Cerebrolysin in Critically Ill Patients With Delirium

Summary

Delirium is a severe problem in critically ill patients, and it is associated with increased morbidity, mortality, and extended stay in hospital. The pathophysiology of delirium is multifactorial and still poorly recognized. Several authors proposed different pathomechanisms of delirium. The most likely of these are a metabolic response to cerebral hypoxia/hyperoxia, oxidative stress with excessive reactive oxygen species production, neuroinflammation following general inflammatory response, disorders in neurotransmitters, especially impaired cholinergic and dopaminergic transmissions and dysregulation of tryptophan metabolisms including kynurenine and serotonin/melatonin pathways. The multifactorial pathomechanism of delirium significantly reduces targeted therapy. Due to cerebrolysin properties, it seems reasonable to conclude that this substance is effective in the prevention and treatment of delirium in critically ill patients. Cerebrolysin is commonly used in neurologic patients treated for dementia and Alzheimer's disease. It possesses antioxidative properties, which reduce the severity of post-ischaemic neuronal dysfunction and improve neuronal plasticity. It also increases acetylcholinesterase and butyrylcholinesterase in a dose-dependent manner, improving neuronal plasticity. Additionally, cerebrolysin reduces neuroinflammation and neuronal cell apoptosis by activating toll-like receptor pathways. These properties closely correspond to the pathomechanism of delirium. Therefore, the aim of this study is to analyze the effectiveness of treatment with Cerebrolysin in critically ill patients with delirium. This study enrolls adult critically ill patients. Prior to delirium detection, the Richmond Agitation-Sedation Scale (RASS) is used to assess the level of consciousness. Patients with RASS-4 or -5 were excluded from the analysis, as these disorders of consciousness preclude the determination of the degree of delirium, which is a requisite component of the study. Delirium is detected by the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Additionally, the Montreal Cognitive Assessment Scale is used to detect mild cognitive impairment. The primary endpoint of this study is an analysis of the prevalence and severity of delirium symptoms. The secondary endpoint is an analysis of the duration of delirium.

Timeline

Start

2024-01-01

Primary completion

2025-06-30

Completion

2025-12-31

Publications

• Results Nakanishi N, Liu K, Kawauchi A, Okamura M, Tanaka K, Katayama S, Mitani Y, Ota K, Taito S, Fudeyasu K, Masuka Y, Yoshihiro S, Utsumi S, Nishikimi M, Masuda M, Iida Y, Kawai Y, Hatakeyama J, Hifumi T, Unoki T, Kawakami D, Obata K, Katsukawa H, Sumita H, Morisawa T, Takahashi M, Tsuboi N, Kozu R, Takaki S, Haruna J, Fujinami Y, Nosaka N, Miyamoto K, Nakamura K, Kondo Y, Inoue S, Nishida O. Instruments to assess post-intensive care syndrome assessment: a scoping review and modified Delphi method study. Crit Care. 2023 Nov 7;27(1):430. doi: 10.1186/s13054-023-04681-6.
• Results Smith HA, Gangopadhyay M, Goben CM, Jacobowski NL, Chestnut MH, Savage S, Rutherford MT, Denton D, Thompson JL, Chandrasekhar R, Acton M, Newman J, Noori HP, Terrell MK, Williams SR, Griffith K, Cooper TJ, Ely EW, Fuchs DC, Pandharipande PP. The Preschool Confusion Assessment Method for the ICU: Valid and Reliable Delirium Monitoring for Critically Ill Infants and Children. Crit Care Med. 2016 Mar;44(3):592-600. doi: 10.1097/CCM.0000000000001428.
• Results Landoure G, Sullivan JM, Johnson JO, Munns CH, Shi Y, Diallo O, Gibbs JR, Gaudet R, Ludlow CL, Fischbeck KH, Traynor BJ, Burnett BG, Sumner CJ. Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology. 2012 Jul 10;79(2):192-4. doi: 10.1212/WNL.0b013e31825f04b2. Epub 2012 Jun 6. No abstract available.
• Results Flores IO, Trevino S, Diaz A. Neurotrophic fragments as therapeutic alternatives to ameliorate brain aging. Neural Regen Res. 2023 Jan;18(1):51-56. doi: 10.4103/1673-5374.331867.
• Results Hoel H, Heggelund L, Reikvam DH, Stiksrud B, Ueland T, Michelsen AE, Otterdal K, Muller KE, Lind A, Muller F, Dudman S, Aukrust P, Dyrhol-Riise AM, Holter JC, Troseid M. Elevated markers of gut leakage and inflammasome activation in COVID-19 patients with cardiac involvement. J Intern Med. 2021 Apr;289(4):523-531. doi: 10.1111/joim.13178. Epub 2020 Oct 8.
• Results Sharma S, Raj K, Singh S. Protective effects of cerebrolysin against chemotherapy (carmustine) induced cognitive impairment in Albino mice. Drug Chem Toxicol. 2022 Nov;45(6):2769-2779. doi: 10.1080/01480545.2021.1991195. Epub 2021 Oct 21.
• Results Liu Z, Hu M, Lu P, Wang H, Qi Q, Xu J, Xiao Y, Fan M, Jia Y, Zhang D. Cerebrolysin alleviates cognitive deficits induced by chronic cerebral hypoperfusion by increasing the levels of plasticity-related proteins and decreasing the levels of apoptosis-related proteins in the rat hippocampus. Neurosci Lett. 2017 Jun 9;651:72-78. doi: 10.1016/j.neulet.2017.04.022. Epub 2017 Apr 27.
• Results Kotfis K, Ely EW, Shehabi Y. Intensive care unit delirium-a decade of learning. Lancet Respir Med. 2023 Jul;11(7):584-586. doi: 10.1016/S2213-2600(23)00222-9. No abstract available.
• Results Ottens TH, Hermes C, Page V, Oldham M, Arora R, Bienvenu OJ 3rd, van den Boogaard M, Caplan G, Devlin JW, Friedrich ME, van Gool WA, Hanison J, Hansen HC, Inouye SK, Kamholz B, Kotfis K, Maas MB, MacLullich AMJ, Marcantonio ER, Morandi A, van Munster BC, Muller-Werdan U, Negro A, Neufeld KJ, Nydahl P, Oh ES, Pandharipande P, Radtke FM, Raedt S, Rosenthal LJ, Sanders R, Spies CD, Vardy ERLC, Wijdicks EF, Slooter AJC. The Delphi Delirium Management Algorithms. A practical tool for clinicians, the result of a modified Delphi expert consensus approach. Delirium (Bielef). 2024;2024:10.56392/001c.90652. doi: 10.56392/001c.90652. Epub 2024 Jan 12.
• Results Kotfis K, Maj P, Szylinska A, Pankowiak M, Reszka E, Ely EW, Marra A. The spectrum of psychological disorders in family members of patients suffering from delirium associated with critical illness: a prospective, observational study. Sci Rep. 2024 Feb 24;14(1):4562. doi: 10.1038/s41598-024-53968-3.
• Results Dabrowski W, Siwicka-Gieroba D, Gasinska-Blotniak M, Zaid S, Jezierska M, Pakulski C, Williams Roberson S, Wesley Ely E, Kotfis K. Pathomechanisms of Non-Traumatic Acute Brain Injury in Critically Ill Patients. Medicina (Kaunas). 2020 Sep 13;56(9):469. doi: 10.3390/medicina56090469.
• Results Cui S, Chen N, Yang M, Guo J, Zhou M, Zhu C, He L. Cerebrolysin for vascular dementia. Cochrane Database Syst Rev. 2019 Nov 11;2019(11):CD008900. doi: 10.1002/14651858.CD008900.pub3.
• Results Seidl LF, Aigner L. Comparing the biological activity and composition of Cerebrolysin with other peptide preparations. J Med Life. 2024 Jan;17(1):24-27. doi: 10.25122/jml-2024-0129.
• Results Ulderich Williams SC, Qaddoumi AI, Meghreblian JT, McBride ME, King SA, Elahi MA, Tuggle D, Heidel RE, Smith LM. Incidence and Risk Factors for ICU-Associated Delirium in the Alert Geriatric Trauma Population. Am Surg. 2024 Jul;90(7):1866-1871. doi: 10.1177/00031348241241707. Epub 2024 Mar 23.
• Results Duprey MS, Devlin JW, van der Hoeven JG, Pickkers P, Briesacher BA, Saczynski JS, Griffith JL, van den Boogaard M. Association Between Incident Delirium Treatment With Haloperidol and Mortality in Critically Ill Adults. Crit Care Med. 2021 Aug 1;49(8):1303-1311. doi: 10.1097/CCM.0000000000004976.
• Results Lu W, Zhu Z, Shi D, Li X, Luo J, Liao X. Cerebrolysin alleviates early brain injury after traumatic brain injury by inhibiting neuroinflammation and apoptosis via TLR signaling pathway. Acta Cir Bras. 2022 Sep 5;37(6):e370605. doi: 10.1590/acb370605. eCollection 2022.
• Results Kotfis K, Marra A, Ely EW. ICU delirium - a diagnostic and therapeutic challenge in the intensive care unit. Anaesthesiol Intensive Ther. 2018;50(2):160-167. doi: 10.5603/AIT.a2018.0011. Epub 2018 Jun 8.
• Results Eman G, Marsh A, Gong MN, Hope AA. Utility of Screening for Cognitive Impairment at Hospital Discharge in Adult Survivors of Critical Illness. Am J Crit Care. 2022 Jul 1;31(4):306-314. doi: 10.4037/ajcc2022447.

Drugs

Indications