Cerebrolysin in Critically Ill Patients With Delirium

Official title

The Usefulness of Cerebrolysin in Alleviating the Severity of Delirium in Critically Ill Patients

Overview

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.

Detailed description

This is an observational, interventional study. Adult critically ill patients treated with mechanical ventilation due to acute respiratory insufficiency complicating sepsis, septic shock, pneumonia, acute respiratory distress syndrome (ARDS) and polytrauma patients without traumatic brain injury are enrolled to this study. All patients should be treated in accordance with the most up-to date recommendations for the specific disease. None of the patients should be treated with neuroprotective medication before the diagnosis of delirium. Patients are randomized into two groups: CBL - patients treated with cerebrolysin and K - control patients treated without cerebrolysin. Cerebrolysin is administered in a daily dose of 50ml, dissolved in 0.9% NaCl. This mixture is infused for one hour. The treatment is initiated when the delirium is detected and continued for seven consecutive days.

The diagnosis of delirium is based on four principal criteria of the CAM-ICU test: 1/ Sudden onset of disturbance, 2/ Lack of focus of attention, 3/ Altered state of consciousness, and 4/ Disorganised thinking. Of these, criterion feature 2 is regarded as the most crucial in establishing a diagnosis of delirium.

The ICDSC method takes into account eight criteria which include: The ICDSC method considers eight criteria that include: 1/ any disturbance of consciousness (RASS other than 0), 2/ attention deficit disorder, 3/ disorientation, 4/ hallucinations, 5/ psychomotor agitation or retardation, 6/ speech or mood disturbances, 7/ disturbance of sleep-wake cycle, 8/ diurnal variability of symptoms. One point is added for each criterion. A score of 4 points or higher indicates a diagnosis of full-blown delirium, while a score of 1 to 3 points indicates subclinical delirium.

The initial detection of delirium using the CAM-ICU and ICDSC scales is conducted one to three days after the cessation of sedative infusion when the patient's sedation level reaches 3 on the RASS scale. Subsequent follow-up analysis is performed on days 7-8 after the diagnosis of delirium.

The MoCA test is performed in the days 7-8. The MoCA test is assessed using the Geriatric Assessment Tool Kit (https://geriatrictoolkit.missouri.edu) with the following points: 1/ Short term memory, 2/ Visuospatial abilities, 3/ Executive functions, 4/ attention and concentration, 5/ working memory, 6/ language, 7/ Orientation to time and place. A score of 24 points or less is the cut-off for mild cognitive impairment, while 19 points or less for dementia diagnosis.

Interventions

• Drug Cerebrolysin
  Patients were randomized into two groups: CBL - patients treated with cerebrolysin at the daily dose of 50 mL, and K - control patients treated without cerebrolysin. Cerebrolysin was administrated intravenously on the day the delirium was detected and then for seven consecutive days.
• Other Saline Solution - IV
  Patients enrolled in group K received the infusion of 0.9% Saline solution at a volume of 250 mL.

Primary outcome measures

• CAM-ICU test [Time frame: seven days]
• ICDSC test [Time frame: seven days]

Secondary outcome measures (1)

• MoCA test [Time frame: seven days]

Eligibility criteria

Inclusion criteria

• age \> 18,
• symptoms of delirium,
• critical illness treated in Intensive Care Unit

Exclusion criteria

• pregnancy
• traumatic brain injury,
• neuroinflammatory diseases

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

Single blind

Primary purpose

Treatment

Study locations

Poland · 1 center

• First Department of Anaesthesiology and Intensive Therapy Medical University of Lublin — Lubin

Publications

• 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. Instrumen PMID 37936249
• 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 PMID 26565631
• 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. PMID 22675077
• 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. PMID 35799508
• 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. PMID 32976665
• 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. PMID 34674598
• 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. PMID 28458021
• 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. PMID 37414511

Identifiers

NCT: NCT06677502 · CEREBDEL · DS352/2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗