Advertisement

Anticholinergic drug exposure at intensive care unit admission affects the occurrence of delirium. A prospective cohort study

  • Ariël M. Vondeling
    Correspondence
    Corresponding author at: Department of Geriatric Medicine, Diakonessenhuis Utrecht, Bosboomstraat 1 3582 KE, Utrecht, the Netherlands.
    Affiliations
    Department of Geriatric Medicine, Diakonessenhuis Utrecht, the Netherlands

    Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Utrecht University, the Netherlands
    Search for articles by this author
  • Wilma Knol
    Affiliations
    Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Utrecht University, the Netherlands
    Search for articles by this author
  • Toine C.G. Egberts
    Affiliations
    Department of Clinical Pharmacy, University Medical Center Utrecht & Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
    Search for articles by this author
  • Arjen J.C. Slooter
    Affiliations
    Department of Intensive Care Medicine and UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
    Search for articles by this author

      Highlights

      • Exposure to drugs with anticholinergic effects before ICU admission increases the risk of developing delirium.
      • The effect is more pronounced in the first days of the ICU admission.
      • Advanced age and septic shock increases the risk for delirium in ICU patients.
      • The ADS scale can be effectively used to measure anticholinergic load in ICU patients.

      Abstract

      Background

      Anticholinergic drugs may increase the risk of delirium in non-critically ill patients, but it is unclear whether exposure to these drugs is also a risk factor for Intensive Care Unit (ICU) delirium. In this study the hypothesis was tested that anticholinergic drug exposure at ICU admission increases the risk to develop delirium during ICU stay, particularly in patients with advanced age and severe sepsis.

      Methods

      A prospective cohort study was performed in the mixed 32-bed medical-surgical ICU of the University Medical Center Utrecht, the Netherlands in the period from January 2011 till June 2013. Included were nonneurological patients that were consecutively admitted for more than 24 hours. The presence of delirium was evaluated each day using a validated algorithm based on the Confusion Assessment Method for the ICU (CAM-ICU), the initiation of delirium treatment as well as chart review by researchers. Anticholinergic drug exposure at ICU admission was assessed using the Anticholinergic Drug Scale (ADS). To evaluate the association between anticholinergic drug exposure at ICU admission and the risk of developing delirium, we performed multivariable competing risk Cox proportional hazard analysis corrected for confounding factors.

      Results

      Approximately half (47%, n=513) of the 1090 included patients developed delirium during ICU admission. The absolute risk for delirium development increased with more anticholinergic drug exposure: 42% in patients with ADS score=0, 49% in patients with ADS score=1, and 53% in patients with ADS higher than 1. Taking competing events (death and discharge) and potential confounding factors into account, the subdistribution hazard ratio (SHR) was 1.13 (95% CI: 0.91-1.40) for ADS score=1 point and 1.35 (95% CI: 1.09-1.68) for ADS ≥2 compared with an ADS score=0 (no anticholinergic drug exposure). The effect was strongest during the first days of ICU admittance and was strongest in patients above 65 year without severe sepsis and/or septic shock (SHR 2.15, 95% CI 1.43-3.25).

      Conclusions

      Anticholinergic drug exposure at ICU admission increases the risk of delirium in critically ill patients. This effect was most pronounced in patients older than 65 years without severe sepsis and/or septic shock, and declining over time.

      Keywords

      Abbreviations:

      ACH (Acetylcholine), ADS (Anticholinergic Drug Scale), APACHE IV (Acute Physiology and Chronic Health Evaluation), ARS (Anticholinergic Risk Scale), CAM-ICU (Confusion Assessment Method – ICU), ICU (Intensive Care Unit), IQR (InterQuartile Range), SD (Standard Deviation), CSHR (Cause-Specific Hazard Ratio), SHR (Subdistribution Hazard Rratio), SOFA (Sequential Organ Failure Assessment)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • van den Boogaard M.
        • Schoonhoven L.
        • van der Hoeven J.G.
        • van A.T.
        Pickkers P Incidence and short-term consequences of delirium in critically ill patients: a prospective observational cohort study.
        Int J Nurs Stud. 2012; 49: 775-783
        • Zaal I.J.
        Slooter AJ Delirium in critically ill patients: epidemiology, pathophysiology, diagnosis and management.
        Drugs. 2012; 72: 1457-1471
        • Milbrandt E.B.
        • Deppen S.
        • Harrison P.L.
        • Shintani A.K.
        • Speroff T.
        • Stiles R.A.
        • Truman B.
        • Bernard G.R.
        • Dittus R.S.
        Ely EW Costs associated with delirium in mechanically ventilated patients.
        Crit Care Med. 2004; 32: 955-962
        • Ely E.W.
        • Gautam S.
        • Margolin R.
        • Francis J.
        • May L.
        • Speroff T.
        • Truman B.
        • Dittus R.
        • Bernard R.
        Inouye SK The impact of delirium in the intensive care unit on hospital length of stay.
        Intensive Care Med. 2001; 27: 1892-1900
        • Lat I.
        • McMillian W.
        • Taylor S.
        • Janzen J.M.
        • Papadopoulos S.
        • Korth L.
        • Ehtisham A.
        • Nold J.
        • Agarwal S.
        • Azocar R.
        Burke P The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients.
        Crit Care Med. 2009; 37: 1898-1905
        • Pandharipande P.P.
        • Girard T.D.
        • Jackson J.C.
        • Morandi A.
        • Thompson J.L.
        • Pun B.T.
        • Brummel N.E.
        • Hughes C.G.
        • Vasilevskis E.E.
        • Shintani A.K.
        • Geevarghese S.K.
        • Canonico A.
        • Hopkins R.O.
        • Bernard G.R.
        • Dittus R.S.
        • Ely E.W.
        Long-term cognitive impairment after critical illness.
        N Engl J Med. 2013; 369: 1306-1316
        • Inouye S.K.
        Delirium in older persons.
        N Engl J Med. 2006; 354: 1157-1165
        • Zaal I.J.
        • Devlin J.W.
        • Peelen L.M.
        • Slooter A.J.C
        A systematic review of risk factors for delirium in the intensive care unit.
        Crit Care Med. 2015; 43: 40-47
        • van Gool W.A.
        • van de Beek D.
        Eikelenboom P Systemic infection and delirium: when cytokines and acetylcholine collide.
        Lancet. 2010; 375: 773-775
        • Han L.
        • McCusker J.
        • Cole M.
        • Abrahamowicz M.
        • Primeau F.
        Elie M Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients.
        Arch Intern Med. 2001; 161: 1099-1105
        • American Psychiatric Association
        Diagnostic and statistical manual of mental disorders.
        5th edn. American Psychiatric Publishing, Arlington, VA2013
        • Pandharipande P.
        • Shintani A.
        • Peterson J.
        • Pun B.T.
        • Wilkinson G.R.
        • Dittus R.S.
        • et al.
        Ely EW Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients.
        Anesthesiology. 2006; 104: 21-26
        • Tune L.
        • Carr S.
        • Cooper T.
        • Klug B.
        Golinger RC Association of anticholinergic activity of prescribed medications with postoperative delirium.
        J Neuropsychiatry Clin Neurosci. 1993; 5: 208-210
        • Trzepacz P.T
        Anticholinergic model for delirium.
        Semin Clin Neuropsychiatry. 1996; 1: 294-303
        • Ray P.G.
        • Meador K.J.
        • Loring D.W.
        • Zamrini E.W.
        • Yang X.H.
        Buccafusco JJ Central anticholinergic hypersensitivity in aging.
        J Geriatr Psychiatry Neurol. 1992; 5: 72-77
        • Zaal I.J.
        • Peelen L.M.
        • van Dijk D.
        • Slooter A.J.
        Development and validation of an eight-step flowchart based on the CAM-ICU: a quick and highly adaptable tool to determine the presence of delirium in ICU patients.
        Critical Care. 2011; : 15
        • Carnahan R.M.
        • Lund B.C.
        • Perry P.J.
        • Pollock B.G.
        Culp KR The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity.
        J Clin Pharmacol. 2006; 46: 1481-1486
        • Klein Klouwenberg P.M.
        • Ong D.S.
        • Bos L.D.
        • de Beer F.M.
        • van Hooijdonk R.T.
        • Huson M.A.
        • Straat M.
        • van Vught L.A.
        • Wieske L.
        • Horn J.
        • Schultz M.J.
        • van der P.T.
        • Bonten M.J.
        Cremer OL interobserver agreement of centers for disease control and prevention criteria for classifying infections in critically ill patients.
        Crit Care Med. 2013; 41: 2373-2378
        • Klein Klouwenberg P.M.
        • Ong D.S.
        • Bonten M.J.
        Cremer OL Classification of sepsis, severe sepsis and septic shock: the impact of minor variations in data capture and definition of SIRS criteria.
        Intensive Care Med. 2012; 38: 811-819
        • Bone R.C.
        • Balk R.A.
        • Cerra F.B.
        • Dellinger R.P.
        • Fein A.M.
        • Knaus W.A.
        • et al.
        Sibbald WJ Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.
        Chest. 1992; 101: 1644-1655
        • Fine J.P.
        Gray RJ A Proportional Hazards Model for the Subdistribution of a Competing Risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Vincent J.L.
        • de M.A.
        • Cantraine F.
        • Moreno R.
        • Takala J.
        • Suter P.M.
        • Sprung C.L.
        • Colardyn F.
        Blecher S 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. 1998; 26: 1793-1800
        • Zimmerman J.E.
        • Kramer A.A.
        Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment for today's critically ill patients.
        Crit Care Med. 2006; 34: 1297-1310
        • Rudolph J.L.
        • Salow M.J.
        • Angelini M.C.
        McGlinchey RE the anticholinergic risk scale and anticholinergic adverse effects in older persons.
        Arch Intern Med. 2008; 168: 508-513
        • Gray R.J
        A class of K-sample tests for comparing the cumulative incidence of a competing risk.
        Ann Stats. 1988; 16: 1141-1154
        • Golinger R.C.
        • Peet T.
        Tune LE Association of elevated plasma anticholinergic activity with delirium in surgical patients.
        Am J Psychiatry. 1987; 144: 1218-1220
        • Tune L.E.
        • Damlouji N.F.
        • Holland A.
        • Gardner T.J.
        • Folstein M.F.
        Coyle JT Association of postoperative delirium with raised serum levels of anticholinergic drugs.
        Lancet. 1981; 2 (651–65345)
        • Wolters A.E.
        • Zaal I.J.
        • Veldhuijzen D.S.
        • Cremer O.L.
        • Devlin J.W.
        • van Dijk D.
        Slooter AJ Anticholinergic medication use and transition to delirium in critical ill patients: a prospective Cohort study.
        Crit Care Med. 2015; 43: 1846-1852
        • Flacker J.M.
        • Cummings V.
        • Mach Jr., J.R.
        • Bettin K.
        • Kiely D.K.
        Wei J The association of serum anticholinergic activity with delirium in elderly medical patients.
        Am J Geriatr Psychiatry. 1998; 6: 31-41
        • Tune L.E
        Anticholinergic effects of medication in elderly patients.
        J Clin Psychiatry. 2001; 62: 11-14
        • Zimmerman K.M.
        • Salow M.
        • Skarf L.M.
        • Kostas T.
        • Paquin A.
        • Simone M.J.
        Rudolph J Increasing anticholinergic burden and delirium in palliative care inpatients.
        Palliat Med. 2014; 28: 335-341
        • Caeiro L.
        • Ferro J.M.
        • Claro M.I.
        • Coelho J.
        • Albuquerque R.
        Figueira ML Delirium in acute stroke: a preliminary study of the role of anticholinergic medications.
        Eur J Neurol. 2004; 11: 699-704
        • Engberts A.C.G.
        • van der Craats S.T.
        • van Wijk M.D.
        • Alkilabe S.
        • Van den Bemt P.M.L.A.
        • Mattace-Raso F.U.S.
        Anticholinergic drug exposure is associated with delirium and postdischarge institutionalization in acutely ill hospitalized older patients.
        Parmacol Res Perspect. 2017; (Jun 5)
        • Welsh T.J.
        • van der Wardt V.
        • Ojo G.
        • Gordon A.L.
        • Gladman J.R.F.
        Anticholinergic dryg burden Tools/Scales and advers outcomes in different clinical settings: a systematic review of reviews.
        Drugs Aging. 2018; 35: 523-538
        • Summers W.K.
        A clinical method of estimating risk of drug induced delirium.
        Life Sci. 1978; 22: 1511-1516
        • Chew M.L.
        • Mulsant B.H.
        • Pollock B.G.
        • Lehman M.E.
        • Greenspan A.
        • Mahmoud R.A.
        • Kirshner M.A.
        • Sorisio D.A.
        • Bies R.R.
        Gharabawi G anticholinergic activity of 107 medications commonly used by older adults.
        J Am Geriatr Soc. 2008;
        • Gerretsen P.
        Pollock BG Drugs with anticholinergic properties: a current perspective on use and safety.
        Expert Opin Drug Saf. 2011; 10: 751-765
        • Salahudeen M.S.
        • Duffull S.B.
        Nishtala PS anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review.
        BMC Geriatr. 2015; 15 (Mar 25): 31
        • Mangoni A.A.
        • van Munster B.C.
        • Woodman R.J.
        de Rooij SE Measures of anticholinergic drug exposure, serum anticholinergic activity, and all-cause postdischarge mortality in older hospitalized patients with hip fractures.
        Am J Geriatr Psychiatry. 2013; 21: 785-793
        • Sajjad A.
        • Wolters A.E.
        • Veldhuijzen D.S.
        • Peelen L.M.
        • Welling M.C.
        • Zaal I.J.
        • van Dijk D.
        • Slooter A.J.C
        Psychopathology prior to critical illness and the risk of delirium onset during intensive care unit stay.
        Intensive Care Med. 2018; 44 (Aug): 1355-1356https://doi.org/10.1007/s00134-018-5195-8
        • Cunningham C
        Systemic inflammation and delirium: important co-factors in the progression of dementia.
        Biochem Soc Trans. 2011; 39: 945-953
        • CM1 Bell
        • SS Brener
        • Gunraj N.
        • Huo C.
        • Bierman A.S.
        • Scales D.C.
        • et al.
        Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases.
        JAMA. 2011; 306 (Aug 24): 840-847
        • Levy M.L.
        • Philips G.S.
        • Shankar HAri M.
        • et al.
        Developing a new definition and assessing new clinical criteria for septic shock.
        JAMA. 2016; (Aug 315): 775-787