REVIEW
Dexmedetomidine for the management of delirium in critically ill patients—A protocol for a systematic review
Mathias Maagaard,
Marija Barbateskovic,
Anders Perner,
Janus C. Jakobsen,
Jørn Wetterslev,
Corresponding Author
Mathias Maagaard
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Correspondence
Mathias Maagaard, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Email: [email protected]
Search for more papers by this authorMarija Barbateskovic
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorAnders Perner
Centre for Research in Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Intensive Care, Department 4131, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorJanus C. Jakobsen
Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Cardiology, Holbaek Hospital, Holbaek, Denmark
Search for more papers by this authorJørn Wetterslev
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Centre for Research in Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorMathias Maagaard,
Marija Barbateskovic,
Anders Perner,
Janus C. Jakobsen,
Jørn Wetterslev,
Corresponding Author
Mathias Maagaard
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Correspondence
Mathias Maagaard, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Email: [email protected]
Search for more papers by this authorMarija Barbateskovic
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorAnders Perner
Centre for Research in Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Intensive Care, Department 4131, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorJanus C. Jakobsen
Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Cardiology, Holbaek Hospital, Holbaek, Denmark
Search for more papers by this authorJørn Wetterslev
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Centre for Research in Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Search for more papers by this authorSystematic review registration: PROSPERO CRD42018115121.
Sources of support: This protocol was written with the support from Copenhagen Trial Unit, Department 7812, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Abstract
Background
Delirium is a common complication in critically ill patients and carries an increased risk of mortality and morbidity. Dexmedetomidine can potentially treat delirium by diminishing predisposing factors. The evidence regarding the use of dexmedetomidine in the management of delirium is conflicting. This protocol aims to identify the beneficial and harmful effects of dexmedetomidine in the management of delirium.
Methods
This protocol uses the recommendations of the Cochrane Collaboration, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We wish to assess in critically ill patients with delirium, if dexmedetomidine vs placebo is effective in managing delirium and improving clinical outcomes. We will include all relevant randomised clinical trials assessing the use of dexmedetomidine in treating delirium. To identify trials, we will search the Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Science Journal Database, and BIOSIS. Two authors will screen the literature and extract data. The Cochrane risk of bias tool will be used to evaluate included trials. Extracted data will be analysed using Review Manager 5 and Trial Sequential Analysis. We will create a ‘Summary of Findings’-table in which we will present our primary and secondary outcomes. We will assess the quality of evidence using GRADE assessment.
Discussion
This systematic review can potentially aid clinicians in decision making and benefit the many critically ill patients developing delirium.
CONFLICTS OF INTEREST
All authors declare that they have no competing interests.
Supporting Information
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REFERENCES
- 1Maagaard M, Barbateskovic M, Perner A, Jakobsen JC, Wetterslev J. Dexmedetomidine for the prevention of delirium in critically ill patients – a protocol for a systematic review. Acta Anaesthesiol Scand. 2019; 63(4): 540-548.
10.1111/aas.13313 Google Scholar
- 2Collet MO, Caballero J, Sonneville R, et al. Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. Intensive Care Med. 2018; 44(7): 1081-1089.
- 3Allen J, Alexander E. Prevention, recognition, and management of delirium in the intensive care unit. AACN Adv Crit Care. 2012; 23(1): 5-11; quiz 2-3.
- 4Zaal IJ, Slooter AJ. Delirium in critically ill patients: epidemiology, pathophysiology, diagnosis and management. Drugs. 2012; 72(11): 1457-1471.
- 5Kalabalik J, Brunetti L, El-Srougy R. Intensive care unit delirium: a review of the literature. J Pharm Pract. 2014; 27(2): 195-207.
- 6Jackson P, Khan A. Delirium in critically ill patients. Crit Care Clin. 2015; 31(3): 589-603.
- 7Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma. 2008; 65(1): 34-41.
- 8Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care. 2005; 9(4): R375-R381.
- 9Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001; 286(21): 2703-2710.
- 10Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW, et al. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med. 2010; 38(12): 2311-2318.
- 11Mehta S, Cook D, Devlin JW, Skrobik Y, Meade M, Fergusson D, et al. Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. Crit Care Med. 2015; 43(3): 557-566.
- 12Jones SF, Pisani MA. ICU delirium: an update. Curr Opin Crit Care. 2012; 18(2): 146-151.
- 13Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. Lancet Neurol. 2015; 14(8): 823-832.
- 14Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010; 304(4): 443-451.
- 15Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010; 38(7): 1513-1520.
- 16Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015; 350: h2538.
- 17Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004; 32(4): 955-962.
- 18Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41(1): 263-306.
- 19Peterson JF, Pun BT, Dittus RS, Thomason JW, Jackson JC, Shintani AK, et al. Delirium and its motoric subtypes: a study of 614 critically ill patients. J Am Geriatr Soc. 2006; 54(3): 479-484.
- 20Meagher D. Motor subtypes of delirium: past, present and future. Int Rev Psychiatry. 2009; 21(1): 59-73.
- 21Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M. Motor subtypes of postoperative delirium in older adults. Arch Surg. 2011; 146(3): 295-300.
- 22Tomasi CD, Grandi C, Salluh J, Soares M, Giombelli VR, Cascaes S, et al. Comparison of CAM-ICU and ICDSC for the detection of delirium in critically ill patients focusing on relevant clinical outcomes. J Crit Care. 2012; 27(2): 212-217.
- 23Gusmao-Flores D, Salluh JI, Chalhub RA, Quarantini LC. The confusion assessment method for the intensive care unit (CAM-ICU) and intensive care delirium screening checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit Care. 2012; 16(4): R115.
- 24Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive care delirium screening checklist: evaluation of a new screening tool. Intensive Care Med. 2001; 27(5): 859-864.
- 25Steiner LA. Postoperative delirium. Part 1: pathophysiology and risk factors. Eur J Anaesthesiol. 2011; 28(9): 628-636.
- 26Gunther ML, Morandi A, Ely EW. Pathophysiology of delirium in the intensive care unit. Crit Care Clin. 2008; 24(1): 45-65, viii.
- 27Williams ST. Pathophysiology of encephalopathy and delirium. J Clin Neurophysiol. 2013; 30: 435-437.
- 28Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med. 2015; 43(1): 40-47.
- 29Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. Eur J Anaesthesiol. 2011; 28(1): 3-6.
- 30Gerlach AT, Dasta JF. Dexmedetomidine: an updated review. Ann Pharmacother. 2007; 41: 245-254.
- 31Duan X, Li Y, Zhou C, Huang L, Dong Z. Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand. 2014; 58(9): 1121-1126.
- 32Wang Y, Han R, Zuo Z. Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage. Br J Anaesth. 2016; 116(3): 384-392.
- 33Degos V, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L, et al. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology. 2013; 118(5): 1123-1132.
- 34Honey BL, Benefield RJ, Miller JL, Johnson PN. a2-receptor agonists for treatment and prevention of iatrogenic opioid abstinence syndrome in critically ill patients. Ann Pharmacother. 2009; 43: 1506-1511.
- 35Anger KE. Dexmedetomidine: a review of its use for the management of pain, agitation, and delirium in the intensive care unit. Curr Pharm Des. 2013; 19: 4003-4013.
- 36Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother. 2009; 43(12): 2064-2074.
- 37Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015; 75(10): 1119-1130.
- 38Man Y, Guo Z, Cao J, Mi W. Efficacy of perioperative dexmedetomidine in postoperative neurocognitive function: a meta-analysis. Clin Exp Pharmacol Physiol. 2015; 42(8): 837-842.
- 39Nguyen J, Nacpil N. Effectiveness of dexmedetomidine versus propofol on extubation times, length of stay and mortality rates in adult cardiac surgery patients: a systematic review and meta-analysis. JBI Database System Rev Implement Rep. 2018; 16(5): 1220-1239.
- 40Peng K, Zhang J, Meng XW, Liu HY, Ji FH. Optimization of postoperative intravenous patient-controlled analgesia with opioid-dexmedetomidine combinations: an updated meta-analysis with trial sequential analysis of randomized controlled trials. Pain Physician. 2017; 20(7): 569-596.
- 41Zhou C, Zhu Y, Liu Z, Ruan L. Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients after general anaesthesia: a meta-analysis. J Int Med Res. 2016; 44(6): 1182-1190.
- 42Nelson S, Muzyk AJ, Bucklin MH, Brudney S, Gagliardi JP. Defining the role of dexmedetomidine in the prevention of delirium in the intensive care unit. Biomed Res Int. 2015; 2015: 635737.
- 43Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med. 2010; 36(6): 926-939.
- 44Fraser GL, Devlin JW, Worby CP, Alhazzani W, Barr J, Dasta JF, et al. Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013; 41(9 Suppl 1): S30-S38.
- 45Pasin L, Greco T, Feltracco P, Vittorio A, Neto CN, Cabrini L, et al. Dexmedetomidine as a sedative agent in critically ill patients: a meta-analysis of randomized controlled trials. PLoS ONE. 2013; 8(12): e82913.
- 46Xia ZQ, Chen SQ, Yao X, Xie CB, Wen SH, Liu KX. Clinical benefits of dexmedetomidine versus propofol in adult intensive care unit patients: a meta-analysis of randomized clinical trials. J Surg Res. 2013; 185(2): 833-843.
- 47Zhang H, Lu Y, Liu M, Zou Z, Wang L, Xu FY, et al. Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials. Crit Care. 2013; 17(2): R47.
- 48Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev. 2015; 1: CD010269.
- 49Serafim RB, Bozza FA, Soares M, do BP, Tura BR, Ely EW, et al. Pharmacologic prevention and treatment of delirium in intensive care patients: a systematic review. J Crit Care. 2015; 30(4): 799-807.
- 50Woods AD, Giometti R, Weeks SM. The use of dexmedetomidine as an adjuvant to benzodiazepine-based therapy to decrease the severity of delirium in alcohol withdrawal in adult intensive care unit patients: a systematic review. JBI Database System Rev Implement Rep. 2015; 13(1): 224-252.
- 51Liu X, Xie G, Zhang K, Song S, Song F, Jin Y, et al. Dexmedetomidine vs propofol sedation reduces delirium in patients after cardiac surgery: a meta-analysis with trial sequential analysis of randomized controlled trials. J Crit Care. 2017; 38: 190-196.
- 52Zhang Z, Chen K, Ni H, Zhang X, Fan H. Sedation of mechanically ventilated adults in intensive care unit: a network meta-analysis. Sci Rep. 2017; 7: 44979.
- 53Ng KT, Shubash CJ, Chong JS. The effect of dexmedetomidine on delirium and agitation in patients in intensive care: systematic review and meta-analysis with trial sequential analysis. Anaesthesia. 2018.
- 54Tamborrino MJJC. Count data analysis in randomised clinical trials. J Biomet Biostat. 2015; 06(01).
10.4172/2155-6180.1000227 Google Scholar
- 55Barbateskovic M, Krauss SR, Collet MO, Larsen LK, Jakobsen JC, Perner A, et al. Pharmacological interventions for prevention and management of delirium in intensive care patients: a systematic overview of reviews and meta-analyses. BMJ Open. 2018.
- 56Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008; 61(8): 763-769.
- 57Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64-75.
- 58Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive - Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009; 38: 287-298.
- 59Thorlund K, Devereaux PJ, Wetterslev J. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol. 2009; 38: 276-286.
- 60Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339: b2535.
- 61Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017; 17(1): 39.
- 62Salluh JI, Dal-Pizzol F, Mello PV, Friedman G, Silva E, Teles JM, et al. Delirium recognition and sedation practices in critically ill patients: a survey on the attitudes of 1015 Brazilian critical care physicians. J Crit Care. 2009; 24(4): 556-562.
- 63Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9): e825-e873.
- 64Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4(1): 1.
- 65Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350: g7647.
- 66International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) adopts consolidated guideline on good clinical practice in the conduct of clinical trials on medicinal products for human use. Int Digital Health Legislation. 1997; 48(2): 231-234.
- 67Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Available from www.cochrane-handbook.org: The Cochrane Collaboration; 2011. www.cochrane-handbook.org. Accessed January 10, 2019.
- 68Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998; 352: 609-613.
- 69Kjaergaard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001; 135: 982-989.
- 70Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008; 336(7644): 601-605.
- 71Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2017; 2: MR000033.
- 72Savovic J, Jones H, Altman D, Harris R, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technol Assess. 2012; 16(35): 1-82.
- 73Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. J Am Med Assoc. 1995; 275: 408-4012.
- 74Gluud LL. Bias in clinical intervention research. Am J Epidemiol. 2006; 163(6): 493-501.
- 75Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11): 1539-1558.
- 76Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414): 557-560.
- 77Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006; 25(20): 3443-3457.
- 78Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629-634.
- 79Begg CB, Mazumdar M. Operating characteristics of a Rank Colleration Test for publication bias. Biometrics. 1994; 50: 1088-1101.
- 80Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol. 2002; 31(1): 140-149.
- 81Keus F, Wetterslev J, Gluud C, van Laarhoven CJ. Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol. 2010; 10: 90.
- 82Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014; 14(120): 120.
- 83 The Cochrane Collaboration. Review Manager. 5.3 ed2014.
- 84DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015; 45(Pt A): 139-145.
- 85Demets DL. Methods for combining randomized clinical trial: strenghts and limitations. Stat Med. 1986; 6: 341-350.
- 86 Copenhagen Trial Unit. Trial Sequential Analysis. http://www.ctu.dk/tsa/. Accessed January 10, 2019.
- 87Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86.
- 88Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010; 2: 57-66.
- 89Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for trial sequential analysis (TSA) http://www.ctu.dk/tsa/files/tsa_manual.pdf2011
- 90Imberger G, Gluud C, Boylan J, Wetterslev J. Systematic reviews of anesthesiologic interventions reported as statistically significant: problems with power, precision, and type 1 error protection. Anest Analg. 2015; 121: 1611-1622.
- 91Imberger G, Thorlund K, Gluud C, Wetterslev J. False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: an empirical review. BMJ Open. 2016; 6(8): e011890.
- 92Thorlund K, Imberger G, Johnston BC, Walsh M, Awad T, Thabane L, et al. Evolution of heterogeneity (I2) estimates and their 95% confidence intervals in large meta-analyses. PLoS ONE. 2012; 7(7): e39471.
- 93Schünemann HJ, Best D, Vist G, Oxman AD. Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations. CMAJ. 2003; 169: 677-680.
- 94Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strenght of recommendations. BMJ. 2008; 336: 924-926.
- 95Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011; 64(4): 380-382.
- 96Storebo OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev. 2018; 5: CD012069.
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