Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) Intensiv symposium 2018

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1 Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) Intensiv symposium 2018 Nina Chris*ne Andersen-Ranberg and S*ne Estrup (coordina*ng inves*gators) Lone Musaeus Poulsen (sponsor) Department of Anaesthesiology and Intensive Care Medicine Zealand University Hospital, Koege

2 Delirium in Intensive Care Unit Cri*cally ill pa*ents are at risk of developing delirium during ICU stay, incidence 32-84% 1,2 Delirium is associated with increased morbidity and mortality 3,4,5 Increased days on mechanical ven*la*on Longer hospital admiwances Long-term cogni*ve impairment Long-term disability Higher cost of care Independent predictor of mortality Delirium is expensive to the individual and society 1) Salluh, J.I., et al., Outcome of delirium in cri/cally ill pa/ents: systema/c review and meta-analysis. BMJ, : p. h ) Brummel, N.E., et al., Delirium in the ICU and subsequent long-term disability among survivors of mechanical ven/la/on. Crit Care Med, (2): p ) Pandharipande, P.P., et al., Long-term cogni/ve impairment aber cri/cal illness. N Engl J Med, (14): p ) Lat, I., et al., The impact of delirium on clinical outcomes in mechanically ven/lated surgical and trauma pa/ents. Crit Care Med, (6): p ) Ely, E.W., et al., Delirium as a predictor of mortality in mechanically ven/lated pa/ents in the intensive care unit. JAMA, (14): p

3 Delirium and mortality Kaplan-Meier survival curve for 1-year mortality post-intensive care unit (ICU) admission (ICU delirium days predictor). Pisani, Kong, Kasl, et al.: Delirium and Mortality in Older ICU Pa*ents. American Journal of respiratory and cri/cal care 2009.

4 Current evidence Review ar*cle: Seda*on and Delirium in the Intensive Care Unit. Reade et al. NEJM, 2014 There is very lidle evidence to guide the management of established delirium, and most exis*ng trials were categorized as pilot studies. Intensive Care Unit Delirium A review of diagnosis, preven*on and treatment. Hayhurst et al. Anaesthesiology 2016 Despite the abundance of liwerature and research on delirium, there remains a paucity of large, randomized controlled trials of pharmacologic treatment of delirium. Pharmacological preven*on and treatment of delirium in intensive care pa*ents: A systema*c review. Rodrigo et al. Journal of Cri/cal Care, No single pharmacologic intervenkon was associated with reduc*on in mortality or hospital length of stay. No evidence based treatment of ICU aquired delirium is currently available

5 AID ICU AID-ICU involves 3 studies Systema*c Review Incep*on cohort study AID-ICU RCT Haloperidol vs. Placebo

6 Aim of the AID-ICU trial To assess the benefits and harms of Haloperidol treatment in cri*cally ill adult pa*ents with delirium Benefits Harms Mortality

7 Design 1000 pakents Interven*on Control Haloperidol 2.5mg x 3 daily Placebo: isotonic saline Primary outcome: Days alive out of the hospital within 90 days

8 Inclusion criteria ü Acute (unplanned) admission to the ICU ü Aged 18 years or above ü Diagnosed delirium with validated screening tool (CAM-ICU, ICDSC)

9 Exclusion criteria û Contraindica*ons to haloperidol û Habitual treatment with any ankpsychokc medicakon or treatment with ankpsychokcs in the ICU prior to inclusion û Permanently incompetent (e.g. demen*a, metal retarda*on) û Delirium assessment non-applicable (language barriers, blind, deaf) û Withdrawal from ac*ve therapy û Fer*le women (<50 years) with posi*ve urine hcg or plasma hcg û Pa*ents under coercive measures by regulatory authori*es û PaKents with alcohol induced delirium (delirium tremens) û Consent unobtainable according to na*onal regula*ons

10 Interven=on Acute ICU admiwance Delirium screening x 2 daily Posi*ve for delirium P.n. haloperidol/placebo to a total of 20 mg daily (5 addi*onal administra*ons) Screening Haloperidol 2.5 mg (0.5ml) x 3 Does not meet exclusion criteria Randomisa*on Escape medicine: Propofol seda*on Benzodiazepines Dexmedetomidine/α2-agonist Placebo: NaCl 0.5 ml x 3

11 Pausing and stopping Pausing criteria: 2 consecu*ve nega*ve delirium scores in the same day OR unexplained coma (and all other relevant medica*on stopped) Stopping criteria: Discharge from the ICU Transfer to another ICU (non AID-ICU trial site) Maximum of 90 day interven*on period Death

12 AID-ICU trial organisation Scandinavian Critical Care Trial Group (SCCTG) Monitoring and Safety Committee Centre for Research in Intensive Care ICU, Rigshospitalet ICU, Aalborg University Hospital ICU, Zealand University Hospital Koege Copenhagen Trial Unit Dept. of BiostaKsKcs, UCPH VIVE Steering Committee Good Clinical Practice (GCP) unit Danish Medicines Agency Regional Ethics Committee Management Committee Nina Andersen-Ranberg, Coordinating investigator Dept. of Intensive Care, Zealand University Hospital National Principal Investigators Stine Estrup, Investigator Dept. of Intensive Care, Zealand University Hospital Denmark Finland Norway Ole Mathiesen, Initiator Dept. of Anaesthesiology, Zealand University Hospital Nina Andersen-Ranberg Johanna Hästbacka Luis George Romundstad Birgit Agerholm Larsen, Project leader, CRIC Lone Musaeus Poulsen, Sponsor, Initiator Dept. of Intensive Care, Zealand University Hospital Anders Perner, Initiator Dept. of Intensive Care 4131, RH/CRIC/SCCTG UK Matthew Morgan Spain Jesus Cabellero Italy Giuseppe Citerio Jørn Wetterslev, Trialist, Copenhagen Trial Unit Bjørn Hylsebeck Ebdrup, Investigator Mental Health Centre Glostrup

13 Contacts CoordinaKng InvesKgators Nina ChrisKne Andersen-Ranberg, MD SKne Estrup, MD Department of Anaesthesiology and Intensive Care Medicine Zealand University Hospital, Koege Phone: (available 24/7) Sponsor Lone Musaeus Poulsen, MD, Head of ICU Department of Anaesthesiology and Intensive Care Medicine Zealand University Hospital, Koege Phone:

14 Incep=on cohort study 14 day incep*on cohort study in 99 ICUs worldwide Most frequent used agents to treat delirium: - Haloperidol - Benzodiazepiner - Dexmedetomidine Power calcula*ons for AID-ICU RCT

15 Overview over Reviews Conclusion: The overall quality and quan*ty of the present evidence underline the necessity of conduc*ng a truly systema*c review on haloperidol and the urgent need for a large pragmakc trial with overall low risk of bias for treatment of delirium with haloperidol and dexmedetomidine on pa*ent important outcomes (days alive out of hospital, mortality, dura*on of delirium, etc.).

16 Current guidelines - The Danish society of Anaesthesiology and Intesive Care Medicine - The Intensive Care Society in the UK - German guidelines Haloperidol Olanzapin Risperidon - The American College of Cri*cal Care Medicine and the Society of Cri*cal Care Medicine (USA) No evidence of haloperidol (no evidence) Olanzapin may reduce delirium durakon (C)

17 Methods Design: Inves*gator-ini*ated, randomised mul*centre placebo-controlled clinical trial with blinding Semng: approx. 25 ICUs in Europe Popula*on: Adult ICU pa*ents with diagnosed Delirium Start 2018 March, Zealand University Hospital Køge