Baden Prevention and Reduction of Incidence of Postoperative Delirium Trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium

Abstract

Background: Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10-80%. Delirium was first described more than half a century ago in the cardiac surgery population, where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population. This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies. Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100β will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery.

Methods/design: The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo.

Discussion: There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium.

Trial registration: ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.

Keywords: DOS; Delirium prevention; Haloperidol; ICDSC; Ketamine; MMSE; NSE; Nu-DESC; Postoperative delirium; Randomised clinical trial; S100β.

Conflict of interest statement

Authors’ information

Harriet Riegger works as a senior resident in anesthesiology at the University Hospital Basel, Switzerland. Alexa Hollinger currently works as a postdoctoral research fellow at the Saint Louis Lariboisière University Hospitals in Paris, France. Burkhardt Seifert has worked as a statistician at the institute for Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland, and has retired in 2017. Katharina Toft works as an attending physician in anesthesiology at the See-Spital Horgen and Kilchberg, Switzerland. Martin Siegemund is deputy chief physician of the Surgical Intensive Care Unit of the University Hospital Basel, Switzerland.

Administrative information: roles and responsibilities

Sponsor

PD Dr. Martin Siegemund, Deputy Chief Physician, Surgical Intensive Care Unit, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Principal Investigator

Dr. Alexa Hollinger, Medical Resident, Critical Care Fellow, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Study centres

Department of Anaesthesia, Intensive Care and OR Management, Cantonal Hospital of Baden, Switzerland

Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Co-investigators

Harriet Riegger, Medical Resident, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Data acquisition

Katharina Toft, Attending Physician, Department for Anesthesia, Intensive Care and Emergency Medicine, See-Spital, Horgen and Kilchberg branches, Switzerland

Dr. Leonie Faller, Medical Resident, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel

Dr. Philipp Bühler, Attending Physician, University Children’s Hospital, Zurich, Switzerland

Andrea Blum, MD Candidate, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Tatjana Zehnder, MD Candidate, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Switzerland

Statistician

Prof. Dr. Burkhardt Seifert, Adjunct Professor/Scientific Staff, Epidemiology, Biostatistics and Prevention Institute, Hirschengraben 84, 8001 Zurich, Switzerland

Insurance

Zürich Versicherungs-Gesellschaft AG, Ruedi Wild and Ralf Bänsch, Global Corporate Switzerland, Austrasse 46, 8045 Zurich, Switzerland

Legal service und compliance

Dr. iur. Jürg Müller, Head Legal Service

Data management, consulting service

Clinical Trials Center (CTC) Zurich, Moussonstrasse 3, 8044 Zurich, Switzerland.

Ethics committees

KEK Kanton Aargau, Bachstrasse 15, 5001 Aarau, Switzerland

EKNZ, Hebelstrasse 53, 4056 Basel, Switzerland

Swissmedic, Schweizerisches Heilmittelinstitut, Hallerstrasse 7, Postfach, 3000 Bern 9, Switzerland

Ethics approval and consent to participate

This study is conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) and all national legal and regulatory requirements. Research Ethics Committee approval has been granted for this study by the Ethics Committee of the canton of Aargau (KEK: 2012–037), the Ethics Committee of Northwestern and Central Switzerland (EKNZ: AGSO 2012/037) and the Competent Authority (Swissmedic: 2013DR4089). Every study participant’s informed consent will be sought to consent for study participation.

Consent for publication

Every study participant’s informed consent will be sought to consent for publication.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Study period overview (SPIRIT figure)