Association between the use of midazolam, fentanyl, propofol, ketamine, and dexmedetomidine and the incidence of delirium in elderly patients in intensive care units: a systematic review
Keywords:
Delirium, Deep sedation, Intensive Care Units, Aged, Sedoanalgesics, ICU, Elderly, Dexmedetomidine, Propofol, MidazolamAbstract
BACKGROUND: Delirium is a common and serious complication among elderly patients in intensive care units (ICUs), and is often associated with increased morbidity and mortality rates. The choice of sedoanalgesic may influence the incidence of delirium; however, the evidence remains unclear, particularly in the elderly population.
OBJECTIVES: To evaluate the association between the use of different sedoanalgesics and the incidence of delirium in elderly ICU patients, based on data from randomized clinical trials.
DESIGN AND SETTING: This systematic review was conducted using data from randomized clinical trials performed in various ICU settings.
METHODS: A systematic search of the MEDLINE, Embase, and CENTRAL databases was performed in January 2024. The review included randomized clinical trials involving patients aged 60 years or older that examined the relationship between sedoanalgesics (midazolam, fentanyl, propofol, ketamine, and dexmedetomidine) and delirium incidence. Studies involving COVID-19 patients and non-randomized studies were excluded.
RESULTS: A total of 1,331 patients from six studies were included. The mean age of the patients ranged from 71 to 74.7 years. Four studies compared dexmedetomidine with propofol; two found no significant difference in delirium incidence, whereas two suggested a lower incidence with dexmedetomidine. The remaining studies compared propofol with ketamine and dexmedetomidine with midazolam and showed no significant differences in the incidence of delirium.
CONCLUSIONS: Dexmedetomidine may be associated with a lower incidence of delirium than propofol or midazolam in elderly ICU patients. However, further research is needed to confirm these findings and explore the factors contributing to delirium in this population.
SYSTEMATIC REVIEW REGISTRATION: Registered with PROSPERO, CRD42024575693, available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=575693.
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References
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5-TR) [Internet]. Washington, DC: American Psychiatric Association; 2022. Available from: https://www.psychiatry.org/psychiatrists/practice/dsm.
Vasilevskis EE, Han JH, Hughes CG, Ely EW. Epidemiology and risk factors for delirium across hospital settings. Best Pract Res Clin Anaesthesiol. 2012;26(3):277–87. PMID: 23040281; https://doi.org/10.1016/j.bpa.2012.07.003.
Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU liberation collaborative in over 15,000 adults. Crit Care Med. 2019;47(1):3–14. PMID: 30339549; https://doi.org/10.1097/CCM.0000000000003482.
Pereira JV, Sanjanwala RM, Mohammed MK, Le ML, Arora RC. Dexmedetomidine versus propofol sedation in reducing delirium among older adults in the ICU: a systematic review and meta-analysis. Eur J Anaesthesiol. 2020;37(2):121–31. PMID: 31860605; https://doi.org/10.1097/EJA.0000000000001131.
Carmo TG. Vantagens e desvantagens do uso de dexmedetomidina na sedação em unidades de terapia intensiva. Revista Saúde e Desenvolvimento. 2017;11(6):268–82.
Sakata RK. Analgesia e sedação em unidade de terapia intensiva. Revista Brasileira de Anestesiologia [Internet]. 2010;60(6):653–8.
Skrobik Y. Chasing the elusive notion of delirium causality. Intensive Care Med. 2015;41(12):2216–7. PMID: 26474993; https://doi.org/10.1007/s00134-015-4097-2.
Muellejans B, Matthey T, Scholpp J, Schill M. Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial. Crit Care. 2006;10(3):R91. PMID: 16780597; https://doi.org/10.1186/cc4939.
Bisinotto FMB, Silveira LAM, Silva RO, Martins LB. Postoperative delirium in the elderly: where are we? Revista Médica de Minas Gerais. 2017;27.
Khan BA, Perkins AJ, Prasad NK, et al. Biomarkers of delirium duration and delirium severity in the ICU. Crit Care Med. 2020;48(3):353–61. PMID: 31770149; https://doi.org/10.1097/CCM.0000000000004139.
Herling SF, Greve IE, Vasilevskis EE, et al. Interventions for preventing intensive care unit delirium in adults. Cochrane Database Syst Rev. 2018;11(11):CD009783. PMID: 30484283; https://doi.org/10.1002/14651858.CD009783.pub2.
Campbell NL, Perkins AJ, Khan BA, et al. Deprescribing in the pharmacologic management of delirium: a randomized trial in the intensive care unit. Journal of the American Geriatrics Society. 2019;67(4):695–702.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10(1):89. PMID: 33781348; https://doi.org/10.1186/s13643-021-01626-4.
Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. Cochrane [Internet]. 2019. Available from: https://training.cochrane.org/handbook/current/chapter-08.
Siripoonyothai S, Sindhvananda W. Comparison of postoperative delirium within 24 hours between ketamine and propofol infusion during cardiopulmonary bypass machine: a randomized controlled trial. Ann Card Anaesth. 2021;24(3):294–301. PMID: 34269257; https://doi.org/10.4103/aca.ACA_85_20.
Djaiani G, Silverton N, Fedorko L, et al. Dexmedetomidine versus propofol sedation reduces delirium after cardiac surgery: a randomized controlled trial. Anesthesiology. 2016;124(2):362–8. PMID: 26575144; https://doi.org/10.1097/ALN.0000000000000951.
Shi C, Jin J, Qiao L, et al. Effect of perioperative administration of dexmedetomidine on delirium after cardiac surgery in elderly patients: a double-blinded, multi-center, randomized study. Clin Interv Aging. 2019;14:571–5. https://doi.org/10.2147/CIA.S194476. Retraction in: Clin Interv Aging. 2022;17:505–6. PMID: 30936687; https://doi.org/10.2147/CIA.S369950.
Shu A, Fu Y, Luo Y, et al. An investigation on delirium and hemodynamics influenced by dexmedetomidine for sedating elderly patients in mechanical ventilation. Int J Clin Exp Med [Internet]. 2019;12(2):1942–6.
Fang H, Jun W, Xinjing Y, et al. Analysis of the sedetative effect of dexmedetomidine on postoperative mechanical ventilation in elderly patients. Chinese Medical Journal. 2014 [cited 2024 Feb 13];94(41):3211–5.
Shin HJ, Woo Nam S, Kim H, et al. Postoperative delirium after dexmedetomidine versus propofol sedation in healthy older adults undergoing orthopedic lower limb surgery with spinal anesthesia: a randomized controlled trial. Anesthesiology. 2023;138(2):164–71. https://doi.org/ 10.1097/ALN.0000000000004438. Erratum in: Anesthesiology. 2023;138(4):456. PMID: 36534899; https://doi.org/10.1097/ALN.0000000000004488.
Pisani MA, Murphy TE, Araujo KL, et al. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med. 2009;37(1):177–83. PMID: 19050611; https://doi.org/10.1097/CCM.0b013e318192fcf9.
Almeida TM, Azevedo LC, Nosé PM, Freitas FG, Machado FR. Risk factors for agitation in critically ill patients. Rev Bras Ter Intensiva. 2016;28(4):413–9. PMID: 28099638; https://doi.org/10.5935/0103-507X.20160074.
Jaber S, Chanques G, Altairac C, et al. A prospective study of agitation in a medical-surgical ICU: incidence, risk factors, and outcomes. Chest. 2005;128(4):2749–57. PMID: 16236951; https://doi.org/10.1378/chest.128.4.2749.
Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML. Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU. Pharmacotherapy. 2000;20(1):75–82. PMID: 10641977; https://doi.org/10.1592/phco.20.1.75.34663.
Prayce R, Quaresma F, Galriça I Neto. Delirium: o 7º parâmetro vital? [Delirium: the 7th vital sign?]. Acta Med Port. 2018;31(1):51–8. Portuguese. PMID: 29573769; https://doi.org/10.20344/amp.9670.
Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104(1):21–6. PMID: 16394685; https://doi.org/10.1097/00000542-200601000-00005.
Tilouche N, Hassen MF, Ali HBS, et al. Delirium in the intensive care unit: incidence, risk factors, and impact on outcome. Indian J Crit Care Med. 2018;22(3):144–9. PMID: 29657370; PMCID: PMC5879855; https://doi.org/10.4103/ijccm.IJCCM_244_17.
Pisani MA, Murphy TE, Araujo KL, et al. Benzodiazepine and opioid use and the duration of intensive care unit delirium in an older population. Crit Care Med. 2009;37(1):177–83. PMID: 19050611; https://doi.org/10.1097/CCM.0b013e318192fcf9.
Li X, Zhang L, Gong F, Ai Y. Incidence and risk factors for delirium in older patients following intensive care unit admission: a prospective observational study. J Nurs Res. 2020;28(4):e101. PMID: 32692119; https://doi.org/10.1097/jnr.0000000000000384.
Micek ST, Anand NJ, Laible BR, Shannon WD, Kollef MH. Delirium as detected by the CAM-ICU predicts restraint use among mechanically ventilated medical patients. Crit Care Med. 2005;33(6):1260–5. PMID: 15942341; https://doi.org/10.1097/01.ccm.0000164540.58515.bf.
Roberts B, Rickard CM, Rajbhandari D, et al. Multicentre study of delirium in ICU patients using a simple screening tool. Aust Crit Care. 2005;18(1):6,8–9,11–4 passim. PMID: 18038529; https://doi.org/10.1016/s1036-7314(05)80019-0.
Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7):1370–9. PMID: 11445689; https://doi.org/10.1097/00003246-200107000-00012.
Gusmao-Flores D, Salluh JI, Chalhub RÁ, 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. PMID: 22759376; https://doi.org/10.1186/cc11407.
Guenther U, Popp J, Koecher L, et al. Validity and reliability of the CAM-ICU flowsheet to diagnose delirium in surgical ICU patients. J Crit Care. 2010;25(1):144–51. PMID: 19828283; https://doi.org/10.1016/j.jcrc.2009.08.005.
Soja SL, Pandharipande PP, Fleming SB, et al. Implementation, reliability testing, and compliance monitoring of the Confusion Assessment Method for the Intensive Care Unit in trauma patients. Intensive Care Medicine. 2008;34(7):1263–8.
Zhang DF, Su X, Meng ZT, et al. Impact of dexmedetomidine on long-term outcomes after noncardiac surgery in elderly: 3-year follow-up of a randomized controlled trial. Ann Surg. 2019;270(2):356–63. PMID: 29742525.37; https://doi.org/10.1097/SLA.0000000000002801.
Deiner S, Luo X, Lin HM, et al. Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: a randomized clinical trial. JAMA Surg. 2017;152(8):e171505. PMID: 28593326; https://doi.org/10.1001/jamasurg.2017.1505.
Li CJ, Wang BJ, Mu DL, et al. Randomized clinical trial of intraoperative dexmedetomidine to prevent delirium in the elderly undergoing major non-cardiac surgery. Br J Surg. 2020;107(2):e123–e132. PMID: 31903588; https://doi.org/10.1002/bjs.11354.
Guo Y, Sun LL, Chen ZF, Li QF, Jiang H. [Preventive effect of dexmedetomidine on postoperative delirium in elderly patients with oral cancer]. Shanghai Kou Qiang Yi Xue. 2015;24(2):236–9. Chinese. PMID: 25938158.
Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353–8. PMID: 26543448; https://doi.org/10.4103/1658-354X.154715.
Maldonado JR, Wysong A, van der Starre PJ, et al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009;50(3):206–17. PMID: 19567759; https://doi.org/10.1176/appi.psy.50.3.206.
Keating GM. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs. 2015;75(10):1119–30. PMID: 26063213; https://doi.org/10.1007/s40265-015-0419-5.
Pasin L, Landoni G, Nardelli P, et al. Dexmedetomidine reduces the risk of delirium, agitation and confusion in critically Ill patients: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2014;28(6):1459–66. PMID: 25034724; https://doi.org/10.1053/j.jvca.2014.03.010.
Wen J, Ding X, Liu C, et al. A comparation of dexmedetomidine and midazolam for sedation in patients with mechanical ventilation in ICU: a systematic review and meta-analysis. PLoS One. 2023;18(11):e0294292. PMID: 37963140; https://doi.org/10.1371/journal.pone.0294292.
Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489–99. PMID: 19188334; https://doi.org/10.1001/jama.2009.56.
Wan LJ, Huang QQ, Yue JX, Lin L, Li SH. [Comparison of sedative effect of dexmedetomidine and midazolam for post-operative patients undergoing mechanical ventilation in surgical intensive care unit]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23(9):543–6. Chinese. PMID: 21944176.
Sampurnanand, Chilana D, Sinha AK. A comparative study of dexmedetomidine and midazolam for sedation in patients on mechanical ventilation in ICU. Int J Acad Med Pharm (JAMP). 2023;5(3):1070–4. https://doi.org/10.47009/jamp.2023.5.3.219.
Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet. 2005;365(9467):1348–53. PMID: 15823387; https://doi.org/10.1016/S0140-6736(05)61034-3.
Shurtleff V, Radosevich JJ, Patanwala AE. Comparison of ketamine- versus nonketamine-based sedation on delirium and coma in the intensive care unit. J Intensive Care Med. 2020;35(6):536–41. PMID: 29607710; https://doi.org/10.1177/0885066618767619.
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