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Received 5 May 2004; received in revised form 15 December 2004; accepted 8 March 2005
Available online 3 June 2005
Abstract
Objective: To study the usefulness of mannitol in spontaneous intracerebral hemorrhage (ICH) patients.
Method: 128 CT proven supratentorial ICH patients within 6 days of ictus were randomized into study and control groups. The study group
received mannitol 20%, 100 ml every 4 h for 5 days, tapered in the next 2 days. The control group received sham infusion. Primary endpoint
was 1-month mortality and secondary endpoint functional disability at 3 months assessed by Barthel index score.
Results: There were 65 patients in study and 63 in control groups. The study and control groups were evenly matched regarding age,
Glasgow coma scale (GCS) score, Canadian Neurological Scale (CNS) score, pupillary asymmetry, pyramidal signs on non-hemiplegic side,
and location, midline shift and ventricular extension of hematoma. At 1 month, 16 patients died in each group. The primary and secondary
endpoints were not significantly different between the two groups.
Conclusion: Low dose mannitol does not seem to be beneficial in patients with ICH.
D 2005 Elsevier B.V. All rights reserved.
randomized controlled trial evaluating the role of mannitol was 1-month mortality. The cause of death, i.e. brain
in ICH. The present study therefore has been undertaken to herniation, pneumonia, septicemia, airway obstruction and
evaluate the role of mannitol in spontaneous supratentorial others, were ascertained as far as possible. Secondary
ICH patients. outcome measure was functional disability at the end of 3
months assessed by Barthel Index (BI) score. The outcome
was classified as poor if BI score was below 12, partial
2. Patients and methods BI = 12 –19 and complete BI = 20 [14]. Sample size was
calculated considering 20% reduction in mortality in the
The patients with CT proven primary supratentorial ICH study group compared to control. Forty patients in each
within 6 days of ictus were enrolled in a tertiary care group in each analysis were planned. The first interim
teaching hospital. The patients with renal and hepatic analysis was planned after recruiting 80 and final analysis
failure, hyperglycemia >250 mg%, past history of ICH, after 160 patients or 2 years whichever is earlier. If there
infratentorial hematoma, vascular malformation, tumor or were superiority of treatment or its absence, the study
anticoagulant bleed and those in whom consent could not be would be terminated. Statistical analysis was done using Z
obtained were excluded. test of proportion with an alternative that the treatment is
All the patients were subjected to detailed neurological effective. The power of test in the first stage was 0.86 and
evaluation. The consciousness was assessed by Glasgow in the final stages 0.96. The level of significance in the
coma scale (GCS) and severity of stroke by Canadian interim analysis was 0.01 and the final analysis 0.04. To
Neurological Scale (CNS) score [11]. Pulse, blood pressure, evaluate the significance of treatment one-tail test was
history of gastric hemorrhage and presence of surrogate used.
markers of raised intracranial pressure such as spontaneous
hyperventilation, papillary asymmetry and pyramidal signs
on the nonhemiplegic side were also noted. Cranial CT scan 3. Results
was carried out using a third generation spiral CT scanner
and 10 mm axial sections were obtained parallel to One hundred and sixty-four patients with ICH were
orbitomeatal line. The location of hematoma on CT scan, admitted during 2000 –2001; 36 of whom were excluded
its size, ventricular extension and midline shift were noted. because of renal failure in 5, diabetes in 1, recurrent ICH in
The size of hematoma was calculated as 4/3p A B C, 2, infratentorial location in 20, late admission 3 and lack of
where A is the largest diameter of hematoma in cm rounded consent in 5. In the study group there were 65 patients and
to nearest half cm, B is the diameter at 90- to A in cm in the control group 63. The age of the patients ranged
rounded to nearest half cm, and C is the number of between 35 and 80 (mean 56) years, 32 were females. The
parenchymal hematoma seen in 1 cm slice [12]. The
hematoma were classified into small (<20 ml), medium Table 1
(20 –40 ml) and large (>40 ml) [13]. The patients were Various clinical and radiological features in patients with intracerebral
managed conservatively and none underwent surgery. Anti- hemorrhage, receiving mannitol and placebo
hypertensive medication was prescribed if BP exceeded Patients details Mannitol (n = 65) Control (n = 63)
180/110 mm of Hg using atenolol or amlodepine. Ranitidine Age mean (range) years 55.0 (35 – 77) 57 (35 – 80)
or sucralfate were prescribed to all the patients. Patients’ Sex (female) 18 14
hydration was ensured by administering 2.0– 2.5 L isotonic Time of admission (days) 0.5 – 6 0.5 – 6
glucose saline daily. Caloric intake was maintained between Hypertension 51 49
Diabetes mellitus 9 7
1800 and 2000 Kcals. Blood sugar was monitored and if
Ischemic heart disease 5 6
exceeded 160 mg% insulin was administered. Seizure 2 1
The patients were randomized using random table Mean GCS (range) 9.6 (3 – 15) 9.4 (3 – 15)
numbers after getting informed consent from the first- Mean CNS score (range) 3.0 (2 – 10) 3.0 (2 – 9.5)
degree relatives if the patient was unable to give consent Pupillary asymmetry 7.0 9.0
Contralateral signs 28 28
because of aphasia or altered sensorium. The Institute’s
Septicemia (FDP+) 9 8
ethics committee approved the trial. The patients were Hematoma
randomized into study and control group. The random- Small 19 22
ization was done by one investigator (JK) and evaluation by Medium 23 21
another (PR). The hematoma was classified into small, Large 23 20
Hematoma location
medium and large and the randomization for each group was
Putaminal 42 42
done separately. The study group received mannitol 20% Thalamic 19 15
100 ml IV every 4 h for 5 days which was tapered in the Lobar 2 2
next 2 days as 100 ml every 8 h on sixth and every 12 h on Caudate 2 4
seventh day. The control group received a sham infusion of Midline shift 39 36
Ventricular extension 34 29
the same amount of normal saline. The primary endpoint
U.K. Misra et al. / Journal of the Neurological Sciences 234 (2005) 41 – 45 43
patients were admitted within 6 days of ictus (mean-3, range radiological parameters. The clinical and radiological
12 h– 6 days). 62 patients were admitted within 24 h, 30 variables other than size of hematoma were not taken into
between 24 and 72 h and 26 between 72 h and 6 days. account before randomization; however these variables were
History of hypertension was present in 61 but on examina- not different between the two groups (Table 1).
tion hypertension was detected in 100 patients. Twenty-nine The profile of this trial is presented in Fig 1. Interim
patients consumed alcohol. The GCS score ranged between analysis after recruiting 80 patients did not reveal any
3 and 15 (mean 9.5) and three patients had generalized tonic significant difference in the primary endpoint between study
clonic seizure. Mean CNS score was 3.0 (range 2 – 10). The and control group. There were 10 deaths in study and 9 in
majority of patients had medium or large hematoma with control group. By the end of second year although 164
dense hemiplegia and had severe stroke as assessed by CNS patients were recruited, but 128 patients were eligible on
score. Pupillary asymmetry was present in 16, spontaneous whom the final analysis was based. There was no difference
hyperventilation in 38 and motor signs on the nonhemiple- in primary outcome in mannitol and control group (Z = 0.12,
gic side in 56 patients. These features were present mainly OR 1.042, CI 1.004 – 1.080, P = 0.80, power of test 80.36%).
in large or medium size hematoma. On CT scan 41 patients 16 deaths occurred in placebo and control groups respec-
had small, 44 medium and 43 large hematoma. The location tively. Three-month outcome between study and control
of hematoma was putaminal in 84, thalamic in 34, lobar in group was also not significantly different (X 2 = 2.83, df = 2,
four and caudate in six patients. Midline shift was present in P = 0.25). In study group, 23 patients had poor, 18 partial
75 patients, which was noted in patients with large and and 8 complete recovery; and in control group 18 poor, 20
medium size hematoma. Ventricular extension of hematoma partial and 9 had poor recovery. The comparison of
was present in 63 patients. The study and control groups mortality and 3-month outcome in study and control group
were evenly matched with respect to their clinical and is presented in Table 2.
Randomization (n=128)
Did not receive standard intervention as Did not receive standard intervention as
Timing of primary and secondary outcome: Timing of primary and secondary outcome:
Fig. 1. Profile of randomized controlled trial to evaluate the role of mannitol in ICH.
44 U.K. Misra et al. / Journal of the Neurological Sciences 234 (2005) 41 – 45
Table 2
Outcome of patients with ICH receiving mannitol and placebo
Outcome Study (65) Control (63)
Small (n = 19) Medium (n = 23) Large (n = 23) Small (n = 22) Medium (n = 21) Large (n = 20)
Death 0 2 14 0 2 14
Outcome
Poor 2 12 9 1 11 6
Partial 10 8 0 14 6 0
Complete recovery 7 1 0 7 2 0
10
8
while latter was contributed by septicemia though no
6
Mannitol autopsy studies were carried out. The analysis of death in
Saline first 7 days of admission and after did not show any
4
2
difference between the two groups.
0
In our study, higher frequency of hyponatremia was
noted in the control group compared to those receiving
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Cause of death in different time scale particularly subarachnoid haemorrhage [18]. These compli-
Fig. 2. The cause of death in intracerebral hemorrhage patients was mainly cations are most likely to develop in critically ill patients
brain herniation within 7 days of admission and infection after 7 days in with large hemorrhages. Hyponatraemia in ICH is attributed
both mannitol and control groups. to syndrome of inappropriate secretion of antidiuretic
U.K. Misra et al. / Journal of the Neurological Sciences 234 (2005) 41 – 45 45
hormone (SIADH) and cerebral salt wasting due to atrial [3] Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes
natriuretic factor [19]. The lower frequency of hyponatremia compensatory vasoconstriction and vasodilatation in response to blood
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