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. 2017 Jan 11;2017(1):CD012494. doi: 10.1002/14651858.CD012494

Cholinesterase inhibitors for the treatment of delirium in non‐ICU settings

Shanshan Wu 1, Zongwang Zhang 1,✉, Tom Dening 2, Sai Zhao 3, Gillian Pinner 4, Jun Xia 5, Ailan Yu 1, Daogui Yang 6
PMCID: PMC6464728

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the effectiveness and safety of cholinesterase inhibitors for treating established delirium in people in a non‐ICU setting.

Background

This is an update of a previous Cochrane Review, 'Cholinesterase inhibitors for delirium', which was first published in Issue 1, 2008 (Overshott 2008).

Description of the condition

Delirium, an acute confusional state, has been described as "a transient global disorder of cognition and attention" (Luxenberg 1996). The presence of delirium may not be recognised due to the transient and fluctuating nature of symptoms and diverse presentations, which include three subtypes according to the patterns of motor activity: hyperactive, hypoactive and mixed when both hypoactive and hyperactive features are present (O'Keeffe 1999). The fifth edition of American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM‐V) and the 10th Revision of the International Classification of Diseases (ICD‐10) provide the current reference diagnostic criteria (Inouye 2014). In clinical practice, it is important to screen at‐risk people for delirium with validated instruments to help clarify the diagnosis. These validated instruments screen for key diagnostic features of delirium including an acute onset and fluctuating course of symptoms, inattention, impaired consciousness and disturbance of cognition (Schwartz 2016). More than 24 delirium instruments have been used in published studies (Inouye 2014). The Confusion Assessment Method (CAM) is probably the most frequently used diagnostic instrument worldwide and has excellent specificity (Steiner 2011).

The causes of delirium are multifactorial and include patient vulnerability factors (dementia or cognitive impairment, ageing, medical comorbidity, malnutrition, history of alcohol abuse and prescription opioid or benzodiazepine use, among others) and potentially modifiable factors (such as infections, dehydration, electrolyte abnormalities, polypharmacy, seizures and surgery) (Martinez 2012; Vasilevskis 2012).

Delirium is common in all hospital settings as many hospitalised people will have risk factors for delirium. The highest incidence rates are noted in intensive care unit (ICU) and in postoperative and palliative care settings. In the ICU, incidence rates of up to 80% are reported (Ely 2004; Ouimet 2007). The ICU is a complex environment, in which the patients appear to differ from other settings, for example they are younger than patients in other settings. Treatment priorities also tend to differ with medical treatment in the ICU focused on the management of life‐threatening illness rather than the rehabilitative focus often needed for elderly people in medical and surgical wards. It is reasonable to suspect potential clinical heterogeneity between ICU and non‐ICU settings. Since the Cochrane Anaesthesia, Critical and Emergency Care Group are investigating delirium in the ICU setting (Greve 2012), this review will cover delirium in non‐ICU settings only. The incidence of postoperative delirium varies with different types of surgery, with reported rates, for example, of 12% to 50% after non‐cardiac surgery (Brouquet 2010; Olin 2005; Shah 2012), up to 51% after cardiac surgery (Zhang 2015), and 12% to 61% after orthopaedic operations (Holmes 2000). The incidence of delirium in palliative care settings ranges from 3% to 45% (Perrar 2013). In general medical and geriatric medicine wards, incidence rates range from 11% to 29% (Inouye 2014). The prevalence of delirium at admission to these wards is also high (18% to 35% in general medical wards, Inouye 2014); when combined with new incidences postadmission, the overall occurrence of delirium in these settings is relatively high. The epidemiology of delirium in the emergency department is not as well established (Vasilevskis 2012). Delirium is not exclusive to hospital settings and one study shows the incidence of delirium is 20% in nursing home residents who experience an acute illness (Flaherty 2013).

Delirious people experience increased mortality, postoperative complications (Raats 2015), readmissions (McKhann 2002), poorer functional outcomes (Inouye 1998), increased length of hospital stay (McCusker 2003), and higher healthcare expenditures (Leslie 2008).

Description of the intervention

Management of delirium aims to enhance recovery, maximise functional status and improve clinical outcomes. A key element of management is the investigation and treatment of any reversible underlying causes of delirium, in addition to the general symptomatic management. Non‐pharmacological approaches are used in the first instance to manage sleep disturbance, anxiety and agitation. However, people with severe agitation who risk interruption of essential medical treatment or self‐injury, or have severe, distressing psychotic symptoms (e.g. hallucinations, delusions) may need pharmacological treatment (Inouye 2014). Currently, there are no drugs approved by the US Food and Drug Administration (FDA) or other medicines licensing bodies specifically to treat delirium. However, in practice, clinicians currently employ various medications to give symptomatic relief.

One meta‐analysis showed that antipsychotic medications are effective for the treatment of delirium in ICU or non‐ICU patients, especially second‐generation antipsychotic drugs, which in comparison to first‐generation antipsychotic drugs (haloperidol), require a shorter time to take effect and produce fewer extrapyramidal symptoms (Kishi 2016). Antipsychotic drugs (olanzapine or haloperidol) are the only drugs currently recommended for treatment of delirium in the UK National Institute for Health and Care Excellence (NICE) guideline (Young 2010), if the person is distressed, or there is risk to the person or others, and if non‐pharmacological measures have been ineffective. Benzodiazepines have a role in the treatment of delirium caused by withdrawal from sedatives or alcohol, but otherwise are not useful in the treatment of delirium for other causes (Catic 2011), because they can cause confusion and drowsiness, particularly in older people. Some research and case reports have demonstrated that dexmedetomidine, an α2‐adrenoceptor agonist, plays a useful role in the treatment of delirium associated with cancer pain, or surgery or alcohol withdrawal (Guyatt 2008; Hilliard 2015; Lucyk 2014; Yapici 2011). Cholinesterase inhibitors, including rivastigmine, donepezil, galantamine, tacrine and physostigmine, have been used to treat delirium, but evidence regarding their effectiveness is inconsistent. One study found that rivastigmine could increase the severity of delirium and might increase mortality in people in ICU when added to standard treatment with haloperidol (Van Eijk 2010), while other primary studies suggested rivastigmine to be a useful therapy for delirium associated with Alzheimer's disease, vascular dementia or stroke in non‐ICU settings (Litvineneko 2010; Oldenbeuving 2008). Other cholinesterase inhibitors such as donepezil and physostigmine have also been studied (Liptzin 2005; Sampson 2007; Marcantonio 2011; Zujalovic 2015; Hail 2013).

How the intervention might work

The mechanisms of delirium are complex and unclear. Several theories have been proposed to explain the processes leading to the development of delirium (Maldonado 2008). One of the leading hypotheses is that delirium results from an impairment of central cholinergic transmission and is considered by some investigators to be 'a common denominator' in delirium (Blass 1981). Acetylcholine is the main neurotransmitter mediating learning and attention, and these functions are profoundly disturbed during delirium. Impaired cholinergic function is correlated with the cognitive and behavioural changes in delirium (Trzepacz 1996). Furthermore, drugs with anticholinergic effects may induce delirium, and cholinergic drugs can improve delirium induced by lithium and anticholinergic medication (Oldenbeuving 2008). Acetylcholinesterase inhibitors, by inhibiting the activity of the enzymes which metabolise acetylcholine, cause increased cholinergic activity at synapses. Therefore, by treating the presumed cholinergic deficiency in people with delirium, acetylcholinesterase inhibitors may have beneficial effects.

Why it is important to do this review

This review will update and replace the previous review "Cholinesterase inhibitors for delirium" which was published in 2008 (Overshott 2008). That review included only one trial (Liptzin 2005) comparing donepezil with placebo in the prevention and treatment of postoperative delirium in people over the age of 50 years without dementia who were undergoing elective total joint replacement. Since then, more studies have been conducted with various cholinesterase inhibitors in different settings. Hence, it is necessary to update this review. As noted above, delirium in people in ICU and its optimal management may be different from that in people in a non‐ICU setting. Therefore, this update will focus on cholinesterase inhibitors for delirium in non‐ICU settings.

Objectives

To evaluate the effectiveness and safety of cholinesterase inhibitors for treating established delirium in people in a non‐ICU setting.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials, published or unpublished, reported in English and Chinese.

Types of participants

We will include participants over 16 years of age, of either gender, diagnosed with delirium by standardised diagnostic criteria (e.g. DSM‐IV, DSM‐V, ICD‐10). If studies state that people had delirium but have not used standardised diagnostic criteria, then we will include these studies in our meta‐analysis and conduct sensitivity analyses to test whether the inclusion criteria influence the results. We will include participants who experience any cause of delirium, such as medical illnesses and adverse effects from medication. We will exclude people with delirium due to alcohol/drug withdrawal. We will include studies conducted in either hospital or community settings, but will exclude ICU settings.

Types of interventions

We will include trials assessing the effect of any of the currently marketed cholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine, tacrine and physostigmine), administered at any dose and at any frequency, compared with placebo. We will also include head‐to‐head comparisons of a cholinesterase inhibitor with another drug intended to treat delirium (e.g. antipsychotic drugs, α2‐adrenoceptor agonists, benzodiazepines, melatonin).

Included trials may involve non‐pharmacological management strategies if we can extract data from groups which differed only in exposure to cholinesterase inhibitor and placebo/comparator medication.

Types of outcome measures

Primary outcomes

  • Response to treatment:

    • Duration of delirium;

    • Severity of delirium measure by validated scales (e.g. Memorial Delirium Assessment Scale (MDAS) (Breitbart 1997), Delirium Rating Scale (DRS) (Trzepacz 1988), or DRS‐R‐98 (Trzepacz 2001)).

  • Adverse effects.

Secondary outcomes

  • Use of rescue medications (e.g. one‐off doses of antipsychotic drug).

  • Persistent cognitive impairment (defined by original studies).

  • Length of hospitalisation.

  • Institutionalisation.

  • Mortality.

  • Cost of intervention (such as direct monetary cost of intervention to participants or healthcare services).

  • Leaving the study early.

  • Quality of life.

Search methods for identification of studies

Electronic searches

We will search ALOIS (www.medicine.ox.ac.uk/alois), which is the Cochrane Dementia and Cognitive Improvement Group's Specialised Register.

ALOIS is maintained by the Trials Search Co‐ordinator and contains dementia and cognitive improvement studies identified from:

  • quarterly search of the Cochrane Central Register of Controlled Trials (CENTRAL).

  • monthly searches of major healthcare databases: MEDLINE, Embase, CINAHL, PsycINFO and LILACS,

  • monthly searches of trial registers: metaRegister of Controlled Trials; Umin Japan Trial Register; World Health Organization portal (which covers ClinicalTrials.gov; ISRCTN; Chinese Clinical Trials Register; German Clinical Trials Register; Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others).

  • monthly searches of a grey literature source: ISI Web of Science Conference Proceedings.

To view a list of all sources searched for ALOIS see About ALOIS.

We will run additional separate searches of many of the above sources to ensure that we retrieve the most up‐to‐date results. The search strategy that we will use for the retrieval of reports of trials from MEDLINE (via the OvidSP platform) is in Appendix 1.

Searching other resources

We will cross‐check the reference lists of included studies to identify any potentially eligible trials.

Data collection and analysis

Selection of studies

Two review authors (AY and SW) will independently assess each abstract and title for relevance. We will obtain the full texts of citations that describe a potentially relevant randomised controlled trial for further assessment. Two review authors will independently determine eligibility of these trials for inclusion. We will resolve disagreements at any stage of study selection by discussion or by the involvement of a third review author (ZZ).

Data extraction and management

Two review authors (AY and SW) will independently extract data using prespecified data extraction forms. A pilot data extraction will be performed before the formal data extraction. We will resolve any discrepancy by discussion. We will collect the following information where possible:

Participants' characteristics

  • Age.

  • Sex.

  • Education.

  • Diagnostic criteria of delirium.

  • Severity of delirium.

  • Underlying aetiology of delirium.

  • Baseline comorbid dementia.

  • Setting (refers to the environment where the clinical trial is conducted, e.g. palliative care settings, general or geriatric wards, emergency departments).

  • Inclusion or exclusion criteria of original studies.

Intervention characteristics

  • Types of cholinesterase inhibitors.

  • Description of the comparator.

  • Dose, route, frequency and duration of cholinesterase inhibitor and comparator.

  • Duration of treatment.

  • Any concomitant treatments.

Outcomes
Methodological characteristics

  • Sample size.

  • Duration of follow‐up.

  • Information needed for risk of bias assessments.

For continuous data, we will extract the mean, standard deviation and number of participants for each treatment group at each time point if available. For dichotomous data, we will retrieve the number in each treatment group and numbers experiencing the outcome of interest where possible. If only treatment effects and their standard errors are reported, then we will extract these.

Assessment of risk of bias in included studies

Two review authors (AY and SW) will independently assess the risk of bias of each included study using the Cochrane 'Risk of bias' tool (Higgins 2011), which evaluates the following risk domains: random sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; incomplete outcome data; selective outcome reporting and other potential sources of bias (including source of financial support). We will use the criteria reported in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The following judgements will be applied to each domain: low risk, high risk or unclear risk (either lack of information or uncertainty over the potential for bias). Review authors will resolve disagreements by consensus, and a third author (ZZ) will be consulted to resolve disagreements if necessary.

Measures of treatment effect

Where trials have used the same rating scale to assess outcome, we will calculate mean difference (MD) with a 95% confidence interval (CI). We will use the standardised mean difference (SMD) for continuous data if different rating scales were used to measure the same outcome. We will express the treatment effect for dichotomous outcomes as a risk ratio (RR) with a 95% CI.

Unit of analysis issues

For studies with multiple eligible treatment group, we will use one of the approaches described in Section 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions to overcome the unit‐of‐analysis error (Higgins 2011). Our preferred approach will be to merge all relevant experimental intervention groups of the study into a single group, and to merge all relevant control intervention groups into a single control group. If this is approach is not suitable, then we will include all relevant experimental groups and split the shared control group.

Dealing with missing data

For all outcomes, we will report on missing outcome data and will consider and discuss the potential impact of the missing data on results. In the case where attrition for a continuous outcome is between 0% and 50%, and data only from people who complete the study to that point are reported, we will reproduce these.

We anticipate that some studies will use the method of last observation carried forward (LOCF) or other imputation methods. If less than 50% of the data has been imputed, we will present and use these data and report the imputation method used. For studies with more than 50% of imputed data, we will use the data but will conduct a sensitivity analysis by excluding these studies to test the robustness of the result.

If standard deviations are not reported, we will first try to obtain the missing values from the study authors. If this is not possible, then we will attempt to calculate standard deviations from statistics available in the study report according to the methods described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011).

Assessment of heterogeneity

Two review authors (AY and SW) will independently assess clinical and methodology heterogeneity, and will only conduct meta‐analyses where study quality, participants, interventions and outcomes are sufficiently similar. We will assess statistical heterogeneity using the I2 statistic (I2 greater than 50% may represent substantial heterogeneity) combined with the P value from the Chi2 test (P < 0.1) (Higgins 2011).

Assessment of reporting biases

We will assess the possibility that publication bias affected the review using a funnel plot to identify small‐study effects where at least 10 studies are available for meta‐analysis.

Data synthesis

Meta‐analyses will be conducted using the Mantel‐Haenszel method for dichotomous outcomes, and the inverse variance method for continuous outcome. We will use random‐effect model for all analyses. Where the statistical heterogeneity is significant (P value from Chi2 test < 0.1 and I2 greater than 50%), we will explore and address the source of heterogeneity as described in the Subgroup analysis and investigation of heterogeneity section.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis

Where data allow, we will conduct subgroup analysis according to:

  • participant age (older than 65 years versus 65 years or younger);

  • different causes of delirium (e.g. postoperative delirium, adverse events to medication or hepatic encephalopathy delirium)

  • presence or absence of pre‐existing dementia or neurocognitive impairment.

Investigation of heterogeneity

Where there is evidence of statistical heterogeneity (P value from Chi2 < 0.1 and I2 greater than 50%) of the treatment effect between trials, we will explore the source of heterogeneity. We will conduct subgroup analysis if we can identify possible sources of variation; otherwise, we will use a random‐effect model to pool the data. Where statistical heterogeneity is significant in a meta‐analysis, we will consider downgrading the certainty of evidence using the GRADE approach (Section 11.5; Higgins 2011).

Sensitivity analysis

Where possible, we will conduct sensitivity analysis to explore the influence of the quality of trials by excluding data from low‐quality trials. We define low‐quality trials as more than 50% data in one arm of the study is lost or studies with high risk of selection bias and high risk of detection bias due to non‐blind outcome assessment. We will also conduct sensitivity analysis to investigate the difference between results from completers only and intention‐to‐treat analysis (for primary outcomes only). We will present results from both approaches separately and discuss the results at the full review stage.

'Summary of findings' table

For each comparison, we will use the GRADE approach to assess the quality of the body of evidence for all outcomes (Guyatt 2008; Higgins 2011). We will present the following results in 'Summary of findings' tables:

  • duration of delirium;

  • severity of delirium;

  • adverse effects;

  • persistent cognitive impairment;

  • length of hospitalisation;

  • mortality;

  • cost of intervention.

Grading of the evidence has four possible ratings: high, moderate, low, and very low. Evidence with 'high certainty' rating indicates that we are confident in our estimate of the effect, and further research is very unlikely to change this. Whereas, a rating of 'very low' certainty implies that we are very uncertain about the estimate of the effect. Initially, the GRADE approach rates evidence from randomised controlled trials as 'high quality'. However, several factors can lead to the downgrading of the evidence, these are: study limitations (risk of bias); inconsistency; indirectness of evidence; imprecision and publication bias (Guyatt 2008; Higgins 2011).

Acknowledgements

None.

Appendices

Appendix 1. MEDLINE search strategy

1. exp Cholinesterase Inhibitors/ 2. "cholinesterase inhibitor*".mp. 3. Galantamine/ 4. (galantamine or galanthamine or galant?amin).mp. 5. (reminyl* or Nivalin* or Razadyne*).mp. 6. donepezil.mp. 7. Aricept*.mp. 8. rivastigmine.mp. 9. rivastigmin.mp. 10. Exelon*.mp. 11. exp Tacrine/ 12. cognex.mp. 13. or/1‐12 14. delir*.mp. 15. confusion.mp. 16. "acute brain failure".mp. 17. "acute organic psychosyndrome".mp. 18. "acute brain syndrome".mp. 19. "metabolic encephalopathy".mp. 20. "acute psycho‐organic syndrome".mp. 21. "clouded state".mp. 22. "clouding of consciousness".mp. 23. "exogenous psychosis".mp. 24. "toxic psychosis".mp. 25. "toxic confusion".mp. 26. exp Delirium/ 27. or/14‐26 28. 13 and 27 29. randomized controlled trial.pt. 30. controlled clinical trial.pt. 31. randomi?ed.ab. 32. placebo.ab. 33. drug therapy.fs. 34. randomly.ab. 35. trial.ab. 36. groups.ab. 37. or/29‐36 38. (animals not (humans and animals)).sh. 39. 37 not 38 40. 28 and 39

Contributions of authors

ZZ: protocol development.

JX: project management, protocol development, Methodological Expectations of Cochrane Intervention Reviews (MECIR) guidance.

TD: content expert, protocol development.

SZ: protocol development.

AY: protocol development.

SW: Protocol development.

GTP: content expert, protocol development.

DY: content expert, protocol development.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • NIHR, UK.

    This protocol was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Dementia and Cognitive Improvement group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service or the Department of Health

Declarations of interest

All authors have no known conflict of interest.

New

References

Additional references

  1. Blass J, Gibson G, Duffy T, Plum F. Cholinergic dysfunction: a common denominator in metabolic encephalopathies. In: Pepeu G, Ladinsky H editor(s). Cholinergic Mechanisms. New York: Plenum, 1981:921‐8. [Google Scholar]
  2. Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment Scale. Journal of Pain and Symptom Management 1997;13(3):128‐37. [PUBMED: 9114631] [DOI] [PubMed] [Google Scholar]
  3. Brouquet A, Cudennec T, Benoist S, Moulias S, Beauchet A, Penna C, et al. Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery. Annals of Surgery 2010;251(4):759‐65. [DOI] [PubMed] [Google Scholar]
  4. Catic AG. Identification and management of in‐hospital drug‐induced delirium in older patients. Drugs & Aging 2011;28(9):737‐48. [DOI] [PubMed] [Google Scholar]
  5. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291(14):1753‐62. [DOI] [PubMed] [Google Scholar]
  6. Flaherty JH, Morley JE. Delirium in the nursing home. Journal of the American Medical Directors Association 2013;14(9):632‐4. [DOI] [PubMed] [Google Scholar]
  7. Greve I, Vasilevskis EE, Egerod I, Bekker Mortensen C, Møller AM, Svenningsen H, Thomsen T. Interventions for preventing intensive care unit delirium (Protocol). Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2012, issue 4:CD009783. [DOI] [PMC free article] [PubMed]
  8. Guyatt 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 strength of recommendations. BMJ (Clinical Research Ed.) 2008;336(7650):924‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hail S L, Obafemi A, Kleinschmidt K C. Successful management of olanzapine‐induced anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine in a pediatric patient. Clin Toxicol (Phila) 2013;51:162‐6. [DOI] [PubMed] [Google Scholar]
  10. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
  11. Hilliard N, Brown S, Mitchinson S. A case report of dexmedetomidine used to treat intractable pain and delirium in a tertiary palliative care unit. Palliative Medicine 2015;29(3):278‐81. [DOI] [PubMed] [Google Scholar]
  12. Holmes JD, House AO. Psychiatric illness in hip fracture. Age and Ageing 2000;29(6):537‐46. [DOI] [PubMed] [Google Scholar]
  13. Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? A three‐site epidemiologic study. Journal of General Internal Medicine 1998;13(4):234‐42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014;383(9920):911‐22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kishi T, Hirota T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of delirium: a systematic review and meta‐analysis of randomised controlled trials. Journal of Neurology, Neurosurgery, and Psychiatry 2016;87(7):767‐74. [DOI] [PubMed] [Google Scholar]
  16. Leslie DL, Marcantonio ER, Zhang Y, Leo‐Summers L, Inouye SK. One‐year health care costs associated with delirium in the elderly population. Archives of Internal Medicine 2008;168(1):27‐32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Liptzin B, Laki A, Garb JL, Fingeroth R, Krushell R. Donepezil in the prevention and treatment of post‐surgical delirium. American Journal of Geriatric Psychiatry 2005;13(12):1100‐6. [DOI] [PubMed] [Google Scholar]
  18. Litvineneko IV, Odinak MM, Khlystov IuV, Perstnev SV, Fedorov BB. Efficacy and safety of rivastigmine (Exelon) in the confusion syndrome in the acute phase of ischemic stroke. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova/Ministerstvo Zdravookhraneniia i Meditsinskoi Promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe Obshchestvo Nevrologov [i] Vserossiiskoe Obshchestvo Psikhiatrov 2010;110(11 Pt 2):36‐41. [PubMed] [Google Scholar]
  19. Lucyk S, Hoffman RS, Nelson LS. Dexmedetomidine in addition to benzodiazepine‐based sedation in patients with alcohol withdrawal delirium. European Journal of Emergency Medicine 2014;21(5):389‐90. [DOI] [PubMed] [Google Scholar]
  20. Luxenberg J. In Geriatrics. Stamford (CT): Appleton Lange, 1996. [Google Scholar]
  21. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence‐based approach to prevention and treatment. Critical Care Clinic 2008;24:789‐856. [DOI] [PubMed] [Google Scholar]
  22. Marcantonio E R, Palihnich K, Appleton P, Davis R B. Pilot randomized trial of donepezil hydrochloride for delirium after hip fracture. J Am Geriatr Soc 2011;59 Suppl 2:S282‐8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Martinez JA, Belastegui A, Basabe I, Goicoechea X, Aguirre C, Lizeaga N, et al. Derivation and validation of a clinical prediction rule for delirium in patients admitted to a medical ward: an observational study. BMJ Open 2012;2(5):1‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McCusker J, Cole MG, Dendukuri N, Belzile E. Does delirium increase hospital stay?. Journal of the American Geriatric Society 2003;51(11):1539‐46. [DOI] [PubMed] [Google Scholar]
  25. McKhann GM, Grega MA, Borowicz LM Jr, Bechamps M, Selnes OA, Baumgartner WA, et al. Encephalopathy and stroke after coronary artery bypass grafting: incidence, consequences, and prediction. Archives of Neurology 2002;59(9):1422‐8. [DOI] [PubMed] [Google Scholar]
  26. O'Keeffe ST. Clinical subtypes of delirium in the elderly. Dementia and Geriatric Cognitive Disorders 1999;10(5):380‐5. [DOI] [PubMed] [Google Scholar]
  27. Oldenbeuving AW, Kort PL, Jansen BP, Kappelle LJ, Roks G. A pilot study of rivastigmine in the treatment of delirium after stroke: a safe alternative. BMC Neurology 2008;8:34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Olin K, Eriksdotter‐Jonhagen M, Jansson A, Herrington MK, Kristiansson M, Permert J. Postoperative delirium in elderly patients after major abdominal surgery. British Journal of Surgery 2005;92(12):1559‐64. [DOI] [PubMed] [Google Scholar]
  29. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Medicine 2007;33(1):66‐73. [DOI] [PubMed] [Google Scholar]
  30. Overshott R, Karim S, Burns A. Cholinesterase inhibitors for delirium. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/14651858.CD005317.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perrar KM, Golla H, Voltz R. Pharmacological treatment of delirium in palliative care patients. A systematic literature review. Schmerz (Berlin, Germany) 2013;27(2):190‐8. [DOI] [PubMed] [Google Scholar]
  32. Raats JW, Eijsden WA, Crolla RM, Steyerberg EW, Laan L. Risk factors and outcomes for postoperative delirium after major surgery in elderly patients. PLoS One 2015;10(8):e0136071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sampson E L, Raven P R, Ndhlovu P N, Vallance A, Garlick N, Watts J, et al. A randomized, double‐blind, placebo‐controlled trial of donepezil hydrochloride (Aricept) for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry 2007;22:343‐9. [DOI] [PubMed] [Google Scholar]
  34. Schwartz AC, Fisher TJ, Greenspan HN, Heinrich TW. Pharmacologic and nonpharmacologic approaches to the prevention and management of delirium. International Journal of Psychiatry in Medicine 2016;51(2):160‐70. [DOI] [PubMed] [Google Scholar]
  35. Shah S, Weed HG, He X, Agrawal A, Ozer E, Schuller DE. Alcohol‐related predictors of delirium after major head and neck cancer surgery. Archives of Otolaryngology ‐ Head & Neck Surgery 2012;138(3):266‐71. [DOI] [PubMed] [Google Scholar]
  36. Steiner LA. Postoperative delirium. Part 2: detection, prevention and treatment. European Journal of Anaesthesiology 2011;28(10):723‐32. [DOI] [PubMed] [Google Scholar]
  37. Trzepacz PT, Baker RW, Greenhouse J. A symptom rating scale for delirium. Psychiatry Research 1988;23(1):89‐97. [PUBMED: 3363018] [DOI] [PubMed] [Google Scholar]
  38. Trzepacz PT. Delirium, advances in diagnosis, pathophysiology, and treatment. Psychiatric Clinics of North America 1996;19(3):429‐48. [DOI] [PubMed] [Google Scholar]
  39. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale‐revised‐98: comparison with the delirium rating scale and the cognitive test for delirium. Journal of Neuropsychiatry and Clinical Neurosciences 2001;13(2):229‐42. [PUBMED: 11449030] [DOI] [PubMed] [Google Scholar]
  40. Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, Jagt M, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double‐blind, placebo‐controlled randomised trial. Lancet 2010;376(9755):1829‐37. [DOI] [PubMed] [Google Scholar]
  41. Vasilevskis EE, Han JH, Hughes CG, Ely EW. Epidemiology and risk factors for delirium across hospital settings. Best Practice & Research. Clinical Anaesthesiology 2012;26(3):277‐87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yapici N, Coruh T, Kehlibar T, Yapici F, Tarhan A, Can Y, et al. Dexmedetomidine in cardiac surgery patients who fail extubation and present with a delirium state. Heart Surgery Forum 2011;14(2):E93‐8. [DOI] [PubMed] [Google Scholar]
  43. Young J, Murthy L, Westby M, Akunne A, O'Mahony R, Guideline Development Group. Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ 2010;341:c3704. [DOI] [PubMed] [Google Scholar]
  44. Zhang WY, Wu WL, Gu JJ, Sun Y, Ye XF, Qiu WJ, et al. Risk factors for postoperative delirium in patients after coronary artery bypass grafting: a prospective cohort study. Journal of Critical Care 2015;30(3):606‐12. [DOI] [PubMed] [Google Scholar]
  45. Zujalovic B, Barth E. Delirium Accompanied by Cholinergic Deficiency and Organ Failure in a 73‐Year‐Old Critically Ill Patient: Physostigmine as a Therapeutic Option. Case Rep Crit Care 2015;2015:793015. [DOI] [PMC free article] [PubMed] [Google Scholar]

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