# Pathophysiology of postoperative delirium and the use of biomimetic sleep as a treatment strategy in the CSICU

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $626,750

## Abstract

Delirium is one of the six leading causes of preventable morbidity and mortality in hospitalized elderly patients.
Individuals with advanced age and Alzheimer's disease are at greatest risk of developing delirium. A
substantial proportion of patients who survive delirium are likely to experience long-term cognitive impairment
similar to mild Alzheimer's disease, and require institutional care. This suggests that delirium and Alzheimer's
disease share pathophysiological features that arise in the context of normal aging. Conditions associated with
delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory
mediators into the bloodstream. A putative mechanism is the high interleukin-6 level that has been associated
with delirium in both laboratory animals and humans. Normal aging is associated with a morphological shift of
glia to an activated state. Following a systemic challenge such as critical illness, these activated glia result in
an exaggerated neuroinflammatory state associated with delirium. Neuroinflammation is further exacerbated by
sleep disturbances. Thus, sleep deprivation may be a modifiable risk factor for the development of delirium.
However, pharmacological treatment with no current medication (benzodiazepines, antipsychotics) induces
natural sleep or reliably reduces the incidence of delirium. We have found that biomimetic sleep, defined here
as pharmacological induction of rapid eye movement sleep (REM) and non-REM I-III sleep states using
dexmedetomidine, can now be achieved in humans. Our Specific Aims seek to: (1) investigate the benefits of
preemptive biomimetic sleep for reducing the risk of developing delirium in a randomize; (2) investigate the
cellular and molecular mechanisms of delirium using combined Positron Emission Tomography/Magnetic
Resonance imaging and serum metabolic profiling; and (3) investigate predictors of delirium from perioperative
electroencephalogram recordings. At the conclusion of these studies, we will have expanded our knowledge of
the pathophysiology of delirium, evaluated a new preemptive therapeutic strategy for delirium, suggest
neurophysiologically based monitoring strategies to reduce significantly the amount of anesthetic administered
to elderly patients – and possibly delirium – while being certain the patient is sufficiently unconscious for
surgery (individualized anesthesia care), and enable continued investigation into the pathophysiology of this
clinically important disorder.

## Key facts

- **NIH application ID:** 10179061
- **Project number:** 3R01AG053582-05S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Oluwaseun Johnson-Akeju
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $626,750
- **Award type:** 3
- **Project period:** 2016-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179061

## Citation

> US National Institutes of Health, RePORTER application 10179061, Pathophysiology of postoperative delirium and the use of biomimetic sleep as a treatment strategy in the CSICU (3R01AG053582-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179061. Licensed CC0.

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