Relative Edema Volume Is a Predictor of Outcome in Patients
With Hyperacute Spontaneous Intracerebral Hemorrhage
James M. Gebel, Jr, MD; Edward C. Jauch, MD; Thomas G. Brott, MD; Jane Khoury, MS;
Laura Sauerbeck, MSN; Shelia Salisbury, MS; Judith Spilker, RN;
Thomas A. Tomsick, MD; John Duldner, MD; Joseph P. Broderick, MD
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Background and Purpose—Little is known about the relationship between perihematomal edema in spontaneous
intracerebral hemorrhage (ICH) and outcome. The purpose of this study was to determine whether absolute or relative
edema volume (edema volume divided by hematoma volume) predicts mortality or functional outcome in patients with
hyperacute spontaneous ICH. We hypothesized that increasing baseline relative edema volume is associated with greater
probability of poor functional outcome.
Methods—This was a secondary analysis of a prospective, population-based study of hematoma growth in 142 patients
with spontaneous ICH. Patients were imaged within 3 hours of onset, then 1 and 20 hours later. Our primary analysis
excluded patients with anticoagulant use (n⫽7), underlying aneurysm/vascular malformation (n⫽9), trauma (n⫽1),
incomplete data (n⫽20), infratentorial ICH (n⫽17), intraventricular extension (n⫽38), and no consent (n⫽2). We
analyzed whether associations existed between baseline edema volumes or other clinical/radiological variables and
either 12-week modified Rankin Scale score ⬎2 or 30-day mortality. Secondary analyses used 20-hour CT scan data,
all patients with supratentorial ICH, and 12-week Barthel Index score ⬍85.
Results—By multivariable logistic regression analysis, baseline relative edema was the strongest independent predictor of
functional outcome and was associated with lesser odds of poor 3-month functional outcome (odds ratio, 0.09 per
1.0-unit [100%] increase; 95% CI, 0.01 to 0.64; P⫽0.016) and 12-week Barthel Index score ⬍85 (odds ratio, 0.12; 95%
CI, 0.02 to 0.91; P⫽0.039) but did not predict mortality. Secondary analyses confirmed this result. Absolute edema
volume predicted neither mortality nor functional outcome.
Conclusions—Relative edema is strongly predictive of functional outcome in patients with hyperacute supratentorial
spontaneous ICH without intraventricular extension. (Stroke. 2002;33:2636-2641.)
Key Words: computed tomography 䡲 intracerebral hemorrhage 䡲 mortality
P
erihematomal edema is present in most patients with spontaneous intracerebral hemorrhage (SICH) (not related to
thrombolysis or anticoagulants), even when imaged within 3
hours of onset.1 Significant, delayed edema growth can occur
days to weeks after SICH and may be associated with increased
mass effect and clinical neurological deterioration.2 There is
minimal information, however, on the early natural history of
edema in hyperacute SICH and regarding whether edema in this
time frame predicts mortality or functional outcome. We recently reported that absolute perihematomal edema volume
doubles, on average, during the first 24 hours after intracerebral
hemorrhage (ICH) in patients with SICH imaged within 3 hours
of onset.3 We also reported that absolute edema volume was not
independently associated with 30-day mortality in the 103
patients studied, largely because absolute edema volume was
strongly correlated with hematoma volume, which, by contrast,
strongly and independently predicted 30-day mortality.3
In this study we sought to define a priori a patient group in
whom to most ideally study the relationship between absolute
and relative edema volume and outcome. This “primary analysis” patient population (defined below) was chosen with the
specific intent of eliminating variables that could confound the
formation or measurement of perihematomal edema volume.
We hypothesized that, within such a study population, increasing
baseline CT scan relative edema volume, which quantifies
perihematomal edema in the context of the associated hematoma, would be independently predictive of increased 30-day
mortality and poorer 12-week functional outcome.
Subjects and Methods
Study Design
This study was a secondary analysis of data prospectively collected
during a previously published 142-patient study of the natural history
of hematoma growth in patients with SICH first imaged within 3
Received April 2, 2002; final revision received May 23, 2002; accepted June 11, 2002.
From the University of Pittsburgh Medical Center, Pittsburgh, Pa (J.M.G.); University of Cincinnati Medical Center, Cincinnati, Ohio (E.C.J., J.K.,
L.S., S.S., J.P.B.); Mayo Clinic Foundation, Jacksonville, Fla (T.G.B.); and Akron General Medical Center, Akron, Ohio (J.D.).
Reprint requests to James M. Gebel, MD, University of Pittsburgh Stroke Institute, 200 Lothrop St, PUH Room C420, Pittsburgh, PA 15213. E-mail
[email protected]
© 2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000035283.34109.EA
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Gebel et al
hours of clinical onset.4 The patient population of this study has been
described in detail elsewhere.4 All patients presented to emergency
departments in the study area and were imaged by noncontrast brain
CT within 3 hours of ICH onset. Most patients underwent a second
brain CT scan 1 hour later, and many underwent a third CT scan 20
hours after the baseline scan.
Data Collection
Relevant demographic, clinical, laboratory, and functional outcome
data were prospectively collected during the original study. Relative
edema volume was calculated several years later when another study
comparing hyperacutely imaged thrombolysis/anticoagulant-related
ICH with hyperacutely imaged SICH was performed.1 All data were
collected before the present study was conceived and implemented.
Patients were classified as hypertensive or diabetic only if they had
a known history of these disorders and not on the basis of actual
blood pressure or glucose levels, the data for which were analyzed
separately.
Creation of Primary Analysis Group
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We first created a primary analysis patient group consisting of
patients with few conceivable variables that might confound the
genesis or measurement of perihematomal edema. From the original
population of 142 patients, we first excluded those patients with
anticoagulant use (n⫽7), underlying aneurysm or vascular malformation (n⫽9), head trauma (n⫽1), incomplete clinical or CT data
(n⫽20), or no consent (n⫽2). This left a group of 103 patients with
true SICH and adequate data, from which we further excluded those
with infratentorial ICH (n⫽17) because of concern about petrous
apex streak artifact obscuring edema borders and preventing accurate
edema volume measurement. Finally, we excluded patients with
initial or subsequent intraventricular extension (n⫽38) because of
concerns about admixture of cerebrospinal fluid and edema confounding edema evolution and measurement. We included patients
subsequently undergoing surgery or having hematoma growth because these represented relatively common events in the overall
population, and we wished to maximize the generalizability of our
results to clinical practice.
Study Hypothesis
Our primary hypothesis was that, within this 48-patient primary
analysis population, increasing amounts of relative edema volume
would be associated with an increased probability of poor 12-week
functional outcome (modified Rankin Scale [MRS] score ⱖ3). We
assumed that hematomas with relatively greater amounts of perihematomal edema would exert more mass effect and/or induce greater
local tissue injury, thereby worsening outcome. Patients who died
(regardless of cause) were assigned a MRS score of 6 and were
included in this poor outcome group. All other patients with MRS
score ⱕ2 were considered to have a good functional outcome.
Primary Analysis
The primary outcome variable was a 12-week MRS score of ⱖ3
(poor functional outcome). Baseline CT scan relative edema and
other relevant clinical and radiological variables were first analyzed
for their univariate association with the primary dependent outcome
variable. Variables found to have a statistically significant association with poor functional outcome were then entered into multivariable logistic regression models to determine whether such associations would remain significant when we controlled for other
variables.
Subsequent (Secondary) Analyses
All secondary analyses were implemented after the primary analysis
to verify its results. First, absolute edema volume was used as the
independent variable of interest instead of relative edema volume for
the outcome of 12-week MRS. We then analyzed the association
between baseline relative edema volume and outcomes using the
12-week Barthel Index (BI), the only other 12-week functional
outcome assessment collected (once again a priori dichotomized as
Edema Volume Predicts ICH Outcome
2637
ⱖ85 [“good” outcome] versus ⱕ80 [“bad” outcome]), and 30-day
mortality. These 2 additional analyses were not repeated for absolute
edema volume. Patients who died were assigned BI scores of zero
and included in the poor outcome group. Subsequent secondary
analyses (relative edema volume only) used the entire supratentorial
ICH patient population (n⫽86) and those with intraventricular
extension (n⫽38) and analyzed 20-hour CT scan relative edema
volume and radiological data instead of baseline CT scan values.
Finally, we repeated the primary analysis excluding 1 patient with
a possible outlier relative edema volume value of 4.13 to ensure that
this value was not the basis of any of the results.
Definition and Measurement of Relative
Perihematomal Edema Volume
Relative edema volume was defined as absolute edema volume
divided by hematoma volume, yielding a unitless ratio variable.
Absolute edema volume was measured by a previously published
computer-assisted volumetric measurement technique.5
Specifically, each brain CT image was scanned and preprocessed
to standardize brightness levels of brain tissue and hematoma
between images. For each image, K-means histogram-based clustering was used to determine standardized brightness (attenuation)
values for background (noise) level, brain tissue level, and skull
level. The skull was then extracted. The study neuroradiologist
(T.A.T.) marked the center of each hematoma, defining the center of
the region of interest for subsequent hematoma and edema volume
measurement. The same K-means clustering algorithm was used to
divide the region of interest into foreground (hematoma) and
background (perihematomal edema and brain parenchyma).
On the basis of the algorithm-generated threshold value to
differentiate hematoma from edema, the number of contiguous
3-dimensional voxels within the foreground (hematoma) is summed
to yield hematoma volume. Analogously, perihematomal edema
measurement is accomplished by “growing” thin layers (rings)
sequentially outward from the edge of the hematoma. Each such ring
of pixels is examined with the use of several computer-generated
K-means clustering algorithm-based threshold values for edema, the
most optimal of which is selected by the operator. For each layer, the
number of pixels falling within the selected range of pixel attenuation is summed and added to the previous layer’s number of edema
pixels. This iterative process is continued until no new pixels are
selected in the current (final) layer. The sum total of pixels is the
absolute edema volume.
The reproducibility and accuracy of this method were verified by
its correlation with conventional volumetric measurement of hematoma and edema volumes, with an overall Spearman correlation
coefficient of 0.9744.5
When very small, unmeasurable amounts of edema were present,
values of zero were assigned for both absolute and relative edema
volume. An example of 2 patients with different amounts of relative
edema volume is shown in the Figure.
Statistical Methods
We used SAS software (SAS Institute) for data management and
analysis. Baseline demographic and risk factor variables are descriptively summarized as mean (SD) for continuous variables and as
percentages for categorical variables. Hematoma volumes, edema
volumes, and other non–normally distributed variables were summarized as median and range. Correlations between relative edema
volume and other continuous variables were performed with the use
of the Spearman correlation coefficient. Multiple logistic regression
was used to analyze the relationship of candidate predictor variables,
including relative edema volume, to categorical functional outcome.
Sample size constraints limited analyses to 3 variables per multiple
logistic regression analysis. Effect values are summarized as odds
ratios per 1.0 unit of each respective independent variable with 95%
CIs. Probability values ⱕ0.05 were considered statistically
significant.
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Stroke
November 2002
Example of 2 patients with different relative perihematomal
edema volumes. Patient on the left has a relative perihematomal
edema volume of 0.10 compared with a relative perihematomal
edema volume of 1.30 for patient on the right.
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Results
Baseline Data
Selected baseline demographic, risk factor, and laboratory
data for the primary study population are shown in Table 1.
No significant differences existed between these values for
the primary analysis group and the entire supratentorial SICH
population. Median baseline CT scan hematoma volume for
the primary patient population was 12.2 cm3 (range, 0.4 to
124.5 cm3); 75% of the hematomas were in deep anatomic
locations, whereas 25% were lobar. Seventy percent of
hematomas exerted at least some mass effect (ventricular
and/or cisternal effacement), and 37% were associated with
measurable horizontal midline shift at the level of the pineal
gland. Median absolute edema volume was 7.4 cm3, with a
range of 0 to 94.7 cm3. Median relative edema volume was
0.524 (52.4%), with a range of 0 to 4.13.
Primary Analysis
Our initial bivariate analysis assessed clinical and radiological variables for their association with an increased probabilTABLE 1. Baseline Demographic and Clinical Risk Factor
Variables for Primary Analysis Patient Population (nⴝ48)
Variable
Percentage or Mean
GCS score
12.8 (2.52)
Age, y
62.4 (11.6)
History of hypertension
66.7%
Diabetes mellitus
Current smoker
8.3%
20.8%
Arterial blood pressure, mm Hg
125.1 (17.7)
Systolic blood pressure, mm Hg
174.0 (25.1)
Diastolic blood pressure, mm Hg
100.8 (16.9)
Blood glucose level, mg/dL
130 (56)
Prothrombin time, s
12.1 (0.80)
Partial thromboplastin time, s
25.2 (2.5)
Fibrinogen level, mg/dL
325 (84)
Platelet count, ⫻103/␮L
273 (80)
Categorical variables are reported as percent prevalence. Continuous
variables are reported as mean (SD).
ity of poor functional outcome. Notably, of major clinical
variables, only time from ICH symptom onset to baseline CT
scan was associated with an increased probability of poor
12-week functional outcome (2-tailed P⫽0.050, Wilcoxon
rank sum test). Neither baseline Glasgow Coma Scale (GCS)
score (P⫽0.145, ␹2 test) nor age (P⫽0.186, 2-tailed t test)
was significantly associated with 12-week functional outcome. By contrast, of major radiological variables, hematoma
volume (odds ratio, 1.6 per cm3; 95% CI, 1.1 to 2.3;
P⫽0.015), presence of mass effect (P⫽0.024, Fisher exact
test), and presence of midline shift (P⫽0.0114, Fisher exact
test) were significantly associated with an increased probability of poor 12-week functional outcome, whereas anatomic
location (deep versus lobar) was not.
Absolute edema volume was not associated with 12-week
functional outcome (P⫽0.820, Wilcoxon rank sum test). By
contrast, relative edema volume was significantly associated
with 12-week functional outcome. However, the nature of
this association was inverse, with an odds ratio of 0.089 per
1.0-unit (100%) increase (95% CI, 0.012 to 0.64; P⫽0.016).
Thus, increasing amounts of relative edema volume were
associated with a decreased probability of poor 12-week
functional outcome (MRS ⬎2), a result diametrically opposite to our a priori hypothesis. Neither baseline absolute
edema volume nor relative edema volume (odds ratio, 0.68;
P⫽0.677) was significantly associated with 30-day mortality.
Finally, no significant association between baseline absolute
or relative edema volume and subsequent hematoma growth
was observed.
When relative edema volume was entered into multiple
logistic regression models with 1 other dependent variable to
control for the effects of other previously reported ICH
outcome predictor variables (Table 2), the observed association between relative edema volume and good functional
outcome remained significant. However, the associations
observed between other clinical and radiological variables
and 12-week functional outcome became nonsignificant,
except for hematoma volume and mass effect, whose associations with 12-week functional outcome remained marginally
statistically significant (Table 2). An insufficient number of
observations were available for a valid logistic regression
model incorporating midline (horizontal pineal) shift. Two
additional analyses were performed. The first incorporated
relative edema volume, baseline GCS score, and baseline
hematoma volume. In this analysis, the observed association
between relative edema volume and lesser probability of poor
functional outcome once again remained significant
(P⫽0.014; odds ratio, 0.035; 95% CI, 0.002 to 0.51), whereas
no significant association persisted between hematoma volume (P⫽0.0984; odds ratio, 1.15 per 1 cm3 volume; 95% CI,
0.98 to 1.35) or GCS score (P⫽0.241; odds ratio, 0.60; 95%
CI, 0.25 to 1.41) and functional outcome. Similar results were
observed in a second 3-variable multiple logistic regression
model incorporating hematoma volume, mass effect, and
relative edema volume.
Secondary Analyses
When categorical 12-week BI score (see above) was used as
the dependent outcome variable in the primary analysis
Gebel et al
Edema Volume Predicts ICH Outcome
2639
TABLE 2. Results of 2 Variable Multiple Logistic Regression Models in Which the First
Variable Was Baseline Relative Perihematomal Edema Volume and the Second Variable Was
That Listed in the Table
Variable
GCS score
ICH location (deep vs lobar)
Odds Ratio for Poor
Functional Outcome
(95% CI), P for Variable
0.58 (0.324–1.046), P⫽0.071
Odds Ratio for Poor
Functional Outcome
(95% CI), P for Relative
Edema Volume
0.062 (0.007–0.547), P⫽0.0122
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0.668 (0.081–5.50), P⫽0.707
0.085 (0.011–0.639), P⫽0.0166
Age
1.036 (0.959–1.12), P⫽0.373
0.093 (0.012–0.747), P⫽0.0255
Mean arterial blood pressure
1.031 (0.975–1.091), P⫽0.285
0.094 (0.012–0.745), P⫽0.0252
Time from ICH onset to baseline CT scan
1.001 (0.986–1.016), P⫽0.907
0.093 (0.013–0.657), P⫽0.0173
Admission glucose
1.004 (0.987–1.021), P⫽0.623
0.090 (0.012–0.651), P⫽0.0171
Prothrombin time
0.550 (0.192–1.57), P⫽0.265
0.068 (0.008–0.572), P⫽0.0133
Partial thromboplastin time
1.205 (0.836–1.739), P⫽0.318
0.078 (0.010–0.614), P⫽0.0154
Platelet count
1.000 (0.990–1.011), P⫽0.960
0.075 (0.009–0.617), P⫽0.0160
Antiplatelet drug use
0.633 (0.049–8.219), P⫽0.727
0.088 (0.012–0.638), P⫽0.0163
Mass effect present
8.00 (0.914–70.1), P⫽0.060
0.072 (0.005–0.941), P⫽0.0449
Hematoma volume
1.191 (0.999–1.420), P⫽0.051
0.055(0.005–0.612), P⫽0.0182
P values for the respective variables inserted into each model and for relative perihematomal edema volume are
shown. Relative risks are per 1.0 unit of each variable.
group, the association between baseline relative edema volume and decreased probability of poor functional outcome
was statistically significant by both bivariate analysis
(P⫽0.0314) and multivariable analysis (multiple logistic
regression, controlling for hematoma volume, P⫽0.039; odds
ratio, 0.12 per 1.0 unit; 95% CI, 0.016 to 0.91). Similarly,
when relative edema volume values recorded 20 hours after
baseline CT scan were substituted for baseline relative edema
volume values in the primary analysis population, the observed association between (20-hour) relative edema volume
and decreased probability of poor functional outcome was
significant by both bivariate (P⫽0.0162, 2-tailed Wilcoxon
rank sum test) and multivariable analyses (multiple logistic
regression, controlling for hematoma volume, P⫽0.016; odds
ratio, 0.020 per 1.0 unit; 95% CI, ⬍0.001 to 0.80).
When the primary analysis was repeated on the entire
supratentorial SICH population (the 48-patient primary analysis population plus those 38 patients with intraventricular
extension), the association between increasing baseline CT
scan relative edema volume and decreased probability of poor
12-week functional outcome (MRS ⱖ3) remained statistically significant by univariate analysis (P⫽0.0126, 2-tailed
Wilcoxon rank sum test) and multivariable analysis (multiple
logistic regression analysis, controlling for hematoma volume, P⫽0.018; odds ratio, 0.08 per 1.0 unit; 95% CI, 0.01 to
0.66).
To exclude the possibility of excessive influence of 1
outlying relative edema volume value of 4.13 (remaining
values ranged from 0 to 2.33) on the results, we repeated the
entire primary analysis with the exclusion of this patient, with
no significant change in any results. To test whether relative
edema volume values were truly independent of hematoma
volume, we studied the correlation between relative edema
volume and hematoma volume at baseline and at 1 and 20
hours. None were significant (r⫽0.010 at baseline, P⫽0.504;
r⫽⫺0.060 at 1 hour, P⫽0.727; r⫽⫺0.125 at 20 hours,
P⫽0.46). We also analyzed the relationship between osmotic
diuretic treatment (after baseline CT) and relative edema
volume and found no associations with 1- or 20-hour relative
edema values. We compared relative edema volumes at each
time point by hematoma location (deep versus lobar). Once
again, no significant differences were observed.
Finally, we analyzed whether relative edema volume was
independently predictive of outcome in only those patients
with intraventricular extension of their hematomas. Of these
38 patients, 37 had poor functional outcomes or death at 12
weeks. Thus, in this subgroup we could not assess whether
other variables (including relative and absolute edema volume) were independently predictive of functional outcome in
multivariable logistic regression analyses, since intraventricular extension was almost perfectly predictive of poor
outcome.
Discussion
This study first newly identifies relative edema as the most
statistically significant independent predictor of (improved)
12-week functional outcome in patients with hyperacute
SICH without intraventricular extension. The observed association between relative edema volume and functional outcome remained statistically and clinically significant regardless of which 12-week functional outcome scale was chosen
as the dependent outcome variable, with maximum likelihood
point estimate odds ratios for poor 12-week functional outcome ranging from 0.055 to 0.094. Translated into clinically
meaningful terms, a patient has an 11- to 18-fold better odds
of surviving and making a good long-term functional recovery for each 1.0-unit (100%) increase in hyperacute to acute
relative edema volume, when one controls for other common
previously reported predictors of outcome in ICH, such as
hematoma volume, GCS score, hematoma location, age, mass
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November 2002
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effect, hydrocephalus, and time from ICH onset to CT scan
(Table 2). Furthermore, when 20-hour postbaseline CT scan
relative edema volume values were substituted for baseline
values (which excluded patients dying or undergoing surgery
after their 1-hour postbaseline CT scan), the association
remained highly significant, with a maximum likelihood
point estimate odds ratio of 0.02 (50-fold greater odds of
good functional outcome) when we controlled for hematoma
volume. Whether perihematomal edema formation beyond 24
hours after ICH bears an association (positive or negative)
with functional outcome cannot be ascertained by our data.
In addition to being a strong predictor of functional
outcome, relative edema volume appears to predict such
outcome in a manner entirely distinct from that of other
common predictors of outcome such as hematoma volume,
GCS score, age, mass effect, and hydrocephalus.6 –17 This is
manifest by the retention of statistically significant associations of relative edema volume with functional outcome in
the respective multivariable models, when one controls for
these other variables. Notably, all these other variables lost or
nearly lost their statistically significant associations with
functional outcome in these models. GCS score did not
independently predict functional outcome in any of our
analyses. We did, however, previously report its association
with 30-day mortality in the total patient population in our
original hematoma growth study report.5 This surprising
result may be explained by the fact that intraventricular
extension was nearly uniformly predictive of poor functional
outcome in our hyperacute patient population and by the
strong correlation between GCS score and intraventricular
extension.
Interestingly, neither absolute nor relative edema volume
predicted 30-day mortality despite relative edema volume
being the strongest and most consistent predictor of 12-week
functional outcome in multivariable analyses. Conversely,
many variables strongly predictive of mortality in our original
study did not predict functional outcome when entered into
these multivariable models. We interpret this loss or reduction of statistically significant association with functional
outcome of these variables (hematoma volume, mass effect,
and time from ICH symptom onset to baseline CT) to indicate
that they predict functional outcome in a similar (highly
correlated) manner rather than that they do not predict
functional outcome. This suggests a common underlying
construct between most previously reported variables predictive of SICH, such as increased intracranial pressure and/or
herniation due to mass effect–related displacement of brain
tissue surrounding the hematoma. While such anatomic
factors may be the most important determinants of death,
their relative inability to differentiate those survivors who
ultimately will versus those who will not achieve meaningful
functional recovery suggests that alternative, physiological
variables may more accurately predict functional outcome.
Relative edema volume appears to be one such variable. The
recent reports of Castillo and colleagues18 analyzing the
relationships between excitotoxic and inflammatory cytokine
substances and outcome and the recent report of Becker and
colleagues19 establishing a relationship between contrast
extravasation on CT angiography and increased hematoma
volume and poor outcome represent other noteworthy recent
examples.
We considered a number of biologically plausible explanations for the seemingly paradoxical association between
increasing relative edema volume and increased probability
of a good functional outcome. One explanation was that
decreased relative edema volume resulted from an actively
bleeding and expanding hematoma obliterating the rim of
perihematomal edema, which might otherwise be more
readily visible. However, we observed no association between relative edema volume and subsequent hematoma
growth. We also excluded the possibilities of any association
between relative edema volume and hematoma location or
volume as the explanation of our observations. Similarly, we
controlled for treatment effects due to osmotic diuretic use
with no change in our results. Finally, we excluded outlier
relative edema volume values as another possible explanation
for our findings. Given our prior observations that hyperacute
thrombolysis/anticoagulant-related ICH lacks perihematomal
edema compared with hyperacute SICH, hyperacute edema
may reflect successful hematoma clotting. This would be a
biologically plausible explanation for the paradoxical association between very early perihematomal edema and improved
functional outcome. Our a priori hypothesis was based on the
assumption that perihematomal edema is injurious. While
such injury has been reported with delayed perihematomal
edema, our results strongly suggest that such delayed edema
is biochemically and physiologically distinct from hyperacute
perihematomal edema. A comparable systematic study of
perihematomal edema evolution in this more delayed time
frame is needed.
As we noted, intraventricular extension was a nearly
perfect predictor of poor functional outcome when present.
Thus, we could not determine whether other variables independently predict functional outcome in patients with intraventricular extension or whether intraventricular extension
confounded measurement of perihematomal edema or its
ability to independently predict functional outcome. While
not the focus of this report, the fact that only 1 of 38 patients
with intraventricular extension had a good 12-week functional outcome indicates that intraventricular extension in a
supratentorial SICH patient who presents to the emergency
department within 3 hours of symptom onset virtually ensures
death or a poor long-term functional outcome. We observed a
significant association between increasing relative edema
volume and improved functional outcome in the entire
supratentorial patient population. However, we do not conclude that relative edema is a significant independent predictor of functional outcome for all such patients given that the
observed association in the overall population can be statistically explained by the association in the subgroup without
intraventricular extension (primary analysis) and given our
aforementioned findings in the patients with intraventricular
extension.
This study has a number of acknowledged and largely
unavoidable limitations. First, we were restricted to available
previously collected data. Because we were limited to radiological data collected in a 24-hour period, our results are not
applicable to more delayed perihematomal edema formation.
Gebel et al
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We also could not systematically identify or control for
differences in individual patient management by the various
treating physicians in the study. Thus, the extent to which
such variation or withdrawal-of-care decisions by patients’
families influenced outcome or the relationship between
relative edema volume and functional outcome is unknown.
The possibility of any bias in the measurements of perihematomal edema volumes with regard to knowledge of the
study hypothesis is minimal because all such measurements
(and all other data) were performed before this study was
conceived. Similarly, our good and bad functional outcome
definitions and primary analysis were defined before any data
analysis and cutoff values were chosen on the basis of their
common use in clinical trials of stroke treatment. We acknowledge, however, that the MRS cutoff value of 0 to 2 to
represent good outcome rather than 0 to 1 was chosen because
we anticipated that the number of excellent or complete
functional recoveries in any SICH population would be low.
We believe that our analyses that substituted categorical BI
for categorical MRS reasonably eliminate the possibility that
the choice of MRS as the primary functional outcome
variable was biased.
Since this was a study of perihematomal edema and its
relationship to outcome in patients with SICH (not related to
thrombolysis or anticoagulants), its results are not applicable
to patients with underlying structural lesions, anticoagulantrelated ICH, or traumatic ICH. Although these types of
patients represented a minority of patients that were excluded
from our study, such patients may be encountered more
frequently in clinical practice, which may limit the generalizability of our results in this context.
Finally, another important potential source of bias or error
is the perihematomal edema measurement technique itself.
Although the method used was semiautomated and hypothetically more objective and accurate than conventional planimetric edema volume measurement, subjective input on the
part of the study neuroradiologist is still required, specifically
in selecting the most appropriate of the computer-generated
threshold values differentiating perihematomal edema from
adjacent brain tissue. The results of this study must be
interpreted within this context. Furthermore, this technique is
not widely available, and its bedside utility has not been
established.
In conclusion, we report that in patients with supratentorial
SICH without intraventricular extension presenting within 3
hours of onset, relative edema volume during the first 24
hours after ICH is the strongest independent predictor of
(paradoxically improved) 12-week functional outcome. Independent confirmation of our results is needed, as are efforts to
establish the bedside utility of relative edema volume as an
outcome measure. Further research is needed to examine the
relationship between more delayed edema and outcome in a
comparably systematic manner and to better understand the
biochemical and physiological bases of brain injury associated with human ICH.
Edema Volume Predicts ICH Outcome
2641
Acknowledgments
This study was supported by the National Institute of Neurological
Disorders and Stroke grants NS26933 and 1K23 NS 02005-01A1.
We would like to gratefully acknowledge the contributions of the
following individuals who were coinvestigators in the original
hematoma growth study, without whose efforts this study would not
have been possible: Rashmi Kothari, MD, and William Barsan, MD.
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Relative Edema Volume Is a Predictor of Outcome in Patients With Hyperacute
Spontaneous Intracerebral Hemorrhage
James M. Gebel Jr, Edward C. Jauch, Thomas G. Brott, Jane Khoury, Laura Sauerbeck, Shelia
Salisbury, Judith Spilker, Thomas A. Tomsick, John Duldner and Joseph P. Broderick
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Stroke. 2002;33:2636-2641
doi: 10.1161/01.STR.0000035283.34109.EA
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