Ketamine vs. haloperidol for prevention of cognitive dysfunction and postoperative delirium: A phase IV multicentre randomised placebo-controlled double-blind clinical trial

Alexa Hollinger; Christoph A Rüst; Harriet Riegger; Bianca Gysi; Fabian Tran; Jonas Brügger; Jan Huber; Katharina Toft; Madlen Surbeck; Hans-Ruedi Schmid; Katharina Rentsch; Luzius Steiner; Martin Siegemund

doi:10.1016/j.jclinane.2020.110099

Ketamine vs. haloperidol for prevention of cognitive dysfunction and postoperative delirium: A phase IV multicentre randomised placebo-controlled double-blind clinical trial

J Clin Anesth. 2021 Feb:68:110099. doi: 10.1016/j.jclinane.2020.110099. Epub 2020 Oct 22.

Authors

Affiliations

¹ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; Department of Clinical Research, University of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. Electronic address: Alexa.Hollinger@usb.ch.
² Institute of Primary Care, University of Zurich, Pestalozzistrasse 24, 8091 Zurich, Switzerland. Electronic address: christoph.ruest@bluewin.ch.
³ Department for Anesthesia, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: HarrietYvonne.Riegger@usb.ch.
⁴ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: bianca.gysi@stud.unibas.ch.
⁵ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: fabian.tran@stud.unibas.ch.
⁶ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: jonas.bruegger@stud.unibas.ch.
⁷ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: jan.huber@vtxmail.ch.
⁸ Department for Anaesthesia, Intensive Care and Emergency Medicine, See-Spital, Horgen and Kilchberg Branches, Asylstrasse 19, 8810 Horgen, Switzerland. Electronic address: Katharina.Toft@gmail.com.
⁹ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: madlen.surbeck@stud.unibas.ch.
¹⁰ Central Laboratory, Cantonal Hospital Baden, Im Ergel 1, 5404 Baden, Switzerland. Electronic address: Hans-Ruedi.Schmid@ksb.ch.
¹¹ Department of Clinical Research, University of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland; Department of Clinical Chemistry and Laboratory Medicine, Petersgraben 4, 4031 Basel, Switzerland. Electronic address: Katharina.Rentsch@usb.ch.
¹² Department of Clinical Research, University of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland; Department for Anesthesia, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland. Electronic address: Luzius.Steiner@usb.ch.
¹³ Intensive Care Unit, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland; Department of Clinical Research, University of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. Electronic address: Martin.Siegemund@usb.ch.

PMID: 33120302
DOI: 10.1016/j.jclinane.2020.110099

Abstract

Study objective: Delirium is frequently observed in the postoperative and intensive care unit (ICU) population. Due to the multifactorial origin of delirium and according to international guidelines (e.g., American Geriatrics Society; Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guideline), there are several but no incontestable options for prevention and symptomatic treatment. The purpose of the Baden PRIDe (Prevention and Reduction of Incidence of postoperative Delirium) trial was to determine whether postoperative cognitive dysfunction and delirium could be prevented by the combination of possible preventive agents such as haloperidol and ketamine. In addition, pre- and postoperative levels of the biomarkers cortisol, neuron specific enolase (NSE) and S100β were measured to investigate their dynamics in delirious and non-delirious patients after surgery.

Design: The Baden PRIDe Trial was an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial.

Setting: Perioperative care.

Patients: 182 adult patients that underwent elective or emergency surgery under general or combined (i.e., general and regional) anaesthesia.

Interventions: Pre-anaesthetic, pharmacologic prevention of postoperative brain dysfunction with haloperidol, ketamine, and the combination of both vs. placebo.

Measurements: Assessment of cognitive performance pre- and postoperatively with the MMSE, the DOS, the Nursing Delirium Screening Scale (Nu-DESC) or the Intensive Care Delirium Screening Checklist (ICDSC) during ICU stay.

Main results: None of the three study arms - haloperidol, ketamine, or both drugs combined - was significantly superior to placebo for prevention of postoperative brain dysfunction and delirium (P = 0.39). Measured levels of postoperative cortisol were significantly higher in delirious patients. S-100β levels were significantly higher in all postoperative outcome groups (cognitive impairment, delirium, no cognitive decline), whereas postoperative NSE levels declined in all groups.

Conclusions: The study results offer no possibility for a novel recommendation for prevention of postoperative cognitive decline including delirium. Perioperative S-100β trajectories in patients with cognitive deterioration suggest affection of glial cells in particular.

Trial registration: ClinicalTrials.govNCT02433041; registered on April 7, 2015.

Keywords: Cortisol; DOS; MMSE; NSE; Nu-DESC; S100β.

Publication types

Clinical Trial, Phase IV
Multicenter Study
Randomized Controlled Trial

MeSH terms

Adult
Cognitive Dysfunction* / etiology
Cognitive Dysfunction* / prevention & control
Delirium* / prevention & control
Double-Blind Method
Haloperidol / adverse effects
Humans
Ketamine*

Substances

Ketamine
Haloperidol

Associated data

ClinicalTrials.gov/NCT02433041