Efficacy and Safety of Dexmedetomidine in Mechanically Ventilated Critically Ill Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Efficacy and Safety of Dexmedetomidine in Mechanically Ventilated Critically Ill Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Dexmedetomidine in Mechanically Ventilated Critically Ill Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials In Kyung Lee, Kyeong Hun Lee, Hye-ji Han, Na Jin Kim, Kyunghoon Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4683655/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Children undergoing mechanical ventilation in the pediatric intensive care unit (PICU) require effective sedation to reduce anxiety and discomfort. Dexmedetomidine, an α2-receptor agonist, presents as a viable sedative alternative, yet its efficacy and safety for critically ill, mechanically ventilated children remain to be fully established. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of dexmedetomidine in such patients. Methods A systematic search was conducted up to April 2024. RCTs that compare dexmedetomidine with other sedatives in mechanically ventilated children were included. This analysis focused on both the efficacy and safety outcomes through meta-analysis. Results Included in the analysis were eight trials, involving a total of 387 mechanically ventilated children. Compared to other sedatives, dexmedetomidine significantly reduced the duration of mechanical ventilation (MD -3.54 h, 95% CI, -6.49 to -0.59), particularly when compared to fentanyl. However, dexmedetomidine did not significantly impact the length of ICU stay, duration of sedation, or the necessity for additional sedatives. Dexmedetomidine was associated with a significantly increased risk of bradycardia (OR 6.14, 95% CI, 2.20 to 17.12) and hypotension (OR 8.14, 95% CI, 1.37 to 48.31), with no significant difference observed in the incidence of delirium (OR 0.61, 95% CI, 0.16 to 2.31) in comparison to other sedatives. Conclusion Although dexmedetomidine notably diminished the duration of mechanical ventilation, the potential for adverse effects necessitates further investigation. Large RCTs are needed to validate our findings and refine sedation management in mechanically ventilated children in PICU. Dexmedetomidine mechanical ventilation sedation pediatric intensive care unit Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Mechanically ventilated children are at a high risk of unplanned extubation, which can lead to airway injuries and life-threatening scenarios like asphyxia ( 1 – 3 ). Effective sedation and analgesia are pivotal in managing these patients to not only reduce anxiety and discomfort from endotracheal tubes and intensive care unit (ICU) procedures but also to improve their overall care outcomes ( 4 – 7 ). The concept of “analgosedation” within the pediatric intensive care unit (PICU) denotes a sedation strategy that combines both analgesia and sedation to enhance the comfort and wellbeing of critically ill patients ( 8 ). Despite its critical importance, the management of sedation in the PICU encounters numerous hurdles and limitations, including the need to strike a balance between adequate sedation levels and the prevention of adverse effects, in addition to the absence of standardized protocols specifically designed for pediatric patients. Traditional sedatives such as benzodiazepines and propofol, though commonly administered to mechanically ventilated critically ill children, carry the risk of tolerance, dependency, and withdrawal symptoms ( 9 , 10 ) . Dexmedetomidine presents as a favorable alternative sedative, recognized for providing milder sedation levels, decreasing delirium, and possessing analgesic qualities. This highly selective α2-receptor agonist, endorsed by the Food and Drug Administration for use in pediatric patients since 2013, achieves its analgesic effect through the activation of \(\alpha 2\) -adrenoreceptors in both the spinal and supraspinal areas ( 11 ). Extensively employed in surgical anesthesia and ICU sedation, dexmedetomidine is acclaimed for its analgesic, sedative, and anti-sympathetic characteristics. In comparison to midazolam or propofol, dexmedetomidine has been shown to afford advantages such as a diminished time to extubation, shortened duration of mechanical ventilation (MV), enhanced ease of arousal, better patient cooperation, and improved communication ( 12 ). Although there is substantial evidence supporting the use of dexmedetomidine in adult populations ( 13 – 15 ), research concerning its effectiveness and safety in critically ill pediatric patients on MV remains scarce. We performed a systematic review and meta-analysis of RCTs to assess the efficacy and adverse effects of dexmedetomidine in critically ill children on mechanical ventilation. Methods Study Design A systematic review of RCTs comparing dexmedetomidine with other sedatives in critically ill, mechanically ventilated children was conducted. A meta-analysis was also performed to evaluate the efficacy and safety of dexmedetomidine. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 16 ). Database and search strategy A meticulously designed peer-reviewed search strategy was developed by a medical librarian (NJK). Searches were conducted in PubMed, Embase, and The Cochrane Library from their inception up to April 4, 2024, utilizing terms related to dexmedetomidine and pediatric age. The details of this search strategy are provided in Supplement 1. Data collection and analysis Titles and abstracts were screened by two independent reviewers (IKL and KHL) to identify trials potentially eligible for inclusion, with full texts being subsequently evaluated for eligibility. Discrepancies between reviewers were resolved through discussion or by consulting a third reviewer as necessary. Inclusion criteria Included were trials that: ( 1 ) RCT; ( 2 ) involved invasively mechanically ventilated children admitted to the PICU; ( 3 ) had an intervention group receiving intravenous dexmedetomidine; and ( 4 ) had a control group receiving other intravenous sedatives. Exclusion criteria Excluded were trials that: ( 1 ) study type: observational studies, case reports, letters, editorials, or not peer -reviewed; ( 2 ) included duplicate samples; ( 3 ) participants restricted to neonates or adults; ( 4 ) studies that used dexmedetomidine solely during anesthesia or before procedures; ( 5 ) studies that administered dexmedetomidine through non-intravenous routes; or ( 6 ) studies that used placebo for the control group. Outcomes The primary outcome focused on sedation efficacy: duration of MV, length of ICU stays, duration of sedation, and total fentanyl bolus administrations. Secondary outcomes included adverse effects like bradycardia and hypotension. Quality assessment The risk of bias in included trials was assessed by two reviewers (IKL and KHL) using a modified version of the Cochrane risk of bias tool ( 17 ). Each trial was examined for bias across various domains, with each domain assessed as having low, unclear, or high risk of bias. The classification of the overall risk of bias for each trial was as follows: low if the risk of bias was low or possibly low in all domains, unclear if there was an unclear risk of bias in at least one domain with no domain having a high risk of bias, or high if there was a high or possibly high risk of bias in at least one domain. Any discrepancies were resolved through discussion and consensus. Statistical analysis The meta-analysis used R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria) to analyze the efficacy and adverse effects of dexmedetomidine in terms of sedation. For continuous outcome data, the mean difference served as the primary measure, with estimates aggregated using the inverse variance method. The Mantel-Haenszel method pooled estimates for binary outcome data, employing odds ratio and risk ratio as main metrics. The choice of either a common or a random effects model was determined by heterogeneity levels, indicated by \({I}^{2}\) exceeding 50%, at which point the random effects model was favored. Results Study selection and characteristics Initially, searches of reference databases identified a total of 348 records. After the screening and eligibility assessment were conducted, eight studies ( 18 – 25 ) satisfied the inclusion criteria and were thus included in the meta-analysis (Fig. 1 ). Of the studies selected, five concentrated on post-operative pediatric patients, whereas the others enrolled medical patients. Importantly, children with atrioventricular block were excluded from four of these studies. The detailed characteristics of each study are outlined in Table 1 . Table 1 Characteristics of included studies. Author, year Primary disease Study period Inclusion criteria Exclusion criteria Number of patients (I/C) Intervention group (dose) Control group (dose) Initiation of DEX Duration of DEX Tobias, 2004 [18] Patients admitted to PICU requiring MV No information available Children and infants CNS dysfunction 30 (20/10) DEX (0.25 mcg/kg/h or 0.5 mcg/kg/h) Midazolam (0.1 mg/kg/h) After intubation After 24 hours on either sedation if MV was still necessary, the patient was switched to the alternative agent Prasad, 2012 [19] Patients undergoing CHD surgery No information available 1–14 years, overnight MV was anticipated 24h 60 (30/30) DEX (0.5 mcg/kg/h) Fentanyl (1 mcg/kg/h) In the post-operative intensive care unit 6AM on the following day to allow an early extubation trial Aydogan, 2013 [20] Patients undergoing scoliosis surgery No information available 12–18 years History of midazolam and/or DEX, delirium, developmental delay, mental retardation, an American Society of Anesthesiologists classification greater than III, known previous reactions to anesthesia, a history of asthma or an anticipated difficult airway, a history of hypertension, chronic opioid, sedative, analgesic, antihypertensive agents or digoxin prior to the procedure, concomitant disease 32 (16/16) DEX (0.4 mcg/kg/h) Midazolam (0.1 mg/kg/h) After surgery At the time of extubation Up to 24 hours on either sedation if MV was still necessary Saleh, 2016 [21] Patients scheduled for abdominal surgery Sep 2013 ~ Dec 2014 1–10 years, overnight MV was anticipated < 1 year, emergency surgeries, severe liver dysfunction, patients requiring MV more than 24 h 50 (25/25) DEX (0.3 mcg/kg/h) Fentanyl (1 mcg/kg/h) At arrival to the SICU After 18 h Garisto, 2018 [22] Patients undergoing complex CHD surgery July 2012 – Dec 2015 1 month – 24 months Newborns, brain or bone malformations, neuromuscular disease, post-surgical delayed sternal closure, post-operative neurological or pulmonary complications, ECMO requirement, AV block, VIS > 30, hepatic failure, renal impairment 48 (22/26) DEX (0.5 mcg/kg/h), midazolam (0.05 mg/kg/h), morphine (10 mcg/kg/h), paracetamol bolus (7.5–15 mg/kg q6 hours) Midazolam (0.1 mg/kg/h), morphine (20 mcg/kg/h), paracetamol bolus (7.5–15 mg/kg q6 hours) After CCU admission Sedative drug weaning proceeded with MV weaning, according to institutional guidelines Erickson, 2020 [23] Patients admitted to PICU requiring MV Jan 2015 – July 2016 − 16 years Acute brain injury, neurologic injury, requirement for continuous neuromuscular blockade, cardiovascular instability 60 (29/31) DEX (1.0 mcg/kg/h) Usual care: propofol, benzodiazepines, chloral hydrate, ketamine, and barbiturates After randomization Until sedation was no longer required or to a maximum of 14 days after enrollment Gulla, 2020 [24] Patients admitted to PICU requiring MV August 2016 – April 2018 1 month – 15 years Catecholamine resistant shock, already on sedative drug infusion, bradycardia, AV block, primary CNS involvement, hepatic impairment, infusion of muscle relaxants, previous participation in the study 47 (23/24) DEX (0.25–0.75 mcg/kg/h) Midazolam (1–4 mcg/kg/min) After randomization Until 7 days or weaning from MV Attia, 2022 [25] Patients undergoing CHD surgery April 2020 – Dec 2021 1 day – 15 years Neuromuscular disorders, demyelinating illness, cerebral palsy, developmental and behavioral issues, inborn metabolic errors, acute severe neurological condition, decompensated heart failure, acute hemodynamic instability, septic shock, HR 60 beats/min, grade II or III AV block 60 (30/30) DEX* (0.2–1.5 mcg/kg/h) Fentanyl (1–3 mcg/kg/h) During anesthesia No information available Abbreviations: I/C, intervention/control; PICU, pediatric intensive care unit; MV, mechanical ventilation; CHD, congenital heart disease; DEX, dexmedetomidine; CNS, central nervous system; SICU, surgical intensive care unit; ECMO, extracorporeal membrane oxygenation; VIS, vasoactive inotropic score; AV, atrioventricular; PAH, pulmonary hypertension; CCU, cardiac intensive care unit * Dexmedetomidine was started with a bolus dose. Regarding interventions, the majority of the studies (7/8, 88%) did not implement a dexmedetomidine bolus at the onset of the infusion. Moreover, in most studies (7/8, 88%) dexmedetomidine was the exclusive sedative agent employed. With respect to the control groups, the included trials exhibited variability. Namely, three trials (3/8, 38%) used midazolam, an equivalent number applied fentanyl, and the two remaining trials (2/8, 25%) utilized combinations of different sedative medications. Risk of bias The risk of bias within the included studies is depicted in Fig. 2 . Efficacy outcomes 1. Mechanical ventilation duration Data from seven studies were incorporated into the meta-analysis for the duration of MV. Dexmedetomidine was shown to significantly reduce the duration of MV when compared to other sedative drugs(MD -3.54 h, 95% CI, -6.49 to -0.59, Fig. 3 A). The subgroup analysis indicated that dexmedetomidine considerably shortened the MV duration in comparison to fentanyl (MD -1.53 h, 95% CI, -1.92 to -1.13, Fig. 3 B). Nevertheless, no significant disparities in MV duration were found when dexmedetomidine was compared to midazolam (MD -14.58 h, 95% CI, -34.11 to 4.94, Fig. 3 C). 2. ICU length of stay Eligible data from three studies were included in the meta-analysis concerning the ICU length of stay. Dexmedetomidine, in comparison to other sedative drugs, showed no significant difference in the length of stay in the ICU (MD -0.20, 95% CI, -1.89 to 1.49, Supplement 2A). 3. Duration of sedation Analysis of four studies’ data on sedation duration revealed no significant reduction when compared to other sedatives (MD 0.16, 95% CI, -0.82 to 1.13, Supplement 2B). 4. Number of fentanyl bolus doses Data on the requirement for additional fentanyl boluses were available from three trials. No significant reduction in the need for fentanyl boluses was observed when compared to other sedatives (MD -0.66, 95% CI, -2.73 to 1.40, Supplement 2C). Safety outcomes Four trials contributed data to the analysis of bradycardia incidence, while two trials did so for the analysis of hypotension incidence. Compared to other sedatives, dexmedetomidine was significantly associated with a higher risk of bradycardia (OR 6.14, 95% CI, 2.20 to 17.12, Fig. 3 A) and hypotension (OR 8.14, 95% CI, 1.37 to 48.31, Fig. 3 B). Moreover, no significant difference in delirium incidence was demonstrated when compared to alternative sedatives across two trials (OR 0.61, 95% CI, 0.16 to 2.31, Fig. 3 C). Discussion This systematic review and meta-analysis, encompassing eight trials with 387 mechanically ventilated children, provides evidence that dexmedetomidine significantly reduces MV duration in this population, particularly when compared to fentanyl. However, dexmedetomidine did not demonstrate significant effects on the length of ICU stays, duration of sedation, or the need for additional sedatives. Moreover, dexmedetomidine was associated with a significantly higher risk of bradycardia and hypotension compared to other sedatives but did not impact the incidence of delirium. Several hypotheses offer explanations for how dexmedetomidine may improve MV duration. First, dexmedetomidine has been found to enhance compliance, reduce resistance, and improve oxygenation during ongoing MV, potentially leading to a quicker extubation time( 26 ). Second, dexmedetomidine’s unique pharmacologic profile, including easy arousability and minimal respiratory depression, may facilitate effective sedation while minimizing complications associated with respiratory suppression ( 27 ). Furthermore, dexmedetomidine has been linked to a reduced risk of adverse events like delirium in adults ( 13 ), possibly aiding in a smoother extubation process. Our study builds upon previous meta-analyses in various important aspects. Prior meta-analyses have mainly concentrated on the efficacy of dexmedetomidine in specific pediatric cohorts, such as those undergoing cardiac surgery ( 28 ). The meta-analysis addressing children undergoing cardiac surgery concluded that perioperative dexmedetomidine administration might reduce MV duration, as well as the lengths of ICU and hospital stays. Our investigation, conversely, broadens this scope to include both post-operative and medical pediatric populations. Unlike the earlier meta-analysis that limited its focus to post-operative children ( 28 ), we excluded studies that administered dexmedetomidine solely during anesthesia to evaluate its efficacy in the context of MV in PICU settings. Furthermore, our meta-analysis assesses both the sedation efficacy and the adverse effects of dexmedetomidine, unlike previous analyses that concentrated primarily on the safety profile of dexmedetomidine ( 29 ). This dual focus offers vital insights for pediatric intensive care, providing a more comprehensive perspective on the application of dexmedetomidine in critically ill children. Additionally, our analysis distinctly focused on trials comparing dexmedetomidine with other sedatives, deliberately excluding those comparisons with placebo. This decision was made under the rationale that placebo-controlled trials might not reflect the practical clinical conditions where dexmedetomidine is usually compared against active sedatives. While placebo-controlled trials are informative regarding dexmedetomidine’s specific effects, our intentional exclusion stems from our objective to evaluate dexmedetomidine’s relative effectiveness against common clinical interventions. However, our study also uncovered a heightened risk of bradycardia and hypotension linked to dexmedetomidine. Acting through α-2a receptor agonism, dexmedetomidine induces sedation by decreasing plasma norepinephrine levels, potentially causing bradycardia and hypotension ( 30 ). Despite noting these adverse effects, it is still ambiguous whether they were reversible with non-invasive interventions or required vasoactive agents for management. Additionally, the dose-dependency of these adverse events deserves further exploration. Previous studies have indicated that bradycardia and hypotension are infrequent in critically ill children treated with dexmedetomidine for extended periods and are typically reversible with minimal interventions ( 29 ). Challenges emerged in evaluating delirium within our meta-analysis because of scarce data on this outcome. Among the included studies, only two explored the assessment of delirium, with a single study focusing primarily on adolescent participants ( 20 ). Although meta-analyses involving adults have underscored dexmedetomidine’s role in reducing delirium compared to other sedatives ( 13 , 31 ), the lack of pediatric-specific data complicates the interpretation of these findings. Notwithstanding the valuable insights derived from our study, it presents several limitations that merit acknowledgment. Firstly, evaluating time in adequate sedation was impractical due to the disparate sedation assessment tools used in the studies. Secondly, assessing delirium and withdrawal syndrome in pediatric patients presents intrinsic challenges. Thirdly, our study’s observed high heterogeneity and significant risk of bias advise caution in interpreting these results. Lastly, the variation in weaning protocols among the studies introduces additional complexity to our analysis. In summation, our study highlights the potential advantages of dexmedetomidine in shortening MV duration in critically ill children, while also underscoring the importance of further research to delineate its safety profile, harmonize sedation protocols, and refine dosing approaches. Consequently, comprehensive RCTs and multicenter studies are necessary to corroborate our findings and establish evidence-based sedation protocols that cater to the specific demands of PICU patients. Incorporating the knowledge obtained from our study into clinical practice enables healthcare professionals to enhance sedation management and improve outcomes for mechanically ventilated children. Declarations Disclosure statement The authors have no conflicts of interest to declare. Funding sources No funding sources. References Klugman D, Melton K, Maynord PON, Dawson A, Madhavan G, Montgomery VL, et al. Assessment of an unplanned extubation bundle to reduce unplanned extubations in critically ill neonates, infants, and children. Jama Pediatr. 2020;174(6):e200268-e. Alberto L, Stefano B, Alessandro G, Stefano E, Cristina N, Stefania V, et al. Unplanned extubations in general intensive care unit: A nine-year retrospective analysis. Acta Bio Medica: Atenei Parmensis. 2018;89(Suppl 7):25. Morris HF, Schuller L, Archer J, Niesen A, Ellsworth S, Egan J, et al. Decreasing unplanned extubation in the neonatal ICU with a focus on endotracheal tube tip position. Resp Care. 2020;65(11):1648-54. Kress JP, Hall JB. Sedation in the mechanically ventilated patient. Critical care medicine. 2006;34(10):2541-6. Shehabi Y, Nakae H, Hammond N, Bass F, Nicholson L, Chen J. The effect of dexmedetomidine on agitation during weaning of mechanical ventilation in critically ill patients. Anaesth Intens Care. 2010;38(1):82-90. Gerlach AT, Dasta JF, Steinberg S, Martin LC, Cook CH. A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients. Journal of critical care. 2009;24(4):568-74. Iirola T, Aantaa R, Laitio R, Kentala E, Lahtinen M, Wighton A, et al. Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients. Critical care. 2011;15(5):1-10. Egbuta C, Mason KP. Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit. J Clin Med. 2021;10(9). Fonsmark L, Rasmussen YH, Carl P. Occurrence of withdrawal in critically ill sedated children. Critical care medicine. 1999;27(1):196-9. Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation. Critical care medicine. 2008;36(8):2427-32. Kaye AD, Urman RD, Rappaport Y, Siddaiah H, Cornett EM, Belani K, et al. Multimodal analgesia as an essential part of enhanced recovery protocols in the ambulatory settings. Journal of Anaesthesiology Clinical Pharmacology. 2019;35(Suppl 1):S40-S5. Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75:1119-30. Lewis K, Alshamsi F, Carayannopoulos KL, Granholm A, Piticaru J, Al Duhailib Z, et al. Dexmedetomidine vs other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials. Intensive Care Med. 2022;48(7):811-40. Zhou WJ, Liu M, Fan XP. Differences in efficacy and safety of midazolam vs. dexmedetomidine in critically ill patients: A meta-analysis of randomized controlled trial. Exp Ther Med. 2021;21(2):156. Heybati K, Zhou F, Ali S, Deng J, Mohananey D, Villablanca P, Ramakrishna H. Outcomes of dexmedetomidine versus propofol sedation in critically ill adults requiring mechanical ventilation: a systematic review and meta-analysis of randomised controlled trials. Br J Anaesth. 2022;129(4):515-26. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Annals of internal medicine. 2009;151(4):W-65-W-94. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj. 2011;343. Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J. 2004;97(5):451-5. Prasad S, Simha PP, Jagadeesh A. Comparative study between dexmedetomidine and fentanyl for sedation during mechanical ventilation in post-operative paediatric cardiac surgical patients. Indian journal of anaesthesia. 2012;56(6):547-52. Aydogan MS, Korkmaz MF, Ozgul U, Erdogan MA, Yucel A, Karaman A, et al. Pain, fentanyl consumption, and delirium in adolescents after scoliosis surgery: dexmedetomidine vs midazolam. Paediatr Anaesth. 2013;23(5):446-52. Saleh RH. Randomized controlled comparative trial between low dose dexmedetomidine sedation and that of fentanyl in children after surgical procedures in surgical pediatric intensive care unit. Egyptian Journal of Anaesthesia. 2016;32(1):137-42. Garisto C, Ricci Z, Tofani L, Benegni S, Pezzella C, Cogo P. Use of low-dose dexmedetomidine in combination with opioids and midazolam in pediatric cardiac surgical patients: randomized controlled trial. Minerva anestesiologica. 2018;84(9):1053-62. Erickson SJ, Millar J, Anderson BJ, Festa MS, Straney L, Shehabi Y, Long DA. Dexmedetomidine sedation in mechanically ventilated critically ill children: a pilot randomized controlled trial. Pediatric Critical Care Medicine. 2020;21(9):e731-e9. Gulla KM, Sankar J, Jat KR, Kabra SK, Lodha R. Dexmedetomidine vs Midazolam for Sedation in Mechanically Ventilated Children: A Randomized Controlled Trial. Indian Pediatr. 2021;58(2):117-22. Attia WA, Aziz OMA, Reheem AMA, Sayed OME-e, Mahmoud MM. Comparison Between Sedative And Analgesic Effects Of Dexmedetomidine Versus Fentanyl For Pediatric Patients Following Cardiac Surgery In Intensive Care Unit. Journal of Pharmaceutical Negative Results. 2022:1058-64. Senoglu N, Oksuz H, Dogan Z, Yildiz H, Kamaz A, Ugur N. Effects of Dexmedetomidine on respiratory mechanics during mechanical ventilation. Journal of Anaesthesiology Clinical Pharmacology. 2009;25(3):273-6. Gupta S, Singh D, Sood D, Kathuria S. Role of dexmedetomidine in early extubation of the intensive care unit patients. Journal of Anaesthesiology Clinical Pharmacology. 2015;31(1):92-8. Liu Y, Bian W, Liu P, Zang X, Gu X, Chen W. Dexmedetomidine improves the outcomes in paediatric cardiac surgery: a meta-analysis of randomized controlled trials. Interact Cardiovasc Thorac Surg. 2018;26(5):852-8. Daverio M, Sperotto F, Zanetto L, Coscini N, Frigo AC, Mondardini MC, Amigoni A. Dexmedetomidine for Prolonged Sedation in the PICU: A Systematic Review and Meta-Analysis. Pediatr Crit Care Med. 2020;21(7):e467-e74. Gerlach AT, Blais DM, Jones GM, Burcham PK, Stawicki SP, Cook CH, Murphy CV. Predictors of dexmedetomidine-associated hypotension in critically ill patients. International Journal of Critical Illness and Injury Science. 2016;6(3):109-14. Pasin L, Landoni G, Nardelli P, Belletti A, Di Prima AL, Taddeo D, et al. Dexmedetomidine reduces the risk of delirium, agitation and confusion in critically Ill patients: a meta-analysis of randomized controlled trials. J Cardiothor Vasc An. 2014;28(6):1459-66. Additional Declarations No competing interests reported. Supplementary Files Supplement1.docx Supplement 1. Details of the search strategy Supplement2.jpg Supplement 2. A forest plot comparing (A) ICU length of stay, (B) duration of sedation, and (C) the number of fentanyl boluses between dexmedetomidine and other sedatives. MD stands for mean difference, and CI denotes confidence interval. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4683655","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":325004442,"identity":"1b30a304-c436-4c98-8cd2-cfed4fea22dc","order_by":0,"name":"In Kyung Lee","email":"","orcid":"","institution":"Seoul St. Mary’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"In","middleName":"Kyung","lastName":"Lee","suffix":""},{"id":325004443,"identity":"2ce8601c-f932-4091-944c-5a4b32917daa","order_by":1,"name":"Kyeong Hun Lee","email":"","orcid":"","institution":"Seoul St. Mary’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kyeong","middleName":"Hun","lastName":"Lee","suffix":""},{"id":325004444,"identity":"f2d58579-e204-42f3-ab15-6cf20b7fb1af","order_by":2,"name":"Hye-ji Han","email":"","orcid":"","institution":"Seoul National University Bundang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hye-ji","middleName":"","lastName":"Han","suffix":""},{"id":325004445,"identity":"3b43e303-f87c-48b9-acc2-b88697a8263b","order_by":3,"name":"Na Jin Kim","email":"","orcid":"","institution":"The Catholic University of Korea","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"Jin","lastName":"Kim","suffix":""},{"id":325004446,"identity":"c4274f3b-815c-46ee-8795-d8568d8ce945","order_by":4,"name":"Kyunghoon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIie3QMQrCMBSA4RcCcYm4Fgr2Cg0FFxWvogi6dFAEcRCNFNql4hpx8AqC4FwIdCpeohcQsovFqmPsKJh/eSHkg0cATKYfDPFyNh0nT153pBrxGB/1q5F3A574bjWCo7ilJguJNjxTahqC0+BkdNMuFmfeQWQS19D2Yu9DYCIhUmiJ8D1cDyVBQf1SHACdoBZoFyvJXVJIaa4K0qtIuLQgo2AXZHACIvUkTmeYpmOXCdKy6dUaCkmGWsKi4Izpsr0+WjhXdN7p7qLQ0xP+HJ/treLftQDAKcfqyzOTyWT66x4j+UC56jtXYAAAAABJRU5ErkJggg==","orcid":"","institution":"Seoul National University Bundang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kyunghoon","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2024-07-04 04:24:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4683655/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4683655/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62140279,"identity":"26f63cbe-9a74-46f7-9167-de17ba2d0b52","added_by":"auto","created_at":"2024-08-09 17:02:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":510637,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of study selection process\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/a834da334853c70dd5b6d98e.jpg"},{"id":62139550,"identity":"97fe7ffb-cff0-4c97-a9f0-14779a99ff64","added_by":"auto","created_at":"2024-08-09 16:54:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":599835,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias of included studies\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/940fbc182d8e93caf64677aa.jpg"},{"id":62139551,"identity":"a9ca56e3-d95f-46d3-878c-554097a4b176","added_by":"auto","created_at":"2024-08-09 16:54:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":943900,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot comparing the duration of mechanical ventilation between (A) dexmedetomidine and alternative sedatives; (B) dexmedetomidine and fentanyl; (C) dexmedetomidine and midazolam. MD stands for mean difference, and CI for confidence interval.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/07986f07f1a1b5e9da26fb16.jpg"},{"id":62139555,"identity":"aa700a06-a519-49e9-a940-8b824dbce513","added_by":"auto","created_at":"2024-08-09 16:54:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":748573,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot comparing (A) bradycardia events, (B) hypotension events, and (C) delirium incidence between dexmedetomidine and other sedatives. OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/fae869e4d88ebb68d0f69639.jpg"},{"id":62141337,"identity":"fa13d46f-855f-42f0-8baa-2c524c153284","added_by":"auto","created_at":"2024-08-09 17:18:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3323889,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/8827c9bc-6987-4dec-a673-f48f6d5f9dc5.pdf"},{"id":62139549,"identity":"c93bba62-a5ad-4453-b24c-e0b7c19e7839","added_by":"auto","created_at":"2024-08-09 16:54:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22576,"visible":true,"origin":"","legend":"\u003cp\u003eSupplement 1. Details of the search strategy\u003c/p\u003e","description":"","filename":"Supplement1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/8c38f7fda44059061a60a0ba.docx"},{"id":62139553,"identity":"e162abd4-f203-4445-b76e-9ef140d362f4","added_by":"auto","created_at":"2024-08-09 16:54:53","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1046942,"visible":true,"origin":"","legend":"\u003cp\u003eSupplement 2. A forest plot comparing (A) ICU length of stay, (B) duration of sedation, and (C) the number of fentanyl boluses between dexmedetomidine and other sedatives. MD stands for mean difference, and CI denotes confidence interval.\u003c/p\u003e","description":"","filename":"Supplement2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4683655/v1/75590c1049e4c59e803319b3.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Dexmedetomidine in Mechanically Ventilated Critically Ill Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMechanically ventilated children are at a high risk of unplanned extubation, which can lead to airway injuries and life-threatening scenarios like asphyxia (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Effective sedation and analgesia are pivotal in managing these patients to not only reduce anxiety and discomfort from endotracheal tubes and intensive care unit (ICU) procedures but also to improve their overall care outcomes (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe concept of \u0026ldquo;analgosedation\u0026rdquo; within the pediatric intensive care unit (PICU) denotes a sedation strategy that combines both analgesia and sedation to enhance the comfort and wellbeing of critically ill patients (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Despite its critical importance, the management of sedation in the PICU encounters numerous hurdles and limitations, including the need to strike a balance between adequate sedation levels and the prevention of adverse effects, in addition to the absence of standardized protocols specifically designed for pediatric patients. Traditional sedatives such as benzodiazepines and propofol, though commonly administered to mechanically ventilated critically ill children, carry the risk of tolerance, dependency, and withdrawal symptoms (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eDexmedetomidine presents as a favorable alternative sedative, recognized for providing milder sedation levels, decreasing delirium, and possessing analgesic qualities. This highly selective α2-receptor agonist, endorsed by the Food and Drug Administration for use in pediatric patients since 2013, achieves its analgesic effect through the activation of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\alpha 2\\)\u003c/span\u003e\u003c/span\u003e-adrenoreceptors in both the spinal and supraspinal areas (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Extensively employed in surgical anesthesia and ICU sedation, dexmedetomidine is acclaimed for its analgesic, sedative, and anti-sympathetic characteristics. In comparison to midazolam or propofol, dexmedetomidine has been shown to afford advantages such as a diminished time to extubation, shortened duration of mechanical ventilation (MV), enhanced ease of arousal, better patient cooperation, and improved communication (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough there is substantial evidence supporting the use of dexmedetomidine in adult populations (\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), research concerning its effectiveness and safety in critically ill pediatric patients on MV remains scarce. We performed a systematic review and meta-analysis of RCTs to assess the efficacy and adverse effects of dexmedetomidine in critically ill children on mechanical ventilation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eA systematic review of RCTs comparing dexmedetomidine with other sedatives in critically ill, mechanically ventilated children was conducted. A meta-analysis was also performed to evaluate the efficacy and safety of dexmedetomidine. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDatabase and search strategy\u003c/h2\u003e \u003cp\u003eA meticulously designed peer-reviewed search strategy was developed by a medical librarian (NJK). Searches were conducted in PubMed, Embase, and The Cochrane Library from their inception up to April 4, 2024, utilizing terms related to dexmedetomidine and pediatric age. The details of this search strategy are provided in Supplement 1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData collection and analysis\u003c/h2\u003e \u003cp\u003eTitles and abstracts were screened by two independent reviewers (IKL and KHL) to identify trials potentially eligible for inclusion, with full texts being subsequently evaluated for eligibility. Discrepancies between reviewers were resolved through discussion or by consulting a third reviewer as necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003eIncluded were trials that: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) RCT; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) involved invasively mechanically ventilated children admitted to the PICU; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) had an intervention group receiving intravenous dexmedetomidine; and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) had a control group receiving other intravenous sedatives.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003eExcluded were trials that: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) study type: observational studies, case reports, letters, editorials, or not peer -reviewed; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) included duplicate samples; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) participants restricted to neonates or adults; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) studies that used dexmedetomidine solely during anesthesia or before procedures; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) studies that administered dexmedetomidine through non-intravenous routes; or (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) studies that used placebo for the control group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome focused on sedation efficacy: duration of MV, length of ICU stays, duration of sedation, and total fentanyl bolus administrations. Secondary outcomes included adverse effects like bradycardia and hypotension.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003eThe risk of bias in included trials was assessed by two reviewers (IKL and KHL) using a modified version of the Cochrane risk of bias tool (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Each trial was examined for bias across various domains, with each domain assessed as having low, unclear, or high risk of bias. The classification of the overall risk of bias for each trial was as follows: low if the risk of bias was low or possibly low in all domains, unclear if there was an unclear risk of bias in at least one domain with no domain having a high risk of bias, or high if there was a high or possibly high risk of bias in at least one domain. Any discrepancies were resolved through discussion and consensus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe meta-analysis used R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria) to analyze the efficacy and adverse effects of dexmedetomidine in terms of sedation. For continuous outcome data, the mean difference served as the primary measure, with estimates aggregated using the inverse variance method. The Mantel-Haenszel method pooled estimates for binary outcome data, employing odds ratio and risk ratio as main metrics. The choice of either a common or a random effects model was determined by heterogeneity levels, indicated by \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({I}^{2}\\)\u003c/span\u003e\u003c/span\u003e exceeding 50%, at which point the random effects model was favored.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and characteristics\u003c/h2\u003e \u003cp\u003eInitially, searches of reference databases identified a total of 348 records. After the screening and eligibility assessment were conducted, eight studies (\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) satisfied the inclusion criteria and were thus included in the meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOf the studies selected, five concentrated on post-operative pediatric patients, whereas the others enrolled medical patients. Importantly, children with atrioventricular block were excluded from four of these studies. The detailed characteristics of each study are outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor,\u003c/p\u003e \u003cp\u003eyear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary disease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInclusion criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExclusion criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNumber of patients (I/C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntervention group (dose)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eControl group (dose)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eInitiation of DEX\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDuration of DEX\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTobias,\u003c/p\u003e \u003cp\u003e2004 [18]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients admitted to PICU requiring MV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo information available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChildren and infants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNS dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30 (20/10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.25 mcg/kg/h or 0.5 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMidazolam (0.1 mg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAfter intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAfter 24 hours on either sedation if MV was still necessary, the patient was switched to the alternative agent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrasad,\u003c/p\u003e \u003cp\u003e2012 [19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients undergoing CHD surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo information available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026ndash;14 years, overnight MV was anticipated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1 year, undergoing re-operation, surgeries done under deep hypothermia, patients with severe liver dysfunction, second and third degree heart block, patients requiring MV\u0026thinsp;\u0026gt;\u0026thinsp;24h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (30/30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.5 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFentanyl (1 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIn the post-operative intensive care unit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6AM on the following day to allow an early extubation trial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAydogan, 2013 [20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients undergoing scoliosis surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo information available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u0026ndash;18 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHistory of midazolam and/or DEX, delirium, developmental delay, mental retardation, an American Society of Anesthesiologists classification greater than III, known previous reactions to anesthesia, a history of asthma or an anticipated difficult airway, a history of hypertension, chronic opioid, sedative, analgesic, antihypertensive agents or digoxin prior to the procedure, concomitant disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 (16/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.4 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMidazolam (0.1 mg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAfter surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAt the time of extubation\u003c/p\u003e \u003cp\u003eUp to 24 hours on either sedation if MV was still necessary\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaleh, 2016 [21]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients scheduled for abdominal surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSep 2013\u0026thinsp;~\u0026thinsp;Dec 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026ndash;10 years, overnight MV was anticipated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1 year, emergency surgeries, severe liver dysfunction, patients requiring MV more than 24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50 (25/25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.3 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFentanyl (1 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAt arrival to the SICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAfter 18 h\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGaristo, 2018 [22]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients undergoing complex CHD surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJuly 2012 \u0026ndash; Dec 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 month \u0026ndash; 24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNewborns, brain or bone malformations, neuromuscular disease, post-surgical delayed sternal closure, post-operative neurological or pulmonary complications, ECMO requirement, AV block, VIS\u0026thinsp;\u0026gt;\u0026thinsp;30, hepatic failure, renal impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48 (22/26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.5 mcg/kg/h), midazolam (0.05 mg/kg/h), morphine (10 mcg/kg/h), paracetamol bolus (7.5\u0026ndash;15 mg/kg q6 hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMidazolam (0.1 mg/kg/h), morphine (20 mcg/kg/h), paracetamol bolus (7.5\u0026ndash;15 mg/kg q6 hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAfter CCU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSedative drug weaning proceeded with MV weaning, according to institutional guidelines\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErickson, 2020 [23]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients admitted to PICU requiring MV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJan 2015 \u0026ndash; July 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;16 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAcute brain injury, neurologic injury, requirement for continuous neuromuscular blockade, cardiovascular instability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (29/31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (1.0 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eUsual care: propofol, benzodiazepines, chloral hydrate, ketamine, and barbiturates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAfter randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUntil sedation was no longer required or to a maximum of 14 days after enrollment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGulla, 2020 [24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients admitted to PICU requiring MV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAugust 2016 \u0026ndash; April 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 month \u0026ndash; 15 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCatecholamine resistant shock, already on sedative drug infusion, bradycardia, AV block, primary CNS involvement, hepatic impairment, infusion of muscle relaxants, previous participation in the study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47 (23/24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX (0.25\u0026ndash;0.75 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMidazolam (1\u0026ndash;4 mcg/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAfter randomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUntil 7 days or weaning from MV\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAttia, 2022 [25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients undergoing CHD surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eApril 2020 \u0026ndash; Dec 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 day \u0026ndash; 15 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeuromuscular disorders, demyelinating illness, cerebral palsy, developmental and behavioral issues, inborn metabolic errors, acute severe neurological condition, decompensated heart failure, acute hemodynamic instability, septic shock, HR 60 beats/min, grade II or III AV block\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (30/30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDEX* (0.2\u0026ndash;1.5 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFentanyl (1\u0026ndash;3 mcg/kg/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDuring anesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo information available\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: I/C, intervention/control; PICU, pediatric intensive care unit; MV, mechanical ventilation; CHD, congenital heart disease; DEX, dexmedetomidine; CNS, central nervous system; SICU, surgical intensive care unit; ECMO, extracorporeal membrane oxygenation; VIS, vasoactive inotropic score; AV, atrioventricular; PAH, pulmonary hypertension; CCU, cardiac intensive care unit\u003c/p\u003e \u003cp\u003e* Dexmedetomidine was started with a bolus dose.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding interventions, the majority of the studies (7/8, 88%) did not implement a dexmedetomidine bolus at the onset of the infusion. Moreover, in most studies (7/8, 88%) dexmedetomidine was the exclusive sedative agent employed.\u003c/p\u003e \u003cp\u003eWith respect to the control groups, the included trials exhibited variability. Namely, three trials (3/8, 38%) used midazolam, an equivalent number applied fentanyl, and the two remaining trials (2/8, 25%) utilized combinations of different sedative medications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias\u003c/h2\u003e \u003cp\u003eThe risk of bias within the included studies is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eEfficacy outcomes\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e1. Mechanical ventilation duration\u003c/h2\u003e \u003cp\u003eData from seven studies were incorporated into the meta-analysis for the duration of MV. Dexmedetomidine was shown to significantly reduce the duration of MV when compared to other sedative drugs(MD -3.54 h, 95% CI, -6.49 to -0.59, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe subgroup analysis indicated that dexmedetomidine considerably shortened the MV duration in comparison to fentanyl (MD -1.53 h, 95% CI, -1.92 to -1.13, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Nevertheless, no significant disparities in MV duration were found when dexmedetomidine was compared to midazolam (MD -14.58 h, 95% CI, -34.11 to 4.94, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e2. ICU length of stay\u003c/h2\u003e \u003cp\u003eEligible data from three studies were included in the meta-analysis concerning the ICU length of stay. Dexmedetomidine, in comparison to other sedative drugs, showed no significant difference in the length of stay in the ICU (MD -0.20, 95% CI, -1.89 to 1.49, Supplement 2A).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3. Duration of sedation\u003c/h2\u003e \u003cp\u003eAnalysis of four studies\u0026rsquo; data on sedation duration revealed no significant reduction when compared to other sedatives (MD 0.16, 95% CI, -0.82 to 1.13, Supplement 2B).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4. Number of fentanyl bolus doses\u003c/h2\u003e \u003cp\u003eData on the requirement for additional fentanyl boluses were available from three trials. No significant reduction in the need for fentanyl boluses was observed when compared to other sedatives (MD -0.66, 95% CI, -2.73 to 1.40, Supplement 2C).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSafety outcomes\u003c/h2\u003e \u003cp\u003eFour trials contributed data to the analysis of bradycardia incidence, while two trials did so for the analysis of hypotension incidence. Compared to other sedatives, dexmedetomidine was significantly associated with a higher risk of bradycardia (OR 6.14, 95% CI, 2.20 to 17.12, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) and hypotension (OR 8.14, 95% CI, 1.37 to 48.31, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eMoreover, no significant difference in delirium incidence was demonstrated when compared to alternative sedatives across two trials (OR 0.61, 95% CI, 0.16 to 2.31, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis, encompassing eight trials with 387 mechanically ventilated children, provides evidence that dexmedetomidine significantly reduces MV duration in this population, particularly when compared to fentanyl. However, dexmedetomidine did not demonstrate significant effects on the length of ICU stays, duration of sedation, or the need for additional sedatives. Moreover, dexmedetomidine was associated with a significantly higher risk of bradycardia and hypotension compared to other sedatives but did not impact the incidence of delirium.\u003c/p\u003e \u003cp\u003eSeveral hypotheses offer explanations for how dexmedetomidine may improve MV duration. First, dexmedetomidine has been found to enhance compliance, reduce resistance, and improve oxygenation during ongoing MV, potentially leading to a quicker extubation time(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Second, dexmedetomidine\u0026rsquo;s unique pharmacologic profile, including easy arousability and minimal respiratory depression, may facilitate effective sedation while minimizing complications associated with respiratory suppression (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Furthermore, dexmedetomidine has been linked to a reduced risk of adverse events like delirium in adults (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), possibly aiding in a smoother extubation process.\u003c/p\u003e \u003cp\u003eOur study builds upon previous meta-analyses in various important aspects. Prior meta-analyses have mainly concentrated on the efficacy of dexmedetomidine in specific pediatric cohorts, such as those undergoing cardiac surgery (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The meta-analysis addressing children undergoing cardiac surgery concluded that perioperative dexmedetomidine administration might reduce MV duration, as well as the lengths of ICU and hospital stays. Our investigation, conversely, broadens this scope to include both post-operative and medical pediatric populations. Unlike the earlier meta-analysis that limited its focus to post-operative children (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), we excluded studies that administered dexmedetomidine solely during anesthesia to evaluate its efficacy in the context of MV in PICU settings. Furthermore, our meta-analysis assesses both the sedation efficacy and the adverse effects of dexmedetomidine, unlike previous analyses that concentrated primarily on the safety profile of dexmedetomidine (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). This dual focus offers vital insights for pediatric intensive care, providing a more comprehensive perspective on the application of dexmedetomidine in critically ill children.\u003c/p\u003e \u003cp\u003eAdditionally, our analysis distinctly focused on trials comparing dexmedetomidine with other sedatives, deliberately excluding those comparisons with placebo. This decision was made under the rationale that placebo-controlled trials might not reflect the practical clinical conditions where dexmedetomidine is usually compared against active sedatives. While placebo-controlled trials are informative regarding dexmedetomidine\u0026rsquo;s specific effects, our intentional exclusion stems from our objective to evaluate dexmedetomidine\u0026rsquo;s relative effectiveness against common clinical interventions.\u003c/p\u003e \u003cp\u003eHowever, our study also uncovered a heightened risk of bradycardia and hypotension linked to dexmedetomidine. Acting through α-2a receptor agonism, dexmedetomidine induces sedation by decreasing plasma norepinephrine levels, potentially causing bradycardia and hypotension (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Despite noting these adverse effects, it is still ambiguous whether they were reversible with non-invasive interventions or required vasoactive agents for management. Additionally, the dose-dependency of these adverse events deserves further exploration. Previous studies have indicated that bradycardia and hypotension are infrequent in critically ill children treated with dexmedetomidine for extended periods and are typically reversible with minimal interventions (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChallenges emerged in evaluating delirium within our meta-analysis because of scarce data on this outcome. Among the included studies, only two explored the assessment of delirium, with a single study focusing primarily on adolescent participants (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Although meta-analyses involving adults have underscored dexmedetomidine\u0026rsquo;s role in reducing delirium compared to other sedatives (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), the lack of pediatric-specific data complicates the interpretation of these findings.\u003c/p\u003e \u003cp\u003eNotwithstanding the valuable insights derived from our study, it presents several limitations that merit acknowledgment. Firstly, evaluating time in adequate sedation was impractical due to the disparate sedation assessment tools used in the studies. Secondly, assessing delirium and withdrawal syndrome in pediatric patients presents intrinsic challenges. Thirdly, our study\u0026rsquo;s observed high heterogeneity and significant risk of bias advise caution in interpreting these results. Lastly, the variation in weaning protocols among the studies introduces additional complexity to our analysis.\u003c/p\u003e \u003cp\u003eIn summation, our study highlights the potential advantages of dexmedetomidine in shortening MV duration in critically ill children, while also underscoring the importance of further research to delineate its safety profile, harmonize sedation protocols, and refine dosing approaches. Consequently, comprehensive RCTs and multicenter studies are necessary to corroborate our findings and establish evidence-based sedation protocols that cater to the specific demands of PICU patients. Incorporating the knowledge obtained from our study into clinical practice enables healthcare professionals to enhance sedation management and improve outcomes for mechanically ventilated children.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding sources.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKlugman D, Melton K, Maynord PON, Dawson A, Madhavan G, Montgomery VL, et al. Assessment of an unplanned extubation bundle to reduce unplanned extubations in critically ill neonates, infants, and children. Jama Pediatr. 2020;174(6):e200268-e.\u003c/li\u003e\n \u003cli\u003eAlberto L, Stefano B, Alessandro G, Stefano E, Cristina N, Stefania V, et al. Unplanned extubations in general intensive care unit: A nine-year retrospective analysis. Acta Bio Medica: Atenei Parmensis. 2018;89(Suppl 7):25.\u003c/li\u003e\n \u003cli\u003eMorris HF, Schuller L, Archer J, Niesen A, Ellsworth S, Egan J, et al. Decreasing unplanned extubation in the neonatal ICU with a focus on endotracheal tube tip position. Resp Care. 2020;65(11):1648-54.\u003c/li\u003e\n \u003cli\u003eKress JP, Hall JB. Sedation in the mechanically ventilated patient. Critical care medicine. 2006;34(10):2541-6.\u003c/li\u003e\n \u003cli\u003eShehabi Y, Nakae H, Hammond N, Bass F, Nicholson L, Chen J. The effect of dexmedetomidine on agitation during weaning of mechanical ventilation in critically ill patients. Anaesth Intens Care. 2010;38(1):82-90.\u003c/li\u003e\n \u003cli\u003eGerlach AT, Dasta JF, Steinberg S, Martin LC, Cook CH. A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients. Journal of critical care. 2009;24(4):568-74.\u003c/li\u003e\n \u003cli\u003eIirola T, Aantaa R, Laitio R, Kentala E, Lahtinen M, Wighton A, et al. Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients. Critical care. 2011;15(5):1-10.\u003c/li\u003e\n \u003cli\u003eEgbuta C, Mason KP. Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit. J Clin Med. 2021;10(9).\u003c/li\u003e\n \u003cli\u003eFonsmark L, Rasmussen YH, Carl P. Occurrence of withdrawal in critically ill sedated children. Critical care medicine. 1999;27(1):196-9.\u003c/li\u003e\n \u003cli\u003eIsta E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation. Critical care medicine. 2008;36(8):2427-32.\u003c/li\u003e\n \u003cli\u003eKaye AD, Urman RD, Rappaport Y, Siddaiah H, Cornett EM, Belani K, et al. Multimodal analgesia as an essential part of enhanced recovery protocols in the ambulatory settings. Journal of Anaesthesiology Clinical Pharmacology. 2019;35(Suppl 1):S40-S5.\u003c/li\u003e\n \u003cli\u003eKeating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75:1119-30.\u003c/li\u003e\n \u003cli\u003eLewis K, Alshamsi F, Carayannopoulos KL, Granholm A, Piticaru J, Al Duhailib Z, et al. Dexmedetomidine vs other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials. Intensive Care Med. 2022;48(7):811-40.\u003c/li\u003e\n \u003cli\u003eZhou WJ, Liu M, Fan XP. Differences in efficacy and safety of midazolam vs. dexmedetomidine in critically ill patients: A meta-analysis of randomized controlled trial. Exp Ther Med. 2021;21(2):156.\u003c/li\u003e\n \u003cli\u003eHeybati K, Zhou F, Ali S, Deng J, Mohananey D, Villablanca P, Ramakrishna H. Outcomes of dexmedetomidine versus propofol sedation in critically ill adults requiring mechanical ventilation: a systematic review and meta-analysis of randomised controlled trials. Br J Anaesth. 2022;129(4):515-26.\u003c/li\u003e\n \u003cli\u003eLiberati A, Altman DG, Tetzlaff J, Mulrow C, G\u0026oslash;tzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Annals of internal medicine. 2009;151(4):W-65-W-94.\u003c/li\u003e\n \u003cli\u003eHiggins JP, Altman DG, G\u0026oslash;tzsche PC, J\u0026uuml;ni P, Moher D, Oxman AD, et al. The Cochrane Collaboration\u0026rsquo;s tool for assessing risk of bias in randomised trials. Bmj. 2011;343.\u003c/li\u003e\n \u003cli\u003eTobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J. 2004;97(5):451-5.\u003c/li\u003e\n \u003cli\u003ePrasad S, Simha PP, Jagadeesh A. Comparative study between dexmedetomidine and fentanyl for sedation during mechanical ventilation in post-operative paediatric cardiac surgical patients. Indian journal of anaesthesia. 2012;56(6):547-52.\u003c/li\u003e\n \u003cli\u003eAydogan MS, Korkmaz MF, Ozgul U, Erdogan MA, Yucel A, Karaman A, et al. Pain, fentanyl consumption, and delirium in adolescents after scoliosis surgery: dexmedetomidine vs midazolam. Paediatr Anaesth. 2013;23(5):446-52.\u003c/li\u003e\n \u003cli\u003eSaleh RH. Randomized controlled comparative trial between low dose dexmedetomidine sedation and that of fentanyl in children after surgical procedures in surgical pediatric intensive care unit. Egyptian Journal of Anaesthesia. 2016;32(1):137-42.\u003c/li\u003e\n \u003cli\u003eGaristo C, Ricci Z, Tofani L, Benegni S, Pezzella C, Cogo P. Use of low-dose dexmedetomidine in combination with opioids and midazolam in pediatric cardiac surgical patients: randomized controlled trial. Minerva anestesiologica. 2018;84(9):1053-62.\u003c/li\u003e\n \u003cli\u003eErickson SJ, Millar J, Anderson BJ, Festa MS, Straney L, Shehabi Y, Long DA. Dexmedetomidine sedation in mechanically ventilated critically ill children: a pilot randomized controlled trial. Pediatric Critical Care Medicine. 2020;21(9):e731-e9.\u003c/li\u003e\n \u003cli\u003eGulla KM, Sankar J, Jat KR, Kabra SK, Lodha R. Dexmedetomidine vs Midazolam for Sedation in Mechanically Ventilated Children: A Randomized Controlled Trial. Indian Pediatr. 2021;58(2):117-22.\u003c/li\u003e\n \u003cli\u003eAttia WA, Aziz OMA, Reheem AMA, Sayed OME-e, Mahmoud MM. Comparison Between Sedative And Analgesic Effects Of Dexmedetomidine Versus Fentanyl For Pediatric Patients Following Cardiac Surgery In Intensive Care Unit. Journal of Pharmaceutical Negative Results. 2022:1058-64.\u003c/li\u003e\n \u003cli\u003eSenoglu N, Oksuz H, Dogan Z, Yildiz H, Kamaz A, Ugur N. Effects of Dexmedetomidine on respiratory mechanics during mechanical ventilation. Journal of Anaesthesiology Clinical Pharmacology. 2009;25(3):273-6.\u003c/li\u003e\n \u003cli\u003eGupta S, Singh D, Sood D, Kathuria S. Role of dexmedetomidine in early extubation of the intensive care unit patients. Journal of Anaesthesiology Clinical Pharmacology. 2015;31(1):92-8.\u003c/li\u003e\n \u003cli\u003eLiu Y, Bian W, Liu P, Zang X, Gu X, Chen W. Dexmedetomidine improves the outcomes in paediatric cardiac surgery: a meta-analysis of randomized controlled trials. Interact Cardiovasc Thorac Surg. 2018;26(5):852-8.\u003c/li\u003e\n \u003cli\u003eDaverio M, Sperotto F, Zanetto L, Coscini N, Frigo AC, Mondardini MC, Amigoni A. Dexmedetomidine for Prolonged Sedation in the PICU: A Systematic Review and Meta-Analysis. Pediatr Crit Care Med. 2020;21(7):e467-e74.\u003c/li\u003e\n \u003cli\u003eGerlach AT, Blais DM, Jones GM, Burcham PK, Stawicki SP, Cook CH, Murphy CV. Predictors of dexmedetomidine-associated hypotension in critically ill patients. International Journal of Critical Illness and Injury Science. 2016;6(3):109-14.\u003c/li\u003e\n \u003cli\u003ePasin L, Landoni G, Nardelli P, Belletti A, Di Prima AL, Taddeo D, et al. Dexmedetomidine reduces the risk of delirium, agitation and confusion in critically Ill patients: a meta-analysis of randomized controlled trials. J Cardiothor Vasc An. 2014;28(6):1459-66.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dexmedetomidine, mechanical ventilation, sedation, pediatric, intensive care unit","lastPublishedDoi":"10.21203/rs.3.rs-4683655/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4683655/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChildren undergoing mechanical ventilation in the pediatric intensive care unit (PICU) require effective sedation to reduce anxiety and discomfort. Dexmedetomidine, an α2-receptor agonist, presents as a viable sedative alternative, yet its efficacy and safety for critically ill, mechanically ventilated children remain to be fully established. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of dexmedetomidine in such patients.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA systematic search was conducted up to April 2024. RCTs that compare dexmedetomidine with other sedatives in mechanically ventilated children were included. This analysis focused on both the efficacy and safety outcomes through meta-analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIncluded in the analysis were eight trials, involving a total of 387 mechanically ventilated children. Compared to other sedatives, dexmedetomidine significantly reduced the duration of mechanical ventilation (MD -3.54 h, 95% CI, -6.49 to -0.59), particularly when compared to fentanyl. However, dexmedetomidine did not significantly impact the length of ICU stay, duration of sedation, or the necessity for additional sedatives. Dexmedetomidine was associated with a significantly increased risk of bradycardia (OR 6.14, 95% CI, 2.20 to 17.12) and hypotension (OR 8.14, 95% CI, 1.37 to 48.31), with no significant difference observed in the incidence of delirium (OR 0.61, 95% CI, 0.16 to 2.31) in comparison to other sedatives.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAlthough dexmedetomidine notably diminished the duration of mechanical ventilation, the potential for adverse effects necessitates further investigation. Large RCTs are needed to validate our findings and refine sedation management in mechanically ventilated children in PICU.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Dexmedetomidine in Mechanically Ventilated Critically Ill Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 16:54:48","doi":"10.21203/rs.3.rs-4683655/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c196ffda-1be9-490d-9978-1c8b7889dd13","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-09T16:54:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-09 16:54:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4683655","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4683655","identity":"rs-4683655","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}