Palmitoylethanolamide/Luteolin Supplementation in Older Adults Undergoing Cardiac Surgery

Official title

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

Overview

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 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 Standard of Care
  Standard of Care

Primary outcome measures

• Change in cognitive performance [Time frame: 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 (12)

• Incidence of Postoperative Cognitive Dysfunction (POCD) [Time frame: Hospital discharge (approximately postoperative day 7-10, depending on clinical course), and 3 months after treatment]
• Incidence, subtype and duration of postoperative delirium (POD) [Time frame: 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) [Time frame: Baseline, 3 months after treatment, and 3 months after the end of treatment]
• Change in Instrumental Activities of Daily Living (IADL) [Time frame: Baseline, 3 months after treatment, and 3 months after the end of treatment]
• Change in Short Physical Performance Battery (SPPB) [Time frame: Baseline, 3 months after treatment, and 3 months after the end of treatment]
• Change in Handgrip Strength [Time frame: Baseline, 3 months after treatment, and 3 months after the end of treatment]
• Rehospitalization [Time frame: From 24 hours after the intervention to 6 months after randomization]
• Mortality [Time frame: From 24 hours after the intervention to 6 months after randomization]
• Incidence of Treatment-Related Adverse Events [Time frame: From first treatment administration up to 3 months after the end of treatment]
• Plasma p-tau217 levels [Time frame: Baseline]
• Plasma Aβ42 levels [Time frame: Baseline]
• Change in plasma IL-6 levels [Time frame: Baseline, Immediately after surgery (within 24 hours, before PEALut administration), and 3 months after treatment]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Supportive care

Study locations

Italy · 1 center

• Fondazione IRCCS San Gerardo dei Tintori — Monza

Publications

• 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. PMID 6981735
• 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. L PMID 9525362
• 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. PMID 39058915
• 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. PMID 39399113
• 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. PMID 38615798
• 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. PMID 34069940
• 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. PMID 36387000
• 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. PMID 26706245

Identifiers

NCT: NCT07681063 · PEGASUS COG

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗