Skip to main content
SpringerLink
Log in

Benzodiazepine-associated delirium in critically ill adults

  • Original
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Purpose

The association between benzodiazepine use and delirium risk in the ICU remains unclear. Prior investigations have failed to account for disease severity prior to delirium onset, competing events that may preclude delirium detection, other important delirium risk factors, and an adequate number of patients receiving continuous midazolam. The aim of this study was to address these limitations and evaluate the association between benzodiazepine exposure and ICU delirium occurrence.

Methods

In a cohort of consecutive critically ill adults, daily mental status was classified as either awake without delirium, delirium, or coma. In a first-order Markov model, multinomial logistic regression analysis was used, which considered five possible outcomes the next day (i.e., awake without delirium, delirium, coma, ICU discharge, and death) and 16 delirium-related covariables, to quantify the association between benzodiazepine use and delirium occurrence the following day.

Results

Among 1112 patients, 9867 daily transitions occurred. Benzodiazepine administration in an awake patient without delirium was associated with increased risk of delirium the next day [OR 1.04 (per 5 mg of midazolam equivalent administered) 95 % CI 1.02–1.05). When the method of benzodiazepine administration was incorporated in the model, the odds of transitioning to delirium was higher with benzodiazepines given continuously (OR 1.04, 95 % CI 1.03–1.06) compared to benzodiazepines given intermittently (OR 0.97, 95 % CI 0.88–1.05).

Conclusions

After addressing potential methodological limitations of prior studies, we confirm that benzodiazepine administration increases the risk for delirium in critically ill adults but this association seems to be limited to continuous infusion use only.

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. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH (2009) Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 180:1092–1097

    Article  PubMed Central  PubMed  Google Scholar 

  2. Zaal IJ, Slooter AJ (2012) Delirium in critically ill patients: epidemiology, pathophysiology, diagnosis and management. Drugs 72:1457–1471

    Article  CAS  PubMed  Google Scholar 

  3. Pandharipande PP, Girard TD, Jackson JC et al (2013) Long-term cognitive impairment after critical illness. N Engl J Med 369:1306–1316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Barr J, Fraser GL, Puntillo K et al (2013) Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 41:263–306

    Article  PubMed  Google Scholar 

  5. Devlin JW, Fraser GL, Riker RR (2011) Drug-induced coma and delirium. In: Papadopoulos B, Cooper S, Kane-Gill SL, Mallow-Corbet JB (eds) Drug-induced complications in the critically ill patient: a guide for recognition and treatment, 1st edn. Society of Critical Care Medicine, Chicago

    Google Scholar 

  6. Young J, Murthy L, Westby M, Akunne A, O’Mahony R (2010) Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ 341:c3704

    Article  PubMed  Google Scholar 

  7. Morandi A, Brummel NE, Ely EW (2011) Sedation, delirium and mechanical ventilation: the ‘ABCDE’ approach. Curr Opin Crit Care 17:43–49

    Article  PubMed  Google Scholar 

  8. Wunsch H, Kahn JM, Kramer AA, Rubenfeld GD (2009) Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med 37:3031–3039

    Article  CAS  PubMed  Google Scholar 

  9. Pandharipande P, Shintani A, Peterson J et al (2006) Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 104:21–26

    Article  CAS  PubMed  Google Scholar 

  10. Kamdar BB, Niessen T, Colantuoni E et al (2015) Delirium transitions in the medical ICU: exploring the role of sleep quality and other factors. Crit Care Med 43:135–141

    Article  PubMed  Google Scholar 

  11. Pandharipande P, Cotton BA, Shintani A et al (2008) Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma 65:34–41

    Article  PubMed Central  PubMed  Google Scholar 

  12. Agarwal V, O’Neill PJ, Cotton BA et al (2010) Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res 31:706–715

    Article  PubMed Central  PubMed  Google Scholar 

  13. Seymour CW, Pandharipande PP, Koestner T et al (2012) Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation and delirium. Crit Care Med 40:2788–2796

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Serafim RB, Dutra MF, Saddy F et al (2012) Delirium in postoperative nonventilated intensive care patients: risk factors and outcomes. Ann Intensive Care 2:51

    Article  PubMed Central  PubMed  Google Scholar 

  15. van den Boogaard M, Pickkers P, Slooter AJ et al (2012) Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 344:e420

    Article  PubMed Central  PubMed  Google Scholar 

  16. Pandharipande PP, Morandi A, Adams JR et al (2009) Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med 35:1886–1892

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Schreiber MP, Colantuoni E, Bienvenu OJ et al (2014) Corticosteroids and transition to delirium in patients with acute lung injury. Crit Care Med 42:1480–1486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Svenningsen H, Egerod I, Videbech P, Christensen D, Frydenberg M, Tonnesen EK (2013) Fluctuations in sedation levels may contribute to delirium in ICU patients. Acta Anaesthesiol Scand 57:288–293

    Article  CAS  PubMed  Google Scholar 

  19. Colombo R, Corona A, Praga F et al (2012) A reorientation strategy for reducing delirium in the critically ill. Results of an interventional study. Minerva Anestesiol 78:1026–1033

    CAS  PubMed  Google Scholar 

  20. Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y (2001) Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 27:1297–1304

    Article  CAS  PubMed  Google Scholar 

  21. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y (2007) Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 33:66–73

    Article  PubMed  Google Scholar 

  22. Shi CM, Wang DX, Chen KS, Gu XE (2010) Incidence and risk factors of delirium in critically ill patients after non-cardiac surgery. Chin Med J (Engl) 123:993–999

    Google Scholar 

  23. Lin SM, Huang CD, Liu CY et al (2008) Risk factors for the development of early-onset delirium and the subsequent clinical outcome in mechanically ventilated patients. J Crit Care 23:372–379

    Article  PubMed  Google Scholar 

  24. Devlin JW, Zaal IJ, Slooter AJ (2014) Clarifying the confusion surrounding drug-associated delirium in the ICU. Crit Care Med 42:1565–1566

    Article  PubMed  Google Scholar 

  25. Skrobik Y, Ahern S, Leblanc M, Marquis F, Awissi DK, Kavanagh BP (2010) Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg 111:451–463

    Article  PubMed  Google Scholar 

  26. Hager DN, Dinglas VD, Subhas S et al (2013) Reducing deep sedation and delirium in acute lung injury patients: a quality improvement project. Crit Care Med 41:1435–1442

    Article  PubMed  Google Scholar 

  27. Ely EW, Inouye SK, Bernard GR et al (2001) Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 286:2703–2710

    Article  CAS  PubMed  Google Scholar 

  28. Zaal IJ, Tekatli H, van der Kooi AW et al (2015) Classification of daily mental status in critically ill patients for research purposes. J Critical Care 30:375–380

    Article  CAS  Google Scholar 

  29. Sessler CN, Gosnell MS, Grap MJ et al (2002) The Richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166:1338–1344

    Article  PubMed  Google Scholar 

  30. van Eijk MM, van den Boogaard M, van Marum RJ et al (2011) Routine use of the confusion assessment method for the intensive care unit: a multicenter study. Am J Respir Crit Care Med 184(3):340–344

    Article  PubMed  Google Scholar 

  31. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J (2012) Introduction to drug pharmacokinetics in the critically ill patient. Chest 141:1327–1336

    Article  CAS  PubMed  Google Scholar 

  32. Vincent JL, de Mendonça A, Cantraine F et al (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 26:1793–1800

    Article  CAS  PubMed  Google Scholar 

  33. Engels JM, Diehr P (2003) Imputation of missing longitudinal data: a comparison of methods. J Clin Epidemiol 56:968–976

    Article  PubMed  Google Scholar 

  34. Andersen PK, Geskus RB, de Witte T, Putter H (2012) Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol 41:861–870

    Article  PubMed Central  PubMed  Google Scholar 

  35. Zaal IJ, Devlin JW, Peelen LM, Slooter AJC (2015) Systematic review of risk factors for delirium in the ICU. Crit Care Med 43:40–47

    Article  PubMed  Google Scholar 

  36. Devlin JW, Roberts RJ (2011) Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Anesthesiol Clin 29:567–585

    Article  CAS  PubMed  Google Scholar 

  37. Skrobik Y, Leger C, Cossette M, Michaud V, Turgeon J (2013) Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med 41:999–1008

    Article  CAS  PubMed  Google Scholar 

  38. Klein Klouwenberg PM, Zaal IJ, Spitoni C et al (2014) The attributable mortality of delirium in critically ill patients: prospective cohort study. BMJ 24:349

    Google Scholar 

  39. Jakob SM, Ruokonen E, Grounds RM et al (2012) Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 307:1151–1160

    Article  CAS  PubMed  Google Scholar 

  40. Maldonado JR, Wysong A, van der Starre PJ, Block T, Miller C, Reitz BA (2009) Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics 50:206–217

    Article  CAS  PubMed  Google Scholar 

  41. Pandharipande PP, Pun BT, Herr DL et al (2007) Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 298:2644–2653

    Article  CAS  PubMed  Google Scholar 

  42. Riker RR, Shehabi Y, Bokesch PM et al (2009) Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 301:489–499

    Article  CAS  PubMed  Google Scholar 

  43. Carson SS, Kress JP, Rodgers JE et al (2006) A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 34(5):1326–1332

    Article  CAS  PubMed  Google Scholar 

  44. Schweickert WD, Pohlman MC, Pohlman AS et al (2009) Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 373:1874–1882

    Article  PubMed  Google Scholar 

  45. Shehabi Y, Chan L, Kadiman S et al (2013) Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med 39:910–918

    Article  PubMed Central  PubMed  Google Scholar 

  46. van den Boogaard M, Schoonhoven L, van der Hoeven JG et al (2012) Incidence and short-term consequences of delirium in critically ill patients: a prospective observational cohort study. Int J Nurs Stud 49:775–783

    Article  PubMed  Google Scholar 

  47. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP (2014) Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med 189:658–665

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

John W. Devlin’s efforts towards this project were supported, in part, by a Visitor’s Grant from the Netherlands Organization for Scientific Research (NWO 040.11.372).

Author information

Authors and Affiliations

  1. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

    Irene J. Zaal, Peter M. C. Klein Klouwenberg, Arendina W. van der Kooi, David S. Y. Ong, Olaf L. Cremer & Arjen J. C. Slooter

  2. School of Pharmacy, Northeastern University, 360 Huntington Ave 140 TF RD218F, Boston, MA, 02118, USA

    John W. Devlin

  3. Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, USA

    John W. Devlin

  4. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Marijn Hazelbag, Peter M. C. Klein Klouwenberg, David S. Y. Ong & Rolf H. Groenwold

  5. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Peter M. C. Klein Klouwenberg & David S. Y. Ong

Authors
  1. Irene J. Zaal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John W. Devlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marijn Hazelbag
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter M. C. Klein Klouwenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arendina W. van der Kooi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David S. Y. Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Olaf L. Cremer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rolf H. Groenwold
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arjen J. C. Slooter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John W. Devlin.

Ethics declarations

Conflicts of interest

None of the authors have potential conflicts of interest regarding this manuscript.

Additional information

Take-home message: Benzodiazepine administration increases the risk for delirium in critically ill adults, although this association is less pronounced than previously reported and seems to be limited to IV infusion use only.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 210 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zaal, I.J., Devlin, J.W., Hazelbag, M. et al. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med 41, 2130–2137 (2015). https://doi.org/10.1007/s00134-015-4063-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-015-4063-z

Keywords

Search

Navigation