http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, 2014; 28(11): 1413–1416 ! 2014 Informa UK Ltd. DOI: 10.3109/02699052.2014.916821

ORIGINAL ARTICLE

Single versus bilateral external ventricular drainage for intraventricular fibrinolysis using urokinase in severe ventricular haemorrhage Bo Du1, Jin Wang1, Xian-liang Zhong1, Jian Liang2, Wei Xiang2, Dong Chen2, Wen Lv1 & Ai-jun Shan1 1

The Emergency Department and 2The Neurosurgery Department, Shenzhen People’s Hospital, the Second Clinical College of Jinan University, Shenzhen, Guangdong Province, PR China Abstract

Keywords

Background: Intraventricular fibrinolysis (IVF) through bilateral external ventricular drains (EVD) may provide better access of the thrombolytic agent to the intraventricular clot, potentially leading to faster clot clearance. Objective: To compare the feasibility and safety between single and bilateral EVD groups. Methods: Patients with spontaneous intraventricular haemorrhage (IVH) (Graeb score  5) were treated with IVF. The selection for placement of one or two EVDs was randomized. The average daily CSF drainage volume, the indwelling EVD time, the time for monitoring in intensive care unit (ICU), intracranial re-haemorrhage and intracranial infection, Glasgow coma score (GCS), Graeb score and the reserved IVH volume have been analysed for patients with one (group I, n ¼ 22) or two EVDs (group II, n ¼ 25). Results: Significant difference was found in the average daily CSF drainage volume between the two groups (85.2 (SD ¼ 13.7) vs. 108.5 (15.9) ml). No difference was found in the indwelling EVD time, the time for monitoring in the ICU. Through repeated measurements of the variance analysis, the test for a difference in IVH volume over time was statistically significant (F ¼ 466.981, p ¼ 0.000) and the test for the interaction between treatment and time was also significant (F ¼ 5.033, p ¼ 0.002), indicating that the IVH volume decreased over time in both groups, with a sharper decrease in Group II. Intracranial re-haemorrhage and infection was not found in this study. Conclusion: The results provide some evidence to support the use of bilateral EVDs for IVF in patients with severe IVH.

External ventricular drainage (EVD), Intraventricular haemorrhage (IVH), Intraventricular fibrinolysis (IVF)

Introduction Intraventricular haemorrhage (IVH) is common and serious. The incidence of IVH accounts for 30–60% among all sorts of cerebral haemorrhage and the mortality rate is as high as 42.6  83.3% [1]. Especially for patients with severe IVH, usually accompanied by involvement of two or more ventricles, the mortality would be almost 100% if they only receive conventional conservative treatment [2]. Previous studies have indicated that intraventricular clot fibrinolysis (IVF) via administration of thrombolytic agents through the external ventricular drainage (EVD) could significantly accelerate IVH clearance without any major side-effects [3, 4]. Theoretically, bilateral EVDs may provide better access of the thrombolytic agent to the IVH, resulting in faster clot lysis and blood removal than single EVD. The placement of single or bilateral EVD in such cases is usually decided by the treating physician according to their own Correspondence: Ai-jun Shan, Professor, Emergency Department, Shenzhen People’s Hospital, the Second Clinical College of Jinan University, Dongmen North Road 1017, Shenzhen, 518020, Guangdong province, PR China. Tel: +86 15914141979. Email: [email protected]

History Received 22 December 2013 Revised 18 February 2014 Accepted 16 April 2014 Published online 15 May 2014

experience. This study aims to evaluate the efficacy of IVF through a single vs bilateral EVD in patients with severe IVH by using urokinase Tianjin Biochem Pharma Co., Ltd, Tianjin, China.

Methods Patient selection and division method This study used the Graeb score [5] to select the patients (for lateral ventricles: no blood (0); trace of blood (1); 550% of ventricle filled with blood (2); 450% (3); ventricle filled with blood and dilated (4); for 3rd and 4th ventricles: trace of blood (1); ventricle filled with blood and dilated (2); maximum score: 12). The Ethical Review Board of the Hospital has approved this study. All patients with severe IVH due to spontaneous ganglionic haemorrhage who need EVD operation were treated with IVF. Inclusion critera: the initial Graeb score 5 on admission; primary IVH or secondary IVH with extraventricular haematoma volume less than 15 millilitres. Exclusion criteria: with severe respiratory, circulatory, digestive, urinary or immunological system complications; with haematoma of the posterior fossa or suspected intracranial aneurysm or arteriovenous malformations; with

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active intracranial haemorrhage; undergoing heparin treatment (not anti-platelet drug) 2 weeks before admission; with obvious coagulation disorder (PT: 3 seconds more than the normal reference value or APTT: 10 seconds more than the normal reference value or PLT: less than 75  1012 L1); the cases who died within 7 days after admission. All the patients were divided into two groups randomly. One was the single EVD group (group I), the other was the bilateral EVD group (group II). Treatment algorithm Basic management IVH were diagnosed immediately after admission by CT and then treated with EVD. An airtight ventricle drainage and monitoring system (Medtronic, Inc. Minneapolis, MN) that was equipped with multiple interfaces and intracranial pressure (ICP) measurement kits facilitated the process of medication injection and ICP measurement after EVD operation. All patients received ceftriaxone sodium antibiotics (Roche, Inc. Shanghai, China) and CSF was analysed for infection every day. IVF management IVF was initiated 12–48 hours after symptom onset; 20 000 U of urokinase dissolved in 10 ml normal saline was injected into the lateral ventricle through the EVD. For Group II, the selection among the two EVDs for urokinase injection was randomized every time. After the administration of urokinase, the EVD was clamped for 1 hour. The administration of urokinase was repeated every 12 hours. IVF would be ceased if the third and fourth ventricles were cleared from blood on CT and the Graeb score for each lateral ventricle was 52. EVD management After clearance of blood in the third and fourth ventricles, the Graeb score for each lateral ventricle 52 and ICP 520 mmHg for more than 24 hours, the EVD removal procedure was initiated. For Group I, the EVD was clamped for 24 hours and removed if ICP remained 520 mmHg and CT showed no increase in ventricular size. For Group II, one of the EVDs was closed for 24 hours and removed if ICP remained 520 mmHg and CT revealed no ventricle enlargement. With one EVD remaining, patients were treated as already described for the single EVD group. If the attempt to clamp the EVD was not successful, extracorporeal CSF outflow was continued by lumbar drainage (LD) and EVD was removed after 24 hours [6]. Imaging and data analysis CT scans were performed on admission, 1 day after IVF and then daily up to day 3, day 5 and day 7. For each time point, the reserved IVH volume, the Graeb score, Glasgow coma score (GCS) was recorded and analysed. The average daily CSF drainage volume, the time for monitoring in intensive care unit (ICU) and the indwelling EVD time was recorded and analysed. The main complications were rehaemorrhagia and intracranial infection due to catheter implantation.

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Statistical analysis A Shapiro-Wilk test was performed to analyse the distribution of the data. Normally distributed data are expressed as mean (SD) and were compared using the unpaired t-test. A Chi-square test was conducted to test whether there was significant difference in the sex distribution between the two groups. The IVH volume, Graeb score and GCS were compared using the repeated measures analysis of variance. A value of p50.05 was considered significant.

Results Between January 2010 and June 2013, a total of 47 patients with spontaneous ganglionic ICH and ventricular haemorrhage were treated with IVF according to the protocol. Relevant demographic, clinical and neuroradiological characteristics are shown in Table I. There was no difference between the two groups with regard to sex, age, GCS, Graeb score and initial volume of IVH on admission. The average daily EVD drainage of CSF significantly differ between groups (t ¼ 6.17, p ¼ 0.000), while there was no difference between groups in time for monitoring in ICU and indwelling EVD time (Table II). No re-haemorrhagia or intracranial infection was found in this study. Through repeated measurements of the variance for statistical analysis, the IVH volume, Graeb score and GCS over time for participants undergoing single EVD and bilateral EVD are displayed. The results are as follows: The test for a difference in IVH volume over time was highly statistically significant (F ¼ 466.981, p ¼ 0.000). The test for the interaction between treatment and time was also significant (F ¼ 5.033, p ¼ 0.002). Thus, the IVH volume decreased over time in both groups, with a sharper decrease in Group II. The test for a difference in Graeb score and GCS over time was also statistically significant (Graeb score: F ¼ 907.721, p ¼ 0.000; GCS: F ¼ 48.120, p ¼ 0.000), indicating that the Graeb score decreased over time and the GCS improved over time in both groups, but the test for the interaction between Table I. Demographic, clinical and neuroradiological characteristics.

Sex (male/female) Age (years) Glasgow Coma Scale on admission Graeb score on admission Intraventricular haemorrhage volume on admission (cm3)

Single EVD (n ¼ 22)

Bilateral EVD (n ¼ 25)

p Value

12/10 51.5 ± 8.7 6.1 ± 1.7

13/12 52.1 ± 8.6 6.1 ± 1.6

0.861 0.071 0.998

9.8 ± 1.7 80.6 ± 11.0

10.0 ± 1.5 79.4 ± 10.5

0.135 0.697

EVD, external ventricular drainage.

Table II. The average daily EVD drainage of CSF, time for monitoring in ICU and indwelling EVD time.

The average daily EVD drainage of CSF Time for monitoring in ICU Indwelling EVD time

Single EVD

Bilateral EVD

p Value

85.4 ± 14.8

108.8 ± 14.1

0.000

14.1 ± 4.2 10.6 ± 3.2

15.8 ± 4.6 12.4 ± 4.1

0.192 0.104

Single vs bilateral EVD

DOI: 10.3109/02699052.2014.916821

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Table III. The IVH volume, Graeb score and GCS on admission, 1 day after IVF treatment and then daily up to day 3, day 5 and day 7.

IVH volume Single EVD Bilateral EVD Graeb score Single EVD Bilateral EVD GCS Single EVD Bilateral EVD

Before EVD

1 day after IVF

3 days after IVF

5 days after IVF

7 days after IVF

89.5 ± 10.8 84.4 ± 9.8

62.8 ± 7.9 45.5 ± 6.7

43.7 ± 6.8 31.2 ± 5.9

33.6 ± 5.2 24.8 ± 4.7

26.4 ± 3.7 14.8 ± 3.2

10 ± 1.2 10 ± 0.9

7.6 ± 0.8 7.4 ± 0.8

5.4 ± 0.6 5.2 ± 0.6

4.3 ± 0.5 4.1 ± 0.5

3.2 ± 0.4 3.0 ± 0.3

6.2 ± 1.8 6.4 ± 1.5

6.0 ± 1.8 6.1 ± 1.7

6.6 ± 1.8 6.8 ± 1.9

7.2 ± 2.1 7.6 ± 2.0

8.2 ± 2.4 8.6 ± 2.1

EVD algorithms and the time did not reveal a statistically significant effect: Graeb score (F ¼ 1.493, p ¼ 0.221), GCS (F ¼ 0.727, p ¼ 0.578) (Table III).

Discussion This study investigated the use of single or bilateral EVDs for IVF in patients with severe IVH and obtained some evidence in support of the use of bilateral EVDs because it could significantly accelerate IVH clearance without any major side-effects. First, the course of IVH resolution in Group II was significantly more effective than Group I. In particular, compared with the single EVD group, the bilateral EVD could significantly increase the average daily drainage volume of CSF, resulting in faster expurgation of IVH. Second, there was no difference in the indwelling EVD time, the time for monitoring in ICU, intracranial re-haemorrhage proportion or intracranial infection complications. Experimental studies [7, 8] have displayed that the IVH volume and the time of CSF exposure to blood could significantly affect the mortality and the outcome of neurological status and this effect was independent of the mass effect or hydrocephalus due to IVH. So, bilateral EVD could lead to earlier clearance of IVH, potentially resulting in lower mortality and better outcome of neurological status. In the present study, the GCS restoration for the two groups revealed no differences, indicating that faster expurgation of IVH via bilateral EVD could not obviously improve early recovery of consciousness. The analysis for post-operative intracranial infection also revealed no differences between the two groups. So, it is concluded that careful pre-operative disinfection, continuous application of ceftriaxone sodium for injection after operation and timely replacement of the wound dressing could make it absolutely possible to avoid intracranial infection. Moreover, application of a high-quality EVD system could also reduce the possibility of infection during ICP measuring, fibriolysis drug injection and CSF sampling. However, a retrospective study performed by Staykov et al. [6], which aimed to evaluate the EVD treatment for severe IVH, demonstrated that the course of intraventricular haematoma resolution was identical between the single and the bilateral EVD group and that bilateral EVD may lengthen the time for removing the catheter and may increase the chance of intracranial infection. It is realized that the major difference between this study and Staykov et al.’s is the selection method for patients. In Staykov et al.’s study, the IVH volume of the

patients was generally much less than that in this study (84.4 ± 9.8 ml vs 34.7 ± 11.3 ml). Thus, it is extrapolated that maybe the bilateral EVD could only benefit the patients with more severe IVH, but, to the authors’ knowledge, it is still difficult to determine the detailed threshold value of IVH volume for implementing different EVD treatment. Theoretically, there may be some disadvantages of an additional EVD including additional brain damage, periprocedural bleeding, intracranial infection and increasing the hospitalization costs. However, compared to such critical ill conditions for the patients, fast drainage of IVH and reduction in mortality are much more important than those potential complications. Since the Graeb score can not quantitatively evaluate the IVH volume, it is unlikely that this approach could exactly reflect dynamic changes of IVH, thereby minimizing difference on the comparison of single vs bilateral EVD. Limitation The eventual outcome analysis for the patients was not included. Thus, the outcome including the eventual recovery of neurological function and the mortality between the two groups merit further study.

Conclusion Compared to the single EVD group, the bilateral EVD can effectively accelerate the IVH clearance in severe patients, especially for those with Graeb score 5. The potential complications due to additional catheter implantation could almost be avoided by careful operation and other protective measurements.

Declaration of interest This study was sponsored by two grants from Shenzhen Science and Technology Fund Committee, Shenzhen, Guangdong, China (grant no. 201203130 and 201201011).

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with urokinase: Effects on 30-Day survival. Stroke 2000;31: 841–847. 3. King NK, Lai JL, Tan LB, Lee KK, Pang BC, Ng I, Wang E. A randomized, placebo-controlled pilot study of patients with spontaneous intraventricular haemorrhage treated with intraventricular thrombolysis. Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society Of Australasia 2012;19: 961–964. 4. Torres A, Plans G, Martino J, Godino O, Garcia I, Gracia B, Acebes JJ. Fibrinolytic therapy in spontaneous intraventricular haemorrhage: Efficacy and safety of the treatment. British Journal of Neurosurgery 2008;22:269–274. 5. Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and Prognosis Radiology 1982;143:91–96.

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6. Staykov D, Huttner HB, Lunkenheimer J, Volbers B, Struffert T, Doerfler A, Ganslandt O, Juettler E, Schwab S, Bardutzky J. Single versus bilateral external ventricular drainage for intraventricular fibrinolysis in severe ventricular haemorrhage. Journal of Neurology Neurosurgery and Psychiatry 2010;81:105–108. 7. Pang D, Sclabassi RJ, Horton JA. Lysis of intraventricular blood clot with urokinase in a canine model: Part 1. Canine intraventricular blood cast model. Neurosurgery 1986;19: 540–546. 8. Mayfrank L, Kissler J, Raoofi R, Delsing P, Weis J, Ku¨ker W, Gilsbach JM. Ventricular dilatation in experimental intraventricular hemorrhage in pigs. Characterization of cerebrospinal fluid dynamics and the effects of fibrinolytic treatment. Stroke 1997; 28:141–148.

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Single versus bilateral external ventricular drainage for intraventricular fibrinolysis using urokinase in severe ventricular haemorrhage.

Intraventricular fibrinolysis (IVF) through bilateral external ventricular drains (EVD) may provide better access of the thrombolytic agent to the int...
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