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January2011 Vol.48 Issue:      1 Table of Contents
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Traumatic Brain Injuries

Mervat M. Khalaf, Ehab Enab, Nael Samir, Ayman A. Heikal

 

Department of Critical Care Medicine, Cairo University; Egypt

 



ABSTRACT

Background: Recent studied proved efficacy of cerebrolysin in dementia and Alzheimer, although studies on traumatic brain injuries still limited. Objective: Investigating the efficacy of cerebrolysin as a neurotrophic drug on the prognosis and morbidity of TBI patients. Methods: Forty TBI patients were divided into 2 equally matched groups, group1 received cerebrolysin for 20 days plus other conventional therapy, and group 2 received only conventional therapy as a control group. Both groups were subjected to GCS, APATCHE II scores and CT brain on admission, and on day twenty, followed by comparing the degree of improvement in each group on day twenty to day one scores. Results: Patients on cerebrolysin compared to the control group on admission had no statistically significant difference as regards GCS, while on day 20 the GCS scores showed a significant difference between both groups (p-value= 0.045). There was a significant increase in GCS score on day 20 than GCS on day one in patients on cerebrolysin, p -value= 0.001 as compared to patients on conventional therapy p-value= 0.79. There was highly significant negative correlation between GCS difference and APACHE II scores in both group 1 & 2 as the p-value 0.05. Conclusions: The use of cerebrolysin as part of the initial management of head trauma is effective in improving the clinical status of patients with TBI after 20 days. [Egypt J Neurol Psychiat Neurosurg.  2011; 48(1): 43-48]


Key Words: TBI, cerebrolysin therapy, GCS, neurotrophic drug and APACHE score.

 

Correspondence to Mervat M. Khalaf. Critical Care Department, Cairo University; Egypt. 

Tel.: 020144913787. E-mail: samasalma@yahoo.com.




INTRODUCTION

 

All over the world, traumatic brain injury (TBI) is one of the leading causes of death. In the United States, it is the main reason of death for individuals under the age of 45 years, respectively the most frequent cause of physical or mental impairment1.

According to the statistics of Kraus and Mac Arthur2, 80% of hospitalized TBI patients suffer from injuries of minor, 10% of medium and 10% of pronounced severity; this bias towards minor risk should not distract from the fact that all these individuals are of relatively young age, which means that the percentage with high severity of injury refers to persons at the beginning of their productive life-period.

Cerebrolysin is a neuropeptide derived synthetic preparation produced by enzymatic breakdown of lipid-free animal neuroproteins. The neurotrophic and neuroprotective effect of Cerebrolysin has been well documented in several studies.3-9

On a cellular level, TBI leads to profound homeostatic changes, NMDA (N-methyl D-aspartate) receptor dysfunction, thus uncontrollable Ca++ ion flux which activates intracellular proteolytic enzyme pathways, resulting in neuronal degradation and death. One of the Ca++-activated proteolytic enzymes involved is the protease, calpain (calcium-dependent cysteine protease), a key enzyme in this degradation process, which under physiological conditions is important for the structure of the cell skeleton10,11.

 

As Wronski et al.12 demonstrated the pathological proteolytic activity of calpain as it is effectively inhibited by Cerebrolysin. This calpain inhibition may possibly be a result of fragments of the physiological calpain antagonist calpastatin, included in Cerebrolysin peptides. A similar effect may be responsible for the protection of the MAP2 (Microtubule associated protein 2) necessary for function positioning and directing of neuronal microtubules13.

In the present approach we tried to identify the role of cerebrolysin as a neurotrophic drug- a drug  that induce the survival, development and function of neurons- and its effect on the prognosis and morbidity of traumatic brain injury (TBI) patients.

 

PATIENTS AND METHODS

 

This was a randomized comparative clinical trial and was conducted on forty TBI patients, within 24 hours of the accident in the ICU of the neurosurgery emergency department; Kasr Al-Aini Hospital, Cairo, Egypt. All of them were victims of Road Traffic Accidents (RTA), during the period of Nov. 2007 to Oct. 2009. They were divided into 2 groups matched to age, sex and APACHE II (Acute Physiologic And Chronic Health Evaluation) scoring system; Group 1: twenty patients received cerebrolysin infusion 20 ml/day in physiological solution over one hour for 20 days with monitoring of hypersensitivity in the first 2 doses. Group 2: Control group, twenty patients received only the conventional therapy (basic drug therapy). Patients excluded from the study were those connected to mechanical ventilation, as the cerebral blood flow during positive pressure ventilation will be affected, patients who developed ARDS (Acute Respiratory Distress Syndrome), as the cerebral oxygen delivery will be affected, patients with severe renal impairment, as the cerebrolysin is contra-indicated in patients with renal impairment and patients who developed allergic reaction to the cerebrolysin.

 

All patients were subjected to the following:

History taking: from the patients or from their first degree relatives, it was done on admission.  History taking included age, sex, complaint, present history, past history of pre-morbid conditions and family history.

General medical examination and neurological examination: Was done to the patients on admission. GCS (Glascow Coma Scale) assessment was done to patients on admission before receiving any medications, and was done again at day twenty after completion of the medication course. The GCS is scored between 3 and 15, 3 being the worst, and 15 the best. It is composed of three parameters: Best Eye Response, Best Verbal Response, and Best Motor Response. A Coma Score of 13 or higher correlates with a mild brain injury, 9 to 12 is a moderate injury, and 8 or less is a severe brain injury.

CT brain: Was done to all patients after admission to assess the size and localization of the brain lesion, and was done after the twenty days in both patient groups.

Laboratory investigations: Were done to exclude any other medical conditions that may impair the conscious level and to complete the assessment of the patient (APACHE II scoring), including the following: arterial blood gases, serum Na & K, serum creatinine and complete blood count.

APACHE II scoring system: Was done to the patients within the first 24 hours from admission to predict the prognosis of the patients and to include patients in both groups with nearly the same predictive progression. APACHE II scoring system is the most common system used in assessment of critically ill patients in ICU. It stands for Acute Physiologic Assessment and Chronic Health Evaluation (APACHE II) score it was introduced in 1985. It generates a point score ranging from 0 to 71 based on 12 physiologic variables, age, and underlying health, the less the score the better the prognosis and vice versa. This scoring system showed reliability as shown in many studies.

Drug Therapy: Basic drug therapy for all patients consisted of steroids 24 mg dexamethazone for 2 weeks and then gradual tapering over one week then discontinued. Antibiotics, bronchodilators and antistress medications such as proton pump inhibitors, the application of any nootropic -smart drugs, memory enhancers, and cognitive enhancers as piracetam, vinpocetine, and selegiline- or psychotropic drugs or L-dopa and dopamine antagonists and glutamate system modulators, additional steroids or diuretics were excluded.

The patients received intravenous infusions of 20 ml/day of Cerebrolysin in the form of four 5ml ampoules in physiological solution (0.9 percent saline solution) over 1 hour.     

 

Statistical Analysis:

Patients’ data were tabulated and processed using SPSS (15.0) statistical package for Windows XP. Quantitative variables were expressed as means and standard deviation.

Descriptive statistics for parametric data of both groups and frequency tables was used for categorical data, T-test when comparison between parametric data of both groups was needed, Pearson correlation coefficients when examining the strength between two parametric variables. A p value of <0.05 is considered significant.

 

RESULTS

 

I.             Descriptive Results:

Groups were matched to sex, age and APACHE II score, each group included 16 males (80%) and 4 females (20%), (p -value=1). The age of the patients ranged from 13 : 63 yrs, with mean of 30.9±12.26  in group 1, and ranged from 19:55 yrs, with mean of 33.3±9.3 in group 2 (p -value = 0.49), As regards the APACHE II scoring system on admission, it ranged from 1:21 with mean of 9.9±5.3 in group 1, and it ranged from 4:22 with mean of 10.8±5.8 in group 2, there was no significant difference between APACHE II scores in both groups  (p-value =0.61) (Table 1).

According to GCS: on admission, in both groups 18 patients (90%) had GCS< 12 which was considered as moderate to severe head injury, and 2 patients (10%)had mild head injury (GCS>13) (Table 2). After 20 days: the GCS became different in group 1 (patients on cerebrolysin therapy), as 9 patients (47%) had GCS>13 (after being 10%), and the percentage of patients with severe head injury decreased from 35% to only 16%. Almost no change in group 2 (patients on conventional therapy) after 20 days as regards severity of head injury by GCS (Table 2).

N.B.: There was only one dead patient in each group through the period of follow up.

According to CT Brain: on admission, 25% of patients had no abnormalities detected (NAD) 35% of patients had contusions, 15% of patients had skull fractures, 10% of patients had brain edema, 5% had multiple hemorrhagic contusions and 10% had intracranial hemorrhage.

CT Brain findings at day 20: Nearly the same results as day 1 with slight increase in the number of patients who had NAD and decrease in patients with contusion, as patients with NAD and patients with contusion became 30% (Table 3).

No seizures occurred in patients of both groups from day one till day twenty.

 

II.           Comparative results:

Comparison of GCS on admission and on day 20 in each group: The GCS in group 1: On day 1, it ranged from (5: 15) with mean of 8.7±2.72 while on day 20 it ranged from (7:15) with mean of 11.75±3.28, There was a significant clinical improvement of the conscious level in group 1 who received Cerebrolysin for 20 days documented by G.C.S, as the p -value = 0.001 (Table 4).

The GCS in group 2: On day one it ranged from (5: 14) with mean of 9.6±2.6 while on day twenty it was 9.7±3, there was no significant difference between day one and twenty in group 2 (Table 4).

Comparison of GCS in both groups on day 1 and day 20: On day 1: Patients on cerebrolysin compared to the control group had no statistically significant difference as regards GCS, while at day20 GCS scores showed a significant difference between both groups as the p –value < 0.05 (Figure 1).

Impact of intracranial injury on APACHE II, GCS 20 & GCS difference (GCS20-GCS1): There was no significant difference between patients with no radiological abnormalities and those with contusion in patients on cerebrolysin as regarding the APACHE II, GCS20 and GCS difference scores. Patients with other radiological findings in both groups were small in number therefore we were not capable of comparing them.

 

III.          Correlative Results:

Correlation between GCS difference and APACHE II score in both cerebrolysin and control group: There was highly significant negative correlation between GCS difference and APACHE II scores in both group 1 & 2 as the p-value <0.05 (Table 5).

Correlation between age and both GCS difference and APACHE II in the control group: There was no significant correlation between age and both APACHE II and GCS difference in the control group.

Correlation between age and both GCS difference & APACHE II in patients received cerebrolysin: There was no significant correlation between age and both APACHE II and GCS difference in patients on cerebrolysin.


 

 

Table 1. Mean ± SD of patients' age and APATCHE II in both groups of patients with traumatic brain injury.

 

Variable

Group

Mean±S.D

p-value

Age

1

30.9±12.26

0.49

2

33.3±9.3

APACHE II

1

9.9±5.31

0.61

2

10.8±5.86

SD standard deviation

 

Table 2. Severity of head injury by GCS in both groups with traumatic brain injury on admission and on day 20.

 

Severity of head injury

On admission

Group 1(n= 20)

On admission

Group 2(n=20)

After 20 days

Group 1 (n=19)

After 20 days

Group 2 (n=19)

Mild head injury (13-15)

2 (10%)

2 (10%)

9 (47%)

2 (10.5%)

Moderate head injury (9–12)

11(55%)

10 (50%)

7 (37%)

10 (52.5%)

Severe head injury (3–8)

7 (35%)

8 (40%)

3 (16%)

7 (37%)

 

 

Table 3. CT Imaging data of all patients with traumatic brain injury on admission and at day 20.

 

CT Imaging data

Frequency

O/A

Percent

O/A

Frequency

After 20 days

Percent After 20 days

NAD

5

25%

6

30%

Contusion

7

35%

6

30%

Skull fracture

3

15%

3

15%

Brain edema

2

10%

2

10%

Multiple hemorrhagic contusions

1

5%

1

5%

Intracerebral hemorrhage

2

10%

2

10%

 

Table 4. Comparison of GCS on admission and on day 20 in each group of patients with traumatic brain injury 

Group

Scales

Mean±S.D

t-value

p-value

        Group I

GCS1

 

GCS20

8.7±2.7

-6.38

0.001**

11.75±3.3

         Group II

GCS1

 

GCS20

9.6±2.6

-0.27

0.79

9.7±3

 

 

 

Figure 1. Comparison of GCS in both groups with traumatic brain injury at day 1 & 20.

 

Table 5. Correlation between GCS difference and APACHE II score in both groups of patients with traumatic brain injury.

 

 

GCS20 – GCS1

APACHE

Group 1

r-value

-0.44

p-value

0.05*

APACHE

Group 2

r-value

-0.54

p-value

0.015*

*Significant at p<0.05

 


DISCUSSION

 

Traumatic brain injury is an important cause of morbidity and mortality, with an annual incidence higher than 200 cases per 100000 population. TBI represents one of the commonest causes of death and disabilities14.

Cerebrolysin is a neuropeptide derived synthetic preparation produced by breakdown of lipid-free animal neuroprotiens. It regulates the neuronal energy metabolism and is supposed to afford brain protection by its neurotrophic stimulation14.

Three intracellular pathways fundamentally contribute to the death of nerve cells after a traumatic brain injury”, said Dr. Robert Wronski12. The first pathway involves an increase of Ca++ concentrations in certain areas inside the cell, resulting from an intracellular Ca++ imbalance. This activates two enzymes, calpain and tissue-bound transglutaminase (tTG). After this activation, the enzyme calpain is chiefly responsible for protein depletion within the cytoskeleton, leading to a reduction of the microtubuli- associated protein 2 (MAP-2).

Apoptosis is the second pathological pathway, and may be triggered by various enzymes from the caspase family (The capsize-cascade system plays vital roles in induction, transduction and amplification of intracellular apoptotic signals). Caspases in turn can be activated by changes in intracellular Ca2+ homeostasis and an increased release of cytochrome C from mitochondria.

The third pathway leading to nerve cell destruction is the splitting of a protein calpastatin, by the enzyme caspase 3. Calpastatin is an inhibitor of both calpain isoforms. The resulting increase in calpain activity leads to an enhanced proteolytic activity inside the cell. Secondary deactivation of caspase 3 induces cell necrosis. Cerebrolysin has a direct influence on these pathophysiological mechanisms12.

In the present study, we tried to identify the true role of cerebrolysin as a neurotrophic drug on the prognosis of TBI patients.

Forty TBI patients were selected and divided into two groups matched to age, sex and a primary prognostic evaluation by using the APACHI II scoring system, then they were subjected to GCS scoring and CT brain on day one and day twenty, followed by defining the degree of improvement on day 20 in comparison to day one scores and GCS difference between day one and day twenty scores.                  

GCS results on day twenty showed a significant increase in patients on cerebrolysin than those on conventional therapy, such finding was supported by Konig et al.15, who found a significant increase in GCS scores in patients after three weeks with Cerebrolysin therapy than in patients on conventional therapy. While Wong et al.16 recruited patients with moderate or severe head injury and introduced  cerebrolysin, they then compared them with a historical cohort study of patients with moderate or severe head injury from trauma data bank, which was matched to their study group. They concluded that there was improvement in GCS scores but not significant in patients on cerebrolysin when compared to those patient from the historical cohort study on conventional therapy.

In a further emphasizes on the favorable role of cerebrolysin, we found a significant increase in GCS score on day twenty than GCS on day one in patients on cerebrolysin, and we didn’t find that significant increase in patients on conventional therapy.

In addition we tried to explore the relation between the primary prognostic scale APACHE II scoring system and degree of improvement in GCS score from day one to day twenty, and we found a simultaneous significant direct correlation in all patients.

Grmec and Gasparovic17 in their work on traumatic brain injury revealed that GCS is as good predictor as APACHE II scoring system in traumatic brain injury patients. The GCS is simpler, less time consuming and effective there for its application is much easier than APACHE II scoring system which has 12 physiologic variables, age and underlying health17.

Our patients showed different types of injuries, but they were mainly contusions (35%) detected by CT brain imaging on day one, and the less common was multiple hemorrhagic contusions. While in day twenty we found no significant changes in CT brain   imaging of patients in both groups.

There was no impact of different injury sites on prognosis, as there was no significant difference between patients with different site of injury as regarding APACHE II scoring system, GCS 20 and GCS difference.

Naseri et al.18 in their work on 800 craniocerebral trauma patients concluded that patients with no radiological findings, pneumocephalus, epidural hemorrhage, isolated cranium fractures and contusions had better prognosis than patients with intraventricular hemorrhage and mixed intracranial lesions with brain edema.

Finally there was no significant relation between patient age and both APACHE II score and GCS difference. 

In conclusion: patients on cerebrolysin showed a highly significant increase in GCS scores at day 20 than day 1 while patients on conventional therapy showed no significant changes in GCS scores on day 20 compared to day 1 so it can be concluded that the use of cerebrolysin as a part of the initial management of head trauma is safe and well tolerated.

 

[Disclosure: Authors report no conflicts of interest]

 

REFERENCES

 

1.      McIntosh T, Smith D, Meaney D, Kotapka M, Gennarelli T, Graham DI. Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. Lab Invest. 1996; 74: 315-42.

2.      Kraus JV, Mac Arthur DL. Epidemiologic aspects of brain injury. Neurol Clin. 1996; 14: 435–50.

3.      Prueller F. In-vitro Effekte potentiell neurotropher Substanzen bei Zytostatika-induzierter Neurotoxizität. Dissertation Univ. Graz, Klassifikation G0803, 2000.

4.      Rockenstein E, Mallory M, Mante M, Alford M, Windisch M, Moessler H, et al. Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer’s disease. J Neurol Transm Suppl. 2002; 62: 327–36.

5.      Sugita Y, Kondo T, Kanazawa A, Itou T, Mizuno Y. Protective effect of FPF 1070 (Cerebrolysin) on delayed neuronal cell death in the gerbil-detection of hydroxyl radicals with salicylate. No To Shinkei. 1993; 45: 325–31.

6.      Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I. The dentate gyrus neurogenesis. A therapeutic target for Alzheimer’s disease. Acta Neuropathol (Berlin). 2003; 105: 225–32.

7.      Wakonigg G. Untersuchung der Wirkung des peptidergen Medikamentes Cerebrolysin auf verschiedene transgene Modelle der Neurodegeneration. Dissertation Univ. Graz, Klassifikation G0646, 2000.

8.      Haninec P, Dubovy P, Samal F, Houstava L, Stejskal L. Reinnervation of the rat musculocutaneous nerve stump after direct reconnection with the C5 spinal cord segment by the neuronal graft following avulsion of the ventral spinal roots: a comparison after intrathecal administration of brain-derived neurotrophic factors in Cerebrolysin. Exp Brain Res. 2004; 159: 425-32.

9.      Haninec P, Houstava L, Stejskal L, Dubovy P. Rescue of rat spinal motoneurons from avulsion-induced cell loss by intrathecal administration of IGF-I and Cerebrolysin. Ann Anat 2003; 185: 233-8.

10.    Kampfl A, Posmantur R, Nixon R, Grynspan F, Zhao X, Liu SJ, et al. mu-calpain activation and calpainmediated cytoskeletal proteolysis following traumatic brain injury. J Neurochem. 1996; 67: 1575-83.

11.    Johnson GVW, Guttmann RP. Calpains intact and active? BioEssays. 1997; 9: 1011-8.

12.    Wronski R, Tompa P, Hutter PB, Crailsheim K, Friedrich P, Windisch M. inhibitory effect of brain derived peptide preparation on the ca++- dependant protease, calpain. J Neural Transm. 2000; 107: 145-57.

13.    Gutmann B, Hutter PB, Skofitsch M, Windisch G, Gmeinbauer R. In vitro models of brain ischemia: the peptidergic drug cerebrolysin protect cultured chick cortical neurons from cell death. Neurotox Res. 2002; 4: 59-65.

14.    Alvarez XA, Lombardi VR, Novoa LF, Garcia M. Cerebrolysin reduces microglial activation in vivo and in vitro: A potential mechanism of neuroprotection. J Neurol Transm, 2000; 59: 281-92.

15.    König P, Waanders R, Witzmann A, Lanner G, Haffner Z, Haninec P, et al. Cerebrolysin; a Neurotrophic and Neurogenic Agent in the Treatment of Acute Traumatic Brain Injury. J für Neurol Neurochirurg Psychiatrie. 2006; 7 (3): 12-20.

16.    Wong GK, Zhu XL, Poon WS. benifitial effect of cerebrolysin on moderate and severe head injury patients; Acta Neurochir Suppl. 2005; 95: 59-60.

17.    Gremec S, Gasparovic V. Comparison of APACHE II, MEES and Glasgow Coma Scale in patients with nontraumatic coma for prediction of mortality. Acute Physiology and Chronic Health Evaluation. Mainz Emergency Evaluation System. Crit Care. 2001; 5(1): 19-23.

18.    Naseri M., Tomasian A, Moghaddas A. Correlation of CT scan findings with the level of consciousness in acute head trauma. Iran J Radiology, 2005; 2: 125-9.


 

الملخص العربى

 

فاعلية مادة السريبروليسين في علاج الصدمة المخية

 

الصدمة المخية هى أحدى الأسباب الهامة لاعتلال واضطراب درجة الوعى وأكثر الأسباب شيوعا للوفاة و العجز بين الأشخاص التى تقل أعمارهم عن 35عاما. أثبتت الدراسات الحديثة فعالية مادة السريبروليسين فى علاج الخرف ومرض الزهايمر فى حين قلت الدراسات  التى أجريت على الصدمة المخية كانت محدودة .السريبروليسين هو عبارة عن مادة دوائية تقوى وتحافظ على الأعصاب.

لذا كان الهدف من هذه الدراسة تقييم التحسن فى المرضى الذين يتلقون علاج السريبروليسين باستخدام مقياس جلاسكو لتحديد درجة الغيبوبة – الأشعة المقطعية – مقياس اباتشى 2 للحالات الحرجة بعد 20 يوما من تلقى علاج السريبروليسين، وتقييم تحسن الوظائف العصبية فى المرضى الذين يتم معالجتهم بالسريبروليسين بالمقارنة مع المرضى الذين يتم معالجتهم بالعلاجات التقليدية الأخرى.

قمنا باختيار 40 مريض بالصدمة المخية وتم تقسميهما إلى مجموعتين متطابقتين فى السن والجنس والتقييم الأولى باستخدام مقياس اباتشى 2 للحالات الحرجة، ثم تم معاينتهم باستخدام مقياس جلاسكو لتحديد درجة الغيبوبة والأشعة المقطعية للمخ فى اليوم الأول واليوم العشرين يليه تقييم درجة التحسن فى اليوم 20 لعشرين مقارنة مع حالة المريض فى اليوم الأول.

وأظهرت نتائج الدراسة زيادة مقياس جلاسكو لتحديد درجة الغيبوبة فى اليوم العشرين زيادة ملحوظة فى المرضى الذين يتم إعطائهم عقار سريبروليسين عن المرضى الذين يتم إعطائهم عقارات تقليدية. مما يؤكد وجود دور ايجابية لهذا العقار من خلال زيادة ملحوظة فى نتائج مقياس جلاسكو لتحديد الغيبوبة المسجل فى اليوم العشرين عن  نتائج مقياس جلاسكو لتحديد درجة الغيبوبة فى اليوم الأول فى المرضى الذين يتم إعطائهم عقار سريبروليسين وأننا لم نجد هذه الزيادة الملحوظة فى المرضى الذين يتم إعطائهم عقارات تقليدية. 

وتوصى الدراسة باستخدام عقار سريبروليسين فى وقت مبكر من بداية الصدمات المخية للمساعدة فى خفض معدلات الوفيات والاعتلال فى المرضى، كما توصى بأجراء دراسات طويلة المدى لمعرفة دور هذا العقار فى خفض معدلات الإصابة بالإعاقة فى مرضى الصدمات المخية.



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