# Neurocognitive Impairment in Acute Respiratory Failure  and Shock: Understanding the Role of Neuronal Excitotoxicity

> **NIH NIH K23** · UNIVERSITY OF PENNSYLVANIA · 2021 · $195,696

## Abstract

Project Summary
Cardiopulmonary failure due to acute respiratory failure or shock is the most common syndrome necessitating
intensive care unit services. Patients with cardiopulmonary failure often develop burdensome neurocognitive
sequelae that threaten both short and long-term outcomes. In the short-term, these patients frequently develop
delirium, a severe alteration in attention and cognition that is associated with increased mortality as well as
longer durations of mechanical ventilation and ICU stay. After recovering, 1 in 4 survivors suffer long-term
cognitive impairment (LTCI) similar to dementia. Despite the impact delirium and LTCI have on these patients,
there are currently no proven pharmacologic therapies aimed at preventing these neurocognitive sequelae.
Sepsis accounts for over 1 million hospitalizations per year and is the most common cause of cardiopulmonary
failure, making it an ideal population to investigate the underlying mechanisms of delirium and LTCI. Our group
and others have shown that delirium and LTCI are characterized by injury to the hippocampus and frontal
cortex. Animal models show a similar pattern of neuronal injury, and implicate alterations in glutamate
homeostasis and kynurenine metabolism as key downstream pathways of neuronal injury that can be
therapeutically targeted. However, a lack of data on these pathways in humans and an inability to identify
which patients would most likely benefit from early therapy are key knowledge gaps limiting the translation of
these findings to clinical trials. To address these knowledge gaps, this proposal will investigate the role of
glutamate and kynurenine dysregulation in an ongoing cohort of septic patients with cardiopulmonary failure
who are followed prospectively for delirium and subsequent cognitive impairment. In addition to the proposed
research, the candidate will engage in a rigorous training program designed to support his transition into an
independent scientist. The specific objectives of this proposal are to: 1) determine the association of glutamate
and kynurenine dysregulation with delirium and cognitive impairment in septic patients with cardiopulmonary
failure, 2) identify risk factors for cognitive impairment and develop a predictive tool that could be used to guide
enrollment in future clinical trials, 3) train the candidate in cognitive neuroscience, mechanisms of neuronal
injury and repair, cohort study design and conduct, molecular laboratory techniques and advanced statistics,
and 4) provide the candidate with individualized mentoring to support his transition to independence. The
candidate's attainment of specific research and training benchmarks will be regularly reviewed by his mentors
and advisory committee. Through completion of this proposal, the candidate will enhance our understanding of
the underlying mechanisms of delirium and LTCI in these patients, and position himself to successfully
compete for R01 funding of future projects aimed at t...

## Key facts

- **NIH application ID:** 10134407
- **Project number:** 5K23HL140482-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Brian J. Anderson
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,696
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134407

## Citation

> US National Institutes of Health, RePORTER application 10134407, Neurocognitive Impairment in Acute Respiratory Failure  and Shock: Understanding the Role of Neuronal Excitotoxicity (5K23HL140482-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134407. Licensed CC0.

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