What is the role of citicoline in traumatic brain injury?

Therefore, given the available evidence, the role of citicoline in patients with TBI should be further investigated and clarified, especially after the controversy arising from the neutral results of the COBRIT. The aim of this study was to assess the benefits and hazards of therapy with citicoline in patients with TBI through a systematic review and meta-analysis of comparative trials.

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Among the neuroprotective drugs used for the management of brain ischemia is citicoline [ 8 ]. Citicoline (cytidine 5&#;-diphosphocholine, or CDP-choline) is an endogenous compound involved in the biosynthesis of phosphatidylcholine, the major neuronal membrane lipid. Exogenous administration of citicoline has been shown to generate phospholipids, thus making it a neuroprotective/neurorestorative agent with an appropriate benefit&#;risk profile in the management of brain-ischemia-related disorders [ 5 14 ]. Citicoline has a pleiotropic effect on the molecular events involved in the pathophysiology of ischemic/traumatic brain injury, and it is widely used as a neuroprotective treatment of stroke and head injuries and the sequelae of both diseases [ 14 ]. In , the Citicoline Brain Injury Treatment Trial (COBRIT) was published. This trial did not reveal an improvement in functional or cognitive status compared with placebo [ 15 ]. In any case, COBRIT was subject to a number of limitations, such as the extremely low adherence and the atypical oro-enteral administration of citicoline. The latter is not approved for TBI in any country, has not yet been scientifically studied, and, among other things, is not suitable for many of the patients included in the study [ 5 16 ]. Additionally, a meta-analysis performed in by Secades [ 17 ] showed that citicoline could have a positive impact on the rates of independence among patients following TBI, whereas the meta-analysis of El Sayed et al. [ 18 ] reported a neutral effect of citicoline on the Glasgow Outcome Scale/Glasgow Outcome Scale extended (GOS/GOSe) score, cognitive performance, and survival. Recently, an exhaustive narrative review on the role of citicoline in TBI has been published [ 5 ].

It is considered that a better comprehension of the complex pathophysiology of TBI will help to decrease the frequency of TBI-associated complications. Alterations in cell membrane integrity, as well as impairments of the lipid metabolism, can lead to cell death after TBI, as in ischemic brain injuries [ 8 10 ]. In this sense, the importance of the role of lipids in cell signaling and tissue physiology has been demonstrated in many central nervous system (CNS) disorders and injuries related to dysregulated metabolism, as a key step in the pathophysiology of the ischemic/traumatic brain injury [ 8 ]. Choline-based phospholipids are involved in the maintenance of the structural integrity of the neuronal and glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neurotransmission in the brain [ 9 ]. Consequently, a therapeutic approach based on the protection and the regeneration of cell membranes and on the normalization of lipid metabolism could prove beneficial [ 5 8 ] as a neuroprotective strategy. As a treatment approach, neuroprotection could be considered beneficial in patients with TBI [ 5 12 ] among other areas of improvement, such as intracranial pressure management, neuromonitoring, and the management of paroxysmal sympathetic hyperactivity [ 12 ].

Traumatic brain injury (TBI) is a acquired insult to the brain from an external mechanical force that can result in a temporary or permanent impairment or death, especially in moderate and severe cases [ 1 ], which is considered a major worldwide neurological disorder of epidemic proportions [ 2 ]. To date, there are still no FDA-approved therapies to treat any forms of TBI [ 2 ]. In , there were 27.08 million (24.30&#;30.30 million) new cases of TBI in the world, with an age-standardized incidence rate of 369 (331&#;412) per 100,000 persons [ 3 ]. In the same year, the number of prevalent cases of TBI was 55.50 million (53.40&#;57.62 million). From to , the age-standardized prevalence of TBI increased by 8.4% (7.7 to 9.2) worldwide [ 3 ]. TBI affects both elderly persons, mainly due to falls, and young individuals, because of road injuries, assault, or sports- and work-related accidents [ 4 5 ]. A high proportion of survivors from moderate or severe head injuries exhibit some grade of disability, with reduced independence [ 4 6 ]. For this reason, TBI is associated with a vast health and economic burden [ 7 ]. Permanent cost estimates ranged from279 million to1.22 billion, depending on the diagnostic criteria used to define TBI [ 7 ]. Therefore, it is imperative to treat TBI, with the aims of reducing severity and improving recovery [ 5 ].

The formal meta-analysis was performed by using metafor (version 2.4-0), a meta-analysis package for R [ 24 ]. Given that we assumed heterogeneity with respect to the studies performed over 4 decades, the main analysis used the random-effects model to obtain a 95% confidence interval (CI) estimate for the effects of citicoline compared with controls. We chose the REML (restricted maximum likelihood estimator) method, that is, the default in the package; confidence intervals are based on a standard normal distribution. The strength of the body of evidence was assessed by using the grading of recommendations assessment, development, and evaluation (GRADE) score [ 25 ]. The results of the meta-analysis were presented as forest plots, with studies listed in order of age, oldest first. In addition to unadjusted random- and fixed-effects models, as subgroups data were analyzed according to the dose (trials with doses higher than 2 g/day vs. 2 g/day or lower) and the administration route (parenteral vs. only oral/enteral) because these study-level variables included in the model might account for part of the heterogeneity in the effects. We also performed a sensitivity analysis restricted to RCT studies.

We applied dichotomous outcomes in the statistical meta-analytic methods, and a weighted estimation (with inverse-variance weights) was used. For the GOS, scores of 4 or 5 were considered as good outcomes (independence), and for GOSe, 7 or 8. The risk ratio (RR) was used to test for the proportional treatment effects of citicoline. The odds ratio (OR) and risk difference (RD) were used in complementary analysis.

The primary efficacy measure was independence at the end of the scheduled clinical trial follow-up. If available, we used the GOS/GOSe for this measure. In studies lacking the GOS/GOSe measurement, we used the most comprehensive measure of disability or handicap available from the study for the classification of patients as dependent or independent, defining independence as the ability to perform almost all the activities of daily life without the assistance of another.

One author (J.J.S.) reviewed the abstracts of the articles retrieved in the search. Full-length papers for any abstract that we thought met the inclusion criteria were obtained. Three authors (J.J.S., H.T., B.S.) reviewed all the retrieved papers to identify those trials meeting the inclusion criteria for the review. One review author (J.J.S.) initially extracted the efficacy data from eligible trials that were then independently confirmed by H.T. and B.S. Discrepancies were resolved by discussion with the other authors (H.T., B.S., J.A.G.) and by referencing the original report. J.A.G. performed all the statistical analyses.

We searched OVID-Medline, EMBASE (access through OVID), Google Scholar, the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, latest issue), and the US National Institutes of Health&#;s ClinicalTrials.gov website, from inception to week three of January , using appropriate controlled vocabulary and free search terms. Search strategies for OVID, MEDLINE, and EMBASE are detailed in Appendix A . For the other searches, the keywords CDP-choline, citicoline, traumatic brain injury, head injury, and craniocerebral trauma were used. Additionally, the reference lists from eligible studies, other reviews on this topic, and the Ferrer bibliographic database were screened to identify relevant studies. No restrictions on language, publication date, or publication status were applied. We did not search the gray literature.

Eligible studies included randomized controlled trials (RCTs), comparative studies, and cohort studies of male and female patients of any age with a diagnosis of TBI and treatment starting in the first 24 h after injury and included the reporting results for independence or functional outcome. The trials included analyses of patients with complicated mild (defined as patients with a baseline Glasgow Coma Scale (GCS) score of 13&#;15 with some lesions on the CT scan), moderate (GCS 9&#;12), and severe TBI (GCS 3&#;8), but not mild TBI. The main reason for including complicated mild patients was because independence results for this category of patients were included in the COBRIT publication [ 15 ]. This systematic review comprised all studies in which the active agent was citicoline, irrespective of whether it was compared with another active treatment.

None of the adjusted analyses yielded a significant difference, and thus, we were unable to find a relationship between the outcome and either the dose of citicoline or the route of administration. Table 3 summarizes the results obtained. Note that the significant effect was maintained when we analyzed only the RCTs (RR = 1.16; 95% CI = 1.01&#;1.33; I2 = 39.4%). According to the results, we can categorize the evidence as moderate certainty (GRADE). There was no difference in mortality rates in the randomized studies. Only in the study of Trimmel et al. [ 35 ] was a significant reduction in mortality for patients with severe TBI treated with citicoline described. Additionally, none of the included studies reported any serious safety problem associated with citicoline.

The effect estimates and the confidence intervals (CIs) are presented as a forest plot. All the results were directly reported, as obtained from the original publication. The administration of citicoline was associated with a significantly higher rate of independence (RR = 1.18; 95% CI = 1.05&#;1.33; I2 = 42.6%) ( Figure 3 ). Complementarily, we performed OR and RD analyses, and in both cases, the results were congruent with the RR obtained (OR = 1.56; 95% CI = 1.15&#;2.12 ( Figure 4 ); RD = 0.12; 95% CI = 0.04&#;0.19 ( Figure 5 )). Thus, the probability of presenting the favorable event was 18% higher with the intervention; alternatively, citicoline increased by 0.12 points with respect to that of a favorable event without the intervention. The Iheterogeneity indicator obtained (42.6%) was not large but was considerable, as described in the funnel plot ( Figure 6 ); nonetheless, we also estimated the effect of citicoline under the fixed-effects model, with similar results ( Table 3 ).

The 11 included studies comprised two cohort studies [ 31 35 ], seven RCTs comparing citicoline with placebo or a control group [ 15 34 ], one RCT comparing citicoline with meclofenoxate [ 29 ], and another RCT comparing citicoline with piracetam [ 30 ]. All the studies assessed the effect of citicoline on the recovery of patients with complicated mild, moderate, or severe head injury. The oldest study was published in , and the most recent study was published in ; thus, there was a gap of 40 years between the first and last studies. As stated above, this may be a source of heterogeneity owing to improvements in the management of TBI during this period, and it justifies an analysis based on the random-effects model. The studies included a total of patients, in whom citicoline was administered at doses ranging from 300 mg to 6 g. The duration of treatment varied from 10 to 90 days. The drug was administered intravenously in six studies [ 26 35 ], intravenously or intramuscularly in two studies [ 27 28 ], intravenously followed by oral administration in one study [ 32 ], and orally in two studies [ 15 34 ]. All the studies included the rate of independence, albeit at different times of evaluation ( Table 1 ). The PEDro score [ 62 ] of the trials ranged from 7 to 11, with an average of 9.6 ( Table 2 ).

The search results and the decisions made during the eligibility process are displayed in the PRISMA flowchart ( Figure 1 ). The search provided records. Another 96 records were identified through the search of the Ferrer bibliographic database. The removal of duplicates left a total of references. After a review of the citations, the abstracts, and the full papers (when available), 96 records were initially screened. In total, 59 references were excluded as they corresponded to animal studies or reviews. Consequently, in the end, 37 full-text clinical studies were assessed for eligibility ( Figure 1 ). Among these clinical studies, only 11 fulfilled the criteria to be included in the qualitative synthesis [ 15 35 ]. Among the 26 studies not selected for the meta-analysis, six were noncomparative studies [ 36 41 ], six were not in the acute phase of TBI [ 42 47 ], six had unavailable independence data [ 48 53 ], three compared different combinations of drugs [ 54 56 ], two analyzed different types of patients (including few with TBI) [ 57 58 ], one assessed cervical trauma [ 59 ], one assessed mild TBI [ 60 ], and one study reported no clear results, with only 10 patients per arm [ 61 ].

4. Discussion

This meta-analysis showed that in nearly patients with acute-phase TBI, treatment with citicoline was associated with a significant improvement in the level of independence, with a moderate level of evidence according to GRADE.

4,9,8,9,10,8,9,10,14,63,64,65,14,

Given the considerable disease burden associated with moderate to severe TBI, there is a need to improve recovery in affected patients. Although the treatment for TBI has improved in recent years, mortality and disability rates remain high [ 3 10 ]. Inflammation, alterations in cell membrane integrity, and the impairment of phospholipid metabolism have all been implicated in the pathophysiology of TBI [ 5 14 ]. Importantly, many studies have shown that citicoline has neuroprotective and neurorestorative properties, including the following: the normalization or stabilization of damaged neuronal cell membranes (i.e., phospholipid content and function, ion exchange); the restoration of some enzymatic activities; a reduction in the generation of damaging free fatty acids and free radicals; the improvement of neurotransmission and cerebral metabolism; anti-inflammatory and antioxidant properties; the enhanced integrity of the blood&#;brain barrier; the accelerated absorption of brain edema and the decreased volume of ischemic lesions; the inhibition of apoptosis; and the enhancement of neurorepair and neuroplasticity properties [ 5 66 ]. Thus, given its biochemical, pharmacological, and pharmacokinetic characteristics, citicoline should considered as a potentially useful drug for the treatment of patients with TBI [ 5 17 ].

14,

Nevertheless, the COBRIT did not show any improvement in outcomes in this population [ 15 ]. The COBRIT has been the largest study performed with citicoline in TBI patients, but there are relevant methodological issues that question the validity and applicability of the results obtained in the study. The first point to consider is the financing of this study; the study was an independent study, financed by the US National Institute of Health, with a limited budget. A relevant point to consider is the sample size calculation. The authors chose an OR of 1.4 as the effect of the treatment, when in the most recent publications, the size of the effect of citicoline was 1.26 in acute ischemic stroke patients, a less heterogeneous pathology than TBI. The sample size was likely calculated on the basis of the number of patients that could be afforded, and then the OR of the treatment was established accordingly, instead of basing it on the real effects of the drug. With a more conservative and realistic OR of 1.2 or less, the sample size should be much higher and would likely have been unaffordable for the authors. Another questionable point to consider is that the authors mixed different populations, confusing mild, moderate, and severe TBI. The pathophysiology, localization, and trajectory for recovery can be quite different among these different groups. To avoid this issue, the authors should have used a randomized, matched sample design. This mixing of lesion severity is a clear source of heterogeneity and would have to be considered an important confounding factor in the analysis and interpretation of the data. Another point is the atypical oro-enteral administration of citicoline used in this trial, which is not approved in any country, has not previously been scientifically tested, and is not appropriate for many of the patients enrolled in the study, particularly in moderate and severe cases. However, the most controversial point is the extremely poor compliance with the treatment. Only 44.4% compliance for patients having taken more than 75% of the medication expected is clearly insufficient and needs further elaboration in the interpretation of the results. Not receiving the active treatment is not the same as not receiving the placebo, in terms of the standard of care being received. This means that fewer than half of the patients received something close to a therapeutic dose of citicoline. Thus, the COBRIT is not the definitive study on citicoline, especially when the methodological confounds just described are taken into consideration [ 5 16 ]). As a result, the evidence provided by the study must be considered controversial [ 5 16 ].

In this context, meta-analyses could prove to be very helpful in clarifying the role of citicoline in clinical practice. In , a previous meta-analysis based on 12 clinical studies enrolling patients with mild to severe TBI treated in the acute phase with/without citicoline showed a significant increase in the rates of independence with citicoline (OR, 1.815 (95% CI, 1.302&#;2.530) under the random-effects model vs. 1.451 (95% CI, 1.224&#;1.721) under the fixed-effects model) [ 17 ]. These results are in line with those in this study. In contrast, another meta-analysis found neutral effects for citicoline in the treatment of patients with TBI, although it is noteworthy that this meta-analysis was restricted to studies published in English, with only patients for the GOS outcome, 1,291 patients for the assessment of cognitive performance, and patients for the assessment of survival [ 18 ]. Therefore, the sample size in this meta-analysis was too limited to find a beneficial impact of citicoline in the study population, owing to the English language restriction, which is a well-known source of heterogeneity [ 5 ].

14,68,

While our study analyzed only the neuroprotective efficacy of citicoline among patients following TBI, clinical trials and real-life studies have confirmed its excellent safety profile [ 5 17 ]. The neuroprotective effects of citicoline should not be limited to patients with TBI but instead could also be extended to patients with other neurological diseases [ 14 ], as some studies have suggested, including COVID-19-related cognitive complications, multiple sclerosis, and dementia [ 67 69 ].

The main limitation of our meta-analysis was the presumed heterogeneity of the included studies. This was the result of marked improvements in the management of patients with TBI over 4 decades. As shown in Figure 6 , a funnel plot suggests that the old, small studies may be overestimating the effect size, although the number of these studies is too few to be conclusive. In addition, our meta-analysis was the largest performed to date and analyzed the level of independence, an outcome that was well defined in the included studies. In any case, our results are quite relevant because no new large-scale clinical trials with citicoline for this indication are expected.

The initial extraction of the data was performed by only one author (J.J.S.) because he was the author of a recent narrative review on the effects of citicoline on TBI [ 5 ]. Despite that, the initially extracted data were confirmed by the other clinical authors (H.T. and B.S.).

As it has been shown in the previous section about the experimental data showing that citicoline can induce significant positive effects in different experimental models of TBI, citicoline seems to be a suitable drug for the management of patients suffering TBI. Thus, it is possible to say that citicoline has a pleiotropic effect on several steps of the ischemic cascade involved in the development of the TBI [84].

Many years ago, the effect of citicoline stimulating the ascending reticular activating system at the brain stem level was postulated to explain the effects of the drug on the consciousness level [84]. As citicoline could be considered as a valid pharmacological treatment for TBI, many clinical studies have been performed over time to assess if the drug would have beneficial effects in the treatment of patients with TBI.

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There are early published clinical data showing that citicoline can lead to recovery from neurological clinical symptoms and a return to a conscious state with an excellent safety profile [86].

3.1. Clinical Studies on Mild, Complicated to Severe Head Injuries

summarizes chronologically all clinical studies evaluating the effects of citicoline in the management of patients with mild, complicated to severe traumatic brain injury.

Table 3

AuthorsYear n SeverityType of StudyControlTime WindowSchedule of TreatmentFollow-upMain ResultsMisbach et al. [87]Moderate to severeDouble blind RCT aPlaceboNA b300 mg/d/14 d IV14 dBetter recovery rate (GCS c)Espagno et al. [90]SevereDouble blind RCT aPlaceboNA b250 mg/d/5 d IV + 250 mg/d/15 d IM30 dBetter recovery of consciousnessCarcasonne & LeTourneau [91]Moderate to severe (children)Double blind RCT aPlaceboNA bNAb20 dFaster recovery from comaRicher & Cohadon [92]SevereDouble blind RCT aPlacebo24 h750 mg/d IV (6 d) + IM (14 d)90 dMore independent patients (clinical evaluation)Lecuire & Duplay [93]Moderate to severeDouble blind RCT aMeclophenoxate24 h750 mg/d/10 d IV10 dMore patients with a favorable outcomeLecuire & Duplay [94]Moderate to severeOpen studyBibliographic data24 h750 mg/d/10 d IV + 250 mg/d/10 d IM20 dSignificant improvement of survival and resolution of neurological deficits and consciousness troublesCohadon et al. [96]SevereDouble blind RCT aPlacebo24 h750 mg/d IV (6 d) + IM (20 d)120 dMore independent patients (~GOS d)Lecuire [95]Moderate to severeDouble blind RCT aPiracetam24 h750 mg/d/10 d IV10 dGlobal result favorable to citicoline (p < 0.01)Deleuze et al. [97]SevereOpen studyNone24 h500 md IV single dose4 dSignificant decrease of lactate and lactate/pyruvate ratio in CSF eDe Blas et al. [100]Moderate to severeOpen RCT aControl24 h200&#;400 mg/8 h IV or IM in the acute phase, followed by 100&#;200 mg/8 h PO during follow-up180 dReduction of coma and neurological and psychological sequelaeRagguenneau & Jarrige [101]SevereCohort studyControl24 h500&#;750 mg/d/20 d IV180 dMore independent patients (~GOS d)Calatayud Maldonado et al. [102]Moderate to severeSingle blind RCT aControl24 h3&#;4 g/d/4 d IV + 2 g/d/26 d PO90 dMore independent patients (GOS d)
Decreased hospital stayLozano [103]SevereSingle blind RCT aControl24 h3&#;6 g/d/14 d IV90 dTrend to have more independent patients (GOS d)
Reduction of brain edema (CTscan)
Decreased hospital stayLazowski et al. [104] RCT aPlaceboNA bNA b30 dGCS 21 is significantly correlated with GOS 30 (r = 0.68; p < 0.01) showing the protective effect of citicolineHinev et al. [105]SevereOpenNone36 h1 g/d/5&#;7 d IVNA b80% of patients recovered from neurological symptoms and un-consciousnessKrishna et al. [106]Moderate to severeSingle blind RCT aPlacebo24 h2 g/d/60 d PO90 dEarlier rate of recovery, less duration of stay, early gaining of full consciousness and relief from cognitive symptomsZafonte et al. [108]Mild, complicated, moderate and severeDouble blind RCT aPlacebo24 h2 g/d/90 d PO or enteral180 dNo differences on the TBI-Clinical Trials Network Core BatteryEl Reweny et al. [109]SevereOpen RCT aControlNA b1 g/d/14 d IVNA bTrend to improve the outcomeSalehpour et al. [114]Severe with diffuse axonal injurySingle blind RCT aControl24 h2 g/d/12 d IV12 dReduction of MDA plasma levelsShokouhi et al. [116]Severe with diffuse axonal injuryDouble blind RCT aControl24 h2 g/d/15 d IV15 dIncreased plasma levels of fetuin-A and matrix Gla-proteinSalehpour et al. [115]Severe with diffuse axonal injurySingle blind RCT aControl24 h2 g/d/15 d IV15 dReduction of MDA plasma levels
No differences on GCS cVaradaraju et al. [110]Mild to moderateOpen RCT aCiticoline + CerebrolysinNAb2 g stat followed by 500 mg IV/PO
twice daily continued for 3 months.180 dThe association had better outcome (GOS) than patients treated with citicoline aloneTrimmel et al. [112]Moderate to severeRetrospective matched pair analysisControl24&#;48 h3 g/d/21 d IV180 dReduction of the rates of mortality
Reduction of the rates of unfavorable outcome (GOS)Ahmadi et al. [113]SevereDouble blind RCT aControlNA b1&#;3 g/d/14 d IV30 dAccording to protocol: significant dose-dependent effect on outcome (GOS)According to article: no positive effectOpen in a separate window

The first double-blind randomized and placebo-controlled clinical trial was presented in by Misbach at al. [87]. In this study, the authors concluded that the use of citicoline was associated with better recovery in patients with severe TBI.

In another double-blind study, performed by Ayuso et al. in , it was demonstrated the effectiveness of citicoline to treat patients with memory disorders of an organic base, in that case induced by bilateral electroshock [88].

De la Herrán et al. [89], in an open study with the 32 patients with severe TBI among other types of brain injuries, concluded that the administration of citicoline accelerated normalization of the consciousness state. Similar results and conclusions were obtained in other double-blind studies performed by Espagno et al. [90] and by Carcasonne and LeTourneau [91], the last one performed in children population.

Richer and Cohadon [92] performed a randomized, double-blind and placebo-controlled trial in a sample of 60 patients with severe TBI. Citicoline was administered at a dose of 750 mg/d intravenously for 6 days, and then intramuscularly for 20 days more. At 60 days, the number of patients who had recovered consciousness was significantly greater in the group receiving citicoline. At 90 days, it was also found that the highest rate of recovery of motor deficits was associated with the treatment with citicoline.

Lecuire and Duplay [93], in a double-blind study, compared the effects of citicoline (750 mg/d/10 d IV) to those of meclofenoxate (3 g/d/10 d IV) in a sample of 25 patients (14 patients treated with citicoline and 11 patients treated with meclofenoxate). Statistical analysis of the results demonstrated significant effects in the citicoline treated group regarding the resolution of consciousness disorders, EEG pattern, and functional recovery. Shortly after, the same authors confirmed these positive results in an open label study performed in a group of 154 patients with TBI injury [94]. Lecuire [95] conducted another double-blind study comparing piracetam (6 g/d) versus citicoline (750 mg/d) in a group of 40 patients with head injury. The results of the study showed a better result on consciousness status, vegetative and electric, and on the global final improvements in the group of patients treated with citicoline.

Cohadon et al. [96] demonstrated the clinical efficacy of citicoline in a double-blind placebo-controlled trial in a sample of 60 patients with severe TBI. A group of 30 patients was treated with citicoline (750 mg/intravenously for 6 days and continued up to 20 days more with intramuscular administration). In the treated group a shortening of the comatose period and an acceleration of the recovery of neurological deficits, especially in the motor area, were observed, these differences being statistically significant compared to placebo. The authors attributed these positive results to the effect of the drug on brain edema. Deleuze et al. [97] correlated the effectiveness of citicoline with its effect on the cerebral metabolism, reflected in a significant reduction of lactate levels in cerebrospinal fluid after the treatment.

Ogashiwa et al. [48] performed a study in a sample of patients with disturbances of consciousness associated with stroke, TBI or brain tumours. Fifty-one patients were treated with citicoline ( mg/d/7 d IV) and 50 patients with the same characteristics were used as controls. The effects were evaluated using the principal component analysis score and the global improvement rate. The results of the principal component analysis scoring correlated closely with those of the global improvement rate, the effects in the citicoline-treated group being significantly greater than those obtained in the control group. Citicoline was more effective on the items related to the performance than on the verbal factor. These authors considered the drug to be safe, and they even administered the drug by the intrathecal route in some cases [98,99].

In another controlled study, De Blas et al. [100] evaluated the effects of citicoline on the short- and long-term evolution in a group of 100 patients with head injuries, compared with a group of 100 patients treated conventionally. The results obtained suggested that the addition of citicoline to the conventional treatment regimen was associated with a decrease in the length of post-traumatic coma and the incidence of neurological and psychological sequelae, accelerating the recovery of these kind of deficits.

Raggueneau and Jarrige [101] published the results of a national inquiry conducted in 24 neurosurgical intensive care units in France. The authors obtained information on 921 cases of severe TBI. Among the total sample, 219 patients were treated with citicoline. This, then, allowed the comparison of the results obtained between patients treated and not treated with citicoline. The improvement of the outcome for all patients was significantly linked to citicoline treatment. Nevertheless, no effects on the mortality rate were seen associated with the use of the drug.

Calatayud Maldonado et al. [102] conducted a single-blind randomized clinical trial in a sample of 216 patients with moderate to severe TBI with the objective of assessing the influence of the addition of citicoline to the standard treatment for head injury. One hundred and fifteen patients received treatment with citicoline (up to 4 g/d parenterally). The total duration of the treatment varied according to the evolution of the patient. The analysis of the results showed that citicoline significantly decreased hospital stay. Similarly, the treatment with citicoline was associated with a significant better global outcome, as evaluated with the Glasgow Outcome Scale, that was more relevant in the subgroup of patients with severe TBI. The duration of outpatient follow-up was also reduced in the group of patients treated with citicoline.

Lozano [103] reported the results of a randomized study to assess the impact of the use of citicoline therapy on the evolution of patients with severe TBI. Citicoline was administered to 39 patients at a dose ranging from 3 to 6 g/d by intravenous infusion for 2 weeks. The results were compared with another group of patients with the same characteristics and not treated with citicoline. After 14 days of treatment, cerebral edema was significantly reduced or normalized in a higher number of patients treated with citicoline. Mean hospital stay was also significantly reduced in the active treatment group (28.718 ± 21.6 days) in comparison with control group (37.323 ± 35.22 days; p < 0.001). Regarding the final outcome, evaluated with the Glasgow Outcome Scale, it was a trend to have a better outcome in the group receiving the active treatment, but these differences did not reach statistical significance, probably due to the small sample size.

Lazowski et al. [104] performed a randomized and placebo-controlled study on a sample of 28 patients with traumatic brain injury caused by isolated head trauma. Citicoline was administered at a dose of 1 g IV for 14 days in addition to typical treatment. The GCS and the Glasgow Outcome Scale (GOS) were used to control patients up to 30 days. In the citicoline-treated group the analysis found no correlation between the GCS scores in day 7 and day 14, and this lack of correlation could be interpreted as a result of treatment with citicoline, and the significant correlation found on the GCS at 14 and 21 days could be interpreted as an expanded effect of treatment up to 21 days. In the citicoline-treated group, the GCS score at 21 days was significantly correlated with GOS scores at 30 days, showing the protective effect of the used drug.

Hinev al. [105] in their study observed that 80% of patients with severe head trauma recovered from neurological symptoms and unconsciousness, concluding that the use of citicoline was associated with reduced coma duration and accelerated recovery of neurological disturbances in patients with severe head trauma, highlighting the safety of the drug.

Krishna et al. [106] conducted a randomized, single-blind, placebo-controlled, single-center, prospective trial in a sample of 100 patients. Patients were randomized to receive citicoline (2 g/d/60 d PO) or placebo and the evaluations of outcomes were made at discharge and after 30 and 90 days. The authors concluded that the rate of recovery was earlier in the citicoline group in terms of a shorter duration of stay, early gaining of full consciousness and relief from cognitive symptoms.

The Citicoline Brain Injury Treatment Trial (COBRIT) was a double-blind randomized and placebo-controlled trial with a special design [107,108]. The objective of the trial was to determine the ability of citicoline to positively affect the functional and cognitive status in patients with complicated mild, moderate, and severe TBI. The primary outcome of the study was the functional and cognitive status at 90 days. The outcome was measured by the nine components of the TBI Clinical Trials Network Battery, that includes the Trail Making Test (parts A and B), the extended Glasgow Outcome Scale (GOS-E), the California Verbal Learning Test II, the Controlled Oral Word Association Test, some of the tests included in the Wechsler Adult Intelligence Scale III (Processing Speed Index and Digit Span), and the Stroop Test (Parts 1 and 2). The sample size was calculated assuming an odds ratio (OR) of 1.4 or higher, and the final sample size was fixed as patients, after adding 15% for presumed losses. The patients were randomized to receive either citicoline (2 g/d/90 d) or placebo by enteral route within 24 h after injury. The clinical trial was stopped early for futility with patients included. Rates of favorable improvement for the GOS-E were 35.4% in the citicoline group and 35.6% in the placebo group. For the other scales, the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. There were no significant differences between groups at the 90-day evaluation: global OR: 0.98 (95% CI: 0.83&#;1.15), nor at the 180-day evaluation: global OR 0.87 (95% CI: 0.72&#;1.04). On the basis of the results obtained, the authors concluded that citicoline, compared with placebo, was not effective in the improvement of the functional and cognitive status of patients with TBI.

Despite the COBRIT trial being the largest study performed with citicoline in the management of TBI, there are some methodological issues that could question the validity and applicability of the results obtained. This study was an independent and academic study, financed by the US National Institute of Health, with a somewhat limited budget. A first point to consider was the sample size calculation that was based on an assumption of an OR of 1.4 as the effect of the treatment; however, this assumption was arbitrary and not based on previous data. Then, it looked as though the sample size was calculated based on the budget rather than on previous data. With a more realistic OR of 1.2 or less the sample size would have been much higher and unaffordable for the authors. Another key point to consider was the inclusion of mixed populations, including mild, moderate, and severe TBI. The pathophysiology and the evolution can be largely different among these groups. To consider these differences, it is mandatory to use a randomized and matched sample design, which was not used in the COBRIT trial. Thus, this is an evident source of heterogeneity, but it has not been considered as an important confounding factor in the analysis and interpretation of the data. Another point to take into the account was the atypical oro-enteral administration of the drug that is not approved in any country and has not previously been tested in any way. The use of this route of administration is not recommended in patients with moderate or severe TBI, at least in the first days. However, the most controversial point was the poor compliance of the treatment. A compliance of only 44.4% of patients having taken more than 75% of the medication expected is exceptionally low and needs to be explained, explanation that was not included in the publication of the trial. We must consider that not receiving the active treatment is not the same as not receiving the placebo, in terms of the standard of care being received. A placebo is a substance or treatment which is designed to have no therapeutic value. In other words, less than half of the patients in the active drug group received something close to a therapeutic dose of citicoline. Thus, this makes it exceedingly difficult to assume a lack of effect of the drug when the patients did not receive the proper treatment regimen.

El Reweny et al. [109] communicated the results of their study on patients with severe head injury. In their study 40 patients were allocated to 2 groups, where patients in Group I were treated with citicoline (1 g/d/14 d IV) in front of patients in Group II that received conventional therapy. They found that those patients in Group I with brain edema had the best outcome. Indeed, patients in Group II with intracerebral hematoma had the worst outcome. The authors concluded that the addition of citicoline to the conventional therapy of patients with severe TBI offered a trend to improve the outcome. Interesting are the results obtained by Varadaraju and Ananthakishan [110], demonstrating a certain synergistic effect when citicoline was administered together with cerebrolysin, as the patients treated with this association had a better outcome than patients treated with citicoline alone. Titov et al. [111] also demonstrated a positive effect of the combination of citicoline and cerebrolysin in the management of TBI in the acute phase.

Trimmel et al. [112] investigated the potential role of citicoline administration in TBI patients treated at the Wiener Neustadt Hospital. In a retrospective subgroup analysis, they compared 67 patients at the study site treated with citicoline (3 g/d/3 weeks IV) and 67 matched patients from other Austrian centers not treated with citicoline. Patients with moderate to severe TBI were included. The analysis found a significant effect of citicoline, expressed by the reduction of the rates of mortality at the intensive care unit mortality (5% vs. 24%, p < 0.01), during the hospital stay (9% vs. 24%, p = 0.035), and after 6 months of follow up (13% vs. 28%, p = 0.031). A significant reduction in the rates of unfavorable outcome (34% vs. 57%, p = 0.015) was also detected and in the observed vs. expected ratio for mortality (0.42 vs. 0.84) in the citicoline group ( ). Ahmadi et al. [113] published a double-blind, randomized clinical trial on 30 patients with severe TBI. According to the protocol (IRCTN7) and the abstract, patients were randomly divided into three groups: A (control), B (citicoline 0.5 g/12 h/24 d IV), and C (citicoline 1.5 g/12 h/14 d IV), but once the authors explained the methods in the article, these groups changed to: A (citicoline 0.5 g/12 h/24 d IV), B (citicoline 1.5 g/12 h/14 d IV), and C (placebo). This incongruence makes it difficult to interpret the results, because if the group assignment was the original, then a significant dose-dependent effect of citicoline can be found, but with the assignment stated in the paper, the results are difficult to interpret, but the authors concluded that citicoline had no positive effect on the outcome of such patients.

In recent years, the roles of inflammation and oxidative stress have been highlighted as targets to neuroprotection in the management of TBI [10,11,12,13,14,15,16]. Thus, the measurement of the effects of these neuroprotective therapies on the levels of established biomarkers of inflammation and oxidative stress could be of interest to evaluate the efficacy of such treatments.

Salehpour et al. [114,115] assessed the effects of citicoline in a sample of patients with diffuse axonal injury in a double-blind and randomized clinical trial. The efficacy of citicoline was assessed by the measurement of malondialdehyde (MDA) levels in plasma as a marker of oxidative stress. The MDA levels at the different times of blood sampling improved significantly, whereas the control group showed no difference. The authors concluded that citicoline is an effective neuroprotective agent and can reduce MDA levels in patients with severe TBI and diffuse axonal injuries.

Shokouhi et al. [116] conducted a double-blind and randomized clinical trial on 58 patients with the diagnosis of diffuse axonal injury and severe TBI to investigate the effects of citicoline on serum levels of fetuin-A and matrix Gla-protein (MGP), that are related with the inflammation and the vascular calcification secondary to head trauma. The findings suggested that citicoline may have protective effects against inflammatory damage and vascular calcification in TBI patients through increasing plasma levels of fetuin-A and MGP.

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