the methodological quality of the included systematic reviews themselves. The second level requires evaluating the risk of bias in the original studies incorporated within these systematic reviews, as reported in their respective documents. To ensure rigor, we will prioritize the use of internationally recognized assessment tools for evaluating the methodological quality of systematic reviews. AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews 2) is currently regarded as the gold standard for evaluating the methodological quality of systematic reviews (SRs) [ 25 ], encompassing both those with randomized controlled trials (RCTs) and non-RCTs. In our study, we will employ its 16 items to conduct a comprehensive evaluation of each included SR. Particular attention will be given to critical areas such as the pre-registration of research protocols, the comprehensiveness of the literature search, the independence of data extraction and risk of bias assessment by two reviewers, the adequacy of addressing bias risks in the original studies, the appropriateness of the meta-analytic methods employed, and the consideration of publication bias. Based on the AMSTAR-2 rating criteria, the overall confidence in each SR will be categorized as "high," "moderate," "low," or "very low." 2.Assessing the risk of bias in the primary studies included in systematic reviews (SRs) The core of an umbrella review is to synthesize high - quality primary evidence. Therefore, we need to examine and summarize how each SR assesses the risk of bias in the primary studies it includes. First, we will extract and aggregate the results of the risk - of - bias assessments of the primary studies reported in each SR [ 26 ]. Many SRs use the Cochrane risk - of - bias assessment tool. According to the standardized Cochrane tool, for randomized controlled trials (RCTs) included in SRs, to use the criteria of the second version of the Cochrane risk - of - bias assessment tool (RoB 2) as the basis for judgment. For potential non-randomized intervention studies (nRCTs), we will use the criteria of the ROBINS - I (Risk of Bias In Non - randomized Studies - of Interventions) tool for review. The Newcastle-Ottawa Scale (NOS) tool was used to evaluate observational studies. Different SRs may vary in the application of the same risk - of - bias assessment tool, and even directly adopting the assessment results of SRs in an umbrella review may introduce bias. Therefore, if we find that the process of a particular SR's assessment of the risk of bias in the included studies is opaque, the criteria are unclear, or the results differ significantly from those of other high - quality SRs, we will independently re - evaluate the key primary studies in that SR based on RoB 2, ROBINS - I or NOS tool. Data collection and analysis When synthesizing multiple systematic reviews (SRs), it is common to encounter instances where divergent or even contradictory results are reported for the same outcome indicator. Such discrepancies may arise from variations in the included primary studies, errors in data extraction, differences in analytical methods, or differing definitions of subgroups. In cases where different SRs report varying data for the same outcome indicator from the same original study, we will conduct a direct search and verification of the original research literature to ensure the use of the most accurate data. When two or more SRs present contradictory conclusions due to the inclusion of different sets of original studies, we will prioritize the results of the SR with the highest methodological quality, as assessed by the AMSTAR-2 tool. Preference will be given to the SR that is more recent and comprehensive. Discrepant findings frequently indicate the presence of clinical or methodological heterogeneity. To explore and elucidate these inconsistencies, we plan to perform subgroup analyses based on variables such as the duration of dexmedetomidine use, dosage or administration duration, and type of surgery. If the data permits, a meta - regression analysis will be performed. If the contradictions remain unresolved through the methods, we will include a narrative description in the results section. This will clearly articulate the existing contradictions and explore their potential causes and implications for clinical practice, rather than attempting to forcibly integrate these results. 2.Handling Missing Data Missing data presents a prevalent challenge in meta-analysis, potentially resulting in bias and diminished precision [ 27 ]. We will implement various strategies to address missing data, tailored to the specific type encountered. Irrespective of the type of missing data, our primary approach involves reaching out to the authors of the systematic reviews or the original studies to obtain the necessary information༻28༽. This process will be meticulously documented. In instances where original studies do not report the core outcome indicators of interest༻29༽, we will document this omission in our analysis and assess its potential impact through sensitivity analysis. According with the guidelines outlined in the Cochrane Handbook, we will endeavor to calculate or estimate the SD from other available statistical data, such as confidence intervals(CIs), standard errors(SE), t-values, or p-values. Imputation will be considered only when the standard deviation cannot be derived through calculation, and the study is deemed critical to the overall analysis. Imputation methods will adhere to a conservative approach. Data Synthesis and Statistical Methods We prefer to conduct a quantitative meta-analysis, but if there's too much clinical heterogeneity or inconsistent data formats among the included SRs, we'll use narrative synthesis. This approach will systematically organize and summarize the findings and critically interpret them alongside the risk of bias assessment. In conducting quantitative data synthesis, such as a new meta-analysis or meta-meta-analysis, we will adhere to established statistical methodologies. For effect size selection, binary outcomes (e.g., mortality rate, incidence of atrial fibrillation) will be evaluated using the risk ratio (RR) or odds ratio (OR), along with their 95% confidence intervals (CI). For continuous outcomes (e.g., length of stay in the ICU, length of Dexmedetomidine), the mean difference (MD) or standardized mean difference (SMD), accompanied by their 95% CI, will be calculated. Regarding the statistical model, due to the anticipated clinical and methodological heterogeneity arising from the diverse sources of systematic reviews (SRs) included in an umbrella review, as well as the variability of the original studies, we will primarily employ the random-effects model for data pooling. This model accounts for both within-study and between-study variations. To assess statistical heterogeneity among studies, we will utilize Cochran's Q test and the I² statistic. The I² statistic is employed to quantify the extent of heterogeneity, with values less than 25% indicating low heterogeneity, values between 25% and 75% indicating moderate heterogeneity, and values exceeding 75% indicating high heterogeneity. In instances where significant statistical heterogeneity is detected (e.g., P 50%), we will undertake a thorough investigation of its sources. To elucidate the origins of heterogeneity, subgroup analyses will be performed based on predetermined covariates, such as patient population characteristics, dexmedetomidine dosing, style of surgical, and the methodological quality of systematic reviews. If the number of subgroups is adequate, meta-regression analysis will be considered to quantify the influence of specific factors on the effect size. Regarding publication bias assessment, when the number of included primary studies is sufficient (typically ≥ 10), we will evaluate potential publication bias by constructing a funnel plot and conducting Egger's test or Begg's test. All statistical analyses will be executed using specialized meta-analysis software, such as the meta and metaumbrella packages in the R programming language, and RevMan. Strength of evidence assessment The GRADE system is predominantly employed in umbrella reviews for the quantitative assessment of systematic reviews [ 30 ]. Applying the GRADE framework to umbrella reviews presents significant challenges༻31༽, primarily due to the "methodological mismatch" between its original design intent and the current application context. The focus of the core downgrading criteria in GRADE has shifted from a single original study to a compilation of multiple studies. Presently, there is an absence of a standardized approach for thoroughly assessing the overall risk of bias across multiple systematic reviews. The GRADE assessment of systematic reviews is highly dependent on the detailed reporting of the original studies included within these reviews༻32༽. If a systematic review fails to adequately report crucial information, such as the risk of bias and sources of heterogeneity in the original studies, it becomes impossible to accurately make downgrading judgments concerning "risk of bias" or "inconsistency." To address the challenges, the evidence evaluation process is bifurcated into two distinct phases. Initially, the methodological quality of the included systematic reviews is assessed utilizing the AMSTAR2 tool. Subsequently, a GRADE assessment is conducted on the body of evidence pertaining to specific outcomes. In instances where the evidence for a particular outcome predominantly originates from systematic reviews deemed to be of "very low" or "low" quality according to AMSTAR2, the evidence for that outcome will be downgraded for "risk of bias" during the GRADE assessment. Managing overlap Overlap of primary studies is a key methodological challenge for umbrella reviews. Different systematic review articles may include one or more identical original studies for data analysis, resulting in the repeated calculation of the same original data [ 33 ]. This redundancy can cause the final effect size to deviate from the true value, potentially leading to conclusions that may misguide clinical practice. Consequently, prior to data extraction and evidence synthesis, it is essential to assess the overlap among all included systematic reviews. Utilize the GROOVE tool to perform an overlap analysis of the selected systematic reviews [ 34 ]. Initially, import the reference lists from these reviews to automatically create an evidence matrix. Subsequently, employ the tool to automatically compute the total Corrected Covered Area (CCA) value and determine the overall overlap level༻35༽. Conduct pairwise CCA analyses and produce a heatmap illustrating paired combinations. For systematic reviews exhibiting significant overlapping, follow the guidelines outlined in the Cochrane Handbook to select the most appropriate systematic review from groups of overlapping reviews༻36༽, prioritizing those that are Cochrane-endorsed, most recent, highest in quality, "most relevant," or "most comprehensive." Disscussion This umbrella review will assess the link between perioperative intravenous dexmedetomidine use and patient outcomes in cardiac surgery, focusing on its effect on postoperative complications. By synthesizing evidence from existing reviews and meta-analyses and evaluating methodological quality and bias, it aims to clarify controversial findings and provide more robust conclusions.We recognize several limitations in this study. Systematic reviews and meta-analyses are not original research, posing a high risk of missing data during extraction, potentially affecting results. To minimize bias, we employed various evaluation methods and re-analyzed data from original studies. Other limitations include language bias from only including English studies, no updates planned for excluded original studies, and potential small-sample effects due to only including peer-reviewed articles. Declarations Acknowledgement Not applicable. Contributions of authors HL is the supervisor of this review. XHB is a context expert and provided critical suggestions on refining the review design. SJ, XTJ, and WW developed the idea for this review. All authors contributed to the development of the selection criteria. YL and XHB developed the search strategy. GYY and HL validated the search strategy. XTJ and MY conducted preliminary searches and scans. YL developed the method for quality assessment and data extraction forms, which were validated by XHB. SJ, GYY, and LY developed the method for managing overlap and data synthesis, which were validated by GYY and HL. YL provided crucial advice on revising the management of overlaps and data synthesis. YL drafted the manuscript. GYY and XHB redrafted the manuscript based on reviewers’ feedback. HL and GYY revised the manuscript based on reviewer’s comments. All authors read, provided feedback, and approved the final version of the manuscript. Ethics and consent This study constitutes a systematic analysis of existing published data. Consequently, in alignment with international research ethics guidelines, it is deemed unnecessary to obtain approval from a formal ethics committee. The findings of this research will be submitted to academic journals that employ rigorous peer-review processes for publication. Funding statement This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Patient and Public Involvement statement Since this study relied on secondary data, patients and the public did not participate in its planning, design, or execution, nor were they consulted for interpreting the results or drafting the manuscript. Declarations of interest The authors declare that they have no competing interests, References Bhushan S, Li Y, Huang X, Cheng H, Gao K, Xiao Z. 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Liangª","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACNmbmA4d//vvPbN/eQKQWPna2xMdAjewGPAeI1CLHz2NsDNTCbyCRQLTDeMykC3jYpM0lH2+8wVBjE02EFrYy6RkSPMaWs9OKLRiOpeU2ENbCvE2Cx0AimeF2jpkEY8NhYrQwmEnwJBjUN9w8Q7QWFmNjngMJzAY3eIjWwpb4cGbDAWbJHqBfEojxi3z/4QMHPgK18LMf3njjQ40NYS3IgPioQdJCqo5RMApGwSgYGQAACqE3AkEyOtwAAAAASUVORK5CYII=","orcid":"","institution":"The Second Affiliated Hospital Of Army Medical University: Xinqiao Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yan","middleName":"","lastName":"Liangª","suffix":""},{"id":573841122,"identity":"79ca4531-b641-42cb-9788-10699b1d3975","order_by":1,"name":"Xiaohang Baoª","email":"","orcid":"","institution":"The Second Affiliated Hospital Of Army Medical University: Xinqiao 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19:16:37","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98164,"visible":true,"origin":"","legend":"","description":"","filename":"SYSRD25013580structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7784119/v1/1d09c683acf01676afb3dcc4.xml"},{"id":100547644,"identity":"88733fbe-4c21-4d68-8a25-a4cae3063b76","added_by":"auto","created_at":"2026-01-19 08:16:09","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":111041,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7784119/v1/3f05df851822d5abcdebdef4.html"},{"id":100554160,"identity":"51745f26-212f-485c-8876-62b6949fa162","added_by":"auto","created_at":"2026-01-19 08:38:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":460132,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7784119/v1/d7654990-eaf9-4ea7-899c-f56949627112.pdf"}],"financialInterests":"","formattedTitle":"Intravenous Dexmedetomidine in adult cardiac surgery: a protocol of an umbrella review","fulltext":[{"header":"Background","content":"\u003cp\u003eCardiac surgery is vital for treating severe heart disease, including congenital heart disease, coronary artery disease, and heart valve disease. However, it often leads to complications like postoperative major adverse cardiovascular events, arrhythmia, neurological complications, and acute kidney injury, which can negatively impact patient outcomes and increase healthcare costs [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Dexmedetomidine, activating α2-adrenergic receptors in the central nervous system, provides sedation, pain relief, and reduces sympathetic activity༻5.6༽. Compared to traditional drugs, it better manages cardiovascular stress during cardiac surgery by lowering plasma catecholamine levels and stabilizing heart rate and blood pressure. Its anti-inflammatory and antioxidant effects may also protect organs like the heart, brain, and kidneys, potentially decreasing postoperative complications༻7.8༽. It is widely used in the perioperative period for cardiac surgery patients.\u003c/p\u003e \u003cp\u003eRecently, there has been an increase in the number of randomized controlled trials examining the use of dexmedetomidine in adult cardiac surgery [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which has resulted in numerous systematic reviews and meta-analyses. The outcomes evaluated include postoperative delirium, atrial fibrillation, organ function, major adverse cardiovascular events, the duration of ICU/hospitalization, and mortality༻14\u0026ndash;16༽. Although some reviews suggest that dexmedetomidine may reduce the incidence of postoperative delirium༻17༽,The expert consensus review on perioperative brain health emphasizes the prioritization of non-pharmacological interventions-such as early mobilization, cognitive stimulation, and effective pain management-as the primary strategy. Conversely, pharmacological interventions, including the use of dexmedetomidine for delirium prevention, require a thorough evaluation of their associated risks and benefits.༻18༽. This recommendation is due to the fact that the systematic review results of different researchers are contradictory to each other༻19.20༽.\u003c/p\u003e \u003cp\u003eUmbrella review (also known as overview of systematic reviews),is a publication type, emerging as the result of explosive growth of systematic reviews. It allows findings of separate reviews to be compared, formulating a comprehensive but concise conclusion, providing decision-makers with the evidence they need [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In term of the hierarchy of evidence synthesis methods, some consider umbrella reviews to be in the highest evidence level, superseding meta-analysis, systematic reviews, and individual studies༻22༽.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis protocol was strictly developed in accordance with the Preferred Reporting Items for Systematic Review and Meta - Analysis Protocols (PRISMA - P) guidelines [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The protocol of review was registered with the International Prospective Register of systematic reviews (PROSPERO). Results of this umbrella review will be published in a peer-reviewed journal. Potential changes to the protocol will be described in the final umbrella review report. The following sections will refer to an umbrella review following Overviews of Reviews guidelines in the Cochrane Handbook for Systematic Reviews of Interventions as a \u0026ldquo;Cochrane overview\u0026rdquo; [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Searches, study selection, data extraction, methodology quality assessment,and strength of evidence assessment will be conducted by two reviewers independently and in duplicate, with disagreements solved through discussion with a third reviewer.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for selecting\u003c/h2\u003e \u003cp\u003eThis study includes all systematic review and meta-analysis of randomized controlled trials, cohort studies, and case-control studies to assess the impact of intravenous dexmedetomidine on outcomes in adult cardiac surgery. The exclusion criteria 1)encompassed studies utilizing dexmedetomidine in combination with other pharmacological agents as an intervention or exposure factor, 2)network meta-analyses, 3)non-English language studies, 4)and research involving animal models or cell cultures.\u003c/p\u003e \u003cp\u003eThe research area focuses on meta-analyses of systematic reviews concerning cardiac surgery patients who received intravenous dexmedetomidine during the perioperative period, regardless of participants' race, gender, country, or region.\u003c/p\u003e \u003cp\u003epopulation\u003c/p\u003e \u003cp\u003eThe population consists of adult cardiac surgery patients.\u003c/p\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003cp\u003eThe intervention is the perioperative administration of intravenous dexmedetomidine\u003c/p\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003ethe control measure involves the use of a placebo or other non-dexmedetomidine medications.\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThe outcomes of interest include any outcomes in the patient, such as Major Adverse Cardiovascular Events, postoperative delirium, post-surgical atrial fibrillation incidence, and acute kidney injury, as well as changes in relevant clinical indicators, including duration of mechanical ventilation, and length of hospital stay.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003eThe search strategy used Mesh terms combining free terms, encompassing data from the inception of the databases up to August 1, 2025. The databases utilized in this process include PubMed, Embase, the Cochrane Systematic Reviews Database, and the Web of Science. The literature search will be limited to English. Citation abstracts and full text of search results will be imported to Zotero software (Detailed search strategy in each database is outlined in Additional file 1.).\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eData extraction involved two reviewers independently gathering key information from each study, including: 1) First author and publication year; 2) Characteristics of the population; 3) characteristics of the Dexmedetomidine and comparator (type, dose, intensity, frequency, duration); 4) surgical type; 5) primary and secondary outcomes; 6) Number of participants; 7) number of primary studies; 8) the type of statistical analysis that was used;9) quality assessment method for reviews, pooled effect size (ES), confidence interval (CI) or standard error (SE), measurement of ES, meta-analyses method, p value of pooled ES, and heterogeneity (Cochrane Q or I\u003csup\u003e2\u003c/sup\u003e statistics). The following information at primary studies level will be extracted in each meta-analyses: name of the first author, year of publication, study design, exposure of interest, comparison, precalculated ES, CI or SE, measurement of ES, effect model type.\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eConducting a rigorous risk-of-bias assessment for each included systematic review (SR) is fundamental to ensuring the quality of an umbrella review. This assessment process will adhere to the principles of dual and hierarchical evaluation to guarantee comprehensiveness and objectivity. To maintain objectivity and reproducibility, all risk-of-bias assessments will be independently conducted by two researchers. Prior to the assessment, the researchers will perform a pilot test on a small sample of literature to standardize their understanding and judgment criteria for each aspect of the assessment tool. In instances of disagreement during the assessment process, resolutions will be sought through discussion and negotiation; if consensus cannot be achieved, a third-party expert will be consulted to make the final decision.\u003c/p\u003e \u003cp\u003e1.Selection and Hierarchical Implementation of Assessment Instruments\u003c/p\u003e \u003cp\u003eThe risk-of-bias evaluation in the umbrella review will conducted at two distinct levels. The first level involves assessing the methodological quality of the included systematic reviews themselves. The second level requires evaluating the risk of bias in the original studies incorporated within these systematic reviews, as reported in their respective documents. To ensure rigor, we will prioritize the use of internationally recognized assessment tools for evaluating the methodological quality of systematic reviews.\u003c/p\u003e \u003cp\u003eAMSTAR-2 (A Measurement Tool to Assess Systematic Reviews 2) is currently regarded as the gold standard for evaluating the methodological quality of systematic reviews (SRs) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], encompassing both those with randomized controlled trials (RCTs) and non-RCTs. In our study, we will employ its 16 items to conduct a comprehensive evaluation of each included SR. Particular attention will be given to critical areas such as the pre-registration of research protocols, the comprehensiveness of the literature search, the independence of data extraction and risk of bias assessment by two reviewers, the adequacy of addressing bias risks in the original studies, the appropriateness of the meta-analytic methods employed, and the consideration of publication bias. Based on the AMSTAR-2 rating criteria, the overall confidence in each SR will be categorized as \"high,\" \"moderate,\" \"low,\" or \"very low.\"\u003c/p\u003e \u003cp\u003e2.Assessing the risk of bias in the primary studies included in systematic reviews (SRs)\u003c/p\u003e \u003cp\u003eThe core of an umbrella review is to synthesize high - quality primary evidence. Therefore, we need to examine and summarize how each SR assesses the risk of bias in the primary studies it includes. First, we will extract and aggregate the results of the risk - of - bias assessments of the primary studies reported in each SR [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Many SRs use the Cochrane risk - of - bias assessment tool. According to the standardized Cochrane tool, for randomized controlled trials (RCTs) included in SRs, to use the criteria of the second version of the Cochrane risk - of - bias assessment tool (RoB 2) as the basis for judgment. For potential non-randomized intervention studies (nRCTs), we will use the criteria of the ROBINS - I (Risk of Bias In Non - randomized Studies - of Interventions) tool for review. The Newcastle-Ottawa Scale (NOS) tool was used to evaluate observational studies.\u003c/p\u003e \u003cp\u003eDifferent SRs may vary in the application of the same risk - of - bias assessment tool, and even directly adopting the assessment results of SRs in an umbrella review may introduce bias. Therefore, if we find that the process of a particular SR's assessment of the risk of bias in the included studies is opaque, the criteria are unclear, or the results differ significantly from those of other high - quality SRs, we will independently re - evaluate the key primary studies in that SR based on RoB 2, ROBINS - I or NOS tool.\u003c/p\u003e\n\u003ch3\u003eData collection and analysis\u003c/h3\u003e\n\u003cp\u003eWhen synthesizing multiple systematic reviews (SRs), it is common to encounter instances where divergent or even contradictory results are reported for the same outcome indicator. Such discrepancies may arise from variations in the included primary studies, errors in data extraction, differences in analytical methods, or differing definitions of subgroups. In cases where different SRs report varying data for the same outcome indicator from the same original study, we will conduct a direct search and verification of the original research literature to ensure the use of the most accurate data. When two or more SRs present contradictory conclusions due to the inclusion of different sets of original studies, we will prioritize the results of the SR with the highest methodological quality, as assessed by the AMSTAR-2 tool. Preference will be given to the SR that is more recent and comprehensive. Discrepant findings frequently indicate the presence of clinical or methodological heterogeneity. To explore and elucidate these inconsistencies, we plan to perform subgroup analyses based on variables such as the duration of dexmedetomidine use, dosage or administration duration, and type of surgery. If the data permits, a meta - regression analysis will be performed.\u003c/p\u003e \u003cp\u003eIf the contradictions remain unresolved through the methods, we will include a narrative description in the results section. This will clearly articulate the existing contradictions and explore their potential causes and implications for clinical practice, rather than attempting to forcibly integrate these results.\u003c/p\u003e \u003cp\u003e2.Handling Missing Data\u003c/p\u003e \u003cp\u003eMissing data presents a prevalent challenge in meta-analysis, potentially resulting in bias and diminished precision [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We will implement various strategies to address missing data, tailored to the specific type encountered. Irrespective of the type of missing data, our primary approach involves reaching out to the authors of the systematic reviews or the original studies to obtain the necessary information༻28༽. This process will be meticulously documented. In instances where original studies do not report the core outcome indicators of interest༻29༽, we will document this omission in our analysis and assess its potential impact through sensitivity analysis. According with the guidelines outlined in the Cochrane Handbook, we will endeavor to calculate or estimate the SD from other available statistical data, such as confidence intervals(CIs), standard errors(SE), t-values, or p-values. Imputation will be considered only when the standard deviation cannot be derived through calculation, and the study is deemed critical to the overall analysis. Imputation methods will adhere to a conservative approach.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData Synthesis and Statistical Methods\u003c/h2\u003e \u003cp\u003eWe prefer to conduct a quantitative meta-analysis, but if there's too much clinical heterogeneity or inconsistent data formats among the included SRs, we'll use narrative synthesis. This approach will systematically organize and summarize the findings and critically interpret them alongside the risk of bias assessment.\u003c/p\u003e \u003cp\u003eIn conducting quantitative data synthesis, such as a new meta-analysis or meta-meta-analysis, we will adhere to established statistical methodologies. For effect size selection, binary outcomes (e.g., mortality rate, incidence of atrial fibrillation) will be evaluated using the risk ratio (RR) or odds ratio (OR), along with their 95% confidence intervals (CI). For continuous outcomes (e.g., length of stay in the ICU, length of Dexmedetomidine), the mean difference (MD) or standardized mean difference (SMD), accompanied by their 95% CI, will be calculated. Regarding the statistical model, due to the anticipated clinical and methodological heterogeneity arising from the diverse sources of systematic reviews (SRs) included in an umbrella review, as well as the variability of the original studies, we will primarily employ the random-effects model for data pooling. This model accounts for both within-study and between-study variations. To assess statistical heterogeneity among studies, we will utilize Cochran's Q test and the I\u0026sup2; statistic. The I\u0026sup2; statistic is employed to quantify the extent of heterogeneity, with values less than 25% indicating low heterogeneity, values between 25% and 75% indicating moderate heterogeneity, and values exceeding 75% indicating high heterogeneity. In instances where significant statistical heterogeneity is detected (e.g., P\u0026thinsp;\u0026lt;\u0026thinsp;0.10 or I\u0026sup2; \u0026gt; 50%), we will undertake a thorough investigation of its sources.\u003c/p\u003e \u003cp\u003eTo elucidate the origins of heterogeneity, subgroup analyses will be performed based on predetermined covariates, such as patient population characteristics, dexmedetomidine dosing, style of surgical, and the methodological quality of systematic reviews. If the number of subgroups is adequate, meta-regression analysis will be considered to quantify the influence of specific factors on the effect size. Regarding publication bias assessment, when the number of included primary studies is sufficient (typically\u0026thinsp;\u0026ge;\u0026thinsp;10), we will evaluate potential publication bias by constructing a funnel plot and conducting Egger's test or Begg's test. All statistical analyses will be executed using specialized meta-analysis software, such as the meta and metaumbrella packages in the R programming language, and RevMan.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStrength of evidence assessment\u003c/h3\u003e\n\u003cp\u003eThe GRADE system is predominantly employed in umbrella reviews for the quantitative assessment of systematic reviews [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Applying the GRADE framework to umbrella reviews presents significant challenges༻31༽, primarily due to the \"methodological mismatch\" between its original design intent and the current application context. The focus of the core downgrading criteria in GRADE has shifted from a single original study to a compilation of multiple studies. Presently, there is an absence of a standardized approach for thoroughly assessing the overall risk of bias across multiple systematic reviews. The GRADE assessment of systematic reviews is highly dependent on the detailed reporting of the original studies included within these reviews༻32༽. If a systematic review fails to adequately report crucial information, such as the risk of bias and sources of heterogeneity in the original studies, it becomes impossible to accurately make downgrading judgments concerning \"risk of bias\" or \"inconsistency.\"\u003c/p\u003e \u003cp\u003eTo address the challenges, the evidence evaluation process is bifurcated into two distinct phases. Initially, the methodological quality of the included systematic reviews is assessed utilizing the AMSTAR2 tool. Subsequently, a GRADE assessment is conducted on the body of evidence pertaining to specific outcomes. In instances where the evidence for a particular outcome predominantly originates from systematic reviews deemed to be of \"very low\" or \"low\" quality according to AMSTAR2, the evidence for that outcome will be downgraded for \"risk of bias\" during the GRADE assessment.\u003c/p\u003e\n\u003ch3\u003eManaging overlap\u003c/h3\u003e\n\u003cp\u003eOverlap of primary studies is a key methodological challenge for umbrella reviews. Different systematic review articles may include one or more identical original studies for data analysis, resulting in the repeated calculation of the same original data [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This redundancy can cause the final effect size to deviate from the true value, potentially leading to conclusions that may misguide clinical practice. Consequently, prior to data extraction and evidence synthesis, it is essential to assess the overlap among all included systematic reviews.\u003c/p\u003e \u003cp\u003eUtilize the GROOVE tool to perform an overlap analysis of the selected systematic reviews [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Initially, import the reference lists from these reviews to automatically create an evidence matrix. Subsequently, employ the tool to automatically compute the total Corrected Covered Area (CCA) value and determine the overall overlap level༻35༽. Conduct pairwise CCA analyses and produce a heatmap illustrating paired combinations. For systematic reviews exhibiting significant overlapping, follow the guidelines outlined in the Cochrane Handbook to select the most appropriate systematic review from groups of overlapping reviews༻36༽, prioritizing those that are Cochrane-endorsed, most recent, highest in quality, \"most relevant,\" or \"most comprehensive.\"\u003c/p\u003e"},{"header":"Disscussion","content":"\u003cp\u003eThis umbrella review will assess the link between perioperative intravenous dexmedetomidine use and patient outcomes in cardiac surgery, focusing on its effect on postoperative complications. By synthesizing evidence from existing reviews and meta-analyses and evaluating methodological quality and bias, it aims to clarify controversial findings and provide more robust conclusions.We recognize several limitations in this study. Systematic reviews and meta-analyses are not original research, posing a high risk of missing data during extraction, potentially affecting results. To minimize bias, we employed various evaluation methods and re-analyzed data from original studies. Other limitations include language bias from only including English studies, no updates planned for excluded original studies, and potential small-sample effects due to only including peer-reviewed articles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions of authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHL is the supervisor of this review. XHB is a context expert and provided critical suggestions on refining the review design. SJ, XTJ, and WW developed the idea for this review. All authors contributed to the development of the selection criteria. YL and XHB developed the search strategy. GYY and HL validated the search strategy. XTJ and MY conducted preliminary searches and scans. YL developed the method for quality assessment and data extraction forms, which were validated by XHB. SJ, GYY, and LY developed the method for managing overlap and data synthesis, which were validated by GYY and HL. YL provided crucial advice on revising the management of overlaps and data synthesis. YL drafted the manuscript. GYY and XHB redrafted the manuscript based on reviewers’ feedback. HL and GYY revised the manuscript based on reviewer’s comments. All authors read, provided feedback, and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and consent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study constitutes a systematic analysis of existing published data. Consequently, in alignment with international research ethics guidelines, it is deemed unnecessary to obtain approval from a formal ethics committee. The findings of this research will be submitted to academic journals that employ rigorous peer-review processes for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and Public Involvement statement\u003c/strong\u003e\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eSince this study relied on secondary data, patients and the public did not participate in its planning, design, or execution, nor were they consulted for interpreting the results or drafting the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests,\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBhushan S, Li Y, Huang X, Cheng H, Gao K, Xiao Z. 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Epub 2023 Jul 27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, Thomas J. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10(10):ED000142. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.ED000142\u003c/span\u003e\u003cspan address=\"10.1002/14651858.ED000142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7784119/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7784119/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eIntroduction\u003c/b\u003e Dexmedetomidine has been widely used in cardiac surgery due to its unique effects such as anti - sympathetic, sedation, and analgesia. However, recent studies and meta-analyses have been shown mixed results on its safety and effectiveness, with some studies indicating possible risks. This study seeks to assess the quality, biases, and effectiveness of all existing systematic reviews on dexmedetomidine in adult cardiac surgery to offer clearer evidence-based insights.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e A quantitative umbrella review will assess the impact of intravenous dexmedetomidine on outcomes in adult cardiac surgery, focusing on major adverse cardiovascular events, postoperative atrial fibrillation, acute kidney injury, delirium, and ICU stay duration. Relevant literature up to August 1, 2025, will be sourced from PubMed, Embase, Cochrane Database of Systematic Reviews, and Web of Science using a comprehensive search strategy. Two independent reviewers (XTJ and MY) initially screened study titles and abstracts, resolving any disagreements with a third reviewer (GYY). Full texts of studies passing this stage were evaluated by two other reviewers (YL and SJ) using set criteria. Data extraction, methodology quality assessment, and evidence level assessment were independently completed by two people (XHB and WW). The meta-analysis was grouped according to the patients' outcomes. Data conflicts and overlaps will be used updated methods like concordance correlation analysis (CCA). Evidence synthesis involved corrected overlap analysis and meta-analysis of original studies.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDiscussion\u003c/b\u003e This umbrella review expects to systematically assess the impact of perioperative intravenous Dexmedetomidine administration on the prognosis of adult cardiac surgery. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, clarified the beneficial or adverse effects of dexmedetomidine on adult cardiac surgery.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrail registration\u003c/b\u003e CRD420251128632\u003c/p\u003e","manuscriptTitle":"Intravenous Dexmedetomidine in adult cardiac surgery: a protocol of an umbrella review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 19:16:32","doi":"10.21203/rs.3.rs-7784119/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-01-26T17:49:55+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-13T10:32:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-01T02:56:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2025-10-05T06:17:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7df12d1-a3f7-426c-9386-01ee38f825f0","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-16T19:16:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 19:16:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7784119","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7784119","identity":"rs-7784119","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}