IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 10863 
Small font sizeDefault font sizeIncrease font size
Navigate Here
Resource Links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (543 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)

In This Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Tables

 Article Access Statistics
    PDF Downloaded20    
    Comments [Add]    

Recommend this journal


 Table of Contents    
Year : 2023  |  Volume : 55  |  Issue : 4  |  Page : 223-228

Citicoline on the Barthel Index: Severe and moderate brain injury

1 Department of Neurosurgery, School of Medicine, Neurosciences Research Center, Kashani Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Neurosurgery, School of Medicine, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Neurosurgery, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of IT, Shahid Beheshti University, Tehran, Iran

Date of Submission19-Jul-2021
Date of Decision26-Jul-2023
Date of Acceptance08-Aug-2023
Date of Web Publication11-Sep-2023

Correspondence Address:
Mohammadreza Hasas
Department of Neurosurgery, Isfahan University of Medical Sciences, Isfahan
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijp.ijp_570_21

Rights and Permissions

 » Abstract 

INTRODUCTION: Traumatic brain injury (TBI) is a paramount factor in mortality and morbidity. The clinical trials conducted to investigate the efficacy of neuroprotective agents, such as citicoline, as a therapeutic alternative for TBI have presented divergent findings. Therefore, this study aimed to evaluate and compare citicoline's effect on the Barthel Index in patients with severe and moderate brain injury.
MATERIALS AND METHODS: The study is a randomized clinical trial. Patients in the case group (35 patients) were treated with citicoline and the control group (34 patients) received a placebo. Data were analyzed using SPSS 16 software.
RESULTS: The results showed that changes in the Glasgow Coma Scale, changes in quadriceps muscle force score, Barthel Index score changes, achieving the status without intubation, and spontaneous breathing in patients treated with citicoline were not a statistically significant difference in the two groups (P > 0.05).
CONCLUSION: Findings revealed that citicoline did not impact the recovery process of severe and moderate TBI patients.

Keywords: Barthel Index, brain injury, citicoline, trauma

How to cite this article:
Mahmoodkhani M, Aminmansour B, Shafiei M, Hasas M, Tehrani DS. Citicoline on the Barthel Index: Severe and moderate brain injury. Indian J Pharmacol 2023;55:223-8

How to cite this URL:
Mahmoodkhani M, Aminmansour B, Shafiei M, Hasas M, Tehrani DS. Citicoline on the Barthel Index: Severe and moderate brain injury. Indian J Pharmacol [serial online] 2023 [cited 2023 Sep 24];55:223-8. Available from: https://www.ijp-online.com/text.asp?2023/55/4/223/385499

 » Introduction Top

Traumatic brain injury (TBI) is a significant cause of disability and death, primarily affecting young individuals.[1],[2],[3] The prevalence of TBI is about 558 people per 100,000 people and is estimated to cause the death of more than 50,000 people per year and the disability of 33 people per 100,000 people per year.[1] It is important to note that most people, who survive TBI, often develop some degree of cognitive, behavioral, and communication disorders.[4] The leading causes of TBI are road accidents, sports, falls, work-related accidents, and physical quarrels, including bullet wounds and cold steel.[5] The Glasgow Coma scale (GCS) score ranges from 3 to 15.[6]

Because nerve tissue, like some other tissues, does not have the power to repair itself spontaneously. Moreover, the damage remains irreversible for the rest of a person's life; therefore, treatment plans for nerve tissue damage have focused on stopping secondary damage by removing free radicals from the environment. Due to the high prevalence of injury and its complications, the need for treatment to reduce its severity is critical. Medication is one of the strategies to reduce the severity of damage to the brain. For this purpose, citicoline has been used in previous studies. Citicoline has protective properties on the brain.[7]

Adenosine triphosphate (ATP) is primarily responsible for maintaining the cell's sodium–potassium membrane pump's function. TBI causes the cell membrane to lose its integrity and excess fluid to accumulate in the extracellular space, leading to cerebral edema and lipid peroxidation. Cholinergic drugs such as citicoline affect cellular oxygenation and ATP production, indirectly affecting cell membrane integrity and reducing cell membrane damage.[8],[9],[10] Citicoline, also known as cytidinediphosphocholine (CDP-Cho), is a substance available in oral and enteral formulations, commercially offered as sodium salt and inner salt. On ingestion or injection, citicoline undergoes rapid hydrolysis and dephosphorylation, resulting in the production of cytidine and choline. These components are then utilized to resynthesize CDP–choline within brain cells.[11]

Multiple investigations have exhibited the dependability and authenticity of the Barthel Index and Functional Independence Measure gauges, primarily in inpatient rehabilitation environments.[9],[10] Citicoline exhibits a favorable side-effect profile in humans, and studies suggest its potential benefits in stroke and dementia.[12],[13],[14] However, treatment strategies for TBI involving neuroprotective agents, such as citicoline, lack conclusive evidence or yield conflicting results in studies. Therefore, given the high prevalence of TBI and the significance of preventing secondary injuries,[15] the present study aimed to investigate and compare the effect of citicoline on the Barthel Index of patients with severe and moderate brain injuries.

 » Materials and Methods Top

Study design and participant

The study is a double-blind randomized clinical trial conducted in 2020. The current investigation's focus cohort was composed of individuals who suffered from severe and moderate TBI and were referred to Kashani Hospital in Isfahan, Iran, within the initial quarter of 2020. Diagnosis of severe and moderate brain injury is through the decreased level of consciousness for more than 6 h and GCS 3–12 and severe concussion.[13]

Sampling method and sample size

Patients were randomly divided into two groups (case and control) using the Random Allocation Software. The required number of samples based on the following formula, at least 32 people in each group, was obtained. According to the probability of a 20% drop from the beginning, 40 people in each group were selected.

Case group (35 patients): Citicoline 2000 mg twice a day for 2 weeks orally.

Control group (34 patients): Placebo twice a day for 2 weeks.

Z1: 1.96, Z2: 0.84, S: 0.5, d: 1.34.

Inclusion criteria and exclusion criteria

Inclusion criteria are patients based on GCS <12; patients should be without primary traumatic lesions in the thorax, abdomen, and limbs, without heart problems. Exclusion criteria include no previous history of brain injury; stroke or neurological disease; contraindication or hypersensitivity to citicoline; presence of comorbidities such as cardiovascular, renal, and hepatic disease; history of malignancy; penetrating injury brain; unstable hemodynamics; major trauma to the thorax, abdomen, and limbs; pregnancy; surgical interventions; and cardiopulmonary resuscitation performed during the first 24 h after trauma, patient reluctance to enter the study and his death while studying.

Data collection

First, demographic information, including age, sex, and mechanism of impact, was examined and recorded. The patient's state of consciousness score was then compared and recorded based on the comparison of GCS, muscle strength of four patient limbs, and Barthel Index score for patients at the time of admission to the emergency department. Patients were assessed again according to the stated criteria, 1 month, 3 months, and 6 months after injury, and the results were recorded.

Data analysis

The data were gathered through the employment of a checklist on the IBM SPSS Statistics for Windows, version 16 (IBM Corp., Armonk, N.Y., USA) and were scrutinized at a significance level of under 0.05. The findings were exhibited as frequency (percentage) or mean ± standard deviation. The variables were juxtaposed utilizing independent t-tests, Mann–Whitney, and Chi-square tests.

 » Results Top

In the present study, 75% were male (n = 52) and 25% were female (n = 17). Comparing the demographic characteristics between the case and control groups, 71% (n = 25) of patients treated with citicoline and 79% (n = 27) of patients in the control group were male [Table 1].
Table 1: Comparison of baseline characteristics of patients with severe and moderate traumatic brain injury

Click here to view

The mean age of patients was 33.75 ± 1589 (95% confidence interval [CI]: 29.94–37.57). The age distribution was similar in the two study groups [Table 1]. The mean BMI of equivalent patients was 24.88 ± 2.79 kg/m2. It was noted that there existed no substantial discrepancy between the two cohorts (P = 0.884). Accident (76.5%; n = 53) and fall (14.5%; n = 10), respectively, were the cause of most brain injuries in the patients under study [Table 1].

The number of hospitalization days in the case group was, on average, 1.27 days shorter than the control group. The average number of hospitalization days in the case group was 7.67 ± 5.34 (95% CI: 4.71–10.62) days and in the control group, 8.94 ± 8.72 (95% CI: 4.29–13.59) days [Table 1].

It must be noted that in case and control groups, 25 (71.4%) and 22 (64.7%) patients had moderate trauma, respectively. Patients with moderate and severe trauma were evaluated in two groups [Table 1].

The mean GCS at the time of admission was 9.64 ± 2.40 (95% CI: 9.06–10.22), and similarly, no noteworthy dissimilarity was observed between the two experimental cohorts [P = 0.540, [Table 2]]. After 6 months, the mean GCS of patients was equal to 13.23 ± 3.24 (95% CI: 12.45–14.01). Examination of GCS changes in the two study groups using repeated measures test showed that the interaction between time and group was not statistically significant (P = 0.252); however, there was a statistically significant time trend in GSC improvement (P < 0.001). In addition, it was observed that the alterations in GCS among individuals subjected to citicoline treatment did not demonstrate any noteworthy deviation from the changes observed in the control cohort (P = 0.995).
Table 2: Comparison of the Glasgow Coma Scale, four-limb muscle force scores, and Barthel Index score of patients with severe and moderate traumatic brain injury in the case and control groups

Click here to view

The mean score of quadriceps muscle force at the time of admission was 3.12 ± 0.79 (95% CI: 2.92–3.31), and there was no statistically significant difference between the two study groups (P < 0.05). The mean score of muscle force in patients' four limbs after 6 months was equal to 4.59 ± 0.90 (95% CI: 4.38–4.81) [Table 2]. There was a statistically significant time trend in improving the four limbs' muscle force score (P = 0.001).

In terms of the Barthel Index score, the mean score at the beginning was 30 ± 22.19 (95% CI: 24.67–35.33). The mean Barthel score at the admission time in patients treated with citicoline was not statistically significantly different from the control group (P = 0.670). The mean Barthel Index of patients after 6 months was equal to 81.73 ± 33.61 (95% CI: 73.66–89.81) [Table 2]. Furthermore, the Barthel Index score changes in the two study groups using repeated measures test showed that the interaction between time and the group was not statistically significant (P = 0.758). However, there was a statistically significant time trend in improving the Barthel Index (P < 0.001). Besides, the Barthel Index score changes in the two groups' patients were not statistically significantly different (P = 0.972).

Respiratory status was 20% (n = 14) of patients after 1 month and 12% (n = 8) after 3 months [Table 3]. The results of the Kaplan–Meyer test showed that the meantime to spontaneous respiration for patients in the case group was 2 months after admission (95% CI: 1.28–2.76), and in the control group, it was similar and equivalent to 2 months after admission time (95% CI: 1.31–2.80) (P = 0.923).
Table 3: Comparison of spontaneous respiratory status of patients with severe and moderate traumatic brain injury in the case and control groups

Click here to view

In terms of intubation status (n = 44, 64%), patients were tracheostomized (without intubation) at the time of admission to the hospital, and for other patients (n = 25, 36%) after 1 month of tracheostomy (without intubation) was obtained [Table 4]. Kaplan–Meyer test results showed that achieving the status without intubation was not statistically significantly different between the two groups (P = 0.847).
Table 4: Comparison of the frequency of tracheostomy (without intubation) in patients with severe and moderate traumatic brain injury in the case and control groups

Click here to view

Regarding the admission status, 70% (n = 48) of patients were admitted to intensive care units (ICUs). Sixty-two percent (n = 43) of patients were discharged after 1 month, 25% (n = 17) after 3 months, and 13% (n = 8) after 6 months [Table 5]. The meantime to discharge was 3 months in the case group (95% CI: 2.42–3.67) and 3.18 months in the control group (95% CI: 32.53-3.83). There was no tolerance between the two groups (P = 0.665).
Table 5: Comparison of hospitalization status of patients with severe and moderate traumatic brain injury in the case and control groups

Click here to view

 » Discussion Top

Citicoline has consistently demonstrated its efficacy as a neuroprotective and regenerative agent in various neurodegenerative disorders, ischemic brain conditions, and traumatic brain injuries and their consequences.[15] Numerous studies have explored the mechanism of action and citicoline's preclinical and clinical pharmacology.[16],[17],[18],[19] These studies have included promising trials[20],[21],[22],[23],[24] related to TBI and recently published reviews.[25],[26],[27]

In terms of patient outcomes, there were no significant differences in the mean GCS scores between the case and control groups at admission, 1 month, 3 months, and 6 months later. Moreover, the alterations observed in GCS measurements among participants administered with citicoline were not found to be statistically significant compared to those in the control cohort. In a study by Secades,[27] it was reported that using citicoline increased the likelihood of improving patients' consciousness based on the Glasgow Outcome Scale, with no specific side effects observed. However, the present study did not find a significant difference in the state of consciousness between the two groups up to 6 months, which contradicts the findings of Secades.

Regarding muscle strength, there were no significant differences in the mean quadriceps muscle force scores, and changes in muscle force scores in all four limbs between the case and control groups were not significantly different.

Similarly, there were no significant differences in the mean Barthel Index scores between the case and control groups at arrival, 1 month, 3 months, and 6 months later. Furthermore, the Barthel Index scores did not significantly differ between the two groups.

Zafonte et al.[7] conducted a comprehensive investigation on individuals who underwent treatment with citicoline and those assigned to the control group throughout a 90-day follow-up phase. The research revealed no notable contrast in the disease enhancement or the incidence of complications between the two cohorts. These outcomes are in alignment with the contemporary investigation. Agarwal and Patel[28] showed no significant difference between the characteristics of neurological assessment, internal adaptation, and cognitive status of patients between the two groups after treatment. However, in terms of patient performance improvement, the difference between the two groups is significant, and the use of citicoline with odds ratio = 1.18 improves the chances of patients' performance. In contrast, the study by Meshkini et al.[29] concluded that there was insufficient evidence to support citicoline's usefulness in improving patients' neurological status with TBI. However, it has been shown that in patients with previous chronic brain injury, the use of citicoline improves the cognitive status of patients and, in some cases, can help patients in terms of psychological status.

Trimmel et al.'s[15] study showed that using citicoline for TBI patients significantly reduced ICU mortality inhospital mortality and 6-month mortality and an unfavorable outcome.

 » Conclusion Top

The study findings revealed that citicoline did not impact the recovery process of TBI patients, indicating that the treatment with citicoline of TBI patients is limited and requires further research.

Ethical approval

In this study, the medical ethics committee's license was obtained from the medical school; then, the goals, advantages, and possible harms of the present study were explained to the patients and their first-degree companions, and informed consent was obtained from the patients. In cases of patient unconsciousness, informed consent was obtained from the first-degree companion. Clinical Trials code: IRCT20200609047706N1.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Thompson K, Pohlmann-Eden B, Campbell LA, Abel H. Pharmacological treatments for preventing epilepsy following traumatic head injury. Cochrane Database Syst Rev 2015;2015:CD009900.  Back to cited text no. 1
Zeng Y, Zhang Y, Ma J, Xu J. Progesterone for acute traumatic brain injury: A systematic review of randomized controlled trials. PLoS One 2015;10:e0140624.  Back to cited text no. 2
Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Cochrane Database Syst Rev 2012;12:CD004609.  Back to cited text no. 3
Fuentes A, Deotto A, Desrocher M, deVeber G, Westmacott R. Determinants of cognitive outcomes of perinatal and childhood stroke: A review. Child Neuropsychol 2016;22:1-38.  Back to cited text no. 4
Bramlett HM, Dietrich WD. Long-term consequences of traumatic brain injury: Current status of potential mechanisms of injury and neurological outcomes. J Neurotrauma 2015;32:1834-48.  Back to cited text no. 5
Andriessen TM, Jacobs B, Vos PE. Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury. J Cell Mol Med 2010;14:2381-92.  Back to cited text no. 6
Zafonte RD, Bagiella E, Ansel BM, Novack TA, Friedewald WT, Hesdorffer DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline brain injury treatment trial (COBRIT). JAMA 2012;308:1993-2000.  Back to cited text no. 7
Tan HB, Wasiak J, Rosenfeld JV, O'Donohoe TJ, Gruen RL. Citicoline (CDP choline) for traumatic brain injury. Cochrane Database Syst Rev 2014;8:1-7.  Back to cited text no. 8
Houlden H, Edwards M, McNeil J, Greenwood R. Use of the barthel index and the functional independence measure during early inpatient rehabilitation after single incident brain injury. Clin Rehabil 2006;20:153-9.  Back to cited text no. 9
Mahoney FI, Barthel DW. Functional evaluation: The barthel index. Md State Med J 1965;14:61-5.  Back to cited text no. 10
Zafonte R, Friedewald WT, Lee SM, Levin B, Diaz-Arrastia R, Ansel B, et al. The citicoline brain injury treatment (COBRIT) trial: Design and methods. J Neurotrauma 2009;26:2207-16.  Back to cited text no. 11
Taylor-Rowan M, Wilson A, Dawson J, Quinn TJ. Functional assessment for acute stroke trials: Properties, analysis, and application. Front Neurol 2018;9:191.  Back to cited text no. 12
Estrada-Barranco C, Cano-de-la-Cuerda R, Abuín-Porras V, Molina-Rueda F. Postural assessment scale for stroke patients in acute, subacute and chronic stage: A construct validity study. Diagnostics (Basel) 2021;11:365.  Back to cited text no. 13
Wales K, Clemson L, Lannin N, Cameron I. Functional assessments used by occupational therapists with older adults at risk of activity and participation limitations: A systematic review. PLoS One 2016;11:e0147980.  Back to cited text no. 14
Trimmel H, Majdan M, Wodak A, Herzer G, Csomor D, Brazinova A. Citicoline in severe traumatic brain injury: Indications for improved outcome: A retrospective matched pair analysis from 14 Austrian trauma centers. Wien Klin Wochenschr 2018;130:37-44.  Back to cited text no. 15
Secades JJ. Citicoline: Pharmacological and clinical review, 2016 update. Rev Neurol 2016;63:S1-73.  Back to cited text no. 16
Synoradzki K, Grieb P. Citicoline: A superior form of choline? Nutrients 2019;11:1569.  Back to cited text no. 17
Grieb P. Neuroprotective properties of citicoline: Facts, doubts and unresolved issues. CNS Drugs 2014;28:185-93.  Back to cited text no. 18
Ma X, Zhang H, Pan Q, Zhao Y, Chen J, Zhao B, et al. Hypoxia/aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline. PLoS One 2013;8:e82604.  Back to cited text no. 19
Tayebati SK, Amenta F. Choline-containing phospholipids: Relevance to brain functional pathways. Clin Chem Lab Med 2013;51:513-21.  Back to cited text no. 20
Secades JJ. Role of citicoline in the management of traumatic brain injury. Pharmaceuticals (Basel) 2021;14:410.  Back to cited text no. 21
Salehpou F, Shokouhi G, Shakeri M, Shimia M, Mahdkhah A, Baradaran A, et al. Neuroprotective effects of citicoline in diffuse axonal injuries. Adv Biosci Clin Med 2013;1:16-9.  Back to cited text no. 22
Coskun C, Avci B, Ocak N, Yalcin M, Dirican M, Savci V. Effect of repeatedly given CDP-choline on cardiovascular and tissue injury in spinal shock conditions: Investigation of the acute phase. J Pharm Pharmacol 2010;62:497-506.  Back to cited text no. 23
Jasielski P, Piędel F, Piwek M, Rocka A, Petit V, Rejdak K. Application of citicoline in neurological disorders: A systematic review. Nutrients 2020;12:3113.  Back to cited text no. 24
Ilcol YO, Gurun MS, Taga Y, Ulus IH. Choline increases serum insulin in rat when injected intraperitoneally and augments basal and stimulated aceylcholine release from the rat minced pancreas in vitro. Eur J Biochem 2003;270:991-9.  Back to cited text no. 25
Secades JJ. Probably role of citicoline in stroke rehabilitation: Review of the literature. Rev Neurol 2012;54:173-9.  Back to cited text no. 26
Secades J. Citicoline for the treatment of head injury: A systematic review and meta-analysis of controlled clinical trials. J Trauma Treat 2014;4:227.  Back to cited text no. 27
Agarwal S, Patel BM. Is aura around citicoline fading? A systemic review. Indian J Pharmacol 2017;49:4-9.  Back to cited text no. 28
[PUBMED]  [Full text]  
Meshkini A, Meshkini M, Sadeghi-Bazargani H. Citicoline for traumatic brain injury: A systematic review and meta-analysis. J Inj Violence Res 2017;9:41-50.  Back to cited text no. 29


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


Print this article  Email this article


Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer | Privacy Notice
Online since 20th July '04
Published by Wolters Kluwer - Medknow