Clinical trial NCT02664831: Immunoinflammatory Response in Post Cardiac Arrest Syndrome (PCAS)
Official title: Immunoinflammatory and Metabolic Responses in Post Cardiac Arrest Syndrome (PCAS)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cardiac Arrest
Inflammation
Obesity
Keywords: cardiac arrest
inflammation
immune
neuregulin
lymphocyte
neutrophil
brown adipose
Lead sponsor: MaineHealth
Sponsor class: OTHER
Collaborators: name: National Institute of General Medical Sciences (NIGMS)
First posted: 2016-01-27
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Cardiac arrest survivors with encephalopathy admitted to the intensive care unit and unresponsive after resuscitation

Brief summary: This is a prospective, observational study to investigate molecular mechanisms mediating the systemic inflammatory process, and changes to metabolism, and their impact on brain injury, survival, and functional outcomes after cardiac arrest. Investigators have shown that cardiac arrest induces changes in the numbers and properties of circulating immune cells, shifting the balance towards a pro-inflammatory phenotype and there is increased interest in the inflammatory pathways and the signaling mechanisms through which they are modulated. Participants will undergo blood sampling during 7 days following cardiac arrest, and analyses performed. Patient characteristics, clinical circumstances, and outcomes will be recorded and their associations with these inflammatory pathways characterized.

Detailed description: Preliminary evidence indicates that inter-individual variables such as immune cell activity and the production of pro-inflammatory factors may differentiate patients with the highest risk of poor neurological outcome, and may reveal novel therapeutic approaches based on promoting molecular pathways of inflammation-resolution and recovery to reduce the severity of hypoxic ischemic encephalopathy (HIE). Additionally, there are intrinsic, modifiable metabolic factors, such as the presence and metabolic activity of brown adipose tissue (BAT) that may modulate injury and recovery.

Comparative analysis showed that cardiac arrest survivors have more CD73+ lymphocytes compared to non-survivors. CD73 is the key enzyme in the generation of anti-inflammatory and immunosuppressive adenosine. We have also identified novel populations of neutrophils (CD14posCD16low and DEspR+) that had amplified response to inflammatory stimuli. The investigators hypothesize that individual variability in the expression and signaling profiles of white blood cells (lymphocytes, neutrophils, monocytes and macrophages) following resuscitation affects inflammation and is independently associated with neurological outcome. To test this hypothesis, investigators will determine levels of various immune cell populations at different time points in peripheral blood of patients. Characterization of blood circulating factors, clinical phenotypes, and neurological outcomes after cardiac arrest is a second aim of this project, with a focus on understanding the heterogeneity of cellular and humoral immune responses and how they relate to different clinical phenotypes of post-resuscitation syndrome.

PCAS metabolism:

IT is known that hyperglycemia is an independent risk factor for poor outcome after cardiac arrest, but it is not known if modification of hyperglycemia reduces this risk. Published studies have not demonstrated benefit with intensive insulin therapy. Our preliminary data suggest correlation between brown adipose tissue activity and good outcome. We have postulated that BAT may be activated by therapeutic hypothermia and may act as a glucose sink reducing the oxidative stress caused by hyperglycemia, and secondarily reducing injury to the brain, heart, and other organs.

In these studies we will also investigate other actionable targets for new therapies.

Eligibility criteria: Inclusion Criteria:

* Aged 18 years or older
* Admitted to the intensive care unit after cardiac arrest episode
* Unresponsive after resuscitation

Exclusion Criteria:

* Moribund / actively dying at the time of evaluation
* Informed consent cannot be obtained within 24 hours of resuscitation
* Hemoglobin less than 7.0 g/dL, active high-volume bleeding, or requiring a transfusion

Primary outcomes:
measure: Correlations between inflammatory markers and clinical outcomes
timeFrame: 14 days
measure: Correlations between inflammatory markers and biomarkers of neurological and cardiac injury
timeFrame: 7 days
Secondary outcomes:
measure: Characterization of post-resuscitation inflammatory mechanisms and their regulators
timeFrame: 7 days
Other outcomes:
Locations:
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
Study officials:
affiliation: MaineHealth Institute for Research
name: Sergey Ryzhov, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: MaineHealth
name: David B Seder, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: deKay JT, Chepurko E, Chepurko V, Knudsen L, Lord C, Searight M, Tsibulnikov S, Robich MP, Sawyer DB, Gagnon DJ, May T, Riker R, Seder DB, Ryzhov S. Delayed CCL23 response is associated with poor outcomes after cardiac arrest. Cytokine. 2024 Apr;176:156536. doi: 10.1016/j.cyto.2024.156536. Epub 2024 Feb 6.
citation: Ryzhov S, May T, Dziodzio J, Emery IF, Lucas FL, Leclerc A, McCrum B, Lord C, Eldridge A, Robich MP, Ichinose F, Sawyer DB, Riker R, Seder DB. Number of Circulating CD 73-Expressing Lymphocytes Correlates With Survival After Cardiac Arrest. J Am Heart Assoc. 2019 Jul 2;8(13):e010874. doi: 10.1161/JAHA.118.010874. Epub 2019 Jun 25.