Skip to main content

Advertisement

SpringerLink
Log in

Association between remimazolam and postoperative delirium in older adults undergoing elective cardiovascular surgery: a prospective cohort study

  • Original Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 21 November 2022

Abstract

Purpose

Postoperative delirium is one of the most common complications after cardiovascular surgery in older adults. Benzodiazepines are a reported risk factor for delirium; however, there are no studies investigating remimazolam, a novel anesthetic agent. Therefore, we prospectively investigated the effect of remimazolam on postoperative delirium.

Methods

We included elective cardiovascular surgery patients aged ≥ 65 years at Hamamatsu University Hospital between August 2020 and February 2022. Patients who received general anesthesia with remimazolam were compared with those who received other anesthetics (control group). The primary outcome was delirium within 5 days after surgery. Secondary outcomes were delirium during intensive care unit stay and hospitalization, total duration of delirium, subsyndromal delirium, and differences in the Mini-Mental State Examination scores from preoperative to postoperative days 2 and 5. To adjust for differences in the groups’ baseline covariates, we used stabilized inverse probability weighting as the primary analysis and propensity score matching as the sensitivity analysis.

Results

We enrolled 200 patients; 78 in the remimazolam group and 122 in the control group. After stabilized inverse probability weighting, 30.3% of the remimazolam group patients and 26.6% of the control group patients developed delirium within 5 days (risk difference, 3.8%; 95% confidence interval −11.5% to 19.1%; p = 0.63). The secondary outcomes did not differ significantly between the groups, and the sensitivity analysis results were similar to those for the primary analysis.

Conclusion

Remimazolam was not significantly associated with postoperative delirium when compared with other anesthetic agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30–9.

    Article  CAS  Google Scholar 

  2. Wolters AE, van Dijk D, Pasma W, Cremer OL, Looije MF, de Lange DW, Veldhuijzen DS, Slooter AJC. Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study. Crit Care. 2014;18:R125.

    Article  Google Scholar 

  3. van den Boogaard M, Schoonhoven L, Evers AWM, van der Hoeven JG, van Achterberg T, Pickkers P. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit Care Med. 2012;40:112–8.

    Article  Google Scholar 

  4. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, Brady SL, Brodsky MB, Denehy L, Elliott D, Flatley C, Harabin AL, Jones C, Louis D, Meltzer W, Muldoon SR, Palmer JB, Perme C, Robinson M, Schmidt DM, Scruth E, Spill GR, Storey CP, Render M, Votto J, Harvey MA. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med. 2012;40:502–9.

    Article  Google Scholar 

  5. Schenning KJ, Deiner SG. Postoperative delirium in the geriatric patient. Anesthesiol Clin. 2015;33:505–16.

    Article  Google Scholar 

  6. Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383:911–22.

    Article  Google Scholar 

  7. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen J-F, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. 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:e825–73.

    Article  Google Scholar 

  8. American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society. J Am Coll Surg. 2015;220:136-148.e1.

    Article  Google Scholar 

  9. Burry LD, Cheng W, Williamson DR, Adhikari NK, Egerod I, Kanji S, Martin CM, Hutton B, Rose L. Pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a systematic review and network meta-analysis. Intensive Care Med. 2021;47:943–60.

    Article  CAS  Google Scholar 

  10. Rajaei M, Tabari M, Soltani G, Alizadeh K, Nazari A, Noroozian M, Morovatdar N. Comparison between the effects of dexmedetomidine and midazolam on postoperative cognitive impairment after coronary artery bypasses graft surgery: a randomized clinical trial. J Tehran Heart Cent. 2019;14:67–73.

    Google Scholar 

  11. Doi M, Hirata N, Suzuki T, Morisaki H, Morimatsu H, Sakamoto A. Safety and efficacy of remimazolam in induction and maintenance of general anesthesia in high-risk surgical patients (ASA Class III): results of a multicenter, randomized, double-blind, parallel-group comparative trial. J Anesth. 2020;34:491–501.

    Article  Google Scholar 

  12. Doi M, Morita K, Takeda J, Sakamoto A, Yamakage M, Suzuki T. Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial. J Anesth. 2020;34:543–53.

    Article  Google Scholar 

  13. Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, Wiard RP, Feldman PL, Collins H, Waszczak BL, Tilbrook GS. CNS 7056: a novel ultra-short-acting benzodiazepine. Anesthesiology. 2007;107:60–6.

    Article  CAS  Google Scholar 

  14. Kilpatrick GJ. Remimazolam: non-clinical and clinical profile of a new sedative/anesthetic agent. Front Pharmacol. 2021;12: 690875.

    Article  CAS  Google Scholar 

  15. Morimoto Y. Efficacy and safety profile of remimazolam for sedation in adults undergoing short surgical procedures. Ther Clin Risk Manag. 2022;18:95–100.

    Article  CAS  Google Scholar 

  16. Yang M, Liu X, Yang D, Bai Y, Qin B, Tian S, Dong R, Song X. Effect of remimazolam besylate compared with propofol on the incidence of delirium after cardiac surgery: study protocol for a randomized trial. Trials. 2021;22:717.

    Article  Google Scholar 

  17. Liu S, Su L, Zhang B, He H, Li Z, Li Q, Wang Q, Smith F, Long Y. The availability and safety study of remimazolam besylate for injection on sedation of ERAS patients under mechanical ventilation in ICU: protocol for a randomized, open-label, controlled trial. Front Med (Lausanne). 2021;8:

    Article  Google Scholar 

  18. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.

    Article  CAS  Google Scholar 

  19. Kuhn E, Du X, McGrath K, Coveney S, O’Regan N, Richardson S, Teodorczuk A, Allan L, Wilson D, Inouye SK, MacLullich AMJ, Meagher D, Brayne C, Timmons S, Davis D. Validation of a consensus method for identifying delirium from hospital records. PLoS ONE. 2014;9:e111823.

    Article  Google Scholar 

  20. Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in older persons: advances in diagnosis and treatment. JAMA. 2017;318:1161–74.

    Article  Google Scholar 

  21. Saczynski JS, Kosar CM, Xu G, Puelle MR, Schmitt E, Jones RN, Marcantonio ER, Wong B, Isaza I, Inouye SK. A tale of two methods: chart and interview methods for identifying delirium. J Am Geriatr Soc. 2014;62:518–24.

    Article  Google Scholar 

  22. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113:941–8.

    Article  CAS  Google Scholar 

  23. Kassie GM, Nguyen TA, Kalisch Ellett LM, Pratt NL, Roughead EE. Preoperative medication use and postoperative delirium: a systematic review. BMC Geriatr. 2017;17:298.

    Article  Google Scholar 

  24. Irie H, Okamoto H, Uchino S, Endo H, Uchida M, Kawasaki T, Kumasawa J, Tagami T, Shigemitsu H, Hashiba E, Aoki Y, Kurosawa H, Hatakeyama J, Ichihara N, Hashimoto S, Nishimura M, JIPAD Working Group in the Japanese Society of Intensive Care Medicine. The Japanese Intensive care PAtient Database (JIPAD): a national intensive care unit registry in Japan. J Crit Care. 2020;55:86–94.

  25. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46:399–424.

    Article  Google Scholar 

  26. Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health. 2010;13:273–7.

    Article  Google Scholar 

  27. Griswold ME, Localio AR, Mulrow C. Propensity score adjustment with multilevel data: setting your sites on decreasing selection bias. Ann Intern Med. 2010;152:393–5.

    Article  Google Scholar 

  28. Rosenbaum PR, Rubin DB. Constructing a control group using multivariate matched sampling methods that incorporate the propensity score. Am Stat. 1985;39:33–8.

    Google Scholar 

  29. Chen T-J, Chung Y-W, Chang H-CR, Chen P-Y, Wu C-R, Hsieh S-H, Chiu H-Y. Diagnostic accuracy of the CAM-ICU and ICDSC in detecting intensive care unit delirium: a bivariate meta-analysis. Int J Nurs Stud. 2021;113:103782.

    Article  Google Scholar 

  30. Sneyd JR, Gambus PL, Rigby-Jones AE. Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review. Br J Anaesth. 2021;127:41–55.

    Article  CAS  Google Scholar 

  31. Sneyd JR, Absalom AR, Barends CRM, Jones JB. Hypotension during propofol sedation for colonoscopy: an exploratory analysis. Br J Anaesth. 2021;S0007–0912(21):00731–5.

    Google Scholar 

  32. Dai G, Pei L, Duan F, Liao M, Zhang Y, Zhu M, Zhao Z, Zhang X. Safety and efficacy of remimazolam compared with propofol in induction of general anesthesia. Minerva Anestesiol. 2021;87:1073–9.

    Article  Google Scholar 

  33. Stöhr T, Colin PJ, Ossig J, Pesic M, Borkett K, Winkle P, Struys MMRF, Schippers F. Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment. Br J Anaesth. 2021;127:415–23.

    Article  Google Scholar 

  34. Paion UK Ltd. A randomized, single-blind, propofol-controlled phase III study evaluating the efficacy and safety of remimazolam in general anesthesia in adult patients undergoing cardiac surgery, including follow-up sedation in the post-anesthesia care unit/intensive care unit [Internet]. clinicaltrials.gov; 2017 Aug. Report No.: NCT02523859. Available from: https://clinicaltrials.gov/ct2/show/NCT02523859

  35. Zaal IJ, Devlin JW, Hazelbag M, Klein Klouwenberg PMC, van der Kooi AW, Ong DSY, Cremer OL, Groenwold RH, Slooter AJC. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med. 2015;41:2130–7.

    Article  CAS  Google Scholar 

  36. Fitzgerald JM, Adamis D, Trzepacz PT, O’Regan N, Timmons S, Dunne C, Meagher DJ. Delirium: a disturbance of circadian integrity? Med Hypotheses. 2013;81:568–76.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan

    Yoshitaka Aoki, Tadayoshi Kurita, Ryo Imai, Yuji Suzuki, Hiroshi Makino, Matsuyuki Doi & Yoshiki Nakajima

  2. Emergency Life-Saving Technique Academy of Tokyo, Foundation for Ambulance Service Development, Tokyo, Japan

    Mikio Nakajima

  3. Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan

    Mikio Nakajima

  4. Department of Anesthesiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Hiroyuki Kinoshita

Authors
  1. Yoshitaka Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadayoshi Kurita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mikio Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryo Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuji Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroyuki Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matsuyuki Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshiki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YA, TK, and MN provided substantial contributions to the study design, and RI, YS, and HM provided substantial contributions to patient recruitment and data acquisition. Statistical analysis was supported by MN, HK, MD, and YN. YA, TK, and MN contributed to manuscript writing, and RI, YS, HM, HK, MD, and YN contributed to manuscript revision. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Yoshitaka Aoki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aoki, Y., Kurita, T., Nakajima, M. et al. Association between remimazolam and postoperative delirium in older adults undergoing elective cardiovascular surgery: a prospective cohort study. J Anesth 37, 13–22 (2023). https://doi.org/10.1007/s00540-022-03119-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-022-03119-7

Keywords

Search

Navigation