Evaluating the Role of Pre-existing Resolvins in the Resolution of ICU Delirium

As patient management is improving, more and more ICU survivors are being confronted with cognitive dysfunction and this well after their hospital stay.

In the ICU, delirium rates have been reported to be as high at 81%. Delirium is associated with patient and family stress, increased hospital costs, increased duration of stay, escalation of care and increased mortality and morbidity.

The physiopathology of ICU cognitive impairment is complex and involves an inflammatory cascade Recently, the role of 'resolvins' derived from omega-3 fatty acids has been studied in the resolution of inflammation.

Therefore, this hypothesis of this study is that ICU patients with higher serum levels of resolvins at ICU admission, ICU day 2 and day 5 will have a lesser degree of cognitive impairment on day 5 of ICU stay.

Study Overview

• Status: Withdrawn
• Conditions: Delirium
• Intervention / Treatment: Other: Study group

Detailed Description

As patient management is improving, more and more ICU survivors are being confronted with cognitive dysfunction and this well after their hospital stay.

Delirium is characterized by an acute onset or fluctuating course, inattention and either disorganized thought (manifesting as memory, language and orientation difficulties) or altered level of consciousness. Multiple forms exist: hyperactive versus hypoactive versus mixed.

In the ICU, delirium rates have been reported to be as high at 81%. Delirium is associated with patient and family stress, increased hospital costs, increased duration of stay, escalation of care and increased mortality and morbidity.

The physiopathology of ICU cognitive impairment is complex. One theory is that, during infection/trauma, the alarmin high molecular group box 1 (HMGB1) is released into the bloodstream by activated platelets.

This damage-associated molecular pattern (DAMP) can bind to pattern recognition receptors on circulating bone marrow-derived monocytes (BM-DMs), causing a platelet-monocyte interaction but also triggering the nuclear translocation of the transcription factor NF-kappaB which activates gene expression and release of pro-inflammatory cytokines. The onset of this inflammatory state disrupts the blood brain barrier.

Within the brain parenchyma the chemokine MCP-1 and, by signaling through its receptor, CCR2, attracts the BM-DMs. The influx of BM-DMs activates the resident quiescent microglia. Together, BM-DMs and activated microglia release HMGB1, IL-6, and IL-1β ; thereby disrupting long-term potentiation and the synaptic plasticity involved in cognitive functions of learning and memory.

Inability to successfully resolve the inflammatory cascade promotes the development of cognitive impairment.

Recently, the role of 'resolvins' derived from omega-3 fatty acids has been studied in the resolution of inflammation.

In a mouse model of perioperative neurocognitive disorder, maresin 1 (a metabolite of omega-3) improved post-operative cognition and prevented surgery-induced glial activation and opening of the blood brain barrier. Similarly, in the same model, aspirine-triggered resolving D1 improved post-operative cognition, reduced systemic IL-6 levels and reserved surgery-induced astrogliosis.

Mechanically ventilated ICU patients who benefitted from omega-3 supplements, had a lesser degree of ICU delirium.

Therefore, the hypothesis of this study is that ICU patients with higher serum levels of resolvins at ICU admission, ICU day 2 and day 5 will have a lesser degree of cognitive impairment on day 5 of ICU stay.

• Study Type: Observational

Contacts and Locations

Study Locations

• Belgium
  • Hainaut
    • Charleroi, Hainaut, Belgium
      • CHU-Charleroi Hopital Civil Marie Curie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Non-ventilated, non-sedated adult patients of all genders with a planned ICU stay >72 hours at the CHU de Charleroi, Charleroi, Belgium between October 2020- May 2021 will be included in this study.

Description

Inclusion Criteria:

• Non-ventilated, non-sedated adult patients with a planned ICU stay >72 hours. - - patients admitted due to an exacerbation of COPD
• patients admitted due to severe trauma
• patients admitted due to cardiogenic shock
• patients admitted due to septic shock

Exclusion Criteria:

• Patients who don't understand English, French or Dutch
• Patients who are visually/auditory impaired (without glasses/ hearing aid)
• Patients with known neuro-psychiatric disorders
• Patients with known recreational drug and alcohol (ab)use
• Patients with a neurological trauma
• Patients on ECMO

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The influence of serum levels of resolvins (RvD1) at ICU admission, and ICU day 2 and day 5 on cognitive impairment (defined by CAM-ICU) on day 5 of ICU stay.	Blood samples will be drawn at the day of ICU admission, day 2 and day 5 after ICU admission to measure resolvins (RvD1; 17SHDHA; DHA) through mass spectrometry. At the same timepoints, cognitive testing will be performed (CAM-ICU) to determine the presence or absence of delirium on day 5 of ICU admission.	5 days
The influence of serum levels of resolvins (DHA) at ICU admission, and ICU day 2 and day 5 on cognitive impairment (defined by CAM-ICU) on day 5 of ICU stay.	Blood samples will be drawn at the day of ICU admission, day 2 and day 5 after ICU admission to measure resolvins (RvD1; 17SHDHA; DHA) through mass spectrometry. At the same timepoints, cognitive testing will be performed (CAM-ICU) to determine the presence or absence of delirium on day 5 of ICU admission.	5 days
The influence of serum levels of resolvins (17SHDHA)) at ICU admission, and ICU day 2 and day 5 on cognitive impairment (defined by CAM-ICU) on day 5 of ICU stay.	Blood samples will be drawn at the day of ICU admission, day 2 and day 5 after ICU admission to measure resolvins (RvD1; 17SHDHA; DHA) through mass spectrometry. At the same timepoints, cognitive testing will be performed (CAM-ICU) to determine the presence or absence of delirium on day 5 of ICU admission.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory markers-delirium-day0	The influence of serum levels of CRP (at ICU admission) on cognitive impairment (defined by CAM-ICU) at ICU admission.	1 day
Inflammatory markers-delirium-day0	The influence of serum levels of TNF-alpha (at ICU admission) on cognitive impairment (defined by CAM-ICU) at ICU admission.	1 day
Inflammatory markers-delirium-day0	The influence of serum levels of HMGB1 (at ICU admission) on cognitive impairment (defined by CAM-ICU) at ICU admission.	1 day
Inflammatory markers-delirium-day0	The influence of serum levels of PF4 (at ICU admission) on cognitive impairment (defined by CAM-ICU) at ICU admission.	1 day
Inflammatory markers-delirium-day0	The influence of serum levels of lactate (at ICU admission) on cognitive impairment (defined by CAM-ICU) at ICU admission.	1 day
Inflammatory markers-delirium-day2	The influence of serum levels of CRP (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers-delirium-day2	The influence of serum levels of TNF-alpha (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers-delirium-day2	The influence of serum levels of HMGB1 (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers-delirium-day2	The influence of serum levels of PF4 (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers-delirium-day2	The influence of serum levels of lactate (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers-delirium-day5	The influence of serum levels of CRP (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers-delirium-day5	The influence of serum levels of TNF-alpha (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers-delirium-day5	The influence of serum levels of HMGB1 (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers-delirium-day5	The influence of serum levels of PF4 (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers-delirium-day5	The influence of serum levels of lactate (at ICU admission) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers2-delirium-2	The influence of serum levels of CRP (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers2-delirium-2	The influence of serum levels of TNF-alpha (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers2-delirium-2	The influence of serum levels of HMGB1 (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers2-delirium-2	The influence of serum levels of lactate (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers2-delirium-2	The influence of serum levels of PF4 (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 2.	2 days
Inflammatory markers2-delirium-5	The influence of serum levels of CRP (on day 2) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers5-delirium-5	The influence of serum levels of TNF-alpha (on day 5) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers5-delirium-5	The influence of serum levels of HMGB1 (on day 5) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers5-delirium-5	The influence of serum levels of PF4 (on day 5) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days
Inflammatory markers5-delirium-5	The influence of serum levels of lactate (on day 5) on cognitive impairment (defined by CAM-ICU) on ICU day 5.	5 days

Collaborators and Investigators

• Sponsor: Université Libre de Bruxelles
• Collaborators: CHU de Charleroi
• Investigators: Study Chair: Michael Piagnerelli, MD; PHD, CHU de Charleroi, Belgium

Publications and helpful links

General Publications

• Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001 Jul;29(7):1370-9. doi: 10.1097/00003246-200107000-00012.
• Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010 Sep;68(3):360-8. doi: 10.1002/ana.22082.
• Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, Jonsson Fagerlund M, Charo IF, Akassoglou K, Maze M. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011 Dec;70(6):986-995. doi: 10.1002/ana.22664.
• Vacas S, Degos V, Tracey KJ, Maze M. High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages. Anesthesiology. 2014 May;120(5):1160-7. doi: 10.1097/ALN.0000000000000045.
• Leslie DL, Inouye SK. The importance of delirium: economic and societal costs. J Am Geriatr Soc. 2011 Nov;59 Suppl 2(Suppl 2):S241-3. doi: 10.1111/j.1532-5415.2011.03671.x.
• Rouhiainen A, Imai S, Rauvala H, Parkkinen J. Occurrence of amphoterin (HMG1) as an endogenous protein of human platelets that is exported to the cell surface upon platelet activation. Thromb Haemost. 2000 Dec;84(6):1087-94.
• Hu J, Feng X, Valdearcos M, Lutrin D, Uchida Y, Koliwad SK, Maze M. Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice. Br J Anaesth. 2018 Mar;120(3):537-545. doi: 10.1016/j.bja.2017.11.096. Epub 2018 Feb 3.
• Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight. 2017 Apr 6;2(7):e91229. doi: 10.1172/jci.insight.91229.
• Saxena S, Lai IK, Li R, Maze M. Neuroinflammation is a putative target for the prevention and treatment of perioperative neurocognitive disorders. Br Med Bull. 2019 Jun 19;130(1):125-135. doi: 10.1093/bmb/ldz010.
• Ishihara T, Yoshida M, Arita M. Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis. Int Immunol. 2019 Aug 23;31(9):559-567. doi: 10.1093/intimm/dxz001.
• Yang T, Xu G, Newton PT, Chagin AS, Mkrtchian S, Carlstrom M, Zhang XM, Harris RA, Cooter M, Berger M, Maddipati KR, Akassoglou K, Terrando N. Maresin 1 attenuates neuroinflammation in a mouse model of perioperative neurocognitive disorders. Br J Anaesth. 2019 Mar;122(3):350-360. doi: 10.1016/j.bja.2018.10.062. Epub 2018 Dec 28.
• Terrando N, Gomez-Galan M, Yang T, Carlstrom M, Gustavsson D, Harding RE, Lindskog M, Eriksson LI. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J. 2013 Sep;27(9):3564-71. doi: 10.1096/fj.13-230276. Epub 2013 May 24.
• Naghibi T, Shafigh N, Mazloomzadeh S. Role of omega-3 fatty acids in the prevention of delirium in mechanically ventilated patients. J Res Med Sci. 2020 Jan 20;25:10. doi: 10.4103/jrms.JRMS_567_18. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Estimated): October 7, 2023
• Primary Completion (Estimated): May 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: October 1, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium
• Other Study ID Numbers: Resolvin-delirium

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will be made available, anonymously, if needed

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No