1. No category

Treatment of acute cerebral hemorrhage with intravenous glycerol. A double-blind,
placebo-controlled, randomized trial.
Y L Yu, C R Kumana, I J Lauder, Y K Cheung, F L Chan, M Kou, C M Chang, R T Cheung and
K Y Fong
Stroke. 1992;23:967-971
doi: 10.1161/01.STR.23.7.967
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967
Treatment of Acute Cerebral Hemorrhage
With Intravenous Glycerol
A Double-Blind, Placebo-Controlled, Randomized Trial
Y.L. Yu, FRCPE; C.R. Kumana, FRCP; I.J. Lauder, PhD; Y.K. Cheung, FRCR;
F.L. Chan, FRCR; M. Kou, HV; CM. Chang, MRCP (UK);
R.T.F. Cheung, MRCP (UK); and K.Y. Fong, MRCP (UK)
Background and Purpose: Hitherto, treatment of acute cerebral hemorrhage with intravenous glycerol
has not been evaluated in rigorous clinical studies with sufficient patient numbers.
Methods: We undertook a double-blind, stratified and randomized, placebo-controlled clinical trial.
Only patients with a first stroke admitted to the hospital within 24 hours after onset of symptoms were
recruited, provided computed tomography confirmed hemorrhage and informed consent was obtained.
After stratification into alert, semicoma, and coma subgroups using the Glasgow Coma Scale, 107 patients
received active treatment (500 ml of 10% glycerol in saline by intravenous infusion over 4 hours on 6
consecutive days) and 109 were given corresponding saline treatment. Using a variety of objective scoring
systems, patients were followed up for up to 6 months.
Results: At follow-up, all measures of outcome in the treated and control groups were very similar. At 6
months, respective mortality rates were 37 of 107 and 33 of 109. Corresponding mean±SD improvements
in Scandinavian Stroke Study Group scores were 8.35±16.9 versus 11.55±15.6 (long-term) and 0.64±7.3
versus 2.40±6.9 (prognostic), and improvements in the Barthel Index ratings were 10.72±24.7 versus
13.95 ±23.3, respectively. Glasgow Coma Scale score improvements in the survivors were 0.81 ±1.5 and
1.16±1.7 in the treated and control groups, respectively. Hemolysis (generally subclinical) was the only
adverse effect of glycerol noted.
Conclusions: In the absence of any clinically or statistically significant difference in outcome between the
treated and control groups, this trial provides no justification for glycerol therapy following acute cerebral
hemorrhage. (Stroke 1992;23:967-971)
KEY WORDS • cerebral hemorrhage • clinical trials • glycerin
A cute spontaneous supratentorial intracerebral
/ \
hemorrhage (SSIH) has considerable mortality
J. \ - and morbidity, and it is believed that edema
around the hemorrhagic lesion contributes to early
death from transtentorial herniation.1-3 In an attempt
to reduce the damaging effects of cerebral edema,
various forms of treatment (in particular, steroids and
hyperosmolar agents) have been advocated in the past.
However, clinical trials now indicate that steroid treatment has no place in the management of acute hemorrhagic stroke.45
It is possible that glycerol may have a beneficial effect
in cerebral hemorrhage. In experimental animals with
cerebral hemorrhage, glycerol reduces cerebral edema
without rebound upon withdrawal6 and normalizes increased vascular tone.7 In an open clinical trial on SSIH
From the Departments of Medicine (Y.L.Y., C.R.K., M.K.,
C.M.C., R.T.F.C, K.Y.F.) and Statistics (I.J.L.), University of
Hong Kong and the Department of Diagnostic Radiology (Y.K.C.,
F.L.C.), Queen Mary Hospital, Hong Kong.
Funded by Strategic Grant No. 336.041.0052 made available by
the University and Polytechnic Grants Committee, Hong Kong.
Address for correspondence: Dr. Y.L. Yu, Division of Neurology, Department of Medicine, University of Hong Kong, Queen
Mary Hospital, Hong Kong.
Received February 5, 1992; accepted March 18, 1992.
patients,8 glycerol was shown to increase cerebral perfusion through hemodilution and reduction of raised
intracranial pressure. Moreover, clinicians have often
used glycerol empirically in cerebral hemorrhage, even
though hitherto there have been no adequate controlled
trials to evaluate its possible benefits.
The current double-blind, placebo-controlled, randomized trial was undertaken to determine whether
treatment of acute SSIH with intravenous glycerol has a
clinically significant favorable influence on mortality
and morbidity over the ensuing 6 months.
Subjects and Methods
Case Selection
Consecutive patients aged 30-80 years with no history of stroke were entered into the study if SSIH was
confirmed on computed tomography (CT). Informed
consent was obtained from the patients or their close
relatives. The exclusion criteria were posterior fossa
hemorrhage, hemorrhage resulting from aneurysm or
arteriovenous malformation, any other condition warranting neurosurgery, or concomitant medical problems
including collagen-vascular disease, bleeding diathesis,
and anticoagulant therapy. Patients commencing trial
medication were to have it withdrawn if they required
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968
Stroke Vol 23, No 7 July 1992
neurosurgical treatment or if it was deemed necessary
by the attending neurologist. However, outcome and
neurological scores were assessed in all patients because
analysis was on an intention-to-treat basis.
Methods and Analysis
Clinical method. History and physical findings, including detailed neurological assessment, were recorded on
admission. In particular, the time from onset of symptoms to admission, history of hypertension, vascular
disease, cardiac arrhythmia, diabetes mellitus, smoking,
drug treatment, and relevant family history were noted.
At each examination, neurological variables were documented without knowledge of the treatment administered. The scoring system of the Scandinavian Stroke
Study Group (SSScand)9 and score on the Glasgow
Coma Scale (GCS)10 were used to assess patients on
admission; before treatment (on the first day they
received trial medication) and on days 3, 7, 14, 21, and
28; and then monthly for 5 months. One month after
entering the trial and at monthly intervals thereafter,
the overall score for activities of daily living was assessed by using the Barthel Index.11 The cause of death
(brain herniation, pneumonia, septicemia, airway obstruction, recurrent stroke, and others) was ascertained
as far as possible.
Laboratory parameters. The following were checked at
the initial examination: complete blood count (hemoglobin concentration, packed cell volume, and white
cell, platelet, and reticulocyte counts), plasma glucose,
serum biochemical indexes, and electrocardiogram. The
complete blood count and serum biochemical indexes
were repeated on day 7.
Computed tomographic method. SSIH was confirmed
by noncontrast brain CT using the GE 9800 system with
standard window settings and 10-mm slices from the
orbitomeatal line to the vertex. CT was performed as
soon as possible and not later than 24 hours following
admission and was repeated between days 7 and 10 and
whenever warranted by the patient's clinical condition.
The size of the lesion (volume of hemorrhage with and
without edema) was measured by computer at the
physician's diagnostic console.
Other investigations. Cerebral angiography was performed in patients in whom an aneurysm or arteriovenous malformation was suspected and in patients with
unusual sites of bleeding.
Treatment. Due to differing prognoses depending on
the initial severity of the stroke, patients were stratified
according to the pretreatment GCS score: coma (score
of 3-7), semicoma (score of 8-11), and alert (score of
12-15). Active treatment was 500 ml of 10% glycerol
(generic) in physiological saline, and placebo was 500 ml
of physiological saline. Each treatment was administered intravenously over 4 hours for 6 consecutive days.
Design and analysis. Based on previous statistics,1213
240 patients were expected to enter the trial over 24
months. A group sequential approach14 was adopted,
and treatment was allocated according to a stratified
randomized block design. Differences from pretreatment values (for GCS score, prognostic and long-term
items on SSScand) or initial findings (score on Barthel
Index) were expressed as 8 scores and used as measures
of outcome. See Appendix for definition of symbols.
TABLE 1.
Clinical Profile of All Patients at Entry
Characteristic
Sex (male/female)
Alert
Semicoma
Coma
Age (mean±SD yrs)
Time to treatment* (mean±SD hrs)
Hypertension
Ischemic heart disease!
Diabetes mellitus
Smokers and ex-smokers
Volume of SSIH (mean±SD ml)
Volume of SSIH+edema (mean±SD ml)
Computed tomographic localization
of SSIH
Midline/bilateral
Left
Right
Glycerol
(n=107)
Placebo
(n = 109)
49/24
8/7
9/12
65±9
28±11
58
3
7
37
28
28.5 ±29.0 32.3 ±30.5
52.9+53.3 69.0±78.1
55/17
7/8
10/10
63±9
29+16
64
2
7
3
51
53
1
55
53
SSIH, spontaneous supratentorial intracerebral hemorrhage.
One in each group had atrial fibrillation. With respect to these
characteristics, there were no clinically important or statistically
significant differences (using x2 °rt tests as appropriate) between
groups.
'Period from onset of symptoms to start of trial medication.
t Angina and/or myocardial infarction.
Analyses were performed on all patients (scoring
death as 0 on the clinical scales) and on survivors only.
A subsidiary analysis was undertaken on the alert
subgroup. Patients whose trial medication was stopped
when gross hemolysis was suspected were also followed
up and included in the analyses on an intention-to-treat
basis.
The 1-month long-term 8 score was selected as the
monitoring variable. One interim analysis was planned
after the entry of 120 patients, using the latter variable
and an overall significance level of 5% for any difference
(A) in the mean 8 scores. Assuming that the 5 scores
follow a normal distribution across strata within each
treatment group, the power is 0.95 at an absolute value
of A of Via, where <ris the (common) SD of the 8 scores.
In practice Vkris about 5-7, and this range was taken as
the measure of clinical significance. Parametric and
nonparametric methods were employed for the interim
and final analyses. Follow-up analyses of corresponding
variables were performed on the respective 5 scores at 2,
3, 4, 5, and 6 months, results at 6 months being taken as
the clinically definitive assessment. The SAS package15
was used for the analyses. For ethical reasons, the trial
was also subjected to continuous informal monitoring of
death rate and side effects (hemolysis).
Results
After 120 patients were recruited, the interim analysis
did not reveal a significant result. The trial was then
continued on its second phase but was not run to final
completion because the probability that A was >5 for the
long-term 8 scores had become negligible based on a
Bayes posterior normal distribution calculation (see Appendix and Table 4). Patients randomized to the two
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Yu et al
TABLE 2.
Glycerol in Cerebral Hemorrhage
969
Status of All Trial Patients 6 Months After Spontaneous Supratentorial Intracerebral Hemorrhage
Treatment
All patients
Placebo
Glycerol
Alert
Placebo
Glycerol
Semicoma
Placebo
Glycerol
Coma
Placebo
Glycerol
Entered
Surviving
Dead
Lost to follow-up
109
107
67(1)
60(7)
33(1)
37(2)
9
10
73
72
57(1)
8(1)
14(2)
8
52(7)
6
15
15
8
8
6
4
1
3
21
20
2
0
19
19
0
1
Values are number of patients. In glycerol group death was attributed to brain stem herniation in 27 patients (only
six of whom were alert at entry), pneumonia in two, septicemia in one, myocardial infarction in two, and unknown or
other causes in five. Corresponding figures for placebo group were 20 (three alert at entry), four, three, three, and
three. Numbers in parentheses refer to patients who developed gross hemoglobinuria, warranting discontinuation of
trial medication.
globin concentration could be regarded as clinically
significant.16
treatment groups (216 in all) were comparable with
respect to age, sex distribution, and prior clinical features
(Table 1) and were recruited over 31 months. No patient
was referred for neurosurgery after randomization.
Table 2 summarizes the status of all patients 6 months
after SSIH, with respect to survival, deaths, and loss to
follow-up. For all accountable trial patients treated with
glycerol or placebo, the neurological and rehabilitation
scores at 6 months are summarized in Table 3. Table 4
is a summary of the predictive analysis based on the
6-month long-term scores. The analysis shows that,
using this regimen of glycerol therapy, no clinically or
statistically significant difference in neurological scores
(outcome) could be expected.
Hemolysis (usually subclinical) was the only drug side
effect observed. Table 2 shows the respective numbers
of patients in whom placebo or glycerol treatment was
withdrawn when gross hemoglobinuria was suspected.
Table 5 summarizes pertinent hematologic findings for
all 216 patients entering the trial. For patients surviving
for up to 7 days, the mean reductions from pretreatment
hemoglobin values were 0.54 and 0.12 g/dl following
treatment with glycerol and placebo, respectively. Thus,
neither the absolute nor the relative changes in hemoTABLE 3.
Discussion
Hitherto, studies purporting to evaluate the possible
beneficial effect of intravenous glycerol in patients with
acute stroke have yielded contradictory and inconclusive results.17"25 Commonly, there was no attempt to
distinguish hemorrhagic from ischemic episodes (especially in earlier trials), and if attempted, objective
confirmation of the diagnosis with CT was lacking or
inconsistent.17"24 The study by Frei et al,25 in which
pretreatment CT was performed on all patients, concerned ischemic stroke. Other important shortcomings
in the design and execution of these investigations
included failure to stratify patients according to stroke
severity (anticipated prognosis), prolonged delays before initiating treatment, limited measures of outcome,
exclusion of the most severely affected patients, too few
patients, and insufficient period of follow-up.
By contrast, our trial entailed CT confirmation of
SSIH, inclusion of both mild and severe cases, corresponding stratification based on level of consciousness
(GCS score), and inclusion of only patients with onset of
symptoms in the 24 hours before admission. In the final
Neurological and Rehabilitation Score Changes at 6 Months
All accountable patients
Score
Long-term
All patients
Alert patients
Prognostic
All patients
Alert patients
Glasgow Coma Scale
All patients
Alert patients
Barthel Index
All patients
Alert patients
n
Placebo
Mean±SD
Glycerol
n
Mean±SD
n
Survivors followed up
Placebo
Glycerol
n
Mean±SD
Mean±SD
100
65
11.55±15.6
13.86±14.89
97
66
8.35±16.9
10.18±18.45
67
57
19.84±10.6
18.04±9.3
60
52
17.92±11.7
17.38±11.3
100
65
2.40±6.9
3.68±6.7
97
66
0.64±7.3
1.18±8.0
67
57
6.24±4.1
5.70±3.9
60
52
4.85±4.2
4.63±3.9
100
65
-1.77±5.0
-1.06+4.8
97
66
-2.56+5.3
-2.32±5.6
67
57
1.16+1.7
0.67±1.0
60
52
0.81±1.5
0.46±1.0
13.95±23.3
17.50±25.8
90*
61*
10.72±24.7
13.11±28.1
63*
21.18±21.2
23.81 ±20.0
55*
23.06±20.2
49*
20.41 ±22.2
54*
•Though 6-month follow-up scores were available, a few patients did not have initial (1-month) Barthel Index score for a variety of logistic
reasons.
96*
62*
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970
Stroke
Vol 23, No 7 July 1992
TABLE 4. Probability Calculations for Difference in Pretreatment and 6-Month Mean Long-Term Scores Between Patients Receiving
Placebo and Glycerol
Glycerol
Placebo
Group
All patients
Alert patients
All survivors
Alert survivors
Probability
A
n
Mean±SEM
n
Mean±SEM
(mean±SEM)
-7<A<;7
-5<A<5
As5
100
11.55±1.56
13.86±1.85
19.84+1.31
18.04±1.23
97
8.39 ±1.72
10.18+2.27
17.92±1.51
17.38±1.56
-3.2±2.32
-3.68 ±2.93
-1.92±1.99
-0.66±1.98
0.95
0.78
0.0002*
0.67
0.94
0.002
0.98
0.002
65
67
57
66
60
52
0.0003
A, mean difference in score change between groups.
"Corresponding value for 1-month scores was 0.0002.
analysis data were available for 216 patients, nearly the
same number as had been projected, and those assigned
to glycerol and placebo treatment had very similar
pretreatment clinical profiles (Table 1). Furthermore,
our measures of outcome included the death rate, a
series of formal neurological deficit scores, and objective evaluation of rehabilitation status, all followed up
for 6 months.
The only important adverse effect of treatment we
encountered was intravascular hemolysis. A critical
study of the extent to which it affected patients entering
our trial and the likely mechanism were reported elsewhere.16 The latter in vivo and in vitro investigation
revealed that hemolysis probably resulted from glycerol
at the site of infusion rapidly entering erythrocytes and
destroying them in more central veins due to osmotically
induced swelling beyond a critical limit. Thus, so long as
the infusion rate did not exceed 125 ml/hr (even temporarily), clinically significant hemolysis did not ensue.
The use of glycerol solutions containing small amounts
of fructose may also overcome hemolysis to some extent,
there being in vitro evidence that osmotic fragility can
be mitigated by this means.26 Japanese clinicians have
infused such mixtures into patients very rapidly, apparently without ill effect.27
Following our preliminary experience, special care
was taken to avoid excessive infusion rates; it was
gratifying that after 7 days, the mean reduction of
hemoglobin concentration in patients receiving glycerol
in our study was much smaller (about Vi) than that
reported by Frei et al.25 Indeed, following 6 days of
glycerol or placebo treatment, mean reductions encountered in our patients were 0.54 and 0.12 g/dl, respectively; the difference of only 0.4 g/dl was statistically but
not clinically significant (Table 5). Furthermore, such
subclinical reductions in hemoglobin concentration after infusion of glycerol in saline may be attributed to a
TABLE S.
composite of rehydration (also noted in controls) and
hemolysis.
While our overall results show no clinically or statistically significant difference in outcome between patients treated with glycerol or saline, there were too few
comatose and semicomatose patients to make any kind
of reliable independent estimate of the effect of treatment within these strata. Conceivably, different treatment regimens (doses, rates of infusion, continuous
versus intermittent administration, earlier initiation of
therapy) might have had a more favorable impact, but
this remains to be proved. However, as already alluded
to, more rapid infusion of glycerol could pose problems
due to an alarming degree of intravascular hemolysis.
Regarding conventional regimens of intravenous glycerol, our relatively large trial in patients with all grades
of acute SSIH provides no evidence in support of such
therapy.
Appendix
Definition of 8 Score
For individual; in group i (i=l for glycerol, i'=2 for placebo)
define Stl as (score at month A:)-(pretreatment score). For
example, in Table 4 k=6 and score=long-term score. Therefore, A,=( X 8,j)/«, estimates the mean change A, in group i,
and A=A,-A 2 estimates the mean difference A=A 1 -A 2 between groups.
Bayes Posterior Density Calculations
The 5 scores here are based on the 6-month long-term
scores in Table 4. The pooled variance estimator for the
variance a2 of the S scores is given by
/(m+n2-2)
;=1
The posterior density for A is taken as normal with mean A
and variance s\=s2{}/nx+l/n^). Then, for example
Hemoglobin Values at Entry and at 1 Week
Day 1
Treatment
All patients
Placebo
Glycerol
Alert patients
Placebo
Glycerol
Difference
Day 7
n
Mean±SD
n
Mean±SD
n
Mean±SD
109
107
13.65 ±1.77
13.83±1.73
86
79
13.72±1.85
13.27±1.87
86
79
-0.12±0.96
-0.54±1.23*
73
72
13.80+1.78
13.80±1.83
64
63
13.71 ±1.90
13.17il.83
63
62
-0.11±0.97
-0.53±1.21*
Values are g/dl.
'Statistically significant difference from 0 and from value in placebo group (p<0.02; 95% confidence interval —0.82
to -0.26 g/dl). Among individual patients in placebo and glycerol groups, largest hemoglobin reductions were 2.6 and
3.1 g/dl, respectively.
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Yu et al
•-(7)
p(A>x)=lwhere <t>(z)= fz
— - = = e ' 2 d t is the standard normal cumu-
lative distribution function.
Acknowledgments
We are indebted to the nursing staff and doctors of the
University Department of Medicine and the Government
Medical Unit at Queen Mary and Tung Wah hospitals for
their unstinting cooperation. We are also grateful to Mr.
T.K.P. Chan, Mr. D.C.N. Cheng, and Mr. J.S. Cheng for
ensuring that the trial ran smoothly and for collecting and
transcribing the necessary patient data, to Mr. M.K.H. Leung
and Mr. K.W.Y. Wong for preparing appropriate computer
software, to Mr. P.W. Lee and his staff for facilitating pharmaceutical aspects of the trial, and to Ms. K. Larm and Ms. M.
Ho for secretarial assistance.
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