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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Delirium

Intervention / Treatment
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* Other: Study group


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|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|

What is the study measuring?
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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 |