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

Delirium Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04575753
• Other study ID #: Resolvin-delirium
• Status: Not yet recruiting
• Start date: October 7, 2023
• Est. completion date: May 30, 2024

Study information

• Verified date: October 2022
• Source: Université Libre de Bruxelles
• Contact: Sarah Saxena, MD
• Phone: +3271921211
• Email: sarah.saxena[@]ulb.ac.be
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: May 30, 2024
• Est. primary completion date: May 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Delirium

Intervention

Other:
• Study group
Blood samples will be taken from ICU patients on the day of ICU admission, day 2 and day 5 after ICU admission. Similarly, patients will be subjected to cognitive testing (CAM-ICU) to determine the presence of delirium

Locations

Country	Name	City	State
Belgium	CHU-Charleroi Hopital Civil Marie Curie	Charleroi	Hainaut

Sponsors (2)

Lead Sponsor	Collaborator
Université Libre de Bruxelles	CHU de Charleroi

Country where clinical trial is conducted

Belgium, 

References & Publications (13)

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. — View Citation

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. 20 — View Citation

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. — View Citation

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 F — View Citation

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. Review. — View Citation

Leslie DL, Inouye SK. The importance of delirium: economic and societal costs. J Am Geriatr Soc. 2011 Nov;59 Suppl 2:S241-3. doi: 10.1111/j.1532-5415.2011.03671.x. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Terrando N, Gómez-Galán M, Yang T, Carlström 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. — View Citation

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. — View Citation

Yang T, Xu G, Newton PT, Chagin AS, Mkrtchian S, Carlström 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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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