Intraventricular Fibrinolysis Does Not Increase
Perihemorrhagic Edema After Intracerebral Hemorrhage
Bastian Volbers, MD; Ingrid Wagner, MD; Wolfgang Willfarth, MS; Arnd Doerfler, MD;
Stefan Schwab, MD; Dimitre Staykov, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Background and Purpose—Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome
after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator
(rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert
proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of
PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume.
Methods—Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and
intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF,
matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days
4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio
of PHE volume and initial ICH volume.
Results—The matching algorithm resulted in similar mean ICH volumes in both groups (20.01±17.5 mL, IVF vs 20.08±17.1
mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8±19.2 mL vs 9.2±13.4 mL). The
mean total rtPA dose used for IVF was 8±6 mg. PHE increased over time in both groups until day 12. At all investigated
time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39; P=0.844).
Conclusions—IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem
to be safe regarding PHE. (Stroke. 2013;44:00-00.)
Key Words: intracerebral hemorrhage ■ intraventricular fibrinolysis ■ intraventricular hemorrhage ■ perihemorrhagic
edema ■ recombinant tissue-type plasminogen activator ■ semiautomatic volumetry ■ X-ray computed tomography
A
dditional intraventricular hemorrhage (IVH) has been
identified as a strong and independent negative prognostic predictor causing higher mortality, morbidity, and disability after spontaneous intracerebral hemorrhage (ICH).1–3
Several different pathophysiological mechanisms seem to
contribute to this deleterious effect. Clotting of the aqueduct
leads to the most severe complication of IVH, namely, acute
obstructive hydrocephalus, which has been shown to further worsen the prognosis in such patients.4 Apart from this
injury mechanism, ventricular blood has been shown to exert
a mass effect and reduce cerebral blood flow in the periventricular brain tissue in animal models of IVH.5,6 Especially
the so-caused damage of brain stem structures may explain
the prognostic significance of third and fourth ventricle blood
volume, demonstrated in clinical studies.7,8 Finally, blood and
its breakdown products cause inflammation of the ependymal
layer and the subependymal brain tissue,5,6,9 and also inflammation and fibrosis of the arachnoid mater, thereby leading to
a delayed communicating hydrocephalus.10
Considering those pathomechanisms, there seems to be a
clear rationale for the fast removal of blood and blood breakdown products from the ventricular system. Intraventricular
fibrinolysis (IVF), that is, the administration of fibrinolytic
agents as recombinant tissue plasminogen activator (rtPA) into
the ventricles, seems to be an emerging and promising treatment strategy,11 which is currently being investigated in a large
phase III multicenter trial (Clot Lysis: Evaluating Accelerated
Resolution of Intraventricular Hemorrhage [CLEAR-III]).12,13
In the context of IVF, rtPA toxicity has been a source of
concern because animal studies have shown that rtPA may
exert dose-dependent proedematous and neurotoxic effects.6
Moreover, a recent small retrospective clinical study has
indicated that there may be an increase in perihemorrhagic
edema (PHE) in ICH patients treated with intraventricular
rtPA.14 Although the influence of PHE on morbidity and
mortality after ICH has not been clearly established yet,15
PHE may play a role as a source of additional mass effect,
especially in large ICH, and thereby lead to neurological
Received August 8, 2012; final revision received November 15, 2012; accepted November 26, 2012.
From the Department of Neurology (B.V., I.W., W.W., S.S., D.S.) and the Department of Neuroradiology (B.V., A.D.), University of Erlangen-Nuremberg,
Erlangen, Germany.
Ralph Sacco, MD, MS, was guest editor for this article.
Correspondence to Bastian Volbers, University of Erlangen-Nure, Schwabachanlage 6, 91054 Erlangen, Germany. E-mail [email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.673228
1
2 Stroke February 2013
deterioration and herniation.16,17 We aimed to investigate the
effect of intraventricular rtPA on PHE evolution after ICH and
compared the course of PHE in a large retrospective cohort
of patients treated with IVF and controls matched for ICH
volume.
Methods
Patient Selection
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The study was approved by our local ethics committee. Patients treated between January 2006 and October 2011 were identified retrospectively from our institutional ICH database. The cohort treated with
IVF (IVF group) consisted of patients with spontaneous ICH <40 mL
and secondary IVH, initially causing acute obstructive hydrocephalus. Controls were selected among patients with spontaneous ICH and
secondary IVH without obstruction of the third and fourth ventricles,
who did not receive IVF (control group). For better comparison of the
course of PHE between the 2 groups, control patients were matched
for initial ICH volume (±5 mL). Spontaneous ICH was diagnosed
when no other cause than hypertension or amyloid angiopathy was
found. To allow sufficient evaluation of the time course of PHE in
both groups, only patients who received >3 computed tomography
(CT) scans covering at least the first 10 days of treatment were included in the analysis.
Neuroimaging and Assessment of PHE and
ICH Volume
Neuroimaging was performed on a fourth-generation CT scanner (Somatom 64, Somatom AS+, Siemens Healthcare, Erlangen,
Germany). Each CT scan consisted of 10 to 12 slices of 4.8 mm thickness for the skull base and 10 to 12 slices of 7.2 mm thickness for the
cerebrum. CT images were acquired using the orbito-meatal plane.
Absolute volumes of ICH and PHE were obtained using a semiautomatic volumetric algorithm as described elsewhere.18 The course of
PHE was assessed on CT scans performed in the course of treatment.
Different time points were merged to time clusters for better comparison between the 2 groups (day 1, days 2–3, 4–6, 7–9, and 10–12).
Relative PHE (rPHE) was calculated as a ratio of PHE volume and
initial ICH volume.
Intraventricular Hemorrhage
According to our institutional protocol, IVF was performed in patients with spontaneous ICH <40 mL and obstructive hydrocephalus
caused by IVH, who were treated with an external ventricular drain
(EVD). IVF was started at the earliest 12 hours after symptom onset
and 6 hours after EVD insertion. No patient was included with IVF
starting later than 48 hours after symptom onset. Before treatment,
the position of the ventricular catheter was confirmed by CT. rtPA
was applied via the EVD under sterile conditions. After application
of the fibrinolytic agent, the EVD was clamped for 30 to 60 minutes
and then reopened. Intracranial pressure was monitored continuously
during the clamping time. Until July 2008, a single dose of 4 mg rtPA
and a dosing interval of 12 hours up to a maximum cumulative dose
of 20 mg rtPA were used. Starting in August 2008, the dosing regimen was altered according to the preliminary results of the Clot Lysis
Evaluation Accelerated Resolution of Intraventricular Hemorrhage
trial (CLEAR-IVH; single dose of 1 mg rtPA, dosing interval 8 hours,
maximum cumulative dose 12 mg rtPA).19 IVF was discontinued as
soon as the third and fourth ventricles were no longer obstructed with
ventricular blood, or if the maximum cumulative dose of rtPA was
reached. During IVF, daily CT scans were performed to evaluate the
resolution of IVH. Lumbar drainage (LD) was inserted as soon as the
third and fourth ventricles had been cleared from blood if clamping
of EVD was not possible over a period of at least 24 hours without
intracranial pressure elevation, as described previously in detail.10
Assessment of Ventriculitis
In all patients treated with EVD or LD, cerebrospinal fluid (CSF)
was examined routinely every other day or when signs indicating
an infection (eg, leukocytosis or fever of unknown origin) occurred.
Ventriculitis was diagnosed according to the criteria described by
Lozier et al20 if low CSF glucose level, high CSF protein, and CSF
pleocytosis was found. Antibiotic therapy was started even if CSF
culture was negative. Thus, a retrospective distinction between aseptic and infective ventriculitis was not sufficiently possible.
Statistics
Data are presented as mean±SD if not indicated differently. Statistical
analyses were performed using the IBM SPSS Statistics 19 software
package. A 2-tailed t test was used to compare differences between
patient characteristics. A repeated-measure ANOVA was performed
to examine the influence of IVF on rPHE at different time points.
A multiple regression analysis was run to identify the impact of different patient characteristics on rPHE as well as the impact of cumulative IVF dose on rPHE. Representatively, regression and correlation
analysis was performed for data of day 1, days 4–6, and days 10–12.
A P value <0.05 was considered statistically significant.
Results
Baseline Clinical Data
Between January 2006 and October 2011, a total of 64 patients
with ICH, IVH, and obstructive hydrocephalus who were
treated with IVF were identified from our institutional ICH
database. Sixty-four controls were selected from the remaining
246 patients with ICH and IVH using ICH volume matching.
The matching algorithm resulted in similar mean ICH volumes
in both groups (IVF group: 20.01±17.5 mL; control group:
20.08±17.1 mL). Time from symptom onset to initial CT was
6.0±6.0 hours in the IVF group and 6.1±6.3 hours in the control
group (P=0.89). Secondary rebleeding with hematoma expansion of >30% of the initial hematoma volume occurred in 11
patients (17.2%) of the IVF group and in 14 patients (21.9%)
of the control group (P=0.51). In the IVF group, 5 patients
receiving 1 mg of intraventricular rtPA per application (14.7%)
and 6 patients (20%) receiving 4 mg of rtPA suffered a hematoma expansion of >30% (P=0.59). There was no relationship
between cumulative dose of ventricular rtPA and the occurrence
of a hematoma expansion of >30% (R²=0.001; P=0.80). Clinical
and radiological characteristics are summarized in Table 1.
Course of PHE
As demonstrated in Figure 1, rPHE increased significantly over
time in both groups (F[1,63]=33.79; P<0.001) and showed an
almost identical course in patients treated with IVF and controls
(F[1,63]=0.39; P=0.844). Maximum rPHE was reached after
9.7±5.8 days after onset in the IVF group and after 9.2±5.5 days
in the control group (P=0.97). Per definition, absolute PHE volume and absolute ICH volume account for rPHE. Absolute PHE
volume at admission was strongly correlated with absolute ICH
volume at admission (R²=0.476; P<0.001). None of the other
clinical characteristics significantly accounted for rPHE. Thus,
absolute ICH volume remains an exclusive factor accounting for
rPHE. IVF had no influence on rPHE at any time point (Table 2).
The evolution of rPHE (changes in rPHE in correlation to rPHE
at admission [Delta-rPHE]) within the examined time course
was not influenced by IVF either (mean Delta-rPHE between
Volbers et al No Effect of Ventricular rtPA on Edema After ICH 3
Table 1. Clinical, Demographic, and Radiological
Characteristics
IVF Group (n=64)
Control Group
(n=64)
v Value
64±10.9
69±15.1
0.04
34
39
0.38
NIHSS (median [IQR])
21 (24)
13 (15.5)
0.001
GCS (median [IQR])
8.5 (11)
13 (4.75)
0.001
mRS (median [IQR])
1 (2)
1 (1)
0.93
3
23
<0.001
59
33
<0.001
2
8
0.02
Age (mean±SD), y
Men (n)
ICH lobar (n)
ICH ganglionic (n)
ICH cerebellar/brain stem (n)
Statin use (n)
14
8
0.16
Hypertonia (n)
59
60
0.74
Warfarin use (n)
9
15
0.20
Aspirin use (n)
18
18
1.00
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Aspirin + Dipyridamole use (n)
0
1
0.32
Osmotic therapy (Mannitol; n)
30
25
0.37
Hypothermia (n)
11
9
0.57
Use of EVD (n)
64
31
<0.001
8.8±8.0
9.2±5.7
0.81
Use of lumbar drainage (n)
44
14
<0.001
Duration of lumbar drainage
(mean±SD), d
7.0±5.0
5.8±2.6
0.38
5
2
0.245
0
…
…
Duration of external ventricular
drainage (mean±SD), d
Ventriculitis (n)
Cumulative dose of IV-rtPA
(mean±SD), mg
8±6.01
ICH volume d1 (mean±SD), mL
20.01±17.5
20.08±17.1
PHE volume d1 (mean±SD), ml
16.7±11.4
18.1±15.5
0.46
IVH volume d1 (mean±SD), ml
26.8±19.2
9.2±13.4
<0.001
GRAEB score d1 (median [IQR])
LOS days (mean±SD)
Intrahospital mortality (n=)
3 (2)
<0.001
22±12.5
8 (2)
18±8.2
0.04
4
3
0.70
d1 indicates day 1; EVD, external ventricular drain; GCS, Glasgow coma scale;
ICH, intracerebral hemorrhage; IQR, interquartile range; IVF, intraventricular
fibrinolysis; IVH, intraventricular hemorrhage; IV-rtPA, intraventricularly adminis­
tered recombinant tissue plasminogen activator; LOS, length of stay; mRS,
modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; and
PHE, perihemorrhagic edema.
day 1 and day 12: IVF group, 0.76±1.1; control group, 0.56±0.7;
P=0.459 and Delta-rPHE between day 1 and day 6: IVF group,
0.46±0.7; control group, 0.36±0.6; P=0.555).
Influence of IVF Dosage
Thirty patients (mean ICH volume 17.45±16.65 mL) had
received 4 mg intrathecal rt-PA per application (high dose
group) and 34 patients (mean ICH volume 22.18±18.26 mL)
1 mg (low dose group). ICH volume did not differ significantly
(P=0.339) between both subgroups. Mean cumulative intra­
ventricularly administered rtPA was 3.79±3.43 mg in the low
dose group and 11.86±5.4 mg in the high dose group. Four
patients in the high dose group received <7 mg intrathecal
rt-PA cumulative, and 5 patients in the low dose group >7 mg
Figure 1. Course of mean relative perihemorrhagic edema (rPHE)
±SE of the mean from onset up to days 10 through 12 of patients
treated with intraventricular fibrinolysis (gray line, intraventricular
fibrinolysis [IVF] group) compared with controls (black line, control group). No difference between rPHE of both groups could be
shown (F[1,63]=0.39; P=0.844).
cumulative. As can be seen in Figure 2, the cumulative dose
had no effect on rPHE at days 10 through 12 (R²=0.014;
P=0.347). There also was no effect on rPHE at days 4 through
6 (R²=0.010; P=0.423; data not shown). Concerning the effect
of a single application dose, no significant difference could be
seen in the rPHE evolution between patients who received 4 mg
of rtPA per application (Delta-rPHE days 10–12; 1.00±1.3) and
patients who received 1 mg of rtPA per application (Delta-rPHE
days 10–12; 0.54±0.83; P=0.09).
Discussion
The key finding of the present study is that patients with ICH,
IVH, and obstructive hydrocephalus treated with intraventricular rtPA applied in a range of doses used in our institution
(4 mg every 12 hours, up to 20 mg or 1 mg every 8 hours up
to 12 mg) did not develop any detectable increase in PHE in
the course of treatment compared with ICH-volume–matched
controls. Furthermore, we could not find any association
between the cumulative rtPA dose applied and rPHE.
Our finding is in contrast to the results of a previously published smaller study.14 Ducruet et al14 compared the evolution
of PHE between 13 patients treated with intraventricular rtPA
and 17 controls. The authors described significantly higher
rPHE in patients treated with IVF. When comparing those
results with the present study, several important differences
Table 2. Evolution of Relative Perihemorrhagic Edema in
Patients Treated With Intraventricular Fibrinolysis (IVF Group)
Compared With Controls (Control Group)
Relative Perihemorrhagic
Edema
IVF Group
(n=64)
Control Group
(n=64)
P Value
Day 1
1.05±0.63
1.16±0.67
0.54
Days 2–3
1.28±0.76
1.32±0.72
0.75
Days 4–6
1.52±0.99
1.53±0.84
0.92
Days 7–9
1.64±1.31
1.66±0.95
0.91
Days 10–12
1.81±1.39
1.73±0.95
0.92
Data are mean±SD.
4 Stroke February 2013
Figure 2. Scatterplot of relative perihemorrhagic
edema (rPHE) at days 10 through 12 (rPHE days
10–12) and cumulative dose of intraventricularly
administered recombinant tissue plasminogen activator (rtPA; cumulative rtPA dose) including regression line. There was no observed dependence of
the rPHE at days 10 through 12 on the administered
cumulative dose of rtPA (R²=0.014; P=0.347).
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should be considered. First, the mean ICH volume in the
treatment and control group of Ducruet et al14 was larger compared with our cohort. Moreover, there was an imbalance in
the ICH size between the 2 groups, although the difference
was not significant. Nevertheless, considering the small sample size of this study, such a difference may have influenced
the findings reported by the authors because previous studies
have shown that rPHE is inversely associated with ICH volume.17,21 Second, PHE is difficult to delineate and to assess
on CT imaging. Ducruet et al14 used the investigator-based
ABC/2 method to determine ICH and PHE volumes on CT,
which may have caused higher inaccuracy compared with the
semiautomatic volumetric algorithm used in the present study.
This algorithm has been developed within a prospective study
and validated against PHE volume assessed on MRI.18
Although the role of PHE as a factor worsening morbidity
and mortality after ICH15 has not been well established, it may
be of particular importance in large ICH,16,17 in which additional mass effect may be detrimental. Our study only included
patients with small hemorrhages with a mean ICH volume of
20±17.5 mL, in which this aspect may be of secondary concern. Moreover, IVF using rtPA has been mainly investigated
and is currently being evaluated in smaller ICH (<30 mL in the
ongoing multicenter phase III CLEAR-IVH trial).11,12,19
Concerning secondary rebleeding, we could not find a
significant difference between the IVF group and controls.
Compared with the published results of the phases A and B
of the CLEAR-IVH trial,12 rebleeding was slightly less common in our study but comparable in the IVF group. However,
we observed more rebleeding in the control group. A possible
explanation can be derived from the retrospective design of
our analysis with all consequences concerning imbalances
between both groups. Furthermore, Naff et al12 evaluated
symptomatic rebleeding, whereas we examined hematoma
expansion of >30%. This definition was necessary, because
>83% of our patients had been mechanically ventilated during the first week after bleeding, and clinical evaluation of
symptomatic rebleeding was strongly limited in this cohort.
A recently published systematic review of studies investigating IVF in patients with secondary IVH reports a lower
overall rebleeding rate compared with our data;11 however, the
studies included in this review were mainly relatively small
case series. Therefore, this aspect remains not satisfyingly
elucidated yet, and the final results of CLEAR-III must be
awaited. We also could not demonstrate a correlation between
the rtPA dose used for IVF and rebleeding rate. However, the
statistical power of our study may have not been sufficient to
detect a possible influence. In this context, our findings support the safety of intraventricularly administered rtPA, considering its possible effect on PHE and rebleeding.
Apart from the possible influence of intraventricular rtPA
on the perihemorrhagic area, animal studies have raised
concerns that periventricular structures and the ependymal
layer may be damaged by dose-dependent rtPA-mediated
neurotoxicity, leading to edema of periventricular tissue.6,22
Furthermore, Ducruet et al14 also reported increased occurrence of aseptic meningitis in rtPA-treated patients.14 In our
study, only the occurrence of ventriculitis without any further
differentiation was recorded, and no significant difference
was found between patients treated with IVF and controls. In
light of the relatively scarce experimental and clinical data,
at this time, it still remains unclear whether mechanisms of
rtPA-mediated neuronal damage, as described in ischemic
injury,22 play an important role in the setting of ICH with
ventricular involvement. Considering the relatively low doses
of rtPA used for IVF, blood breakdown products, released in
higher concentrations after IVF, may be more harmful to the
surrounding brain tissue than the fibrinolytic agent itself. In
this context, faster and more effective drainage of IVH after
lysis may be crucial to attenuate inflammatory damage.23 Of
course, in the absence of experimental or histopathologic
data, those interpretations remain speculative. Prospective
data are necessary to possibly confirm our data and to address
further questions such as influence of ventricular rtPA on
periventricular matter.
Our study has several limitations that should be considered
when the results are interpreted. First, this was a retrospective study; however, it was performed at a single center and,
therefore, institutional protocols for management of increased
intracranial pressure and severe IVH were consistent within
the investigated groups. Moreover, a relatively large number
of patients could be included in our analysis. Despite this, we
cannot exclude that statistical power may have not been sufficient to detect small rPHE differences between both groups.
Second, because of a change in our institutional protocol for
IVF in 2008, 2 different dosing regimens were used for IVF.
Volbers et al No Effect of Ventricular rtPA on Edema After ICH 5
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
However, the rtPA doses applied before and after the change in
our treatment protocol varied within an acceptable range and
were close to the doses currently investigated in the CLEARIII trial.13 The 2 dosing subgroups were not matched for ICH
volume, leading to a nonsignificant imbalance, which may
have influenced the rPHE comparison. However, the cumulative rtPA dose had no effect on rPHE, independent from the
dosing group. Third, for comparison of PHE on follow-up CTs,
we merged several days to time clusters and analyzed them
as single time points, thereby combining different stages of
PHE evolution. Fourth, the volumetric assessment of PHE on
CT is difficult, and there might be inaccuracies in delineating
the PHE area. We resolved this problem by using a validated
semiautomatic volumetric algorithm, as described previously
in detail.18 Fifth, we only analyzed PHE evolution within 10
to 12 days after ICH; therefore, our conclusions are limited
to that time period. Sixth, obstructive hydrocephalus was a
selection criterion in the treatment group, and because of its
characteristic appearance on neuroimaging, blinding of PHE
measurement was not possible. Therefore, results could have
been biased because of this fact. Seventh, there were some
imbalances in the characteristics of the IVF and control group
concerning age, ICH location, use of EVD and LD, originating mainly from the retrospective design of this study and the
slightly different drainage management strategies depending
on the severity of IVH. EVD and LD were only inserted when
necessary according to an institutional protocol. Previous studies indicate that ganglionic ICH is associated with more severe
IVH.24 This fact, as well as the more frequent need of extracorporeal CSF diversion in severe IVH, may have led to an
overrepresentation of drainage use and ganglionic hemorrhage
in the IVF group. Thus, we could not exclude a possible impact
of those characteristics on the evolution of PHE, even if regression analysis did not show any significant influence. Although,
as far as having been addressed in previous research, age, ICH
location, and use of EVD and LD have not been shown to affect
the evolution of PHE.17,21,25 However, the most important variable influencing PHE, namely ICH volume,17,21,26 was identical
in both groups resulting from our strict matching algorithm.
In conclusion, we did not observe an effect of IVF with
rtPA on PHE evolution after ICH with severe ventricular
involvement.
Disclosures
None.
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Intraventricular Fibrinolysis Does Not Increase Perihemorrhagic Edema After
Intracerebral Hemorrhage
Bastian Volbers, Ingrid Wagner, Wolfgang Willfarth, Arnd Doerfler, Stefan Schwab and
Dimitre Staykov
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