Citicoline for traumatic brain injury: a systematic review & meta-analysis

Abstract: Background: Traumatic Brain Injury (TBI) is the leading cause of mortality and morbidity especially in young ages. Despite over 30 years of using Neuroprotective agents for TBI management, there is no absolute recommended agent for the condition yet. Methods: This study is a part of a scoping review thesis on "Neuroprotective agents using for Traumatic Brain Injury: a systematic review & meta-analyses", which had a wide proposal keywords and ran in "Cochrane CENTRAL", "MedLine/PubMed", "SCOPUS", "Thomson Reuters Web of Science", "SID.ir", "Barket Foundation", and "clinicaltrials.gov" databases up to September 06, 2015. This study limits the retrieved search results only to those which used \citicoline for TBI management. The included Randomized Clinical Trials’ (RCTs) were assessed for their quality of reporting by adapting CONSORT-checklist prior to extracting their data into meta-analysis. Meta-analyses of this review were conducted by Glasgow Outcome Scale (GOS) in acute TBI patients and total neuropsychological assessments in both acute and chronic TBI management, mortalities and adverse-effects. Results: Four RCTs were retrieved and included in this review with 1196 participants (10 were chronic TBI impaired patients); the analysis of 1128 patients for their favorable GOS outcomes in two studies showed no significant difference between the study groups; however, neuropsychological outcomes were significantly better in placebo/control group of 971 patients of three studies. Mortality rates and adverse-effects analysis based on two studies with 1429 patients showed no significant difference between the study groups. However, two other studies have neither mortality nor adverse effects reports due to their protocol. Conclusions: Citicoline use for acute TBI seems to have no field of support anymore, whereas it may have some benefits in improving the neuro-cognitive state in chronic TBI patients. It’s also recommended to keep in mind acute interventions like Psychological First Aid (PFA) during acute TBI management.

Introduction raumatic Brain Injury (TBI), also known as Head Injury, 1-3 is the leading cause of mortality and morbidity 1,4-6 and mostly affects young people. 1 It has an incidence ratio of 558 new cases per 100,000 people each year with more than 50,000 mortalities, it's also estimated to cause 33 new disabilities per 100,000 people in a year; and to cost more than $48 billion a year. About 2.5 to 6.5 million Americans have experienced a TBI event through their life. 1,4 It is important to mention that "Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities". 7 Adenosine Tri-Phosphate (ATP) is responsible for Cell Membrane Sodium-Potassium (Na-K) ATPase Pump's Function. TBI related cell membrane un-integrity and accumulation of extracellular water lead to the brain edema and formation of lipid peroxidase. Cholinergic agents (e.g. Citicoline) have effects on cell-oxygenation cycles and formation of ATP, which may indirectly rebuild cell wall integrity, reducing further secondary injuries. 8

Study Design
This is a systematic review and meta-analysis of RCTs.

Search Strategy and Inclusion Criteria
This study is a part of a scoping review thesis on "Neuroprotective agents using for traumatic brain injury: a systematic review & meta-analyses" whose search strategy was not restricted by date, race, gender, and publication status; however, date limitation to the reference databases (i.e. SCOPUS and Thomson Reuters Web of Science) was implemented for studies after 2000.
The "Cochrane CENTRAL", "Medline through PUBMED", "SCOPUS", "Thomson Reuters Web of Science", "SID.ir", "Barekat Knowledge Deployment Foundation (formerly known as IRAN-MEDEX)" and "clinicaltrials.gov" databases were searched by September 06, 2015 (appendices 1-7, present the full search strategies). Other related articles not retrieved from database search results were also included. These were related articles encountered during internet search process for full-text articles, full-text requests through www.researchgate.net; skimming bibliographies of articles and contacting experts in the field. Study's PICO design could be summarized as following:  Patients of any age, and with any severity (mild, moderate, severe) of focal or diffuse, acute or chronic TBI. Animal studies or pre-clinical (in-vivo) trials were excluded from this study.
 Intervention (Specified to current study): any form and dosage of citicoline use;  Compared to placebo/conventional treatment control group patients;  Outcomes assessed as: (1) favorably outcome of intervention (good recovery and mild disability based on GOS or improvement in Neuropsychological state), (2) mortality and vegetative-state (based on GOS), (3) probable side-effects of citicoline.

Review Method and Study-Selection
After eliminating duplicates from search results with Zotero v.4.0.28 (available from www.zotero.org which was used as reference manager too), retrieved articles were screened via their titles and abstracts by two review authors. Further assessment of retrieved RCTs for their quality of reporting and eligibility to extract data for quantitative analysis was done by applying Consolidated Standards Of Reporting Trials (CONSORTchecklist) 2010 (available from http://www.consortstatement.org/) on full-texts of the articles by two review authors (appendix 8 demonstrates CONSORT 2010 Checklist). It was planned to refer to any disagreements in screening-phase and the decision on including studies to the third author. However, no such conflict was encountered in this review. There were also other reviews and protocol papers in search results that were excluded from the study process due to being a pre-clinical study or using non-English language. The flow of identification and selection of studies was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart, which was modified for citicoline topic in current paper (Figure1).

Assessment of Potential Biases in Studies
Two authors assessed RCTs using the Cochrane risk of bias tool. 9

Data Extraction and Data Sources
One author extracted data from the included studies into extraction table including sample size, patients' condition (acute/chronic TBI), outcome measures (favorable outcomes, mortality, and side-effect), citicoline's dosage and route of use. While other authors checked accuracy and completeness of the extracted data.

Analysis
The outcomes were analyzed in two main groups for acute TBI management. Mortality and vegetative state (assessed in a single group) as well as good recovery and mild disability (as a favorable outcome) assessed with Glasgow Outcome Scale (GOS) after 3-6 months of patients' follow-up were considered primary outcomes. Severe disabilities were not included in this analysis. Occurrence of any citicoline adverse effects was analyzed as secondary outcome. For chronic TBI management, outcomes were analyzed for improvement in Neuropsychological state.
A p<0.05 was considered statistically significant through all statistical methods applied in this review. The effect sizes pooled in this meta-analysis included Risk Ratios (RR) and Standardized Mean Difference (SMD) along with their Confidence Interval (CI)=95%. Heterogeneity among the studies was assessed using I 2 statistic and tested through and an I 2 greater than 0.5 was considered for using random effects models. 10  Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11b If relevant, description of the similarity of interventions Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12b

Results
Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome 13b For each group, losses and exclusions after randomization, together with reasons

Results
Articles related to citicoline intervention use for TBI management were published from 1991 to 2014. [11][12][13][14] Zafonete et al.'s study was a big multicentric study a.k.a COBRIT (Citicoline Brain Injury Treatment) and halted in its 4 th interim analysis due to non-significant outcome differences between placebo and intervention groups, but patients followed up to 180 days after injury, the data for 180-day results are included in this metaanalysis. Sources of funding and other support (such as supply of drugs), role of funders *We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomized trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.
A parallel study to COBRIT showed an overall improvement process of psychiatric characteristics in TBI patients over 180 days of assessment, with better outcomes on days 30-90. Better outcomes were observed for female participants in comparison to the males. Hispanic had better improvement and African-Americans had less improvement process when compared to the Whites as the ethnic/race's analysis reference group. 15 There was also a study by Salehpour et al. that has reported neuroprotective effect of Citicoline on the reduction of serum levels of MalonDiAldehyde (MDA) as a marker of oxidative stress, but the study was excluded from our review because no clinical outcome was reported. 16 An analysis of outcomes showed no significant change in GOS outcome (p=0.76; RR 1.03, 95% CI 0.86 to 1.24; participants = 1128; studies = 2; I 2 = 71%, Figure 2), but significant favorable Neuro-cognitive changes in placebo-control group despite studies' heterogeneity (p<0.00001; SMD 1.00, 95% CI 0.75 to 1.25; participants = 971; studies = 3, Figure 3). However, the comparison of COBRIT study's days-90 and 180 GOS outcomes demonstrated improvements in day 180 outcomes. 11 With respect to mortality and vegetative-state outcomes, only two studies by Maldonado et al. and COBRIT trials have reported these outcomes that were analyzed as a joint outcome in the present review (p=0.96; RR 1.02, 95% CI 0.49 to 2.14; participants = 1429; studies = 2; I 2 = 67%, Figure 4). No significant difference was detected in side-effects of the intervention between trial groups (p=053; RR 1.03, 95% CI 0.94 to 1.12; participants = 1429; studies = 2; I 2 = 57%, Figure 5).

Discussion
COBRIT study for citicoline use in TBI management seems to be like CRASH, SYNAPSE and ProTECT-III or EPO-TBI in their own fields of interest, 4,11,[17][18][19] as it was a big multi-centric placebo-control RCT of citicoline. Its halt in 4 th interim analysis may resulted in less participation of patients during follow-up process, but it was not found to have a significant difference between groups. Overall assessment of outcomes didn't demonstrate any significant effect of citicoline favorable outcomes especially in GOS. However, assessment of GOS for days 90 and 180, improvements were slightly better but not significant in COBRIT study (from P=0.97 to P=0.43). There is significant improvement of placebo-control group patients in neurocognitive state rather than intervention group. Neither mortality nor side-effects of citicoline versus control groups were significantly different. Maldonado et al.'s was the 2 nd largest study after COBRIT in these search results. This study along with the studies by Leon-Carrion et al. and Shokouhi et al. had supported a beneficence in citicoline use for severe and moderate TBIs. Nevertheless, it was questioned by CO-BRIT that didn't report such an effect in outcomes neither in day-90 nor day-180. [11][12][13][14] Also, a significant better outcome change was obvious in mildly complicated cases on day-180 outcome in COBRIT study. 11 Considering the large weight of COBRIT study, the variations of citicoline doses and outcome assessments reported by other three studies could easily be suppressed by COBRIT results. However, current use of citicoline for TBI in acute or chronic phase is no more recommended by the results of this review. Nevertheless, neuro-cognitive benefits of citicoline need to be investigated through further research for chronic TBI patients. Improvement in psychiatric assessments of TBI patient after an assault differs among individuals. There should be supportive Psychological First Aid (PFA) tools for primary survivors of the assault. The Johns Hopkins University's course of PFA-RAPID which stands for Rapport and Reflective Listening, Assessment of needs, Prioritization, Intervention, and Disposition is available at https://www.coursera.org/course/psychfirstaid to guide the triage and primary effective intervention of healthcare providers for trauma assaults survivors, as further than the insult, sub-acute complications during recovery of patients especially in two-third of severe impaired TBI patients 20 which may affect their families' lives, too.

Conclusions
The available evidence doesn't support current routine use of Citicoline for acute TBI management. Citicoline use for managing impaired neuro-cognitive conditions in chronic TBI patients is weak and needs further research.

Acknowledgments
Our kind regards and appreciations belong to Mrs. Fathifar and Mr.Saeidi, the librarians of Tabriz Nutritional Sciences Faculty and Tabriz University of Medical Sciences Central Library, who also commented on our primary search strategy to revise it into a better applicability and helped us access the full-texts of related articles; also Mr. Ahadi, MA in English literature and language, who reviewed our primary draft and his precious recommendations made a better outfit of this manuscript.
The following authors made the meaningfulness of "Standing on the shoulders of Giants" & "Open Accessed World Wide Web (WWW)" for us by providing their own papers' full-texts for our study, despite the limitations of known routes in WWW, via www.researchgate.net; our appreciations belongs to them and to whom else endeavors on making these And We used bunch of Libre/Open Source Softwares to surf the web, collect information, analyze data and publish the paper; our kind pleasures belongs to alumni of "Mozilla FireFox", "LibreOffice", "Zotero", "uGet" & "Cochrane RevMan" (hope the last one someday will be published under software freedoms Two and Three, too); and at last "Richard Stallman" founder of "Free Software Foundation (www.fsf.org)" for bringing these useful elaborate software and the philosophy of software freedom for human beings.

Funding:
There was no fund of support for this study.