Journal of the Neurological Sciences, 103 (1991) S!

5-S18
1991 Elsevier Science Publishers B.V. 0022-510X/91/$03.50 JNS 03587

S15

Effects of CDP-choline on the recovery of patients with head injury

V. C a l a t a y u d M a l d o n a d o , J.B. C a l a t a y u d P 6 r e z a n d J. A s o E s c a r i o
Department of Neurosurgery, Hospital Cl[nicode Zaragoza, Zaragoza (Spain)

Summary

A single blind randomized study has been conducted in 216 patients with severe or moderate head injury, with the aim of comparing the evolution of those that received only conventional treatment with the evolution of those treated with CDP-choline. Our results indicate that CDP-choline improves the global outcome of patients. We have found a trend towards a greater improvement in motor, cognitive and psychic alterations in the patients treated with CDP-choline, as well as a shortening of the stay in the hospital ward in the patients receiving this drug that initially presented with severe head injuries.

Introduction

Experimental studies have shown that brain injuries cause a decrease in the amount of cell membrane phospholipids. This structural alteration causes a failure of the sodium-potassium pump and the consequent accumulation in intracellular water. This cytotoxic edema adds to the vasogenic edema that is caused by the breakdown of the hematoencephalic barrier [1,2]. CDP-choline is an essential precursor in the synthesis of brain glycerophospholipids [3] and its administration to animals suffering an experimental brain injury is associated with a decrease in cerebral edema [4,5] and in electroencephaiographic alterations [6,7]. Some clinical studies in patients suffering head injuries compared the effects of CDP-choline added to conventional treatment with the effects of conventional treatment alone. A decrease in the duration of coma and in the persistence of neurologic alterations was observed [8,9]. The aim of the present study has been to assess the efficacy of CDP-choline in a large series of patients. It included 216 patients that were randomly assigned to conventional treatment or CDP-choline added to conventional treatment.

Material and methods

During the period of the study, we included in our trial the patients that were attended in our hospital presenting with a head injury and having an initial score comprised between 5 and 10 in the Glasgow Come Scale (GCS) [10]. Thus, the patients included in our trial had severe or moderate head injuries. Patients

with open cerebral trauma or severe systemic disease were excluded from the study. After giving their informed consent, patients were randomly assigned to one of 2 treatment groups: conventional treatment or CDP-choline added to conventional treatment. The dose of CDP-choline was 1 g every 6 h by intravenous infusion during the first and second day, and 1 g every 8 h by intravenous infussion during the third and fourth days. Thereafter, the patients that wore a phleboclisis received the same dose until discharge, and those without a phleboclisis received 1 g every 12 h. After discharge, the dose of CDP-choline was 200 mg every 8 h by mouth. The total duration of treatment was variable, depending on the evolution of the patient. Patients left the intensive care unit (ICU) when they presented a stable hemodynamics and did not require assisted ventilation. They left the ward when they fulfilled the following criteria: they were conscious and had interaction with their environment, they walked alone or with only minimal help and they were not dependent on others in the activities of daily living. The evolution of the patients was assessed three months after injury by the Glasgow Outcome Scale (GOS) (Table 1). The presence of the following symptoms was assessed at the moment the patient left the ICU and 3 months after injury: headache, dizziness, motor disfunction, memory problems, superior neurological disfunctions and changes in character. The memory problems were assessed by an adaptation of the Hodkinson Brief Mental Test [12] that includes 10 simple questions. The presence of superior neurological disfunctions was assessed by the WAIS. Finally, the total days spent in the ICU and in the

S16
TABLE l DESCRIPTION OF THE GLASGOW OUTCOME SCALE [l l]
! Good recovery: the patient has the capacity to resume normal occupational and social activities, although there may be minor physical or mental deficits. Moderate disability: independent life, but some previous activities are no longer possible. Severe disability: the patient is conscious, but needs the assistance of another person for some activities of daily living. Vegetative state: the patient shows no evidence of meaningful responsiveness. Death. Patients (n) 50 40 30 20 10 0 CDP-choline Control 1~40 2~0 4~560

II III IV V

Age (years)
/ CDP-choline ~ Control Fig. l. Distribution of patients by age.

ward were other parameters that we used for the assessment of the patient's evolution. We used the chi-square test to compare the scores in the GOS for the patients treated with CDP-choline with the scores in the same scale for the patients that received only conventional treatment. The same statistical test was used to compare the percentages of patients whose symptoms had remitted at three months. Finally the Student's t test was used to compare the two groups of patients for their stay in the ICU and their stay in the ward.

Results

One hundred and ~dfteen patients were treated with CDP-choline, and 101 patients received only conventional treatment. There were no significant differences between the treatment groups in the distribution of patients by age, sex and the initial severity of the head injury (Figs. 1 and 2). Eighteen patients in the CDP-choline group and 10

patients in the control group died during their stay in the ICU (difference non significant by chi-square test). Therefore, 97 patients in the CDP-choline group and 91 patients in the control group were valid for posterior outcome comparisons. Mean stay in the ICU (Fig. 3) and the percentage of patients initially presenting each symptom (Fig. 4) were not significantly different in the two treatment groups. However, mean stay in the ward was significantly greater in the control patients that had presented an initial GCS of 5-7 (Fig. 3). The evaluation of the improvement for each of the initially present symptoms (Fig. 5) showed a greater proportion of improved patients in the CDP-choline group for all of the symptoms. Difference for changes in character was significant (P < 0.05). Finally (Table 2), the distribution of patients by their scores in the GOS showed significantly better results (P < 0.05) for the CDP-choline group in the

B) GCS 5-7
60403020" 10-

A) GCS 8 - 1 0
Patients (n) 60 40 80 20 10 0 I COP-cholinq Control

/
/ / / /

Patients (n)

O" /__.

ICOP-choline Control
l COP-choline ~ Control

CDP-chollne

Control

Fig. 2. Distribution of patients by sex and initial score in the GCS in each treatment group.

S17

A) GCS 5-7
IOU ICU

B) GCS 8-10

6.86

Wwd

Ward !

10

18 Days

20

28

80

8 Days

8 Control

i
p.06

COP-choline

Control

CDP-chollne

Fig. 3. Mean stay in the ICU and the ward, adjusting for initial severity in the GCS.

percentage of patients with "good recovery", with no significant difference for the percentage of fatalities.

Discussion Results of our study show that CDP-choline improves the overall outcome of patients with head injury, although there are no significant differences in the death rate. As regards the percentage of improved patients for each of the symptoms, there is a significant difference favouring CDP-choline for the changes in character and a similar trend for the other symptoms. The differences that we observe for motor disfunction and superior neurological disfunction might have attained statistical significance if more patients had been included in the trial. It is also interesting to note that mean days spent in the ward were significantly less in the patients treated

with CDP-choline that had presented with an initial GCS of 5-7. Our results are in accordance with those obtained by Raggueneau and Jarrige [13,14]. These authors made a restrospective study on 921 patients with severe head injury from several centers in France. They included in their study the patients that had presented with an initial GCS inferior or equal to 7. They found that CDP-choline did not modify the mortality rate, nor the frequency of vegetative states, but improved the outcome of patients with an initial GCS of 6 or 7, reducing the frequency of dependent states in favour of independent states and improving the quality of survival with more frequent family and social reinsertion. Cohadon and Richer [8] found that patients in traumatic coma treated with CDP-choline had a better evolution than those receiving only conventional treatment as regards the level of consciousness at 60 days from injury and the percentage of patients without focal neurological signs at 60 and 90 days.

Headache Dizziness Motor disfunction Memory problems

Headache

2.7;268

*~7.58

Motor diefunction

41.66

,io:0

Memory problems

90.76

S.N.D.
Changes in character

.
0

14.26

S.N.D. ~ 91.83 *
I

t o m t i t
20 4O
CDP-choline

so,I,

Changes in character
i

6O Patients (%)

80

100

20

80 Improved Patients (%) COP-choline ~

40

60

100

120

~ W i Control S.N.D.- Superior Neurological Disfunction

Control pc .05

S.N.D.- Superior Neurological Oiafunction

Fig. 4. Percentage of patients presenting each symptom in the CDP-choline and control groups when leaving the ICU.

Fig. 5. Percentage of patients improved at 3 months for each initially present symptom.

S18
TABLE 2 DISTRIBUTION OF PATIENTS BY THEIR SCORES IN THE GOS AT 3 MONTHS G.O.S.
I

CDP-choline
77 *

Control 51 31
7

I! I!I IV V * P <0.05.

19
1

0 18

2 10

Results obtained by Bias et al. [9] indicated that CDP-choline shortens the duration of coma in patients with head injury and decreases the percentage of those showing neurological signs or psychological troubles 6 months after injury. Therefore, our results and those of other authors indicate that CDP-choline is effective and safe in the treatment of patients with moderate or severe head injuries.

References
1 Virier, A., M. Jomin, G. l_~es, F. Lesoin (1984) L'oed~me cer6bral Post-traumatique. Phystb?athologie et th6rapeutique. Sem. Hosp. Paris, 60(10): 673-677. 2 Gannushkina, I.V. (1986) Pathogenesis of traumatic brain edema. In: G. Mchedlishvili, J. Cerv6s-Navarro, K.A. Hossmann and I. Klatso (Eds.), Brain Edema, A pathogenetic analysis. Akad6miai Kiad6, Budapest, pp. 290-292. 3 Arienti, G., L. Corazzi, P. Mastrofini et al. (1979) Involvement of CDP-choline in phospholipid metabolism of brain tissue "in vivo". Ital. J. Biochem., 28: 39-45.

4 Cohadon, F., M. Rigoulet, B. Guerin and M. Vandendriessche (1979) Oed~me c~r~bral vasog~nique. Alt~rations des ATPases membranaires. Restauration par un pr~curseur des phospholipides. Nouv. Presse M~d., 8: 1589-1591. 5 Lafuente, J.V. and J. Cerv6s-Navarro (1986) "Estudio por microgravimetrla del efecto de la CDP-colina en el edema cerebral experimental inducido por radiaciones ultravioletas". Med. Clin. (Barc.) (Suppl. I), 87: 5-8. 6 Algate, D.R., D.J. Beard, A. Sacrist:~n, J.A. Ortiz and J.E. Davies (1983) Study of the effects of oral administration of CDP-choline on EEG changes and lethality induced by epidural compression in the anaesthesized cat. Arzneim. -Forsch. Drug Res., 33(11): 1013-1016. 7 Majem, X., A. Bidon-Chanal and J. Vila Bad6 (1986) Estudio del tratamiento oral con CDP-colina rgbre los cambios inducidos por el edema encef~lico experimentai cn el electroencefalograma de la rata no anestesiada. Med. Clin. (Barc) (Suppl. I) 87: 23-25. 8 Cohadon, F. and E. Richer (1985) CDP-choline in severe traumatic coma: a double blind study. In: V. Zappia, E.P. Kennedy, B.J. Nilsson and P. Galletti (Eds.), Novel Biochemical, Pharmacological and Clinical Aspects of Cytidine Diphosphocholine. Elsevier Science Publishing Co., New York, pp. 299-304. 9 De Bias, A., J.M. Cubells and C. Hernando (1986) Valoraci6n de la efectividad de la citicolina en el tratamiento de los traumatismos craneoencef:~licos. Med. Clin. (Barc.) (Suppl. I), 87: 41-44. I0 Teasdale, G. and B. Jennet (1974) Assessment of coma and impaired consciousness. A. practical scale. Lancet, ii: 81-84. II Jennett, B., J. Snoek, M.R. Bond and N. Brooks (1981) Disability after severe head injmy: observations on the use of the Glasgow Outcome Scale. J. Neurol. Neurosurg. Psychiat., 44: 285-293. 12 Hodkinson H.M. (1972) Evaluation of a mental test score for the assessment of mental impairment in the elderly. Ageing, I: 233238. 13 Raggueneau, J.L. and B. Jarrige (1988a) Epid~miologie: pronostic et devenir de 921 traumatis~s crani~ns graves. Agressologie, 29: 433-438. 14 Raggueneau, J.L. and B. Jarrigue (1988b) Enqu~:te nationale sur les suites des traumatismes crfiniens graves: analyse des 219 traumatismes trait6s par CDP-choline. Agressologie, 29: 439-443.