Palmitoylethanolamide/Luteolin Supplementation in Older Adults Undergoing Cardiac Surgery

Palmitoylethanolamide/Luteolin for the Maintenance of Cognitive Performance in Older Adults Undergoing Cardiac Surgery

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Cognitive Dysfunction
• Intervention / Treatment: Other: Standard of Care; Dietary supplement: co-ultramicronized Palmitoylethanolamide + Luteolin (700 mg + 70 mg in 10 ml)

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Giuseppe Bellelli; Phone Number: +39 039 233 3472; Email: giuseppe.bellelli@unimib.it

Study Locations

• Italy
  • Monza, Italy
    • Fondazione IRCCS San Gerardo dei Tintori
    • Contact: Clinical Office; Email: ricerca.clinica@irccs-sangerardo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PEALut® + Standard of Care; Participants receive co-ultramicronized Palmitoylethanolamide + Luteolin (700 mg + 70 mg in 10 ml) in addition to Standard of Care	Other: Standard of Care; Standard of Care; Dietary supplement: co-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; Other Names: Glialia® oral suspension; PEALut® oral suspension
Active Comparator: Standard of Care; Participants receive only the Standard of Care	Other: Standard of Care; Standard of Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive performance	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.	Baseline, hospital discharge (approximately postoperative day 7-10, depending on clinical course), 3 months after treatment, and 3 months after the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Postoperative Cognitive Dysfunction (POCD)	Incidence of POCD will be defined as a decrease of at least 1 standard deviation from baseline MoCA score.	Hospital discharge (approximately postoperative day 7-10, depending on clinical course), and 3 months after treatment
Incidence, subtype and duration of postoperative delirium (POD)	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.	Daily, from 24 hours after the intervention until hospital discharge (approximately postoperative day 7-10, depending on clinical course)
Change in Activities of Daily Living (ADL)	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.	Baseline, 3 months after treatment, and 3 months after the end of treatment
Change in Instrumental Activities of Daily Living (IADL)	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.	Baseline, 3 months after treatment, and 3 months after the end of treatment
Change in Short Physical Performance Battery (SPPB)	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.	Baseline, 3 months after treatment, and 3 months after the end of treatment
Change in Handgrip Strength	Muscle strength will be assessed using a handgrip dynamometer. Handgrip strength will be recorded in kilograms (kg), with higher values indicating greater muscle strength.	Baseline, 3 months after treatment, and 3 months after the end of treatment
Rehospitalization	Incidence of rehospitalization	From 24 hours after the intervention to 6 months after randomization
Mortality	Incidence of mortality	From 24 hours after the intervention to 6 months after randomization
Incidence of Treatment-Related Adverse Events	Safety and Adherence assessment will be assessed by monitoring the incidence and severity of adverse events occurring during the study period.	From first treatment administration up to 3 months after the end of treatment
Plasma p-tau217 levels	Plasma levels of phosphorylated tau (p-tau217) will be measured in blood samples using standard clinical laboratory assays.	Baseline
Plasma Aβ42 levels	Plasma levels of Amyloid beta 42 (Aβ42) will be measured in blood samples using standard clinical laboratory assays.	Baseline
Change in plasma IL-6 levels	Plasma levels of Interleukin-6 (IL-6) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma s-RAGE levels	Plasma levels of soluble Receptor for Advanced Glycation End-products (s-RAGE) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma GDF-15 levels	Plasma levels of Growth Differentiation Factor-15 (GDF-15) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma GFAP levels	Plasma levels of Glial Fibrillary Acidic Protein (GFAP) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma NSE levels	Plasma levels of Neuron-Specific Enolase (NSE) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma NfL levels	Plasma levels of Neurofilament Light Chain (NfL) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma FGF-1 levels	Plasma levels of Fibroblast Growth Factor-1 (FGF-1) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment
Change in plasma BDNF levels	Plasma levels of Brain-Derived Neurotrophic Factor (BDNF) will be measured in blood samples using standard clinical laboratory assays.	Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment

Collaborators and Investigators

• Sponsor: Fondazione IRCCS San Gerardo dei Tintori
• Investigators: Principal Investigator: Giuseppe Bellelli, School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

Publications and helpful links

General Publications

• Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci. 2021 May 18;22(10):5305. doi: 10.3390/ijms22105305.
• Suraarunsumrit P, Srinonprasert V, Kongmalai T, Suratewat S, Chaikledkaew U, Rattanasiri S, McKay G, Attia J, Thakkinstian A. Outcomes associated with postoperative cognitive dysfunction: a systematic review and meta-analysis. Age Ageing. 2024 Jul 2;53(7):afae160. doi: 10.1093/ageing/afae160.
• Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. doi: 10.1016/s0140-6736(97)07382-0.
• Savageau JA, Stanton BA, Jenkins CD, Frater RW. Neuropsychological dysfunction following elective cardiac operation. II. A six-month reassessment. J Thorac Cardiovasc Surg. 1982 Oct;84(4):595-600.
• Zhang L, Qiu Y, Zhang ZF, Zhao YF, Ding YM. Current perspectives on postoperative cognitive dysfunction in geriatric patients: insights from clinical practice. Front Med (Lausanne). 2024 Sep 27;11:1466681. doi: 10.3389/fmed.2024.1466681. eCollection 2024.
• Nobili S, Micheli L, Lucarini E, Toti A, Ghelardini C, Di Cesare Mannelli L. Ultramicronized N-palmitoylethanolamine associated with analgesics: Effects against persistent pain. Pharmacol Ther. 2024 Jun;258:108649. doi: 10.1016/j.pharmthera.2024.108649. Epub 2024 Apr 12.
• Colizzi M, Bortoletto R, Colli C, Bonomo E, Pagliaro D, Maso E, Di Gennaro G, Balestrieri M. Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence. Front Psychiatry. 2022 Oct 28;13:1038122. doi: 10.3389/fpsyt.2022.1038122. eCollection 2022.
• Caltagirone C, Cisari C, Schievano C, Di Paola R, Cordaro M, Bruschetta G, Esposito E, Cuzzocrea S; Stroke Study Group. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man. Transl Stroke Res. 2016 Feb;7(1):54-69. doi: 10.1007/s12975-015-0440-8. Epub 2015 Dec 26.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 11, 2026
• First Submitted That Met QC Criteria: June 26, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Neuroinflammation; Cognitive Impairment; Cardiac Surgery; Postoperative Cognitive Dysfunction; Palmitoylethanolamide; Luteolin
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Neurocognitive Disorders; Inflammation; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Postoperative Cognitive Complications; Neuroinflammatory Diseases; Cognitive Dysfunction; Health Services Administration; Health Care Quality, Access, and Evaluation; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Quality of Health Care; Quality Indicators, Health Care; Benzopyrans; Flavonoids; Chromones; Flavones; Standard of Care; Luteolin
• Other Study ID Numbers: PEGASUS COG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No