Jacques Lee: Understanding Delirium Pathophysiology using Urine Metabolomics from Older People with Hip Fractures

Background and Importance: Delirium, or acute confusion, is common -10% to 34% of the 3 million Canadians who are hospitalized annually. The 30,000 Canadians treated each year for hip fractures have amongst the highest risk of delirium of any population– up to 62%. Delirium is serious, doubling mortality, costs, cognitive impairment and nursing home admission. Unfortunately, busy clinicians miss 50- 75% of delirium which triples mortality vs. recognized delirium. Despite being targeted by guidelines over 20 years, little evidence of improved delirium recognition exists. Diagnostic biomarkers could help. Previous studies to develop such biomarkers have been confounded by including people with a wide variability in their delirium triggers (e.g. sepsis, drug interactions) and delirium duration. Individual risk factors that predispose people to delirium (e.g. dementia) have not been controlled for. Thus biomarker studies have found conflicting results.

Novel Approach: We will take advantage of the “natural experiment” offered by people with hip fractures to address these challenges. This model addresses confounding due to delirium cause. Since 86% of people with hip fractures develop delirium within 3 days, variability in duration of delirium is reduced. We will control for individual susceptibility to delirium by using patients as their own controls, collect urine samples when patients first arrive in the ED (96% are delirium) and then collect daily urine samples. Our previous research shows that 22 – 28% develop delirium within 5 days. Our novel approach – urine metabolomics – can detect all metabolomic biomarkers excreted in the urine and use big-data computational methods to identify changes in the metabolite patterns to diagnose delirium.

Overall Goals: To improve detection of delirium and ultimately to decrease the morbidity, mortality, costs and care deficits first in people with hip fractures, but ultimately in all people at risk for delirium.

Objective 1: Identify statistical differences in the pattern of biomarker excretion in the urine of people with hip fractures who develop post-operative delirium. Objective 2: Develop clinically useful laboratory tests to diagnose post-operative delirium. Objective 3: Gain important new insights into the pathophysiologic mechanisms leading to delirium by studying the differences identified in Objective 1.

Methods: Prospective observational study– we will replicate methods that recruited 840 seniors with hip fractures. Urine will be collected daily, frozen immediately on site then shipped to the central site for storage and analysis. Expected Outcomes: 1) Developing biomarkers will address the care gap associated with unrecognized delirium which will have immediate clinical applications for the large number of people suffering from hip fractures. 2) This study will help fill a critical knowledge gap in the underlying pathophysiologic mechanism that leads to delirium. 3) Future studies of these biomarkers in other populations (ED, medical wards) will lead to better understanding of the similarities and differences in the mechanisms producing delirium in different populations as well as allowing the development of biomarkers for use in other settings. 4) Cost-effective storage of excess samples will create a significant opportunity for international collaboration to rapidly improve the understanding, diagnosis and treatment of delirium.