Postoperative Cognitive Dysfunction
Conditions
Keywords
Neuroinflammation, Palmitoylethanolamide, Luteolin, Postoperative Cognitive Dysfunction, Cardiac Surgery, Cognitive Impairment
Brief summary
Postoperative Cognitive Dysfunction (POCD) is a common complication after surgery, particularly among older adults. It is characterized by cognitive impairment, reduced functional independence, and decreased quality of life. Growing evidence suggests that neuroinflammation plays a relevant role in POCD development and persistence. Palmitoylethanolamide (PEA) is an endogenous lipid mediator involved in the regulation of neuroinflammatory processes through the modulation of non-neuronal cells, while luteolin is a flavonoid with well-known antioxidant properties. Under conditions of prolonged neuroinflammation, endogenous PEA levels may be insufficient to adequately counteract pro-inflammatory signaling, making exogenous administration necessary. In this context, exogenous micronized and ultramicronized PEA (mPEA and umPEA) supplementation has been shown to modulate cognitive and executive functions, working memory, language, and activities of daily living. Moreover, the combination of umPEA and luteolin (PEALut) may produce synergistic effects by modulating neuroinflammation and supporting neuronal function. This study aims to evaluate whether postoperative administration of co-ultramicronized PEA and luteolin (700 mg + 70 mg in 10 mL), added to standard of care, may contribute to the mitigation of POCD in older adults undergoing elective cardiac surgery, compared to standard care alone.
Interventions
DIETARY_SUPPLEMENTco-ultramicronized Palmitoylethanolamide + Luteolin (700 mg + 70 mg in 10 ml)
Oral suspension, 10 ml twice daily (every 12 hours), starting within 24 hours post-surgery and for 3 months, in add-on to the Standard of Care
OTHERStandard of Care
Standard of Care
Sponsors
Fondazione IRCCS San Gerardo dei Tintori
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 65 years * Both genders * Undergoing elective aortic or mitral valve replacement/reconstruction with or without coronary artery bypass grafting (CABG), at the Cardiac Surgery Unit of IRCCS San Gerardo dei Tintori Foundation (Monza, Italy) * Prognosis quoad vitam ≥ 3 months * Availability of a formal or informal caregiver who can assist the participant in taking the prescribed dose and following the visit schedule * Any concomitant therapy should be stable * Written informed consent obtained prior to randomization (from the participant or caregiver if the participant is unable to sign but clearly expresses the will to participate)
Exclusion criteria
* Severe dementia diagnosis * Preoperative clinical diagnosis of delirium * Other treatments/medications that may improve cognition * Current treatment with m/umPEA or PEALut (Glialia®), or its use within 90 days prior to enrollment * Contraindications to the use of PEALut, including allergy to excipients contained in the supplement and previous adverse reactions to PEALut * Other clinical conditions or situations that could interfere with the study or prevent optimal participation, as judged by the researchers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in cognitive performance | Baseline, hospital discharge (approximately postoperative day 7-10, depending on clinical course), 3 months after treatment, and 3 months after the end of treatment | Cognitive performance will be assessed using the Montreal Cognitive Assessment (MoCA), a 30-item screening tool that evaluates multiple cognitive domains, including memory, visuospatial ability, executive function, attention, language, and orientation. Scores range from 0 to 30, with higher scores indicating better cognitive performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma p-tau217 levels | Baseline | Plasma levels of phosphorylated tau (p-tau217) will be measured in blood samples using standard clinical laboratory assays. |
| Plasma Aβ42 levels | Baseline | Plasma levels of Amyloid beta 42 (Aβ42) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma IL-6 levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Interleukin-6 (IL-6) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma s-RAGE levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of soluble Receptor for Advanced Glycation End-products (s-RAGE) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma GDF-15 levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Growth Differentiation Factor-15 (GDF-15) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma GFAP levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Glial Fibrillary Acidic Protein (GFAP) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma NSE levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Neuron-Specific Enolase (NSE) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma NfL levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Neurofilament Light Chain (NfL) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma FGF-1 levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Fibroblast Growth Factor-1 (FGF-1) will be measured in blood samples using standard clinical laboratory assays. |
| Change in plasma BDNF levels | Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment | Plasma levels of Brain-Derived Neurotrophic Factor (BDNF) will be measured in blood samples using standard clinical laboratory assays. |
| Mortality | From 24 hours after the intervention to 6 months after randomization | Incidence of mortality |
| Rehospitalization | From 24 hours after the intervention to 6 months after randomization | Incidence of rehospitalization |
| Incidence of Postoperative Cognitive Dysfunction (POCD) | Hospital discharge (approximately postoperative day 7-10, depending on clinical course), and 3 months after treatment | Incidence of POCD will be defined as a decrease of at least 1 standard deviation from baseline MoCA score. |
| Incidence, subtype and duration of postoperative delirium (POD) | Daily, from 24 hours after the intervention until hospital discharge (approximately postoperative day 7-10, depending on clinical course) | Postoperative delirium will be assessed using the 4AT screening tool. A score of ≥4 suggests possible delirium (with or without cognitive impairment), with higher scores indicating greater severity of cognitive disturbance. Positive screenings will be confirmed using DSM-5 criteria. Delirium subtype will be classified using the Delirium Motor Subtyping Scale-4 (DMSS-4), and duration will be recorded in days from onset to resolution. |
| Change in Activities of Daily Living (ADL) | Baseline, 3 months after treatment, and 3 months after the end of treatment | Activities of daily living will be assessed using the six-item Katz Activities of Daily Living (ADL) Index. Scores range from 0 to 6, with higher values indicating greater function. |
| Change in Instrumental Activities of Daily Living (IADL) | Baseline, 3 months after treatment, and 3 months after the end of treatment | Functional status will be assessed using the Instrumental Activities of Daily Living (IADL) scale. Scores range from 0 to 8, with higher scores indicating better functional ability. |
| Change in Short Physical Performance Battery (SPPB) | Baseline, 3 months after treatment, and 3 months after the end of treatment | Physical performance will be assessed using the Short Physical Performance Battery (SPPB), which evaluates balance, gait speed, and chair stand performance. Scores range from 0 to 12, with higher scores indicating better physical performance. |
| Incidence of Treatment-Related Adverse Events | From first treatment administration up to 3 months after the end of treatment | Safety and Adherence assessment will be assessed by monitoring the incidence and severity of adverse events occurring during the study period. |
| Change in Handgrip Strength | Baseline, 3 months after treatment, and 3 months after the end of treatment | Muscle strength will be assessed using a handgrip dynamometer. Handgrip strength will be recorded in kilograms (kg), with higher values indicating greater muscle strength. |
Countries
Italy
Contacts
CONTACTGiuseppe Bellelli
PRINCIPAL_INVESTIGATORGiuseppe Bellelli
School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
Outcome results
None listed