Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial

Abstract

BackgroundDelirium is associated with substantial morbidity and mortality rates in elderly hospitalised patients, and a growing problem due to increase in life expectancy. Implementation of standardised non-pharmacological delirium prevention strategies is challenging and adherence remains low. Pharmacological delirium prevention with haloperidol, currently the drug of choice for delirium, seems promising. However, the generalisability of randomised controlled trial results is questionable since studies have only been performed in selected postoperative hip-surgery and intensive care unit patient populations. We therefore present the design of the multicenter, randomised, double-blind, placebo-controlled clinical trial on early pharmacological intervention to prevent delirium: haloperidol prophylaxis in older emergency department patients (The HARPOON study).Methods/DesignIn six Dutch hospitals, at-risk patients aged 70 years or older acutely admitted through the emergency department for general medicine and surgical specialties are randomised (n = 390) for treatment with prophylactic haloperidol 1 mg or placebo twice daily for a maximum of seven consecutive days. Primary outcome measure is the incidence of in-hospital delirium within seven days of start of the study intervention, diagnosed with the Confusion Assessment Method, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for delirium. Secondary outcome measures include delirium severity and duration assessed with the Delirium Rating Scale Revised 98; number of delirium-free days; adverse events; hospital length-of-stay; all-cause mortality; new institutionalisation; (Instrumental) Activities of Daily Living assessed with the Katz Index of ADL, and Lawton IADL scale; cognitive function assessed with the Six-item Cognitive Impairment Test, and the Dutch short form Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be contacted by telephone three and six months post-discharge to collect data on cognitive- and physical function, home residency, all-cause hospital admissions, and all-cause mortality.DiscussionThe HARPOON study will provide relevant information on the efficacy and safety of prophylactic haloperidol treatment for in-hospital delirium and its effects on relevant clinical outcomes in elderly at-risk medical and surgical patients.Trial registrationEudraCT Number: 201100476215; ClinicalTrials.gov Identifier: NCT01530308; Dutch Clinical Trial Registry: NTR3207

Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit

“…Patients with slight, or more, clinically relevant cognitive dysfunction before surgery and those diagnosed with cerebrospinal lesions were excluded. Patients taking tranquilizers before surgery that could have a prophylactic effect on delirium [19] were also excluded. Further, we excluded patients who required neurosurgery for lesions located in the brain and spinal cord, or cardiothoracic surgery with a cardiopulmonary bypass, because such procedures can lead to nerve destruction and ischemia in the brain and spinal cord, and consequently increase serum pNF-H levels.…”

Prescription of Potentially Inappropriate Medication in Older Inpatients of an Internal Medicine Ward: Concordance and Overlap Among the EU(7)-PIM List and Beers and STOPP Criteria

“…Several studies report that delirium is associated with substantial rates of morbidity and mortality in inpatients, which becomes a growing problem due to increased life expectancy. Haloperidol is currently the drug of choice for the treatment of delirium (Schrijver et al, 2014;Ostinelli et al, 2017;Herling et al, 2018a;Herling et al, 2018b).…”

Postoperative Delirium in the Geriatric Patient

“…[12, 49–53] Currently there is an ongoing Dutch multicenter trial (Haloperidol Prophylaxis in Older Emergency Department Patients, HARPOON study) to determine efficacy and safety of haloperidol prophylaxis in at-risk patients. [54] Medical and surgical patients identified as high risk for delirium in the emergency department will be randomized to 1 mg haloperidol prophylaxis twice daily for seven days with delirium incidence as the primary endpoint, and secondary endpoints including delirium free days, length of stay, and mortality. Regarding the use of antipsychotics for the purpose of treating delirium the current guidelines recommend the “lowest effective dose” for the shortest duration, and only after nonpharmacologic interventions have failed.…”