original article
Wien Klin Wochenschr
DOI 10.1007/s00508-017-1240-9
Citicoline in severe traumatic brain injury: indications for
improved outcome
A retrospective matched pair analysis from 14 Austrian trauma centers
Helmut Trimmel · Marek Majdan · Andrea Wodak · Guenther Herzer · Daniel Csomor · Alexandra Brazinova
Received: 7 April 2017 / Accepted: 11 July 2017
© Springer-Verlag GmbH Austria 2017
Summary Goal-oriented management of traumatic
brain injury (TBI) can save the lives and/or improve
the long-term outcome of millions of affected patients
worldwide. Additionally, enhancing quality of life
will save enormous socio-economic costs; however,
promising TBI treatment strategies with neuroprotec-
tive agents, such as citicoline (CDP-choline), lacked
evidence or produced contradictory results in clinical
trials. During a prehospital TBI project to optimize
early TBI care within 14 Austrian trauma centers, data
on 778 TBI patients were prospectively collected. As
Author contributions H. Trimmel concepted, initiated and
designed the study, collected, analyzed and interpreted data,
drafted and critically revised the manuscript. M. Majdan
performed the statistical analysis, contributed to data
interpretation and helped to draft and revise the manuscript.
A. Wodak, G. Herzer and D. Csomor contributed to data
acquisition and data analysis, and helped to revise the
manuscript. A. Brazinova conceived the INRO prehospital
TBI project, participated in its design, coordination and data
analysis, and critically revised the manuscript. All authors
read and approved the final manuscript.
Electronic supplementary material The online version of
this article (doi: 10.1007/s00508-017-1240-9) contains
supplementary material, which is available to authorized
users.
H. Trimmel () · A. Wodak · G. Herzer · D. Csomor
Department of Anesthesiology, Emergency Medicine and
Intensive Care and Karl Landsteiner Institute of Emergency
Medicine, General Hospital Wiener Neustadt, Wiener
Neustadt, Austria
helmut.trimmel@wienerneustadt.lknoe.at
M. Majdan
Department of Public Health, Faculty of Health Sciences and
Social Work, Trnava University, Trnava, Slovakia
A. Brazinova
International Neurotrauma Research Organization (INRO),
Vienna, Austria
K Citicoline in severe traumatic brain injury: indications for improved outcome
preceding evaluations suggested a beneficial outcome
in TBI patients treated at the Wiener Neustadt Hospi-
tal (WNH), we aimed to investigate the potential role
of citicoline administration, solely applied in WNH,
in those patients. In a retrospective subgroup analysis
we compared 67 patients from WNH with citicoline
administration and 67 matched patients from other
Austrian centers without citicoline use. Patients with
Glasgow Coma Scale score <13 on site and/or Ab-
breviated Injury Scale of the region “head” >2 were
included. Our analysis revealed significantly reduced
rates of intensive care unit (ICU) mortality (5% vs.
24%, p < 0.01), in-hospital mortality (9% vs. 24%, p =
0.035) and 6-month mortality (13% vs. 28%, p = 0.031),
as well as of unfavorable outcome (34% vs. 57%, p =
0.015) and observed vs. expected ratio for mortality
(0.42 vs. 0.84) in the WNH (citicoline receivers) group.
Despite the limitations of a retrospective subgroup
analysis our findings suggest a possible correlation
between early and consequent citicoline adminis-
tration and beneficial outcomes. Therefore, we aim
to set up an initiative for a prospective, multicenter
randomized controlled trial with citicoline in sTBI
(severe TBI) patients.
Keywords Traumatic brain injury · Neuroprotective
agents · Citicoline · Outcome · Intensive care medicine
Introduction
Traumatic brain injury (TBI) is a leading cause of
death and long-term disability across the world, par-
ticularly in young adults, thus constituting a serious
global health problem and creating a substantial so-
cioeconomic burden. The so-called silent epidemic
affects approximately 10 million people worldwide [1]
and 303 per 100,000 inhabitants per year in Austria
 original article
with a growing incidence rate in the elderly popula-
tion [2].
The complex and heterogeneous pathophysiology
of TBI hinders the identification of new effective phar-
macological approaches to reduce the impact of sec-
ondary brain injury factors, a cascade of cellular and
molecular processes subsequent to the primary brain
injury. The pathophysiological mechanisms mediat-
ing injury severity after TBI [3] are known to include
the breakdown of membrane phospholipids with sub-
sequent release of free fatty acids [4, 5] as well as de-
creased acetylcholine neurotransmission [5–7].
Cytidine 5 -diphosphocholine (CDP-choline or citi-
coline) is a pharmaceutical substance chemically
identical to the essential endogenous intermediate in
the biosynthetic pathway of phosphatidylcholine [8,
9]. Once absorbed, citicoline is rapidly hydrolyzed to
choline and cytidine triphosphate, dispersed through-
out the body, crossing the blood-brain barrier and
reassembled to citicoline inside the brain [8–11]. As
such, citicoline increases choline availability [12], acti-
vates the biosynthesis of structural phospholipids [13,
14] and mediates neuronal membrane integrity and
repair by preventing the accumulation of fatty acids
[15] and the formation of free radicals subsequent to
brain injury [9, 16, 17]. Accordingly, citicoline has
been shown to accelerate the reabsorption of cerebral
edema and the restoration of the blood-brain bar-
rier integrity after TBI and/or hypoxia [5, 9, 18, 19].
Several reports demonstrated that citicoline may be
an effective neuroprotective agent on secondary le-
sions following TBI without exerting acute or chronic
toxicity [5, 8, 9, 12, 20]; however, despite consider-
able research and efforts in investigating citicoline
absorption and metabolism, its pharmacological ac-
tion has not yet been completely delineated [8, 9].
Some clinical studies in patients with head injuries
revealed accelerated recovery from posttraumatic
coma, improved functional outcome and shortened
hospitalization periods under citicoline therapy [9,
20, 21]. Citicoline has a low toxicity and a favorable
side-effect profile in humans [22]. Minor transient
adverse effects are rare and most commonly include
stomach pain and diarrhea [23]. In long-term and
high-dose use for cognitive disorders (e. g. dementia
or Alzheimer’s disease) or stroke [24] there are some
reports of insomnia, diarrhea, low or high blood pres-
sure, nausea, blurred vision and chest pain.
Within the framework of the Austrian TBI study
group coordinated by the International Neurotrauma
Research Organization (INRO) and supported by the
Federal Ministry of Health, the Wiener Neustadt Hos-
pital (WNH) took part in a project to reveal potential
for further improvement of prehospital and early in-
hospital care of TBI patients together with 13 other
Austrian trauma centers [25, 26]. Within the scope
of data evaluation it became clear that patients who
were treated at WNH revealed considerably enhanced
rates of hospital survival as well as notably improved
Citicoline in severe traumatic brain injury: indications for improved outcome
functional outcome although there were no signifi-
cant differences in neither prehospital nor early in-
hospital treatment. Subsequent analyses comparing
the outcome of patients with a TBI treated at WNH
with matched controls from other Austrian centers
confirmed these observations (in-hospital mortality
21% vs. 37%, p = 0.019; 6-month unfavorable outcome
44% vs. 60%, p = 0.024). Matching was performed with
respect to age, Abbreviated Injury Scale (AIS) [27] and
Glasgow Coma Scale (GCS) [28]. While being aware of
the great variability of patient prognostic factors and
the possible variation in treatment delivered between
facilities, we nevertheless considered the patient col-
lective of 13 residual participating Austrian centers to
be representative of TBI treatment in Austria in ad-
dition to adjusting for TBI severity using a matching
process; however, we could not detect equivalent dif-
ferences in the outcome among the other participat-
ing centers. Ensuing efforts to identify the underly-
ing cause for these unusual results exposed just one
major difference: the treatment protocol for TBI at
WNH comprises the immediate intravenous adminis-
tration of citicoline thereby obviously contrasting the
TBI treatment practice of any other participating Aus-
trian center. Hence, we initiated a retrospective sub-
group analysis with the aim to elucidate whether the
lower mortality and the better long-term outcome of
patients treated at WNH could have been associated
with the administration of citicoline.
Methods
Study participants, design and setting
In the course of the INRO prehospital TBI project,
data on 778 patients from 14 Austrian centers with
TBI were collected prospectively (2009–2012) with the
goal of investigating and improving the outcome of
patients in Austria [25]. All TBI patients with a GCS
score <13 on site and/or AIS of the region “head”
>2 not later than 48 h after the injury were included.
Data on demographic characteristics, injury type
and severity, prehospital care, trauma room treat-
ment, monitoring, surgical procedures, computed
tomography (CT) scans, intensive care unit (ICU)
treatment (first 5 days) and outcome (ICU, hospital
and 6 months) were recorded. The Glasgow Outcome
Scale-Extended (GOSE) was used to categorize the
outcome at hospital discharge and 6 months after
injury [29, 30]. Data of 733 patients were eligible
for evaluation. The prehospital TBI project was per-
formed in accordance with the Declaration of Helsinki
and approved by the Ethics Committee of the Allge-
meine Unfallversicherungsanstalt (AUVA, the Austrian
Workers’ Compensation Board) as leading ethics com-
mittee and additionally by the ethics committee of
the federal state of Lower Austria as well as the ethical
care committees of all participating centers [25]. The
entire methodology of the prehospital TBI project,
K

patient eligibility criteria and the results of the study
have been previously reported [25].
In the present analysis, a subset of 67 citicol-
ine (Startonyl©, 125 mg/ml injection solution, Chiesi
Pharmaceuticals, Vienna) treated sTBI patients from
WNH enrolled in the INRO prehospital TBI project
was retrospectively studied in order to evaluate their
specific clinical outcome. Data from patients at WNH
included all details on TBI severity and outcome as
obtained in the INRO prehospital study as well as
some additional clinical information. The standard
dose of citicoline was 3 g per 24 h (=120 mg/h) by
continuous intravenous drip infusion starting imme-
diately after admission to the ICU up to an intended
maximum of 21 days [31].
In order to create a valid control group, 67 sub-
jects without any citicoline administration (exclusion
criterion) were selected from the INRO prehospi-
tal database of the remaining 13 Austrian centers.
Matching was done by using three predicting vari-
ables: age [32], GCS score assessed in the field and
number of extracranial injuries with a severity score
of >2 as assessed using the AIS. Differences in prehos-
pital and/or emergency room treatment between the
matched pairs were precluded.
Data analysis
Data analysis followed the comparison of a treatment
group with a matched control group. In order to ad-
dress possible differences between the two groups,
a descriptive comparative primary analysis was per-
formed with additional relevant predictors and indica-
tors of injury severity and treatment. These included
the Rotterdam CT score [33], the Injury Severity Score
(ISS) [34], the predicted 6 months mortality, the pre-
dicted 6 months unfavorable outcome (calculated us-
ing models that had been validated for the Austrian
population) [35] and the prehospital use of capnogra-
phy as a surrogate parameter for adequate ventilation
in the field [36]. A complete overview of all evaluated
therapeutic measures within the scope of the INRO
prehospital TBI project is given by Brazinova et al.
[25].
The GOSE was used to categorize the outcome of
TBI patients at hospital discharge (dead or alive) and
during a long-term follow-up (6 months postinjury)
[30]. The long-term outcome at 6 months was defined
as unfavorable when GOSE was 1–4 (death, vegetative
state or severe disabilities) and favorable when GOSE
was 5–8 (referred as moderate disabilities or good re-
covery). Univariate comparisons of severity and out-
come in both groups were used to detect a possible
effect of citicoline use in TBI patients. Ratios of ob-
served versus expected 6 months mortality and unfa-
vorable outcome (O/E ratios) were used to further as-
sess and evaluate the obtained results within groups.
A considerable improvement mediated by any ther-
apeutic intervention should be significantly reflected
K Citicoline in severe traumatic brain injury: indications for improved outcome
original article
in an O/E ratio <1 (percentage of mortality and of un-
favorable outcome were lower than expected). Crude
and adjusted odds ratios (OR) were calculated with
95% confidence intervals to reveal possible effects of
citicoline use on the outcome at various stages (ICU
discharge, hospital discharge, 6-month follow-up).
The intensive care physicians from all participating
Austrian centers conformed to the current guidelines
published by the Brain Trauma Foundation (BTF) [37,
38]. The consensus among Austrian trauma surgeons,
neurosurgeons and intensive care physicians to con-
form to standard treatment guidelines and algorithms,
especially the BTF guidelines and the concept of evi-
dence-based care in the management of TBI patients
was proactively encouraged and has been extensively
investigated [38–44]. Based on the published evidence
we presumed the standard treatment for TBI being
comparable among Austrian trauma centers. This has
been recently been proven by a survey among all Aus-
trian centers treating patients with severe TBI [38]. To
evaluate the outcome at WNH as well as the patterns
of citicoline administration, we secondarily assessed
the baseline characteristics and demographic data of
the citicoline treatment group (comparative analysis
between survivors and non-survivors). Due to in-
house quality standards at WNH, a variety of vital,
laboratory and medication parameters were available
beyond the data collected in the course of the INRO
prehospital TBI project. These data were additionally
evaluated in order to determine potential differences
between survivors and deceased patients.
Statistics
Means were expressed along with standard devia-
tions (SD) and medians with interquartile ranges
(IQR, range between the 25th and 75th percentile).
Categorical data were expressed as frequencies with
percentages from totals in the respective categories.
The T-test for two independent samples was used
to test for significance of differences of means, the
Wilcoxon test was used to test the difference be-
tween medians and the χ2-test was used to test for
differences in proportions (%). For the analysis of
relationships to outcome (crude and adjusted ORs),
the binomial logistic regression was used. P values
of <0.05 were considered as statistically significant
differences.
Results
Study participants
In the present examination, data of 134 TBI patients
from the INRO database were categorized as either
having received citicoline, referred to as citicoline
group (n = 67, WNH) or not having received any citico-
line during hospitalization referred to as control group
(n = 67, 13 Austrian centers). (S1 Fig. Flow diagram of
 original article

Table 1 Demographic and Variable Citicoline WNH Control Austrian centers p

baseline characteristics of (N = 67) (N = 67)
the treatment groups (citico-
Age (years), mean (SD) 54.6 (21.2) 54.8 (21.2) 0.904
line vs. control)
Extracranial injuries with AIS >2, mean (SD) 1.7 (0.9) 1.6 (0.9) 0.922
Total GCS assessed in the field, mean (SD) 7.8 (4) 7.7 (4) 0.961
Sex, N (% male) 52 (78%) 50 (75%) 0.839
ISS, mean (SD) 27.4 (12.4) 31.7 (17.3) 0.1
Total GCS assessed at admission, mean (SD) 6.4 (4.7) 6.0 (4.2) 0.662
Pupil reactivity in field, N (%)
Both reactive 41 (61%) 36 (54%) 0.702
One reactive 2 (3%) 2 (3%)
None reactive 3 (5%) 6 (9%)
Unknown 21 (31%) 23 (34%)
Pupil reactivity at admission, N (%)
Both reactive 28 (42%) 29 (43%) 0.416
One reactive 2 (3%) 5 (8%)
None reactive 1 (2%) 3 (5%)
Unknown 36 (54%) 30 (45%)
Rotterdam CT score, N (%)
1 2 (3%) 2 (3%) 0.052
2 22 (34%) 19 (31%)
3 31 (48%) 17 (28%)
4 7 (11%) 19 (31%)
5 2 (3%) 3 (5%)
6 0 1 (2%)
Subarachnoid hemorrhage, N (% Yes) 39 (58%) 41 (61%) 0.861
Epidural hematoma, N (% Yes) 8 (12%) 13 (19%) 0.342
Subdural hematoma, N (% Yes) 37 (55%) 43 (64%) 0.379
Prehospital hypotension, N (% Yes) 1 (2%) 4 (6%) 0.328
Prehospital hypoxia, N (% Yes) 5 (8%) 12 (18%) 0.19
Prehospital intubation, N (% Yes) 33 (49%) 40 (60%) 0.057
Use of capnography, N (%) 52 (93%) 46 (90%) 0.883
Predicted 6 months mortality, mean % (SD) 30.7% (18.6) 33.4% (21.7) 0.682
Predicted 6 months unfav. outcome, mean % (SD) 51.8% (21.6) 53.9% (23.7) 0.626
AIS Abbreviated Injury Scale, CT computed tomography, GCS Glasgow Coma Scale, ISS Injury severity score, SD standard
deviation, unfav. unfavorable outcome (dead, vegetative state or severe disability)

participating Austrian centers and patients from the
INRO prehospital database). Patient baseline char-
acteristics of the two groups are depicted in Table 1.
Demographic aspects were well-balanced among both
grpoups. With respect to the three matching criteria
no significant differences were revealed in our analy-
sis as to trauma severity measured by age (p = 0.904),
AIS (p = 0.922) and GCS assessed in the field or early
hospital phase (p = 0.961). In most cases the variables
were exactly matched. Comparison of additional
severity predictors and treatment indicators between
the two comparator groups revealed marginally worse
Rotterdam CT scores (p = 0.052) and ISS values (p =
0.1) in the control group; however, neither of the two
was statistically significant, indicating no association
or impact on differences in outcome between groups.
With respect to gender, predicted 6 months mortality
or unfavorable outcomes and the use of capnography
the groups did not differ significantly either.
Patients were administered a standard dose of
120 mg/h citicoline via continuous intravenous perfu-
sion from the first day of ICU admission for scheduled
21 days or until ICU discharge (S1 Table. Patterns of
citicoline use at WNH). Eventual lower average daily
dosage was caused by inevitable lower dosage at day 1
(depending on time of hospital admission) and dur-
ing the last day which was typically not a full 24 h
treatment day. Beyond that, these averages were also
influenced by periods when the administration of
citicoline was stopped (e. g. during surgery, CT scans
or other procedures) as well as the varying number
of ICU days in different patients. No significant dif-
ferences between survivors and non-survivors were
observed neither concerning the number (p = 0.795)
and percentage of days of citicoline administration

Citicoline in severe traumatic brain injury: indications for improved outcome K

 original article

Table 2 Outcomes at hos- Variable Citicoline WNH Control Austrian centers p-value
pital discharge and 6 months (N = 67) (N = 67)
post trauma
ICU mortality, % (N) 5% (3) 24% (16) <0.01
In-hospital mortality, % (N) 9% (6) 24% (16) 0.035
6 months mortality, % (N) 13% (9) 28% (19) 0.031
Predicted 6 months mortality, mean % (SD) 30.7% (18.6) 33.4% (21.7) 0.682
Observed vs. expected ratio for mortality 0.42 0.84 –
6 months unfavorable outcome, % (N) 34% (23) 57% (38) 0.015
Predicted 6 months unfavorable outcome, mean % (SD) 51.8% (21.6) 53.9% (23.7) 0.626
Observed vs. expected ratio for unfavorable outcome 0.66 1.06 –
P-values indicating significant differences are in bold
ICU intensive care unit, SD standard deviation, unfavorable outcome dead, vegetative state or severe disability

Table 3 Results for survival and for 6 months favorable outcome (citicoline group vs. control group)
Factor ICU survival p Hospital survival p 6-months favorable p 6-month survival p
outcome
Crude 6.7 (1.8–24.3) <0.01 3.2 (1.2–8.8) 0.024 2.5 (1.3–5.0) <0.01 2.6 (1.05–6.1) 0.037
OR (CI 95%)
Adjusteda 6.7 (1.6–28.8) 0.014 2.8 (0.9–9.1) 0.077 2.6 (1.1–6.0) 0.022 2.3 (0.8–6.1) 0.102
OR (CI 95%)
P-values meaning significant differences are in bold
CI confidence interval, ICU intensive care unit, OR odds ratio
a
Adjusted for age, first available Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS)

(p = 0.557) nor the daily dose of citicoline (p = 0.572).
We could not observe any remarkable side effects
during the entire study period.
Additional data further describing the patients
treated with citicoline at WNH are available (S2 Ta-
ble. Laboratory parameters of citicoline patients by
clinical outcome. S3 Table. Medication parameters
of citicoline patients at WNH. S2 Fig. Hemodynamic
parameters of survivors and non-survivors under citi-
coline therapy. S3 Fig. Mean S100B levels of survivors
and non-survivors under citicoline therapy by day of
treatment). Unfortunately, the data could not be ob-
tained from other centers in this analysis, as they were
not collected in the course of the INRO prehospital
project.
Outcome citicoline (WNH) group vs. control group
ing a significantly improved long-term survival rate
and functional outcome for citicoline users.
Logistic regression was used to assess the observed
differences and to adjust for potential effects of pre-
dictors (age, GCS and ISS). The odds ratios (ORs)
for survival at various time points and for favorable
outcome (moderate disability or good recovery) at 6
months postinjury are listed in Table 3. Patients in
the citicoline group had significantly higher odds of
ICU survival (OR 6.7; p < 0.01), hospital survival (OR
3.2; p = 0.024), 6 months favorable outcome (OR 2.5;
p < 0.01) and 6 months survival (OR 2.6; p = 0.037).
After controlling for the effects of age, first available
GCS score and ISS by multivariate analysis, adjusted
ORs still revealed significantly better odds for ICU
survival (p = 0.014) and 6 months favorable outcome
(p = 0.022) in the citicoline group.

The comparison of ICU mortality (p < 0.01), in-hospi- Discussion

tal mortality (p = 0.035), 6 months mortality (p = 0.031)
and 6 months unfavorable outcome (p = 0.015) of pa-
tients with citicoline administration vs. patients from
the matched control group revealed significant differ-
ences. At various time points, all outcome measure-
ments as well as the functional outcome at 6 months
were significantly better in the citicoline group, as pre-
sented in Table 2. The 6 months mortality was 13% in
patients with citicoline administration vs. 28% in the
control group. At the same time only 34% of patients
with citicoline administration vs. 57% of the controls
experienced an unfavorable outcome. The compari-
son of observed vs. predicted mortality and unfavor-
able outcome at 6 months revealed O/E ratios of 0.42
vs. 0.84 and 0.66 vs. 1.06, respectively, thus suggest-
In this retrospective analysis we aimed to investigate
the correlation of continuous, immediate, intravenous
citicoline administration and the outcome of patients
with TBI. In order to establish the optimal settings for
a comparison we created matched pairs to the pa-
tients of WNH and aligned them with respect to age
and TBI injury severity.
Key findings
The comparison of citicoline treated patients with
matched control subjects revealed significantly en-
hanced survival rates after ICU, hospital discharge
and 6 months after trauma, as well as significantly

K Citicoline in severe traumatic brain injury: indications for improved outcome

 original article
higher odds for a favorable outcome. After adjusting
for indicators of trauma severity and age, multivari-
ate logistic regression analysis indicated significantly
better odds of ICU survival and favorable outcome in
the citicoline group.
Recognizing the abovementioned surveys and the
consensus among Austrian trauma surgeons, neuro-
surgeons and intensive care physicians, our results
suggest a possible association between citicoline use
at WNH and the notably enhanced survival rates as
well as improved physical outcome in patients treated
after severe head injury.
Citicoline treatment patterns
Citicoline has repeatedly shown to be an effective neu-
roprotective and regenerative agent in a variety of
neurodegenerative disorders, brain ischemic condi-
tions as well as traumatic brain injuries and its se-
quelae. Over time, a great number of studies have
been issued, covering the mode of action [8, 9, 45] as
well as preclinical and clinical pharmacology of citi-
coline [11, 13, 19, 46, 47], including promising TBI-
related trials [5, 31, 48–50] and recently published re-
views [9, 51–53].;however, many preclinical and clini-
cal studies have been carried out more than 30 years
ago, thus lacking relevance to the current situation.
In recent years, especially after the publication of the
COBRIT study (a large, randomized, multicenter trial
including 1213 patients with TBI) [22] not only the
study methodology but also the effect and role of citi-
coline administration in TBI patients have been re-
peatedly called into question [52–54]. The negative
outcome of the COBRIT trial contradicts both the en-
couraging findings of animal and preliminary clini-
cal pilot studies and our own beneficial experience
with the substance in patients with TBI. With respect
to the heterogeneity of the disease, the wide thera-
peutic range (mild, moderate and sTBI) and several
available routes of administration, our strict clinical
assessment prior to the administration of citicoline is
a fundamental difference to the methodology of the
COBRIT trial. First, we adhere to early, continuous,
intravenous drip route of administration at 120 mg/h
from the day of ICU admission for scheduled 21 days
in order to ensure adherence and reach high citico-
line plasma concentrations from the very beginning
following the dose regimen of Calatayud et al. [10, 19,
31]. At WNH the administration pattern was changed
from bolus to continuous administration to optimize
the provision of substrate for lecithin metabolism of
brain cell membranes. Although citicoline bioavail-
ability is assumed to be virtually the same between
the oral vs. intravenous route, animal studies have
revealed a four times higher brain uptake with in-
travenous administration (2%) compared to the oral
route (0.5%) [45, 53, 55]. The atypical oro-enteral ad-
ministration of citicoline [22] has been criticized [52,
53] since it may cause poor compliance, while in ven-
Citicoline in severe traumatic brain injury: indications for improved outcome
tilated patients enteral absorption may already be im-
paired due to catecholamine administration and/or
deep sedation. A fundamental review of experimen-
tal and clinical studies on citicoline efficacy led to the
conclusion that patients with an initial GCS score of
5–7 particularly benefit from the addition of citicoline
to their therapeutic regimen [9, 31].
We are aware that the potential beneficial effects
of citicoline [9] subsequent to brain trauma may be
obscured by age-related factors, the heterogeneous
pathology of TBI and the great variability in treat-
ment and rehabilitation protocols. It is therefore all
the more important to establish a consistent manage-
ment starting immediately after the trauma [25] with
particular attention to the complex nature of the dis-
ease [3], the variety of influencing factors [56] and
the presence of several coexistent pathological mech-
anisms in individual patients.
Study limitations
The following limitations of our study necessitate
a cautious approach when interpreting our findings:
We conducted a retrospective, post hoc analysis of
a subset of patients, comprising a relatively small
sample size (i. e. citicoline non-survivors) with lim-
ited statistical power. We are aware of potential bias
in alternatively utilizing matched controls with simi-
lar injury severity from other Austrian centers. As we
did not have access to the medication patterns and
laboratory parameters of the matched control sub-
jects, our analysis was restricted to comparisons of
outcome measures and checks against the respective
prognostic scores. Due to the retrospective character
of this trial, the complex nature of the disease and
the variety of system factors and possible individual
treatment approaches it seemed preposterous to cor-
rect for the so-called center effect without further loss
of power. Nevertheless, the results of this preliminary
study suggest that citicoline may play a role in the
treatment of TBI thus confirming the clear need for
more carefully controlled studies [5, 9, 10, 20, 49, 57].
In accordance with other authors we are convinced
that the optimal management of TBI requires mul-
tiple therapeutic agents and structured protocols [3,
54]. Therefore, we call for further investigation on this
topic and feel encouraged to resume the discussion
about the benefits of citicoline administration in sTBI
patients. Thus, we are starting to set up a multicen-
ter, prospective, randomized, double-blind trial in
Austria with well-defined cohorts of sTBI patients, in-
vestigating all essential variables in terms of injuries,
prehospital and clinical treatment as well as outcome
parameters to clarify a possible effect of the citicoline
treatment as described (S4 Table. Preliminary RCT
study design for continuous and early citicoline in
sTBI in Austria). This trial will be supported by the
Austrian Society of Anesthesiology, Resuscitation and
Intensive Medicine (OEGARI).
K

Acknowledgements The authors acknowledge the members
of the International Neurotrauma Research Organization
(INRO) and collaborative partners for their work and the
collection of data used for analyses in this article. In partic-
ular, we want to express our special thanks and dedicate this
publication to Walter Mauritz who provided the impetus for
this investigation. Walter passed away in May 2015. He was
Vice President of the INRO and Professor of Anesthesiology
and Intensive Care Medicine at Trauma Hospital “Lorenz
Boehler” 2 in Vienna. We thank Chiesi Pharmaceuticals for
providing a research grant to facilitate data analysis and writ-
ing assistance. We thank Ulrike Posch for providing medical
writing services on behalf of Chiesi Pharmaceuticals.
Funding The INRO prehospital project was funded jointly
by the Austrian Ministry of Health (Contract Oct. 15, 2008)
and by the Austrian Worker’s Compensation Board (AUVA; FK
11/2008 and FK 11/2010). Data analysis was supported by
a grant from AUVA (FK 09/13). INRO is supported by an an-
nual grant from Mrs. Ala Auersperg-Isham and Mr. Ralph
Isham through the Neurotrauma Foundation, and by small
donations from various sources. Chiesi Pharmaceuticals pro-
vided a non-educational grant to facilitate initial data analy-
sis at INRO and writing assistance.
Conflict of interest H. Trimmel reports non-financial sup-
port from Chiesi Pharmaceuticals during the conduct of
the study. M. Majdan, A. Wodak, G. Herzer, D. Csomor and
A. Brazinova declare that they have no competing interests.
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