Scheduled Prophylactic 6-Hourly IV AcetaminopheN to Prevent Postoperative Delirium in Older CaRdiac SurgicAl Patients (PANDORA): protocol for a multicentre randomised controlled trial

Abstract

Introduction: Postoperative delirium is common among older cardiac surgery patients. Often difficult to predict and address prophylactically, delirium complicates the postoperative course by increasing morbidity and mortality as well as prolonging both hospital and intensive care unit (ICU) lengths of stay. Based on our pilot trial, we intend to study the effect of scheduled 6-hourly acetaminophen administration for 48 hours post-cardiac surgery with cardiopulmonary bypass (CPB) on the incidence of in-hospital delirium and long-term neurocognitive outcomes. Additionally, effect on duration and severity of delirium, rescue analgesic consumption, acute and chronic pain scores and lengths of hospital and ICU stay will also be explored.

Methods and analysis: This multicentre, randomised, placebo-controlled, quadruple-blinded trial will include 900 older (>60 years) cardiac surgical patients requiring CPB. Patients meeting the inclusion criteria and not meeting any exclusion criteria will be enrolled at seven centres across the USA with Beth Israel Deaconess Medical Center (BIDMC), Boston, as the central coordinating centre. Additional sites may be included to broaden or speed accrual. The primary outcome measure is the incidence of in-hospital delirium till day 30. Secondary outcomes include the duration and severity of in-hospital delirium, hospital and ICU lengths of stay, postoperative pain scores, postoperative rescue analgesic consumption, postoperative cognitive function and chronic sternal pain. Creation of a biorepository and the use of intraoperative-blinded electroencephalogram (EEG) and cerebral oximetry data will support exploratory endpoints to determine mechanistic predictors of postoperative delirium.

Ethics and dissemination: This trial is approved and centrally facilitated by the Institutional Review Board at BIDMC. An independent Data Safety and Monitoring Board is responsible for maintaining safety oversight. Protocol # 2019 P00075, V.1.4 (dated 20 October 2020).

Trial registration number: NCT04093219.

Keywords: adult intensive & critical care; anaesthesia in cardiology; cardiac surgery; delirium & cognitive disorders.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study schema. FRAIL, 5-item Frailty Questionnaire; FuncAQ, Functional Assessment Questionnaire; MoCA, Montreal Cognitive Assessment; NPRS, Numeric Pain Rating Scale; POD: postoperative day; SF-12, Short Form 12; T-MoCA, Telephonic MoCA.

Figure 2

Standard Protocol Items: Recommendations for Interventional Trials figure. The schedule of enrolment, interventions and assessment in the study. (a) Study day 0, day of surgery; study day 1, postoperative day 1, etc. (b) Whichever comes first. (c) Use clinically available liver function tests (LFTs) (Aspartate transaminase (AST), Alanine transaminase (ALT), Alkaline phosphatase (ALP)) within 30 days, otherwise place order for research. (d) Intravenous acetaminophen/placebo administered in 6-hourly intervals for eight doses total. (e) In order to ensure appropriate identification, the CAM is assessed in-hospital until discharge with a standard daily cognitive assessment including three-object registration, DOWB, MOYB, recall, digits forward, digits backwards and orientation. (f) Clinically available data include medication administration, intraoperative blood pressures and routine labs; intraoperative sedation data. (g) Pain scores will be collected three times daily; NPRS at 6 and 12 months. (h) Sample no.1 (baseline sample) to be collected after enrolment (at the time of the preoperative study assessments or on day of surgery), prior to study drug administration and sample no. 2 (postoperative sample) to be drawn on postoperative day 1 and sample no. 3 on postoperative day2, preferably in the afternoon when patient is in the ICU. (i) Major postsurgical outcomes obtained from Society of Thoracic Surgeons database 1 month from discharge: reoperation (bleeding), deep sternal infection, stroke, pneumonia, renal failure, atrial fibrillation and death. (j) Monitoring for all adverse events will take place daily during the patient’s hospital stay for a maximum of 5 days from the final dose of study medication. (k) LFTs will be ordered on the morning of POD 2. CAM, Confusion Assessment Method; DOWB, days of the week backwards; DSI, delirium symptom interview; FRAIL, 5-item Frailty Questionnaire; FuncAQ, Functional Assessment Questionnaire; GDS, Geriatric Depression Scale; MoCA, Montreal Cognitive Assessment; MOYB, months of the year backwards; NPRS, Numeric Pain Rating Scale; POD, postoperative day; SF-12, Short Form 12; T-MoCA, Telephonic MoCA.

Figure 3

AE reporting schema. AE, adverse event; CC, coordinating centre; d, days; DSMB, Data Safety and Monitoring Board; eCRF, electronic Case Report Forms; h, hours; IMM, Independent Medical Monitor; MoCA, Montreal Cognitive Assessment; NIA, National Institute of Ageing; SAE, Serious Adverse Events; sIRB, Single Institutional Review Board; STS, Society for Thoracic Surgeons; UP, unanticipated problem; wd, working days.