From the Departments of Neurological Surgery (W.M.C., F.C.V., J.M.A.,
R.B., D.B.M., F.G.D., J.P.M.) and Neurology (W.M.C.), Detroit Receiving and
Grace Hospitals, Detroit Medical Center, Wayne State University, Detroit,
Mich.
Correspondence to William M. Coplin, MD, Departments of Neurology and Neurological Surgery, Wayne State University, 4201 St Antoine–6E-UHC, Detroit, MI 48201. E-mail wcoplin{at}med.wayne.edu
Methods—Using medical records, we identified all patients who
received ventriculostomies for CT-confirmed
nonaneurysmal nontraumatic spontaneous IVH from
December 1992 through November 1996. We reviewed charts and CT images
and examined the data for associations with specific outcomes.
Results—We identified 40 patients, 18 treated with
ventriculostomy alone and 22 receiving adjunctive
intraventricular UK. The initial Glasgow Coma Scale
(GCS) scores of the two groups were similar (P=0.5).
While there was a trend for patients with any intraparenchymal
hemorrhage (IPH) to receive UK (P=0.07), the
mean size of IPH in those who received ventriculostomy alone was larger
than in those who received adjunctive UK (P=0.002).
There was lower mortality in the group treated with UK (31.8 versus
66.7%; P=0.03), but there was only a trend toward an
increase in favorable outcome (22.2% versus 36.4%;
P=0.3). Overall, the most significant association with
outcome was neurological condition at presentation (GCS >5
versus
Conclusions—Intraventricular UK remains a
safe and potentially beneficial intervention. While it appeared to
lower mortality, a randomized, placebo-controlled trial is needed to
explore whether the therapy can increase the incidence of favorable
outcomes.
We present a retrospective cohort study of 4 years'
experience with ventriculostomy treatment of IVH, with or without
adjunctive intraventricular UK administration. In
this study, we attempted to examine the safety and efficacy of this
treatment modality in consecutive patients who presented with
spontaneous symptomatic IVH. This study was undertaken to
assess the influence that adjunctive UK therapy has on speeding
hematoma resolution and on outcome. The hypothesis was that this
relatively simple therapy would improve neurological prognosis in
patients presenting with IVH.
Treatment and Evaluation
The goals were a substantial reduction of hematoma volume and
re-establishment of normal CSF flow and absorption.
Ventricular catheters were removed when patients no longer
had symptomatic intracranial hypertension and/or CT scan
did not show persistent hydrocephalus. Failing these end points,
patients received implanted ventricular CSF shunts if they
had symptomatic hydrocephalus.
Urokinase-Treated Group
Urokinase (Abbokinase, Abbott Laboratories) is available as a
lyophylized powder cake that when reconstituted with 5 mL sterile water
becomes a 50 000-IU/mL solution. A dose of 10 000 U (2 mL of a 1:9
dilution of the above solution) was administered slowly through a
frontal ventriculostomy catheter-, every 12 hours. The catheter was
then flushed with 3 mL preservative-free normal saline, closed for 1
hour, then opened to drain against a pressure gradient of 10 to 15
mm Hg (above the level of the external auditory meatus) for at
least 1 hour. Patients had repeat CT scans, and drug administration was
continued until the third and fourth ventricles cleared of blood on CT
or until the patients fully recovered or died.
Radiographic Findings
Outcome
Complications
Statistical Analysis
The age range of the population was 22 to 95 years (median, 57.0
years). All patients had a history of premorbid concomitant
hypertension. The range of admission GCS scores was 3 to 14. There were
6 patients (15%) with documented intracranial hypertension (initial
ICP of >20 mm Hg) at the time of ventriculostomy placement; the
incidence of intracranial hypertension was split between the two
treatment groups (P=0.36). There was no difference between
the treatment groups in the percentage of those who were hypertensive,
with a systolic blood pressure of >185 mm Hg
(P=0.71) or >220 mm Hg (P=0.38).
Demographic and initial clinical data are presented in Table 1
Treatment
Radiographic Findings
Outcome
Certain factors helped predict a favorable outcome. Patients with
higher GCS scores either at admission (P=0.001) of after
ventriculostomy (P=0.005) were more likely to have a
favorable outcome. This finding was more robust for patients with
higher GCS scores after ventriculostomy who then received UK versus
those who did not (P=0.03 versus P=0.2). An
initial change in GCS with the ventriculostomy did not otherwise
influence the GOS (P=0.5). Posturing at
presentation (GCS motor score of
There were 6 patients (15%) who required ventriculoperitoneal
shunting. Four of these patients received UK, although receiving a
permanent shunt was unrelated to having received UK (P=0.7).
Of survivors, 30% were discharged from the hospital with
ventriculoperitoneal shunts. For survivors, prior to consideration of
shunting, 22% of ventricular catheters required
replacement because of unrelieved obstruction; only 1 of the patients
requiring catheter replacement had not received UK.
There was no difference in hospital LOS between survivors who received
adjunctive UK and those who did not. The median LOS for survivors
treated with ventriculostomy alone was 22.5 days (range, 8 to 97 days)
(n=6). This compares with a median LOS of 27.0 days (range, 4 to 105)
for those who were treated with adjunctive
intraventricular UK and who survived (n=15). This
difference was not significant (P=0.5). As expected,
patients who died had a shorter LOS (P=0.0003).
Complications
Our results indicate that there was a significant increase in survival
for a cohort of patients with spontaneous IVH who received adjunctive
UK; however, there was only a trend toward having a favorable outcome
(survival to better-than-vegetative state) with the treatment.
Receiving the drug did not increase the incidence of complications or
the hospital LOS for survivors. While a CT scan consistent with
acute hydrocephalus was common, of interest is that only 15% of our
cohort had initial intracranial pressures of >20 mm Hg. This
suggests that, at least initially, CSF flow may not be impaired to a
clinically significant degree, or that compensation occurred by the
time of measurement. The strongest features associated with outcome
were the initial neurological examination and the extent and duration
of involvement of the third ventricle with IVH.
In this cohort, patients presenting with complete casting of the
third ventricle but not the fourth were more likely to have
subsequently received UK. There was no significant difference in the
times to clear the lateral or fourth ventricles of blood; however, the
third ventricles cleared a median of 3.5 days sooner in patients who
received UK. This is not surprising; these mostly supine patients had
frontal horn placement of their ventriculostomies. Infused UK would be
expected to distribute in a dependent fashion, and the frontal horns,
especially contralateral to the ventriculostomy catheter, would be
expected to take longer to clear. The third ventricle, in this
retrospective study, might be considered an interesting confounder, as
its clearance was used to decide when to stop UK therapy. This feature
of the protocol for UK administration was based on previous
findings.9 In our cohort, clearance of the third
ventricle occurred sooner in patients who received UK, and clearance of
the third ventricle portended better outcome. This suggests that relief
of third ventricular obstruction may be the key observation
to guide successful treatment of UK therapy of IVH, and perhaps
clearance of third ventricular hemorrhage should be
the end point of treatment. Again, in the present cohort, the
fourth ventricle never failed to clear if the third cleared.
This retrospective cohort analysis cannot account for what are
likely unmeasured factors in the decision to treat some patients and
not others with UK. The only clear factors we could find separating the
treatment groups at presentation were those of complete
casting of the third ventricle and the size of any associated IPH. Most
probably, physician preference also played a role in the decision of
whom to treat (other decision-making factors are listed in "Subjects
and Methods"). This study does not take into account patients who
never received a ventriculostomy, presumably because their
hemorrhages were either too small or too large. Additionally,
because the role of surgery appears quite clear, we did not include
those who ultimately were diagnosed with an aneurysm or an
arteriovenous malformation or those with a posterior fossa source for
their IVH (eg, intraventricular rupture of a
cerebellar hemorrhage). Because of the potential confounding in
assessing outcome, we did not include those in whom the underlying
diagnosis was a brain tumor or who had primarily traumatic
hemorrhages (ie, a clear immediate history of external force to
the head).
Causes and Natural History of IVH
Pathophysiology of IVH
Clot lysis depends on the conversion of the plasma protein
plasminogen to the active enzyme plasmin, a nonspecific
proteolytic enzyme capable of digesting fibrin, fibrinogen, and other
proteins. Lysis of an intraventricular clot does
not necessarily depend on the fibrinolytic state of the circulation,
but rather on the fibrinolytic activity of the cerebrospinal fluid,
which is less effective and often referred to as
incomplete.33 The rate of IVH clearance has not
been studied systematically in a large number of patients. Available
data suggest that these clots diminish in CT density over several
weeks, becoming isodense and eventually hypodense with respect to brain
tissue6 ; however, pathologically, hematomas can
persist for months.34
Management by Ventriculostomy Drainage
Development of Delayed Hydrocephalus
The goals of ventriculostomy in patients with IVH include draining CSF
and intraventricular blood and measuring
intracranial pressure. Ventriculostomy alone does not seem to achieve
these goals for several reasons; perhaps most important, except in rare
cases, the ventricular catheter is inadequate in draining
the intraventricular blood.18
A series of 68 patients with IVH found no significant relationship
between delayed hydrocephalus and the presence of a clot in the third
or fourth ventricle.4 The prognosis for
developing chronic communicating hydrocephalus may be related more to
the severity of SAH associated with IVH than the amount of
intraventricular blood
itself.9 43 We had repeatedly experienced the
problem of catheter obstruction with ventriculostomy alone; therefore,
it did not appear to suffice for meeting the above goals acutely, and
this protocol was undertaken.
Effect of Fibrinolytic Therapy for IVH
The early clearance of intraventricular blood seems
to be important for both the relief of hydrocephalus and the clearance
of blood products. Intracerebral hematomas release
products (eg, thrombin) that may be toxic to the adjacent nervous
tissue44 ; therefore, early evacuation of these
products may improve outcome.
Complications
Prognosis
Administering fibrinolytic therapy to patients with IVH appears to
offer benefit, but there are still many questions to address: which
agent (eg, UK, r-tPA, or hirudin) is the most efficacious and cost
effective; how often should what dose be used; how long should the
ventriculostomy be clamped after drug administration; should third
and/or fourth ventricular clearing be used to decide when
to stop therapy or should the entire CT be clear of IVH; and is there a
difference in outcome for patients with IVH from ruptured IPH as
opposed to those with IVH in the setting of aneurysmal SAH?
These are among the questions that will need to be addressed in a
prospective, randomized, placebo-controlled multicenter study to
establish clearly the optimal indications and ultimate value of this
treatment for patients with spontaneous IVH. The hypothesis of such a
trial is that more rapid clot lysis will permit more prompt and
effective CSF and blood drainage. This, in turn, could shorten ICU
and/or hospital LOS and potentially decrease the incidence of
posthemorrhagic hydrocephalus and improve neurological outcome. Such a
protocol should aim to improve the negative predictive value of an
initial low GCS (ie, presenting with hypertonic posturing) for
patients without structural brain stem lesions. We are currently
preparing such a trial.
Received February 13, 1998;
revision received April 13, 1998;
accepted May 6, 1998.
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© 1998 American Heart Association, Inc.
Original Contributions
A Cohort Study of the Safety and Feasibility of Intraventricular Urokinase for Nonaneurysmal Spontaneous Intraventricular Hemorrhage
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Small case
series have reported potential benefit from
thrombolysis after spontaneous
intraventricular hemorrhage (IVH). Our
objective was to review our experience using
intraventricular urokinase (UK) in treating
selected patients with IVH. 
5; P=0.003). Receiving UK did not increase the
occurrence of complications or hospital length of stay for survivors
(P=0.5).
Key Words: intraventricular hemorrhage • outcome • thrombolysis • thrombolytic therapy
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Spontaneous
(nontraumatic) IVH, with or without other hemorrhagic lesions (eg,
intraparenchymal or aneurysmal subarachnoid
hemorrhage), frequently carries a grave prognosis. Associated
risk factors include diabetes mellitus, bleeding diatheses, and
systemic hypertension, which is the most frequent
cause.1 Patient presentation ranges
from headache, to confusion, to coma. A large part of the morbidity
seen after IVH is related to intracranial hypertension from
hydrocephalus that cannot be adequately treated with standard external
ventricular drainage. The failure of ventriculostomy alone
to clear IVH is frequently related to clots within or around the
catheter, which obstruct attempts at therapeutic CSF drainage. Anatomic
correlates of this impaired CSF outflow include compression of
periventricular structures and brain stem
injury.2 Patients initially may not have
significant parenchymal injury, and relief of persistent IVH may
prevent subsequent significant brain damage. Reported mortality from
IVH is in the neighborhood of 80%, regardless of surgical
interventions such as ventriculostomy or stereotactic or
transcortical hematoma evacuation.3 4 5 6 7 8 9 CT
studies6 reveal that spontaneous IVH resolution
usually occurs within 3 weeks. Others have reported some improvement of
outcome by speeding intraventricular
thrombolysis (with hematoma resolution occurring often
within a few days) with use of either UK9 10 11 12 13 14 15 or
r-tPA.16 17 18
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patient Population
The Wayne State University Human Investigation Committee
approved these research activities. Diagnosis codes were used to
identify all patients presenting with IVH over 4 years' time, from
December 1992 (when intraventricular UK was first
used at Detroit Receiving and Grace Hospitals) through November 1996.
Detailed chart abstraction was performed to confirm the diagnosis of
spontaneous, nontraumatic IVH not associated with intracranial tumor,
arteriovenous malformation, or cerebellar hematoma. We included all
patients who were treated with ventriculostomy. We excluded those
patients eventually found to have IVH secondary to an intracranial
aneurysm. Patients' charts and serial CT images were reviewed
in detail to determine neurological, other clinical, demographic,
comorbid, and radiographic characteristics of the patients
and their treatments (with or without adjunctive
intraventricular UK). An attempt was made to define
the cause of IVH for all patients.
All patients were managed in an ICU with ICP monitoring,
aggressive hemodynamic support, and, when indicated,
mechanical ventilation. Laboratory monitoring included routine
coagulation studies (eg, prothrombin and partial thromboplastin times).
The GCS score19 was recorded at admission and
hourly, while in the ICU. Patients presenting with
symptomatic IVH received frontal horn ventriculostomies
through a frontal twist drill hole, under at least local
anesthesia. Patients had CT confirmation of
intraventricular location of the ventriculostomy
catheter prior to the decision to administer UK.
The decision to treat an individual patient with UK was made by
the senior neurosurgical resident or fellow in consultation with the
attending neurosurgeon. Among the criteria used to make this decision
were continued neurological deterioration despite ventriculostomy;
failure of ventriculostomy to drain because of clots in or around the
catheter; and dissection of blood into the brain stem (eg, from a
thalamic hemorrhage).
After admission, follow-up CT images were obtained as medically
indicated, at the discretion of the attending neurosurgeon. We scored
CT images using a system derived from others' previous
work.4 20 The review of these images sought to
delineate the ventricles involved and the degree (ie, estimated
hematoma volume) of that involvement. The presence and degree (if
present) of hydrocephalus and intraparenchymal and/or
subarachnoid hemorrhage was also recorded.
Suspicion of aneurysms or other vascular abnormalities prompted
biplane contrast angiography; the findings of this study (if obtained)
were also reviewed.
The primary outcome measure used at the time of hospital
discharge was the GOS21 ; this scale accounts for
in-hospital death as a possible outcome. Because of the nature of the
study, it was difficult to retrospectively apply other neurological
outcome scales.
Among the complications we sought to define were death,
ventriculitis (chemical or infectious), rebleeding, and the need for
subsequent ventricular shunting. To screen for
ventriculostomy-related infection, CSF samples were routinely sent for
cell count, glucose, protein, Gram stain, and culture at least every 3
days. The presence of fever, leukocytosis, developing meningeal signs,
and/or a change in the color or clarity of CSF sometimes prompted more
frequent sampling from the proximal port of the closed
ventricular drainage system.
Data were entered into a computerized database (SPSS for
Macintosh, Version 6.1.1, SPSS Inc). Wayne State University computer
resources were used to analyze the data. Data were
presented as means, medians, and ranges. We examined these data
for associations with specific outcomes. The GOS was dichotomized as
poor (GOS 1 to 2) and favorable (GOS 3 to 5) outcomes for some
analyses. Fisher exact (2-sided) and 
2
analyses were used to calculate P values for
categorical variables. Comparison of medians, for ordinal
variables, was done with Wilcoxon rank sum
analysis. Spearman rank correlation was used when there were
more than 2 groups (eg, to assess the correlation of clinical status,
such as GOS, with a variable of interest). Significant differences
were assumed with P< 0.05.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patient Population
We included in the data analysis 40 patients who
presented with spontaneous nonaneurysmal IVH
and received ventriculostomy drainage at 1 of the 2 hospitals over the
4-year study period. Thirty patients were treated at Detroit Receiving
Hospital and the remaining 10 at Grace Hospital. There were 18 patients
treated with ventriculostomy alone and 22 who received adjunctive
intraventricular UK. The most common cause of IVH
was presumed hypertensive hemorrhage; 39 patients
presented with focal, lateralizing neurological signs. We
included 1 patient who had associated head trauma. He fell with his
ictus, but had no significant external signs of trauma or any contusion
or fracture on CT scan; we presumed the cause of his fall was a
spontaneous intracranial hemorrhage. We excluded from
analysis 2 patients later identified as having
aneurysms not initially suspected as the cause of their IVH.
These 2 patients were initially managed not as patients with
aneurysms but as those with nonaneurysmal IVH;
however, neither received adjunctive UK. 
.
View this table:
[in a new window]
Table 1. Clinical Features of 40 Patients With
Intraventricular Hemorrhage
We examined the data to ascertain if there was any relation
between certain clinical factors after presentation to the
emergency department and the chance of receiving adjunctive UK.
Patients not treated with UK received their ventriculostomies a median
of 196 minutes (range, 70 to 720 minutes) after arrival in the
emergency department; those who later received UK received their
ventriculostomies a median of 330 minutes (range, 60 to 2880 minutes)
after arrival (P=0.2). The clinical response to
ventriculostomy (before any patient received UK) included 7 patients
(17.5%) whose neurological condition improved and 30 patients (75.0%)
whose neurological condition was similar to that before
ventriculostomy. There were 3 patients (7.5%) whose clinical
deterioration continued, despite ventriculostomy, before any decision
was made concerning adjunctive UK therapy; all 3 received UK. A change
in a patient's GCS from the ventriculostomy was not related to later
receiving UK (P=1.0). The first dose of UK was given a
median of 620 minutes (maximum of 8570 minutes) after ventriculostomy
placement and CT confirmation of catheter tip location. Those receiving
adjunctive intraventricular UK received a median of
3.0 (range, 0.5 to 10) days of therapy.
Patients who received UK had significantly greater blood casting
of the third ventricle and a trend that did not quite achieve
significance to complete blood casting of the fourth ventricle (Table 1
). The mean size of IPH in those who had ventriculostomy alone was
substantially larger than in those who received the adjunctive UK;
however, there was a trend that did not quite achieve significance to
patients having any associated IPH to receive the adjunctive UK. There
was no difference between the groups in the initial CT response to
ventriculostomy alone (before any patient received a dose of UK)
(P=0.5). There was no significant difference between the two
treatment groups in the time required to clear any of the ventricles of
blood, except in the case of the third ventricle, which cleared a
median of 3.5 days sooner in patients receiving UK (Table 2).
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Table 2. Treatment and Outcome Factors
Of the 18 patients treated with ventriculostomy alone, 12 (66.7%)
died in the hospital. This compares with 7 deaths among the 22 patients
(31.8%) treated with adjunctive UK (P=0.03). We tested to
see whether this improved survival translated into outcome better than
vegetative state. Treatment with UK tended to reduce the chance of
dying or remaining in a vegetative state from 77.8% (n=14/18) to
63.6% (n=14/22) (P=0.3; Tables 2 and 3).
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Table 3. Glasgow Outcome Scale Scores for 40 Patients
With IVH 3 and total GCS score
of 5) was predictive of having a poor outcome
(P=0.003) (Figure 1). The
presence of intracranial hypertension (initial ICP of >20 mm Hg)
at presentation did not influence the GOS
(P=0.3). There was no association between the GOS and
hypertension at admission (P=0.07). The size of any
associated IPH was not associated with having a poor outcome
(P=0.6).
View larger version (16K):
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Figure 1. A 2x2 table showing prognostic performance of
admission GCS score with a cut off of 5. Poor outcome is defined as
being dead or vegetative (GOS score of 1 to 2).
Complications were not clearly increased by the use of adjunctive
UK (Table 4). Seven (31.8%) of the 22
patients who received UK had a complication possibly related to either
treatment with ventriculostomy or the drug. No allergic reactions to UK
were observed. Development of fever (core temperature of 
38.5°C)
during one's hospital course was associated neither with receiving UK
(P=0.2) nor with a poor outcome (P=0.3). Only 1
patient underwent surgery for an intracranial hemorrhagic complication
related to UK (evacuation of an enlarged IPH). No patient suffered any
extracranial hemorrhagic complications.
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Table 4. Frequency of Complications by Treatment Group
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
We present, to our knowledge, the largest cohort of
spontaneous IVH patients yet reported in which the influence of
adjunctive intraventricular
chemothrombolysis on outcome can be assessed. Other
series9 12 15 16 17 18 have reported a combined total
of 59 patients given intraventricular
thrombolytics for spontaneous IVH from either
aneurysmal or presumed parenchymal rupture; of these, 17
received UK.9 12 15 None of these series looked
at the same outcome measures we used (eg, LOS), nor did any have a
sizable contemporaneous cohort managed without adjunctive
thrombolytics.
Nontraumatic IVH in adults is a relatively rare condition. Most
frequently, a hypertensive lobar, thalamic, or putaminal hematoma
spontaneously ruptures into the ventricular
system.22 23 The estimated incidence of IVH is
approximately 3.1% of all spontaneous intracerebral
hemorrhages.24 Additionally, there are
recognized associations of nontraumatic IVH in adults with choroid
plexus tumors or hamartomas,25 26 choroidal
arteriovenous malformations,27 28
intraventricular
aneurysms,29 30 bleeding diatheses,
moyamoya disease, and hypertension. The ventricles initially are
involved with the following frequency: lateral (86.2%), third (7.5%),
and fourth (5.0%).31 These estimates likely
relate to the relative ependymal surface and size of choroid plexus
contained within the different ventricles.24
The pathophysiology of IVH is quite variable. Hematomas can
expand, producing rapid neurological deterioration and death, or they
can resolve slowly. The pathogenesis of coma and early death after IVH
may result from an acute rise in intraventricular
pressure transmitted to the brain stem reticular formation. Milder
cases present with clinical features of bilateral hemispheric
dysfunction: confusion, disorientation, vomiting, hypertonic posturing,
hyperthermia, and pupillary changes. Focal lateralizing signs, seen in
most of our patients, may suggest an associated IPH. The presence of
diencephalic or mesencephalic signs may suggest a third
ventricular hematoma. Mass effect from clots distending the
ventricular walls may be the major factor responsible for
the poor prognosis from IVH. Others have suggested that casting of the
fourth ventricle may be the most important outcome
predictor.32 In the present cohort, third
ventricular casting appears to have been a more important
factor relating to outcome; although third ventricular
clearance was used as an end point for IVH treatment, fourth
ventricular clearance always preceded third
ventricular clearance on CT scan.
Before the use of intraventricular
chemothrombolysis, acute medical therapy of IVH was
entirely supportive. Small, nonobstructing IVHs can be managed
conservatively, but larger IVHs (particularly those obstructing the
foramina of Monro or lower frequently cause acute obstructive
hydrocephalus and require external ventricular drainage.
Ventricular drainage alone is often ineffective in managing
the ventricular dilatation and intracranial hypertension
resulting from large intraventricular hematomas.
While a patent ventricular drain is able to divert CSF, it
cannot evacuate a solid clot. External ventricular drainage
alone may be of little benefit, because the catheters invariably become
obstructed with clotted blood.6 Therein lies the
rationale of adjunctive chemothrombolysis.
Impaired cerebrospinal fluid circulation is a frequent consequence
of IVH. Intraventricular hematomas can produce
acute obstructive hydrocephalus with quick neurological deterioration,
or the proteinaceous clot lysis products can complicate recovery by
producing chronic, posthemorrhagic communicating hydrocephalus.
Although 15% of the patients in our cohort (30% of survivors)
required ventriculoperitoneal shunting, the reported incidence of
hydrocephalus after IVH ranges upward from 45% of patients surviving a
severe hemorrhage; most of this information comes from neonatal
IVH.35 36 Clinical studies of patients with IVH
have suggested a relationship between the incidence of posthemorrhagic
hydrocephalus and the quantity of intraventricular
blood.35 36 37 Numerous theories attempt to
explain the incidence of delayed, posthemorrhagic hydrocephalus. These
include obstructive effects of red blood cells on the arachnoid villi,
obstruction of villi by fibrin, fibrosis of the arachnoid villi, and
ventricular wall injury.38 39 40 41 42
Compared with studies in which r-tPA was used for
intraventricular lysis,16 17 18
there is a suggestion that UK may act more slowly in clearing the
ventricles, taking as little 24 to 72 hours in at least 1 r-tPA
study18 and 7 to 10 days in the present
study. This is perhaps because UK is a nonspecific fibrinolytic and
fibrinogenolytic, whereas r-tPA has a specific fibrinolytic action.
There are no good animal or human comparative trials of the 2
drugs.
Except for 1 case, there was no significant increase in the volume
of intracranial hemorrhage after UK administration, which
suggests that the product is relatively safe to use. Adjunctive UK
instillation did not appear to increase the incidence of any other
complications, such as infection. These data need to be interpreted
cautiously because of the sample size.
Even from the pre-CT era (with the diagnosis of IVH made by CSF
sampling and/or echoencephalography),1 reported
mortality from IVH has remained in the neighborhood of 80%, regardless
of surgical interventions such as ventriculostomy or
stereotactic or transcortical hematoma
evacuation.3 4 5 6 7 8 9 While we demonstrated a decreased
mortality for the UK group, there was only a trend toward improving
outcome to better than vegetative state (from 22% to 36%). This
result in our ventriculostomy-only group is consistent with
those in other IVH studies. The lack of statistical significance may be
attributable to the sample size. Another factor, although not
statistically important in this study, may be the time to starting
therapy. Indication bias also possibly played a role; however,
intergroup differences had little impact on outcome in this, the
largest reported consecutive cohort of IVH patients, 55% of whom
received UK. Again, IPH size did not predict outcome, and while more
patients with third ventricular casting received UK, they
cleared the third ventricle more quickly and completely.
Selected Abbreviations and Acronyms
CSF
=
cerebrospinal fluid
GCS
=
Glasgow Coma Scale
GOS
=
Glasgow Outcome Scale
ICP
=
intracranial pressure
ICU
=
intensive care unit
IPH
=
intraparenchymal hemorrhage
IVH
=
intraventricular hemorrhage
LOS
=
length of stay
r-tPA
=
recombinant tissue plasminogen activator
UK
=
urokinase
Acknowledgments
This work was supported in part by the Detroit Neurotrauma
Institute. We would like to acknowledge Richard Fessler, MD, Robert J.
Johnson, MD, and Paul K. King, MD, for their clinical expertise in
being among the attending neurosurgeons caring for the patients in this
study and their continued involvement in and support of clinical
research, and Mary S. Cochran, RN, CCRN, and M. Ellen St. Pierre, RN,
BS, for data management support.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Pia HW. The surgical treatment of
intracerebral and intraventricular
hematomas. Acta Neurochir (Wien). 1972;27:149–164.[Medline]
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