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Efficacy of Low-Dose Tissue-Plasminogen Activator Intracisternal Administration for the Prevention of Cerebral Vasospasm After Subarachnoid Hemorrhage
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Efficacy of Low-Dose Tissue-Plasminogen Activator Intracisternal Administration for the Prevention of Cerebral Vasospasm After Subarachnoid Hemorrhage Takuji Yamamoto, Takanori Esaki, Yasuaki Nakao, Kentaro Mori
Key words 䡲 Cisternal irrigation 䡲 Interleukin-6 䡲 Matrix metalloproteinase-9 䡲 Subarachnoid hemorrhage 䡲 Tissue plasminogen activator 䡲 Vasospasm Abbreviations and Acronyms CSF: Cerebrospinal fluid CT: Computed tomography IL-6: Interleukin-6 LDA: Low density area MMP-9: Matrix metalloproteinase-9 m-RS: Modified Rankin scale SAH: Subarachnoid hemorrhage t-PA: Tissue plasminogen activator WBC: White blood cell WFNS: World Federation of Neurosurgical Societies From the Department of Neurosurgery, Juntendo University Shizuoka Hospital, Izunokuni, Shizuoka, Japan To whom correspondence should be addressed: Takuji Yamamoto, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2010) 73, 6:675-682. DOI: 10.1016/j.wneu.2010.04.002 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
䡲 BACKGROUND: Vasospasm is one of the important factors associated with the functional prognosis after subarachnoid hemorrhage (SAH). Intracisternal administration of thrombolytic agents to dissolve subarachnoid clots may be responsible for bleeding complications. The efficacy and safety of cisternal irrigation therapy using low-dose tissue plasminogen activator were evaluated. 䡲 METHODS: Sixty patients with SAH were treated by surgical clipping, and randomly divided into three groups: 1) the control group (n ⴝ 20) treated only with baseline treatment; 2) the intermittent group (n ⴝ 20) received intermittent administration of clotlysis agent (tisokinase 960,000 IU); and 3) the continuous group (n ⴝ 20) received continuous irrigation using pH-adjusted lactate Ringer’s solution containing tisokinase (96 IU/mL) infused at 20 mL/hr for 48 hours. The clearance of subarachnoid clots was measured by laboratory examinations and postoperative computed tomography. Ischemia-related vasospasm was evaluated by neurological status and computed tomography. Neurological outcome was evaluated by the modified Rankin scale at 3 months after onset. 䡲 RESULTS: The subarachnoid clot was efficiently and significantly removed without major complication in the intermittent and continuous groups (P < 0.05). The incidence of ischemic lesion in the intermittent group was significantly lower than in the control group (P < 0.05). The intermittent group had significantly better neurological outcome than the control group (P < 0.05). 䡲 CONCLUSIONS: Cisternal irrigation therapy using low-dose tissue plasminogen activator is effective and safe. Intermittent injection is most effective and may decrease the risk of symptomatic vasospasm in patients with SAH.
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INTRODUCTION Delayed cerebral vasospasm remains a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). The severity of cerebral vasospasm may be correlated with the volume and distribution of the subarachnoid clots. Many patients have been treated by evacuation of the subarachnoid hematoma in the early stages of ruptured aneurysm to prevent cerebral vasospasm (4, 7, 9, 13, 16, 20, 25). Fibrinolytic agents, such as urokinase or tissue plasminogen activator (t-PA), may be effective, but treatment with intracisternal t-PA might not prevent cerebral vasospasm caused by aneurysmal SAH (23). This treatment is also associated with se-
vere risk of hemorrhagic complications such as intracranial hemorrhage. Therefore, evacuation of subarachnoid hematoma to prevent cerebral vasospasm is commonly accepted, but the optimal administration and dosage of fibrinolytic agents have not been established. Repeated low-dose administration with t-PA or continuous irrigation with urokinase might prevent cerebral vasospasm without severe complications (6, 7, 17, 18, 26). We believe that cisternal irrigation therapy with fibrinolytic agents is a potentially effective option if an appropriate dosage and safe administration method can be established, although previous investigations have not been promising (23). The present study attempted to improve the functional outcome of patients with
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SAH by prevention of vasospasm, tried to confirm the efficacy of cisternal irrigation therapy with t-PA, and tried to establish the optimal protocol for t-PA by comparing intermittent administration and continuous irrigation with t-PA in patients with aneurysmal SAH.
MATERIALS AND METHODS Patient Selection The clinical trial protocol was reviewed and approval by Juntendo University Shizuoka Hospital ethical community. All patients or their legally authorized representatives provided written informed consent. This study included 60 consecutive patients presenting with SAH from February 2006 to May
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Table 1. Clinical Characteristics of the Patients Control Group (n ⴝ 20)
Intermittent Group (n ⴝ 20)
Continuous Group (n ⴝ 20)
Total No. of Patients (n ⴝ 60)
7/13
6/14
7/13
20/40
Men/women Age (mean ⫾ SD, year)
64.6 ⫾ 13.2
63.1 ⫾ 9.6
66.8 ⫾ 11.8
64.8 ⫾ 11.5
⬍ 70 year
12 (60.0%)
15 (75.0%)
13 (65.0%)
40 (66.7%)
ⱖ 70 year
8 (40.0%)
5 (25.0%)
7 (35.0%)
20 (33.3%)
5.0
5.0
0
3.3
45.0
45.0
35.0
41.7
Antiplatelet agents (%)* Smoking rate WFNS grade (mean ⫾ SD) I
1 (5.0%)
3 (15.0%)
6 (30.0%)
10 (16.7%)
II
8 (40.0%)
8 (40.0%)
7 (35.0%)
23 (38.3%)
III
1 (5.0%)
1 (5.0%)
1 (5.0%)
3 (5.0%)
IV
4 (20.0%)
4 (20.0%)
2 (10.0%)
10 (16.7%)
V
6 (30.0%)
4 (20.0%)
4 (20.0%)
14 (23.3%)
WFNS, World Federation of Neurosurgical Societies. *Percentage of patients taking antiplatelet agents (aspirin, clopidogrel, or ticlopidine).
2007. The etiology of SAH was the ruptured aneurysm in all patients. All patients were treated by surgical clipping. They were randomized into three groups by the stratified block randomization method using the following factors: age, sex, World Federation of Neurosurgical Societies (WFNS) SAH grade, Fisher’s computed tomography (CT) group, and location of aneurysm. The control group was treated only with baseline treatment without cisternal irrigation therapy; the intermittent group received intermittent administration of clotlysis agent; and the continuous group received continuous irrigation incorporating clotlysis agent. We excluded patients with untreated aneurysm. We also excluded patients with suspected incomplete clipping.
Baseline Treatment Protocol Patients with SAH were surgically treated within 72 hours after onset, then basically managed under normovolemic and normotensive conditions. During the aneurysm clipping surgery, Liliequist’s membrane was opened and the cisternal drainage tube was placed in the basal cistern. Induced hypertension was attempted in patients with deteriorated neurological status due to vasospasm. Fasudil hydrochloride 90 mg (Eril S, Asahi Kasei Pharma; Tokyo, Japan) was administered every day for 14 days (22, 24).
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Decompression surgery consisting of decompressive craniectomy with extended duroplasty was performed in patients with acute brain swelling. Intermittent Drug Administration Protocol As a clotlysis agent, tisokinase 160,000 IU (Plasvata, Asahi Kasei Pharma) was administered into the basal cistern through the cisternal drainage tube every 8 hours for 2 days. After administration, the drainage catheters were closed for 2 hours. The total dose of tisokinase was 960,000 IU. Continuous Cisternal Irrigation Protocol Continuous cisternal irrigation used pHadjusted lactate Ringer’s solution containing tisokinase (96 IU/mL), infused at 20 mL/hr for 48 hours through an external ventricular drainage catheter, and drained from the cisternal drainage or spinal drainage catheters. The total dose of tisokinase was 960,000 IU, and the total volume of irrigation solution was 1000 mL. The infusion flow rate was controlled by the infusion mechanical pump. The overflow root was set at a height of 15 cm H2O to avoid excessive infusion. During irrigation, all drainage catheters were carefully maintained to avoid drainage problems such as overdraining or increased intracranial pressure.
Evaluation Definition of Symptomatic Vasospasm. Symptomatic vasospasm was defined as clinical neurological deterioration attributable to vasospasm, after exclusion of hydrocephalus, seizures, surgical invasions, or other causes. However, symptomatic vasospasm was difficult to define based only on clinical deterioration, particularly in high grade patients. Therefore, we defined low density areas (LDA) on CT as symptomatic vasospasm after other causes had been excluded by repeated postoperative CT (4, 5). A neurosurgeon unaware of the clinical details agreed that the LDA might be caused by delayed ischemic neurological deficit after SAH. Postoperative Evaluation. CT was performed on postoperative days 1, 3, 5, 7, 10, and 14. All surgical and hemorrhagic complications were recorded. To evaluate the clearance of the subarachnoid hematoma clot, CT number (in Hounsfield units) of the basal cistern was measured preoperatively, and on days 5 and 14. Appearance of LDA due to vasospasm was recorded and the volume of the LDA was measured on day 14. The CT number of the cistern and the LDA were measured by a neurosurgeon unaware of the patient’s clinical status. Cerebrospinal Fluid Analysis. Routine cerebrospinal fluid (CSF) analysis (white blood
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2010.04.002
PEER-REVIEW REPORTS TAKUJI YAMAMOTO ET AL.
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Table 2. CT-based Diagnosis Control Group (n ⴝ 20)
Intermittent Group (n ⴝ 20
Continuous Group (n ⴝ 20)
Total No. of Patients (n ⴝ 60)
Fisher’s CT group (mean ⫾ SD) II
2 (10.0%)
4 (20.0%)
3 (15.0%)
9 (15.0%)
III
12 (60.0%)
11 (55.0%)
8 (40.0%)
31 (51.7%)
6 (30.0%)
5 (25.0%)
9 (45.0%)
20 (33.3%)
Hydrocephalus at surgery
IV
11 (55.0%)
9 (45.0%)
12 (60.0%)
22 (53.3%)
Permanent V-P shunt (%)*
77.8%
61.1%
56.3%
62.3%
Side of aneurysm†
7/9/4
7/3/10
9/4/7
23/16/22
4
9
1
14
Site of aneurysm IC ACA
8
5
11
24
MCA
7
4
8
19
VA-BA Ant./post. Size of aneurysm (mean ⫾ SD, mm)
1
2
0
3
19/1
18/2
20/0
57/3
7.7 ⫾ 5.1
5.8 ⫾ 3.2
5.9 ⫾ 3.2
6.4 ⫾ 4.0
ACA, anterior cerebral artery; Ant./post., anterior circulation/posterior circulation; CT, computed tomography; IC, internal carotid artery; MCA, middle cerebral artery; VA-BA, vertebral artery-basilar artery; V-P, ventriculoperitoneal. *Ratio of patient placed V-P shunt in survival patients at 3 month. †Values on the left/midline/right.
cell [WBC], protein, glucose, specific gravity) was performed on days 1, 3, 5, 7, 10, and 14. Interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) were measured on day 10. All drained CSF was accumulated for 5 postoperative days, and the volume of washed out red blood cells was calculated by hematocrit (percentage) of the CSF.
younger than 70 years old. The distribution of WFNS grades showed no statistical differences therefore the average neurological condition was moderate. The three groups had no significant differences in age, sex, or WFNS grade. The percentages of patients taking antiplatelet agents before onset were
also not significantly different. The CTbased diagnosis and treatment are presented in Table 2. Acute hydrocephalus at the surgical point was recognized in approximately 50% of all patients, with no statistical differences between groups. The necessity for permanent ventriculoperitoneal
Neurological Outcomes. Neurological outcome and mortality was evaluated by Glasgow Outcome Scale and modified Rankin scale (m-RS) at 3 months.
Statistical Analysis The data were collected and analyzed using the 2 test, Fisher’s exact test, Kruskal-Wallis test, and Spearman’s rank test. Significance was defined as P ⬍ 0.05.
RESULTS Patient Profile The clinical characteristics of the 60 patients are summarized in Table 1. Mean age was 64.8 years old, and 40 patients were
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Figure 1. Chronologic changes in density of the basal cistern in Hounsfield units were significantly decreased in both the intermittent group and the continuous group on day 5 (*P ⬍ 0.05, **P ⬍ 0.05), and were significantly different in all groups on day 14.
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Figure 2. Representative case of a 61-year-old woman with World Federation of Neurosurgical Societies grade 4 and Fisher’s computed tomography (CT) group III. (A) Preoperative CT scan revealing subarachnoid hemorrhage caused by a ruptured anterior communicating artery aneurysm. (B) CT scan showing that most of the subarachnoid clot had
been removed on day 5. (C) CT scan showing no low density area related to ischemic event on day 14, and complete removal of the hematoma in the basal cistern. CT number in the basal cistern was measured at the same point (*) in each patient.
Table 3. Chronologic Change of CSF Parameters Day 1
Day 3
Day 5
Day 7
Day 10
Day 14
Control group
2.08 ⫾ 0.13
0.94 ⫾ 0.04
0.96 ⫾ 0.08
0.97 ⫾ 0.04
1.06 ⫾ 0.10
0.24 ⫾ 0.01
Intermittent group
2.97 ⫾ 0.21
2.56 ⫾ 0.19
1.08 ⫾ 0.05
0.69 ⫾ 0.03
0.39 ⫾ 0.01
0.41 ⫾ 0.03
Continuous group
2.18 ⫾ 0.19
1.48 ⫾ 0.07
1.06 ⫾ 0.06
0.87 ⫾ 0.05
0.73 ⫾ 0.10
0.25 ⫾ 0.01
Control group
0.24 ⫾ 0.01
0.68 ⫾ 0.05
0.91 ⫾ 0.04
0.70 ⫾ 0.03
0.63 ⫾ 0.03
0.42 ⫾ 0.02
Intermittent group
0.29 ⫾ 0.01
1.17 ⫾ 0.03
0.99 ⫾ 0.02
0.74 ⫾ 0.04
0.49 ⫾ 0.02
0.34 ⫾ 0.01
Continuous group
0.19 ⫾ 0.01
0.53 ⫾ 0.02
0.89 ⫾ 0.03
0.72 ⫾ 0.02
0.47 ⫾ 0.02
0.39 ⫾ 0.02
⬎WBC (mean ⫾ SE, 103/m)
Total bilirubin (mean ⫾ SE, mg/dL)
FDP (mean ⫾ SE, g/mL) Control group
114.0 ⫾ 5.6
95.9 ⫾ 5.0
117.3 ⫾ 5.6
99.3 ⫾ 3.8
73.4 ⫾ 4.0
52.1 ⫾ 4.0
Intermittent group*
228.8 ⫾ 10.3
500.5 ⫾ 26.5
118.7 ⫾ 8.7
65.1 ⫾ 2.1
50.1 ⫾ 1.9
33.1 ⫾ 1.4
Continuous group
226.8 ⫾ 15.1
144.8 ⫾ 5.7
78.3 ⫾ 4.8
65.2 ⫾ 2.2
39.4 ⫾ 1.5
37.5 ⫾ 1.8
Control group
148.4 ⫾ 3.1
147.1 ⫾ 6.1
147.0 ⫾ 6.9
147.9 ⫾ 7.7
149.2 ⫾ 6.7
146.0 ⫾ 5.5
Intermittent group
148.8 ⫾ 3.9
147.2 ⫾ 4.4
147.7 ⫾ 5.7
147.5 ⫾ 6.1
144.5 ⫾ 8.4
145.7 ⫾ 5.9
Continuous group
149.3 ⫾ 5.7
149.1 ⫾ 8.3
149.3 ⫾ 7.6
146.4 ⫾ 7.9
146.2 ⫾ 6.6
148.8 ⫾ 7.5
Na (mean ⫾ SD, mEq/L)
K (mean ⫾ SD, mEq/L) Control group
3.10 ⫾ 0.55
2.86 ⫾ 0.60
2.61 ⫾ 0.35
2.58 ⫾ 0.42
2.61 ⫾ 0.22
2.71 ⫾ 0.31
Intermittent group
3.01 ⫾ 0.37
2.80 ⫾ 0.42
2.73 ⫾ 0.62
2.53 ⫾ 0.27
2.55 ⫾ 0.19
2.68 ⫾ 0.18
Continuous group
2.98 ⫾ 0.42
2.80 ⫾ 0.34
2.59 ⫾ 0.28
2.65 ⫾ 0.30
2.68 ⫾ 0.26
2.81 ⫾ 0.22
CSF, cerebrospinal fluid; FDP, fibrin/fibrinogen degradation products; WBC, white blood cell. *P ⬍ 0.05 compared with other groups.
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uous group (40%, 8/20) and the intermittent group (20%, 4/20). The control group had more severe LDA in patients with cerebral infarction (69.7 ⫾ 12.4 mL), but with no significant difference (22.7 ⫾ 8.5 mL in the intermittent group and 25.2 ⫾ 3.2 mL in the continuous group). Decompressive surgery was performed in 18 patients (30.0%): 9 patients in the control group, 4 in the intermittent group, and 5 patients in the continuous group. There was no significant difference between groups, although more patients required decompression surgery in the control group because of the higher incidence of cerebral infarction as a result of vasospasm.
Figure 3. Chronological changes of fibrin/fibrinogen degradation products (FDP) in cerebrospinal fluid (CSF). The FDP level in the intermittent group was significantly elevated on day 3. The FDP levels in all groups gradually decreased.
shunting tended to be lower in the intermittent and continuous groups than in the control group, but without significance. Thirtyone patients were classified as Fisher’s group III, 20 patients had intracerebral hematoma combined with SAH as Fisher’s group IV, and only 9 patients presented with Fisher’s group II. No significant difference was present between groups.
Clearance of Subarachnoid Hematoma The volume of drained CSF during 5 days was significantly larger in the continuous group (1565.9 mL) than in the control group (919.6 mL) and the intermittent group (1004.5 mL), because irrigation fluid was included. The ratio of blood in the drained CSF calculated from the hematocrit and the daily amount of drained CSF was (mean ⫾ SE) 17.9 ⫾ 1.1 mL for the intermittent group, which was significantly higher than 7.5 ⫾ 0.4 mL for the control group, and 11.6 ⫾ 0.5 mL for the continuous group (P ⬍ 0.05), which was higher than the control group without significance. The CT number (in Hounsfield units) in the basal cistern was significantly lower in both the intermittent group (mean ⫾ SD; 20.27 ⫾ 6.8) and the continuous group (21.6 ⫾ 10.7) on day 5 than in the control group (43.6 ⫾ 13.8, P ⬍ 0.05), occurring immediately after administration of t-PA. The CT number was significantly decreased in the control group (61.4 ⫾ 8.8 on day 0 and 26.6 ⫾ 7.3 on day 14), similar to those in the intermittent group
(57.97 ⫾ 7.4 on day 0 and 18.0 ⫾ 8.5 on day 14) and the continuous group (56.0 ⫾ 12.0 on day 0 and 17.4 ⫾ 7.4 on day 14), on day 14 (Figure 1). An illustrative case in the intermittent group is presented in Figure 2.
Cerebral Infarction as a Result of Vasospasm Cerebral infarction as a result of vasospasm was analyzed on day 14. The ratio of patients with LDA was highest in the control group (55%, 11/20 patients), followed by the contin-
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CSF Analysis The chronological changes of WBC count and other chemical markers are shown in Table 3. The WBC in CSF significantly changed during the 14 days after surgery, but without differences between the groups. Three patients were clinically diagnosed with meningitis— two patients in the control group and one in the continuous group. These patients were treated with standard antibiotic drugs. The fibrin/fibrinogen degradation products in CSF in the intermittent group were significantly higher than in the other two groups at more than 500 g/mL on day 3, then decreased to the same level as in the control group (P ⬍ 0.05). The fibrin/fibrinogen degradation products were higher in the continuous group than in the control group for the first 3 days after surgery, but without significant differ-
Figure 4. Chronologic changes of Na and K in cerebrospinal fluid (CSF).
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Table 4. Neurological Outcome at 3 month After Onset GOS* at 3 month (%)
m-RS†
GR
MD
SD
VS
D
Favorable outcome
Mean
Control group
3 (15.0%)
5 (25.0%)
7 (35.0%)
3 (15.0%)
2 (10.0%)
6 (30.0%)
3.5
Intermittent group
8 (40.0%)
4 (20.0%)
7 (35.0%)
1 (5.0%)
0
12 (60.0%)‡
3.2‡
Continuous group
4 (20.0%)
5 (25.0%)
6 (30.0%)
1 (5.0%)
4 (20.0%)
4 (20.0%)
3.9
15 (25.0%)
14 (23.3%)
20 (33.3%)
5 (8.3%)
6 (10.0%)
22 (36.7%)
3.2
Total
GOS; Glasgow Outcome Scale; mRS, modified Rankin scale. *According to GOS: GR, good recovery; MD, moderately disabled; SD, severely disabled; VS, vegetative state; D, dead. †According to m-RS. Favorable outcome was defined as m-RS scores 2 or less. ‡P ⬍ 0.05 compared with other groups.
ence (Figure 3). The sodium levels in CSF varied in a similar range (145–150 mEq/L). The potassium level followed a similar course in all groups, which decreased to approximately 2.6 mEq/L by 5 days after surgery, and slowly increased until day 14, but did not return to the initial level (Figure 4).
Examination of IL-6 and MMP-9 in CSF The drained CSF on day 10 was analyzed for IL-6 and MMP-9. The mean IL-6 was highest in the control group (mean ⫾ SE; 5258.9 ⫾ 320.1 pg/mL), followed by the intermittent group (3419.4 ⫾ 3.0 pg/mL) and the continuous group (1961.8 ⫾ 101.6 pg/mL), with a significant difference between the control group and the continuous group (P ⬍ 0.05). The mean MMP-9 was highest in the control group (mean ⫾ SE; 58.4 ⫾ 7.4 ng/mL), followed by the intermittent group (31.9 ⫾ 3.0 ng/mL) and the continuous group (23.6 ⫾ 2.3 ng/mL), with no significant difference between groups. There was no evidence that MMP-9 level was increased by t-PA administration.
Outcome Analysis The outcomes at 3 months after surgery are shown in Table 4. Favorable outcome evaluated by the Glasgow Outcome Scale (good recovery and moderately disabled) was achieved in 8 patients in the control group, 12 patients in the intermittent group, and 9 patients in the continuous group. The intermittent group showed significantly better m-RS outcome than the other groups (P ⬍ 0.05), with 12 patients with m-RS scores of 2 or less. The mortality rate was 10% in the
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control group, 0 in the intermittent group, and 20% in the continuous group. Overall data analysis of the correlation between the outcome and both MMP-9 and IL-6 are shown in Figure 5. The level of IL-6 in the CSF was correlated with m-RS in patients with SAH (P ⬍ 0.01). The level of MMP-9 in the CSF was also correlated with m-RS (P ⬍ 0.01). Higher levels tended to indicate poor prognosis regardless of patient group. Hemorrhagic complication occurred in one patient of the continuous group, who suffered minor SAH around the treated aneurysm. This aneurysm had a very complicated neck shape that was difficult to obliterate. Incomplete clipping may have caused the hemorrhage. DISCUSSION Extensive removal of subarachnoid clot in the acute stage reduces the occurrence of
vasospasm associated with ruptured aneurysm, as substances in the subarachnoid clot are widely accepted to induce vasospasm. Many previous investigations have shown that intracisternal administration of fibrinolytic agents can effectively remove subarachnoid clot and prevent the development of clinical vasospasm (3, 7, 9, 13, 20, 25). The present study confirmed that fibrinolytic therapy is effective in patients with SAH. Various methods for administering fibrinolytic agents into the cisterns for prevention of vasospasm have been reported. The intraoperative bolus injection method directly introduces a relatively high dose of t-PA (⬎10 mg) into the basal cisterns. Intracisternal administration of t-PA is effective for the prevention of vasospasm (4, 15). Postoperative injection after early treatment of ruptured aneurysm is another safe and
Figure 5. Correlations between the outcome of all patients and both interleukin-6 (IL-6) (A) and matrix metalloproteinase-9 (MMP-9) levels (B). Increased IL-6 and MMP-9 levels were significantly correlated with modified Rankin scale (m-RS) (IL-6: *y ⫽ 821.48x ⫹ 1097.1, P ⬍ 0.01; MMP-6: **y ⫽ 7.3677x ⫹ 6.3868, P ⬍ 0.01) analyzed by Spearman’s rank test.
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effective method (6, 9, 27). However, unfavorable results have been obtained in some studies (3, 23). Continuous cisternal drainage to remove subarachnoid hematoma is one of the most common procedures in Japan. Cisternal irrigation therapy using urokinase is widely practiced to prevent vasospasm, and achieves a low ratio of vasospasm in patients treated (7, 17, 26). Intraoperative cisternal fibrinolysis using t-PA combined with continuous cisternal drainage prevents symptomatic vasospasm after SAH (6). However, the efficacy of t-PA for the prevention of vasospasm could not be confirmed by multicenter randomized study, possibly because the relatively complicated administration method might not have been established as a routine procedure. In addition, the dosage of intraoperative t-PA might be too high, resulting in hemorrhagic complications. Repeated intrathecal administration of 0.1 mg t-PA three times daily for 5 days was useful for reducing vasospasm (18). The hemorrhagic complication may be avoided by using a lower dosage of t-PA. In the present study, t-PA was used as a fibrinolytic agent to obtain a stronger action to dissolve the subarachnoid clot, with a shorter administration period or decreased number of doses. The dosage was determined by referring to the previous study (6). Tisokinase (960,000 IU) was administered for 2 days in both the intermittent group and the continuous group, corresponding to 2.4 mg of alteplase. The total dosage without intraoperative injection was less than the dosage of the original study (1.6 – 3.2 mg of t-PA). This study compared intermittent injection and continuous irrigation. The efficacy of hematoma clearance evaluated by CT number was almost equal, which should depend on the dosage of t-PA. The significant decreases in CT number in both the intermittent group and the continuous group compared with the control group suggest that the dosage was effective. However, the intermittent injection method was more effective for the prevention of vasospasm. The number of patients with cerebral infarction due to vasospasm was significantly lower, and the most favorable outcome was found in the intermittent group. Continuous irrigation has some disadvantages (26). If the drainage catheter is incorrectly placed, irrigation fluid with fi-
PREVENTION OF CEREBRAL VASOSPASM USING T-PA
brinolytic agent could pass directly to the outlet tube without diffusion into the cistern. The injection rate and the amount of the excretion must be kept equal in continuous irrigation, which is very complicated. Using the intermittent injection is a better way to administer postoperative fibrinolytic therapy than continuous cisternal irrigation (25). On the other hand, the effect of the composition of irrigation fluid must be considered. Although continuous irrigation methods seem to facilitate the rapid washout of both periarterial hematoma and spasmogenic substance, our irrigation fluid based on Ringer’s solution contained no natural trace elements (15). The important vasodilator substances, such as magnesium, could be removed from the CSF. Magnesium in the CSF may be one of the most effective vasodilator factors, as intrathecal magnesium injection improved vasospasm in the SAH experimental model (11, 12). The intermittent injection method has the advantage of relatively consistent diffusion of t-PA into the cisterns without direct drainage, and should prevent the loss of essential trace elements in the CSF. The administration of the drug and the management of the CSF drainage system are simpler than for continuous irrigation. Fibrinolytic therapy can suppress the inflammatory response around injured arteries by removing the subarachnoid clot in the early stage. SAH causes the inflammatory response that may lead to vasospasm (2, 21). The level of IL-6 in CSF was increased in patients after SAH (8). The level of IL-6 in CSF is significantly correlated with the occurrence of delayed cerebral ischemia associated with vasospasm (19). In our study, continuous irrigation with t-PA solution resulted in the lowest level of IL-6 in the CSF. The level of IL-6 in the group treated by intermittent t-PA injection was clearly less than in the control group. The level of IL-6 in the CSF was correlated with the m-RS score. This result may suggest that the inflammatory response in cisterns could be suppressed by aggressive clearance of subarachnoid clot. Previous studies reported that early MMP-9 concentrations are associated with poststroke intracranial hemorrhage, whereas t-PA therapy is associated with increased levels of active MMP-9 and MMP-9 substances in patients with acute stroke (1, 10, 14). Change in MMP-9 in the CSF was
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unknown, although the change in MMP with SAH was investigated (28). In our study, the concentration of MMP-9 in CSF was measured to evaluate the effect on the neurovascular matrix, and to examine the relationship between hemorrhagic complications and t-PA administration in the CSF space. We assumed that the change in MMP-9 level in the CSF was more sensitive than in the serum. The concentration of MMP-9 was lower in the t-PA administration groups compared with the control group. Therefore, microvascular injury and damage to the neurovascular matrix, which should cause changes in the MMP-9 concentration, may not have occurred. The correlation between the concentration of MMP-9 in CSF and the overall prognosis may suggest use as a predictor of the severity of SAH. Further investigations are needed including the experimental model, but the relationship between t-PA and MMP-9 is not easy to clarify.
CONCLUSIONS Low-dose t-PA administration into the CSF space is safe and effective for clearance of subarachnoid clot, and may avoid hemorrhagic complications. The intermittent injection method effectively prevents the vasospasm after SAH. Further clinical study by randomized trials in multicenter studies is necessary.
REFERENCES 1. Castellanos M, Leira, R, Serena, J, Blanco M, Pedraza S, Castillo J, Davalos A: Plasma cellular– fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke 35:1671-1676, 2004. 2. Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, Kassell NF, Lee KS: Cerebral vasospasm after subarachnoid hemorrhage: Putative role of inflammation. Neurosurgery 53:123135, 2003. 3. Findlay JM, Kassell NF, Weir BK, Haley EC, Kongable G, Germanson T, Truskowski L, Alves W, Holness RO, Knuckey NW, Yonas H, Steinberg GK, West M, Winn HR, Ferguson G: A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 37:168-178, 1995. 4. Findlay JM, Weir BK, Steinke D, Tanabe T, Gordon P, Grace M: Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg 69:723-735, 1988.
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5. Frontera JA, Fernandez A, Schmidt JM, Claassen J, Wartenberg KE, Badjatia N, Connolly ES, Mayer SA: Clinical response to hypertensive hypervolemic therapy and outcome after subarachnoid hemorrhage. Neurosurgery 66:35-41, 2010. 6. Kinouchi H, Ogasawara K, Shimizu H, Mizoi K, Yoshimoto T: Prevention of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage by intraoperative cisternal fibrinolysis using tissue-type plasminogen activator combined with continuous cisternal drainage. Neurol Med Chir (Tokyo) 44:569-575, 2004. 7. Kodama N, Sasaki T, Kawakami M, Sato M, Asari J: Cisternal irrigation therapy with urokinase and ascorbic acid for prevention of vasospasm after aneurysmal subarachnoid hemorrhage. Outcome in 217 patients. Surg Neurol 53:110-117, 2000. 8. Mathiesen T, Andersson B, Loftenius A, von Holst H: Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage. J Neurosurg 78:562-567, 1993. 9. Mizoi K, Yoshimoto T, Takahashi A, Fujiwara S, Koshu K, Sugawara T: Prospective study on the prevention of cerebral vasospasm by intrathecal fibrinolytic therapy with tissue-type plasminogen activator. J Neurosurg 78:430-437, 1993. 10. Montaner J, Molina CA, Monasterio, J, Abilleira, S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J: Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107:598-603, 2003. 11. Mori K, Miyazaki M, Hara Y, Aiko Y, Yamamoto T, Nakao Y: Novel vasodilatory effect of intracisternal injection of magnesium sulfate solution on spastic cerebral arteries in the canine two-hemorrhage model of subarachnoid hemorrhage. J Neurosurg 110:73-78, 2009. 12. Mori K, Miyazaki M, Iwata J, Yamamoto T, Nakao Y: Intracisternal infusion of magnesium sulfate solution improved reduced cerebral blood flow induced by experimental subarachnoid hemorrhage in the rat. Neurosurg Rev 31:197-203, 2008. 13. Moriyama E, Matsumoto Y, Meguro T, Kawada S, Mandai S, Ghoda Y, Sakurai M: Combined cisternal drainage and intrathecal urokinase injection therapy for prevention of vasospasm in patients with aneu-
bral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebocontrolled double-blind trial. J Neurosurg 76:571577, 1992.
rysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo) 35:732-736, 1995. 14. Ning M, Furie KL, Koroshetz WJ, Lee H, Barron M, Lederer M, Wang X, Zhu M, Sorensen AG, Lo EH, Kelly PJ: Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 66:1550-1555, 2006. 15. Ohman J, Servo A, Heiskanen O: Effect of intrathecal fibrinolytic therapy on clot lysis and vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:197-201, 1991. 16. Sasaki S, Ohta S, Kuwabara H, Shiraishi M: The role of ventricular and cisternal drainage in the early operation for ruptured intracranial aneurysm. Acta Neurochir (Wien) 88:87-94, 1987. 17. Sasaki T, Kodama N, Kawakami M, Sato M, Asari J, Sakurai Y, Watanabe K, Onuma T, Matsuda T: Urokinase cisternal irrigation therapy for prevention of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a study of urokinase concentration and the fibrinolytic system. Stroke 31: 1256-1262, 2000. 18. Sasaki T, Ohta T, Kikuchi H, Takakura K, Usui M, Ohnishi H, Kondo A, Tanabe H, Nakamura J, Yamada K, Kobayashi N, Ohashi Y: A phase II clinical trial of recombinant human tissue-type plasminogen activator against cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 35:597-604, 1994. 19. Schoch B, Regel J, Wichert M, Gasser T, Volbracht L, Stolke D: Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage. Neurosurgery 60:828-836, 2007.
23. Steinberg GK, Vanefsky MA, Marks M, Adler JR Jr, Koenig GH: Failure of intracisternal tissue plasminogen activator to prevent vasospasm in certain patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 34:809-814, 1994. 24. Suzuki Y, Shibuya M, Satoh S, Sugimoto Y, Takakura K: A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg Neurol 68:126-131, 2007. 25. Usui M, Saito N, Hoya K, Todo T: Vasospasm prevention with postoperative intrathecal thrombolytic therapy: a retrospective comparison of urokinase, tissue plasminogen activator, and cisternal drainage alone. Neurosurgery 34:235-244, 1994. 26. Yamada K, Yoshimura S, Enomoto Y, Yamakawa H, Iwama T: Effectiveness of combining continuous cerebrospinal drainage and intermittent intrathecal urokinase injection therapy in preventing symptomatic vasospasm following aneurysmal subarachnoid haemorrhage. Br J Neurosurg 22:649-653, 2008. 27. Zabramski J, Spetzler R, Lee K, Papadopoulos S, Bovill E, Zimmerman R, Bederson J: Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:189-196, 1991. 28. Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day IN, Ye S: Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke 32:2198-202, 2001.
20. Seifert V, Stolke D, Zimmerman M, Feldges A: Prevention of delayed ischaemic deficits after aneurysmal subarachnoid haemorrhage by intrathecal bolus injection of tissue plasminogen activator (rTPA): a prospective study. Acta Neurochir (Wien) 128:137-143, 1994.
Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
21. Sercombe R, Dinh YR, Gomis P: Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol 88:227-249, 2002.
Citation: World Neurosurg. (2010) 73, 6:675-682. DOI: 10.1016/j.wneu.2010.04.002
22. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka H, Nakashima M: Effect of AT877 on cere-
received 14 December 2009; accepted 05 April 2010
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Efficacy of Low-Dose Tissue-Plasminogen Activator Intracisternal Administration for the Prevention of Cerebral Vasospasm After Subarachnoid Hemorrhage Takuji Yamamoto, Takanori Esaki, Yasuaki Nakao, Kentaro Mori
Key words 䡲 Cisternal irrigation 䡲 Interleukin-6 䡲 Matrix metalloproteinase-9 䡲 Subarachnoid hemorrhage 䡲 Tissue plasminogen activator 䡲 Vasospasm Abbreviations and Acronyms CSF: Cerebrospinal fluid CT: Computed tomography IL-6: Interleukin-6 LDA: Low density area MMP-9: Matrix metalloproteinase-9 m-RS: Modified Rankin scale SAH: Subarachnoid hemorrhage t-PA: Tissue plasminogen activator WBC: White blood cell WFNS: World Federation of Neurosurgical Societies From the Department of Neurosurgery, Juntendo University Shizuoka Hospital, Izunokuni, Shizuoka, Japan To whom correspondence should be addressed: Takuji Yamamoto, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2010) 73, 6:675-682. DOI: 10.1016/j.wneu.2010.04.002 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com
䡲 BACKGROUND: Vasospasm is one of the important factors associated with the functional prognosis after subarachnoid hemorrhage (SAH). Intracisternal administration of thrombolytic agents to dissolve subarachnoid clots may be responsible for bleeding complications. The efficacy and safety of cisternal irrigation therapy using low-dose tissue plasminogen activator were evaluated. 䡲 METHODS: Sixty patients with SAH were treated by surgical clipping, and randomly divided into three groups: 1) the control group (n ⴝ 20) treated only with baseline treatment; 2) the intermittent group (n ⴝ 20) received intermittent administration of clotlysis agent (tisokinase 960,000 IU); and 3) the continuous group (n ⴝ 20) received continuous irrigation using pH-adjusted lactate Ringer’s solution containing tisokinase (96 IU/mL) infused at 20 mL/hr for 48 hours. The clearance of subarachnoid clots was measured by laboratory examinations and postoperative computed tomography. Ischemia-related vasospasm was evaluated by neurological status and computed tomography. Neurological outcome was evaluated by the modified Rankin scale at 3 months after onset. 䡲 RESULTS: The subarachnoid clot was efficiently and significantly removed without major complication in the intermittent and continuous groups (P < 0.05). The incidence of ischemic lesion in the intermittent group was significantly lower than in the control group (P < 0.05). The intermittent group had significantly better neurological outcome than the control group (P < 0.05). 䡲 CONCLUSIONS: Cisternal irrigation therapy using low-dose tissue plasminogen activator is effective and safe. Intermittent injection is most effective and may decrease the risk of symptomatic vasospasm in patients with SAH.
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INTRODUCTION Delayed cerebral vasospasm remains a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). The severity of cerebral vasospasm may be correlated with the volume and distribution of the subarachnoid clots. Many patients have been treated by evacuation of the subarachnoid hematoma in the early stages of ruptured aneurysm to prevent cerebral vasospasm (4, 7, 9, 13, 16, 20, 25). Fibrinolytic agents, such as urokinase or tissue plasminogen activator (t-PA), may be effective, but treatment with intracisternal t-PA might not prevent cerebral vasospasm caused by aneurysmal SAH (23). This treatment is also associated with se-
vere risk of hemorrhagic complications such as intracranial hemorrhage. Therefore, evacuation of subarachnoid hematoma to prevent cerebral vasospasm is commonly accepted, but the optimal administration and dosage of fibrinolytic agents have not been established. Repeated low-dose administration with t-PA or continuous irrigation with urokinase might prevent cerebral vasospasm without severe complications (6, 7, 17, 18, 26). We believe that cisternal irrigation therapy with fibrinolytic agents is a potentially effective option if an appropriate dosage and safe administration method can be established, although previous investigations have not been promising (23). The present study attempted to improve the functional outcome of patients with
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SAH by prevention of vasospasm, tried to confirm the efficacy of cisternal irrigation therapy with t-PA, and tried to establish the optimal protocol for t-PA by comparing intermittent administration and continuous irrigation with t-PA in patients with aneurysmal SAH.
MATERIALS AND METHODS Patient Selection The clinical trial protocol was reviewed and approval by Juntendo University Shizuoka Hospital ethical community. All patients or their legally authorized representatives provided written informed consent. This study included 60 consecutive patients presenting with SAH from February 2006 to May
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Table 1. Clinical Characteristics of the Patients Control Group (n ⴝ 20)
Intermittent Group (n ⴝ 20)
Continuous Group (n ⴝ 20)
Total No. of Patients (n ⴝ 60)
7/13
6/14
7/13
20/40
Men/women Age (mean ⫾ SD, year)
64.6 ⫾ 13.2
63.1 ⫾ 9.6
66.8 ⫾ 11.8
64.8 ⫾ 11.5
⬍ 70 year
12 (60.0%)
15 (75.0%)
13 (65.0%)
40 (66.7%)
ⱖ 70 year
8 (40.0%)
5 (25.0%)
7 (35.0%)
20 (33.3%)
5.0
5.0
0
3.3
45.0
45.0
35.0
41.7
Antiplatelet agents (%)* Smoking rate WFNS grade (mean ⫾ SD) I
1 (5.0%)
3 (15.0%)
6 (30.0%)
10 (16.7%)
II
8 (40.0%)
8 (40.0%)
7 (35.0%)
23 (38.3%)
III
1 (5.0%)
1 (5.0%)
1 (5.0%)
3 (5.0%)
IV
4 (20.0%)
4 (20.0%)
2 (10.0%)
10 (16.7%)
V
6 (30.0%)
4 (20.0%)
4 (20.0%)
14 (23.3%)
WFNS, World Federation of Neurosurgical Societies. *Percentage of patients taking antiplatelet agents (aspirin, clopidogrel, or ticlopidine).
2007. The etiology of SAH was the ruptured aneurysm in all patients. All patients were treated by surgical clipping. They were randomized into three groups by the stratified block randomization method using the following factors: age, sex, World Federation of Neurosurgical Societies (WFNS) SAH grade, Fisher’s computed tomography (CT) group, and location of aneurysm. The control group was treated only with baseline treatment without cisternal irrigation therapy; the intermittent group received intermittent administration of clotlysis agent; and the continuous group received continuous irrigation incorporating clotlysis agent. We excluded patients with untreated aneurysm. We also excluded patients with suspected incomplete clipping.
Baseline Treatment Protocol Patients with SAH were surgically treated within 72 hours after onset, then basically managed under normovolemic and normotensive conditions. During the aneurysm clipping surgery, Liliequist’s membrane was opened and the cisternal drainage tube was placed in the basal cistern. Induced hypertension was attempted in patients with deteriorated neurological status due to vasospasm. Fasudil hydrochloride 90 mg (Eril S, Asahi Kasei Pharma; Tokyo, Japan) was administered every day for 14 days (22, 24).
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Decompression surgery consisting of decompressive craniectomy with extended duroplasty was performed in patients with acute brain swelling. Intermittent Drug Administration Protocol As a clotlysis agent, tisokinase 160,000 IU (Plasvata, Asahi Kasei Pharma) was administered into the basal cistern through the cisternal drainage tube every 8 hours for 2 days. After administration, the drainage catheters were closed for 2 hours. The total dose of tisokinase was 960,000 IU. Continuous Cisternal Irrigation Protocol Continuous cisternal irrigation used pHadjusted lactate Ringer’s solution containing tisokinase (96 IU/mL), infused at 20 mL/hr for 48 hours through an external ventricular drainage catheter, and drained from the cisternal drainage or spinal drainage catheters. The total dose of tisokinase was 960,000 IU, and the total volume of irrigation solution was 1000 mL. The infusion flow rate was controlled by the infusion mechanical pump. The overflow root was set at a height of 15 cm H2O to avoid excessive infusion. During irrigation, all drainage catheters were carefully maintained to avoid drainage problems such as overdraining or increased intracranial pressure.
Evaluation Definition of Symptomatic Vasospasm. Symptomatic vasospasm was defined as clinical neurological deterioration attributable to vasospasm, after exclusion of hydrocephalus, seizures, surgical invasions, or other causes. However, symptomatic vasospasm was difficult to define based only on clinical deterioration, particularly in high grade patients. Therefore, we defined low density areas (LDA) on CT as symptomatic vasospasm after other causes had been excluded by repeated postoperative CT (4, 5). A neurosurgeon unaware of the clinical details agreed that the LDA might be caused by delayed ischemic neurological deficit after SAH. Postoperative Evaluation. CT was performed on postoperative days 1, 3, 5, 7, 10, and 14. All surgical and hemorrhagic complications were recorded. To evaluate the clearance of the subarachnoid hematoma clot, CT number (in Hounsfield units) of the basal cistern was measured preoperatively, and on days 5 and 14. Appearance of LDA due to vasospasm was recorded and the volume of the LDA was measured on day 14. The CT number of the cistern and the LDA were measured by a neurosurgeon unaware of the patient’s clinical status. Cerebrospinal Fluid Analysis. Routine cerebrospinal fluid (CSF) analysis (white blood
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Table 2. CT-based Diagnosis Control Group (n ⴝ 20)
Intermittent Group (n ⴝ 20
Continuous Group (n ⴝ 20)
Total No. of Patients (n ⴝ 60)
Fisher’s CT group (mean ⫾ SD) II
2 (10.0%)
4 (20.0%)
3 (15.0%)
9 (15.0%)
III
12 (60.0%)
11 (55.0%)
8 (40.0%)
31 (51.7%)
6 (30.0%)
5 (25.0%)
9 (45.0%)
20 (33.3%)
Hydrocephalus at surgery
IV
11 (55.0%)
9 (45.0%)
12 (60.0%)
22 (53.3%)
Permanent V-P shunt (%)*
77.8%
61.1%
56.3%
62.3%
Side of aneurysm†
7/9/4
7/3/10
9/4/7
23/16/22
4
9
1
14
Site of aneurysm IC ACA
8
5
11
24
MCA
7
4
8
19
VA-BA Ant./post. Size of aneurysm (mean ⫾ SD, mm)
1
2
0
3
19/1
18/2
20/0
57/3
7.7 ⫾ 5.1
5.8 ⫾ 3.2
5.9 ⫾ 3.2
6.4 ⫾ 4.0
ACA, anterior cerebral artery; Ant./post., anterior circulation/posterior circulation; CT, computed tomography; IC, internal carotid artery; MCA, middle cerebral artery; VA-BA, vertebral artery-basilar artery; V-P, ventriculoperitoneal. *Ratio of patient placed V-P shunt in survival patients at 3 month. †Values on the left/midline/right.
cell [WBC], protein, glucose, specific gravity) was performed on days 1, 3, 5, 7, 10, and 14. Interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) were measured on day 10. All drained CSF was accumulated for 5 postoperative days, and the volume of washed out red blood cells was calculated by hematocrit (percentage) of the CSF.
younger than 70 years old. The distribution of WFNS grades showed no statistical differences therefore the average neurological condition was moderate. The three groups had no significant differences in age, sex, or WFNS grade. The percentages of patients taking antiplatelet agents before onset were
also not significantly different. The CTbased diagnosis and treatment are presented in Table 2. Acute hydrocephalus at the surgical point was recognized in approximately 50% of all patients, with no statistical differences between groups. The necessity for permanent ventriculoperitoneal
Neurological Outcomes. Neurological outcome and mortality was evaluated by Glasgow Outcome Scale and modified Rankin scale (m-RS) at 3 months.
Statistical Analysis The data were collected and analyzed using the 2 test, Fisher’s exact test, Kruskal-Wallis test, and Spearman’s rank test. Significance was defined as P ⬍ 0.05.
RESULTS Patient Profile The clinical characteristics of the 60 patients are summarized in Table 1. Mean age was 64.8 years old, and 40 patients were
WORLD NEUROSURGERY 73 [6]: 675-682, JUNE 2010
Figure 1. Chronologic changes in density of the basal cistern in Hounsfield units were significantly decreased in both the intermittent group and the continuous group on day 5 (*P ⬍ 0.05, **P ⬍ 0.05), and were significantly different in all groups on day 14.
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Figure 2. Representative case of a 61-year-old woman with World Federation of Neurosurgical Societies grade 4 and Fisher’s computed tomography (CT) group III. (A) Preoperative CT scan revealing subarachnoid hemorrhage caused by a ruptured anterior communicating artery aneurysm. (B) CT scan showing that most of the subarachnoid clot had
been removed on day 5. (C) CT scan showing no low density area related to ischemic event on day 14, and complete removal of the hematoma in the basal cistern. CT number in the basal cistern was measured at the same point (*) in each patient.
Table 3. Chronologic Change of CSF Parameters Day 1
Day 3
Day 5
Day 7
Day 10
Day 14
Control group
2.08 ⫾ 0.13
0.94 ⫾ 0.04
0.96 ⫾ 0.08
0.97 ⫾ 0.04
1.06 ⫾ 0.10
0.24 ⫾ 0.01
Intermittent group
2.97 ⫾ 0.21
2.56 ⫾ 0.19
1.08 ⫾ 0.05
0.69 ⫾ 0.03
0.39 ⫾ 0.01
0.41 ⫾ 0.03
Continuous group
2.18 ⫾ 0.19
1.48 ⫾ 0.07
1.06 ⫾ 0.06
0.87 ⫾ 0.05
0.73 ⫾ 0.10
0.25 ⫾ 0.01
Control group
0.24 ⫾ 0.01
0.68 ⫾ 0.05
0.91 ⫾ 0.04
0.70 ⫾ 0.03
0.63 ⫾ 0.03
0.42 ⫾ 0.02
Intermittent group
0.29 ⫾ 0.01
1.17 ⫾ 0.03
0.99 ⫾ 0.02
0.74 ⫾ 0.04
0.49 ⫾ 0.02
0.34 ⫾ 0.01
Continuous group
0.19 ⫾ 0.01
0.53 ⫾ 0.02
0.89 ⫾ 0.03
0.72 ⫾ 0.02
0.47 ⫾ 0.02
0.39 ⫾ 0.02
⬎WBC (mean ⫾ SE, 103/m)
Total bilirubin (mean ⫾ SE, mg/dL)
FDP (mean ⫾ SE, g/mL) Control group
114.0 ⫾ 5.6
95.9 ⫾ 5.0
117.3 ⫾ 5.6
99.3 ⫾ 3.8
73.4 ⫾ 4.0
52.1 ⫾ 4.0
Intermittent group*
228.8 ⫾ 10.3
500.5 ⫾ 26.5
118.7 ⫾ 8.7
65.1 ⫾ 2.1
50.1 ⫾ 1.9
33.1 ⫾ 1.4
Continuous group
226.8 ⫾ 15.1
144.8 ⫾ 5.7
78.3 ⫾ 4.8
65.2 ⫾ 2.2
39.4 ⫾ 1.5
37.5 ⫾ 1.8
Control group
148.4 ⫾ 3.1
147.1 ⫾ 6.1
147.0 ⫾ 6.9
147.9 ⫾ 7.7
149.2 ⫾ 6.7
146.0 ⫾ 5.5
Intermittent group
148.8 ⫾ 3.9
147.2 ⫾ 4.4
147.7 ⫾ 5.7
147.5 ⫾ 6.1
144.5 ⫾ 8.4
145.7 ⫾ 5.9
Continuous group
149.3 ⫾ 5.7
149.1 ⫾ 8.3
149.3 ⫾ 7.6
146.4 ⫾ 7.9
146.2 ⫾ 6.6
148.8 ⫾ 7.5
Na (mean ⫾ SD, mEq/L)
K (mean ⫾ SD, mEq/L) Control group
3.10 ⫾ 0.55
2.86 ⫾ 0.60
2.61 ⫾ 0.35
2.58 ⫾ 0.42
2.61 ⫾ 0.22
2.71 ⫾ 0.31
Intermittent group
3.01 ⫾ 0.37
2.80 ⫾ 0.42
2.73 ⫾ 0.62
2.53 ⫾ 0.27
2.55 ⫾ 0.19
2.68 ⫾ 0.18
Continuous group
2.98 ⫾ 0.42
2.80 ⫾ 0.34
2.59 ⫾ 0.28
2.65 ⫾ 0.30
2.68 ⫾ 0.26
2.81 ⫾ 0.22
CSF, cerebrospinal fluid; FDP, fibrin/fibrinogen degradation products; WBC, white blood cell. *P ⬍ 0.05 compared with other groups.
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uous group (40%, 8/20) and the intermittent group (20%, 4/20). The control group had more severe LDA in patients with cerebral infarction (69.7 ⫾ 12.4 mL), but with no significant difference (22.7 ⫾ 8.5 mL in the intermittent group and 25.2 ⫾ 3.2 mL in the continuous group). Decompressive surgery was performed in 18 patients (30.0%): 9 patients in the control group, 4 in the intermittent group, and 5 patients in the continuous group. There was no significant difference between groups, although more patients required decompression surgery in the control group because of the higher incidence of cerebral infarction as a result of vasospasm.
Figure 3. Chronological changes of fibrin/fibrinogen degradation products (FDP) in cerebrospinal fluid (CSF). The FDP level in the intermittent group was significantly elevated on day 3. The FDP levels in all groups gradually decreased.
shunting tended to be lower in the intermittent and continuous groups than in the control group, but without significance. Thirtyone patients were classified as Fisher’s group III, 20 patients had intracerebral hematoma combined with SAH as Fisher’s group IV, and only 9 patients presented with Fisher’s group II. No significant difference was present between groups.
Clearance of Subarachnoid Hematoma The volume of drained CSF during 5 days was significantly larger in the continuous group (1565.9 mL) than in the control group (919.6 mL) and the intermittent group (1004.5 mL), because irrigation fluid was included. The ratio of blood in the drained CSF calculated from the hematocrit and the daily amount of drained CSF was (mean ⫾ SE) 17.9 ⫾ 1.1 mL for the intermittent group, which was significantly higher than 7.5 ⫾ 0.4 mL for the control group, and 11.6 ⫾ 0.5 mL for the continuous group (P ⬍ 0.05), which was higher than the control group without significance. The CT number (in Hounsfield units) in the basal cistern was significantly lower in both the intermittent group (mean ⫾ SD; 20.27 ⫾ 6.8) and the continuous group (21.6 ⫾ 10.7) on day 5 than in the control group (43.6 ⫾ 13.8, P ⬍ 0.05), occurring immediately after administration of t-PA. The CT number was significantly decreased in the control group (61.4 ⫾ 8.8 on day 0 and 26.6 ⫾ 7.3 on day 14), similar to those in the intermittent group
(57.97 ⫾ 7.4 on day 0 and 18.0 ⫾ 8.5 on day 14) and the continuous group (56.0 ⫾ 12.0 on day 0 and 17.4 ⫾ 7.4 on day 14), on day 14 (Figure 1). An illustrative case in the intermittent group is presented in Figure 2.
Cerebral Infarction as a Result of Vasospasm Cerebral infarction as a result of vasospasm was analyzed on day 14. The ratio of patients with LDA was highest in the control group (55%, 11/20 patients), followed by the contin-
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CSF Analysis The chronological changes of WBC count and other chemical markers are shown in Table 3. The WBC in CSF significantly changed during the 14 days after surgery, but without differences between the groups. Three patients were clinically diagnosed with meningitis— two patients in the control group and one in the continuous group. These patients were treated with standard antibiotic drugs. The fibrin/fibrinogen degradation products in CSF in the intermittent group were significantly higher than in the other two groups at more than 500 g/mL on day 3, then decreased to the same level as in the control group (P ⬍ 0.05). The fibrin/fibrinogen degradation products were higher in the continuous group than in the control group for the first 3 days after surgery, but without significant differ-
Figure 4. Chronologic changes of Na and K in cerebrospinal fluid (CSF).
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Table 4. Neurological Outcome at 3 month After Onset GOS* at 3 month (%)
m-RS†
GR
MD
SD
VS
D
Favorable outcome
Mean
Control group
3 (15.0%)
5 (25.0%)
7 (35.0%)
3 (15.0%)
2 (10.0%)
6 (30.0%)
3.5
Intermittent group
8 (40.0%)
4 (20.0%)
7 (35.0%)
1 (5.0%)
0
12 (60.0%)‡
3.2‡
Continuous group
4 (20.0%)
5 (25.0%)
6 (30.0%)
1 (5.0%)
4 (20.0%)
4 (20.0%)
3.9
15 (25.0%)
14 (23.3%)
20 (33.3%)
5 (8.3%)
6 (10.0%)
22 (36.7%)
3.2
Total
GOS; Glasgow Outcome Scale; mRS, modified Rankin scale. *According to GOS: GR, good recovery; MD, moderately disabled; SD, severely disabled; VS, vegetative state; D, dead. †According to m-RS. Favorable outcome was defined as m-RS scores 2 or less. ‡P ⬍ 0.05 compared with other groups.
ence (Figure 3). The sodium levels in CSF varied in a similar range (145–150 mEq/L). The potassium level followed a similar course in all groups, which decreased to approximately 2.6 mEq/L by 5 days after surgery, and slowly increased until day 14, but did not return to the initial level (Figure 4).
Examination of IL-6 and MMP-9 in CSF The drained CSF on day 10 was analyzed for IL-6 and MMP-9. The mean IL-6 was highest in the control group (mean ⫾ SE; 5258.9 ⫾ 320.1 pg/mL), followed by the intermittent group (3419.4 ⫾ 3.0 pg/mL) and the continuous group (1961.8 ⫾ 101.6 pg/mL), with a significant difference between the control group and the continuous group (P ⬍ 0.05). The mean MMP-9 was highest in the control group (mean ⫾ SE; 58.4 ⫾ 7.4 ng/mL), followed by the intermittent group (31.9 ⫾ 3.0 ng/mL) and the continuous group (23.6 ⫾ 2.3 ng/mL), with no significant difference between groups. There was no evidence that MMP-9 level was increased by t-PA administration.
Outcome Analysis The outcomes at 3 months after surgery are shown in Table 4. Favorable outcome evaluated by the Glasgow Outcome Scale (good recovery and moderately disabled) was achieved in 8 patients in the control group, 12 patients in the intermittent group, and 9 patients in the continuous group. The intermittent group showed significantly better m-RS outcome than the other groups (P ⬍ 0.05), with 12 patients with m-RS scores of 2 or less. The mortality rate was 10% in the
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control group, 0 in the intermittent group, and 20% in the continuous group. Overall data analysis of the correlation between the outcome and both MMP-9 and IL-6 are shown in Figure 5. The level of IL-6 in the CSF was correlated with m-RS in patients with SAH (P ⬍ 0.01). The level of MMP-9 in the CSF was also correlated with m-RS (P ⬍ 0.01). Higher levels tended to indicate poor prognosis regardless of patient group. Hemorrhagic complication occurred in one patient of the continuous group, who suffered minor SAH around the treated aneurysm. This aneurysm had a very complicated neck shape that was difficult to obliterate. Incomplete clipping may have caused the hemorrhage. DISCUSSION Extensive removal of subarachnoid clot in the acute stage reduces the occurrence of
vasospasm associated with ruptured aneurysm, as substances in the subarachnoid clot are widely accepted to induce vasospasm. Many previous investigations have shown that intracisternal administration of fibrinolytic agents can effectively remove subarachnoid clot and prevent the development of clinical vasospasm (3, 7, 9, 13, 20, 25). The present study confirmed that fibrinolytic therapy is effective in patients with SAH. Various methods for administering fibrinolytic agents into the cisterns for prevention of vasospasm have been reported. The intraoperative bolus injection method directly introduces a relatively high dose of t-PA (⬎10 mg) into the basal cisterns. Intracisternal administration of t-PA is effective for the prevention of vasospasm (4, 15). Postoperative injection after early treatment of ruptured aneurysm is another safe and
Figure 5. Correlations between the outcome of all patients and both interleukin-6 (IL-6) (A) and matrix metalloproteinase-9 (MMP-9) levels (B). Increased IL-6 and MMP-9 levels were significantly correlated with modified Rankin scale (m-RS) (IL-6: *y ⫽ 821.48x ⫹ 1097.1, P ⬍ 0.01; MMP-6: **y ⫽ 7.3677x ⫹ 6.3868, P ⬍ 0.01) analyzed by Spearman’s rank test.
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effective method (6, 9, 27). However, unfavorable results have been obtained in some studies (3, 23). Continuous cisternal drainage to remove subarachnoid hematoma is one of the most common procedures in Japan. Cisternal irrigation therapy using urokinase is widely practiced to prevent vasospasm, and achieves a low ratio of vasospasm in patients treated (7, 17, 26). Intraoperative cisternal fibrinolysis using t-PA combined with continuous cisternal drainage prevents symptomatic vasospasm after SAH (6). However, the efficacy of t-PA for the prevention of vasospasm could not be confirmed by multicenter randomized study, possibly because the relatively complicated administration method might not have been established as a routine procedure. In addition, the dosage of intraoperative t-PA might be too high, resulting in hemorrhagic complications. Repeated intrathecal administration of 0.1 mg t-PA three times daily for 5 days was useful for reducing vasospasm (18). The hemorrhagic complication may be avoided by using a lower dosage of t-PA. In the present study, t-PA was used as a fibrinolytic agent to obtain a stronger action to dissolve the subarachnoid clot, with a shorter administration period or decreased number of doses. The dosage was determined by referring to the previous study (6). Tisokinase (960,000 IU) was administered for 2 days in both the intermittent group and the continuous group, corresponding to 2.4 mg of alteplase. The total dosage without intraoperative injection was less than the dosage of the original study (1.6 – 3.2 mg of t-PA). This study compared intermittent injection and continuous irrigation. The efficacy of hematoma clearance evaluated by CT number was almost equal, which should depend on the dosage of t-PA. The significant decreases in CT number in both the intermittent group and the continuous group compared with the control group suggest that the dosage was effective. However, the intermittent injection method was more effective for the prevention of vasospasm. The number of patients with cerebral infarction due to vasospasm was significantly lower, and the most favorable outcome was found in the intermittent group. Continuous irrigation has some disadvantages (26). If the drainage catheter is incorrectly placed, irrigation fluid with fi-
PREVENTION OF CEREBRAL VASOSPASM USING T-PA
brinolytic agent could pass directly to the outlet tube without diffusion into the cistern. The injection rate and the amount of the excretion must be kept equal in continuous irrigation, which is very complicated. Using the intermittent injection is a better way to administer postoperative fibrinolytic therapy than continuous cisternal irrigation (25). On the other hand, the effect of the composition of irrigation fluid must be considered. Although continuous irrigation methods seem to facilitate the rapid washout of both periarterial hematoma and spasmogenic substance, our irrigation fluid based on Ringer’s solution contained no natural trace elements (15). The important vasodilator substances, such as magnesium, could be removed from the CSF. Magnesium in the CSF may be one of the most effective vasodilator factors, as intrathecal magnesium injection improved vasospasm in the SAH experimental model (11, 12). The intermittent injection method has the advantage of relatively consistent diffusion of t-PA into the cisterns without direct drainage, and should prevent the loss of essential trace elements in the CSF. The administration of the drug and the management of the CSF drainage system are simpler than for continuous irrigation. Fibrinolytic therapy can suppress the inflammatory response around injured arteries by removing the subarachnoid clot in the early stage. SAH causes the inflammatory response that may lead to vasospasm (2, 21). The level of IL-6 in CSF was increased in patients after SAH (8). The level of IL-6 in CSF is significantly correlated with the occurrence of delayed cerebral ischemia associated with vasospasm (19). In our study, continuous irrigation with t-PA solution resulted in the lowest level of IL-6 in the CSF. The level of IL-6 in the group treated by intermittent t-PA injection was clearly less than in the control group. The level of IL-6 in the CSF was correlated with the m-RS score. This result may suggest that the inflammatory response in cisterns could be suppressed by aggressive clearance of subarachnoid clot. Previous studies reported that early MMP-9 concentrations are associated with poststroke intracranial hemorrhage, whereas t-PA therapy is associated with increased levels of active MMP-9 and MMP-9 substances in patients with acute stroke (1, 10, 14). Change in MMP-9 in the CSF was
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unknown, although the change in MMP with SAH was investigated (28). In our study, the concentration of MMP-9 in CSF was measured to evaluate the effect on the neurovascular matrix, and to examine the relationship between hemorrhagic complications and t-PA administration in the CSF space. We assumed that the change in MMP-9 level in the CSF was more sensitive than in the serum. The concentration of MMP-9 was lower in the t-PA administration groups compared with the control group. Therefore, microvascular injury and damage to the neurovascular matrix, which should cause changes in the MMP-9 concentration, may not have occurred. The correlation between the concentration of MMP-9 in CSF and the overall prognosis may suggest use as a predictor of the severity of SAH. Further investigations are needed including the experimental model, but the relationship between t-PA and MMP-9 is not easy to clarify.
CONCLUSIONS Low-dose t-PA administration into the CSF space is safe and effective for clearance of subarachnoid clot, and may avoid hemorrhagic complications. The intermittent injection method effectively prevents the vasospasm after SAH. Further clinical study by randomized trials in multicenter studies is necessary.
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Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Citation: World Neurosurg. (2010) 73, 6:675-682. DOI: 10.1016/j.wneu.2010.04.002
22. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka H, Nakashima M: Effect of AT877 on cere-
received 14 December 2009; accepted 05 April 2010
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