PROfylactic Haloperidol in Patients Defined as High Risk for DElirium With Delirium Risk mOdel

Overview

The hospital pharmacy at the Zuyderland Medical Centre developed the DElirium MOdel (DEMO) to predict which patients are at risk of developing a delirium in patients aged 60 or older. With this delirium risk prediction model we aim to predict more accurately which patients are at high risk of developing a delirium and want to investigate if these patients can benefit from prophylactic haloperidol.

Full Title of Study: “Delirium: Is Prophylactic Drug Therapy Useful in High Risk Patients as Defined by the Delirium Risk Prediction Model?”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: November 23, 2018

Detailed Description

Intro: Delirium is a common postoperative complication within geriatric patients. It is described delirium as a very stressful experience for the patient which can lead to prolonged hospital stay, higher cost, additional morbidity and increased mortality.

In 2013 the hospital pharmacy at the Zuyderland Medical Center developed the delirium risk prediction model to determine the chance of development of a delirium in patients aged 60 or older. Electronically available data such as age, polypharmacy, use of anti-dementia drugs, anti-depressants, anti-parkinsonian drugs, anti-diabetics, analgesics and/or sleeping medication were used in the study. The delirium risk prediction model was validated prospectively after retrospective development. The model will be used in this study to predict the risk of developing delirium postoperatively.

We expect prophylactic haloperidol to be effective in patients with a high risk of developing a delirium according to the delirium risk prediction model.

Aim: The PRODEO-study aims to reduce the incidence of postoperative delirium by administering prophylactic haloperidol to patients with a high risk of developing delirium according to the delirium risk prediction model.

Methods: The study is a randomized and double blind single center study with two parallel groups. Subjects ≥60 years with increased risk of postoperative delirium according to the delirium risk prediction model undergoing elective chirurgical or elective orthopedic surgery are eligible. Subjects will be excluded if they already use anti-psychotic drugs, are not able to take oral medication or when there are contra-indications. Haloperidol (1mg) or placebo will be administered at set times postoperatively. Subjects receive haloperidol 2dd1mg or a placebo 2dd during a maximum of five days during admission. On day 3 blood samples will be obtained in order to determine the true concentration levels of haloperidol. The primary endpoint is delirium incidence within 5 days after surgery. Secondary endpoints are costs of treatment, number of admission days, adverse events, true concentration levels of haloperidol and duration and severity of delirium.

Results: The study will start in June 2017 with an inclusion rate of 20 patients per week. An incidence reduction of 30% in the intervention group is expected. To reach sufficient statistical power a study population of 1366 subjects is needed. Duration of the inclusion period is expected to be 18 months.

Interventions

  • Drug: Haloperidol
    • Haloperidol 2dd1mg (08.00am – 10.00pm)
  • Drug: Placebo Oral Tablet
    • Placebo oral 2dd (08.00am – 10.00pm)

Arms, Groups and Cohorts

  • Experimental: Prophylactic Haloperidol arm
    • Patients will receive oral haloperidol 2dd1mg (08.00am & 10.00pm)
  • Placebo Comparator: No treatment
    • Patients will receive oral placebo 2dd (08.00am & 10.00pm)

Clinical Trial Outcome Measures

Primary Measures

  • Occurence of delirium
    • Time Frame: Delirium within 5 days postoperative
    • Will prophylactic haloperidol in high risk patients as established with DEMO reduce the incidence of delirium?

Secondary Measures

  • Costs of treatment
    • Time Frame: up to 2 years
    • Total costs of hospital stay
  • Days admitted to hospital
    • Time Frame: an average of two weeks
    • Total amount of days admitted to the hospital
  • Adverse events of intervention medication
    • Time Frame: an average of two weeks
    • Adverse events during admission in the hospital
  • Circulating concentration of Haloperidol
    • Time Frame: up to 2 years
    • Blood sample collection at day, trough concentration haloperidol in blood sample
  • Duration of delirium
    • Time Frame: an average of two weeks
    • Days DOS (Delirium observation scale) positive after surgery,
  • Severity of delirium
    • Time Frame: an average of two weeks
    • DOS scores during admission

Participating in This Clinical Trial

Inclusion Criteria

  • Age >60 years
  • Planned elective surgery
  • General surgery or orthopaedic surgery
  • At least one night postsurgical admission
  • High-risk developing delirium according to the DEMO-model
  • Absence of delirium pre-operatively

Exclusion Criteria

  • Less than 1-day postoperative admission in hospital
  • Hypersensitivity to butyrophenone derivates
  • Use of antipsychotics
  • Not being able to take oral medication
  • Presence of contraindications (lesions of basal ganglia, clinical significant heart disease (eg. recent acute myocardial infarction, non-compensated heart failure, arrythmias treated with drugs out of the NYHA(New York Heart Association)-class Ia and II anti-arrythmics), known prolongation of the QT interval, history of ventricular arrythmia and torsades de pointes, uncorrected hypokalemia.

Gender Eligibility: All

Minimum Age: 60 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Zuyderland Medisch Centrum
  • Provider of Information About this Clinical Study
    • Principal Investigator: Hugo Van der Kuy, Principle Investigator – Zuyderland Medisch Centrum
  • Overall Official(s)
    • Hugo van der Kuy, Principal Investigator, Zuyderland MC
  • Overall Contact(s)
    • Hugo van der Kuy, 088 4595945, h.vanderkuy@zuyderland.nl

References

Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc. 2007 May;55(5):780-91. Review.

Demeure MJ, Fain MJ. The elderly surgical patient and postoperative delirium. J Am Coll Surg. 2006 Nov;203(5):752-7. Epub 2006 Sep 26. Erratum in: J Am Coll Surg. 2007 Jan;204(1):191.

Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015 Jun 3;350:h2538. doi: 10.1136/bmj.h2538. Review.

Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008 Jan 14;168(1):27-32. doi: 10.1001/archinternmed.2007.4.

Fukata S, Kawabata Y, Fujisiro K, Katagawa Y, Kuroiwa K, Akiyama H, Terabe Y, Ando M, Kawamura T, Hattori H. Haloperidol prophylaxis does not prevent postoperative delirium in elderly patients: a randomized, open-label prospective trial. Surg Today. 2014 Dec;44(12):2305-13. doi: 10.1007/s00595-014-0859-7. Epub 2014 Feb 16.

Wang W, Li HL, Wang DX, Zhu X, Li SL, Yao GQ, Chen KS, Gu XE, Zhu SN. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial*. Crit Care Med. 2012 Mar;40(3):731-9. doi: 10.1097/CCM.0b013e3182376e4f.

de Wit HA, Winkens B, Mestres Gonzalvo C, Hurkens KP, Mulder WJ, Janknegt R, Verhey FR, van der Kuy PH, Schols JM. The development of an automated ward independent delirium risk prediction model. Int J Clin Pharm. 2016 Aug;38(4):915-23. doi: 10.1007/s11096-016-0312-7. Epub 2016 May 13.

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