Is there a real treatment for stroke? Clinical and statistical... treatments in 300 patients.

Is there a real treatment for stroke? Clinical and statistical comparison of different
treatments in 300 patients.
S Santambrogio, R Martinotti, F Sardella, F Porro and A Randazzo
Stroke. 1978;9:130-132
doi: 10.1161/01.STR.9.2.130
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STROKE
130
VOL 9, No 2, MARCH-APRIL 1978
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Is There a Real Treatment for Stroke? Clinical
and Statistical Comparison of Different
Treatments in 300 Patients
SERGIO SANTAMBROGIO, M.D.,
RENATO MARTINOTTI, M.D.,
FERNANDO PORRO, M.D.,
FRANCESCO SARDELLA,
AND ANTONIO RANDAZZO,
M.D.,
M.D.
SUMMARY In the absence of universally accepted criteria for the
medical treatment of stroke, we made a rigorously randomized comparative study of different treatments in 300 patients. One group of
patients received only a general supportive treatment designed to ensure adequate supplies of water, electrolytes and calories, plus
whatever was needed to prevent infection and correct extant
associated pathology. Three other groups of patients were treated in
the same way but were also given, respectively, one of the following
medications: Hydergine (Sandoz) (a mixture of three ergot
alkaloids), dexamethasone, and mannitol.
No statistically significant difference emerged among any of the
treatment groups and the reference group in terms of objective
therapeutic results. The authors concluded that, at least with the
dosage used in this study, none of the treatments proved more useful
than conventional supportive therapy in the first 10 days after a
stroke.
TREATING PATIENTS with stroke is often unrewarding.
As in other fields of medicine, the lack of a basic reference
treatment for stroke has generated a multitude of drug
therapies, each being thought of as a cure, only to be soon
abandoned. It is likely that some deaths in the first several
days after a stroke are due to cerebral edema around the infarcted area rather than to the infarct itself.13 Edema
reaches its peak about 3 to 4 days after the stroke, and can
be responsible for transtentorial herniation of the brain,
rostrocaudal deterioration, and impaired cerebral blood
flow. Drugs thought to reduce edema reduce intracranial
pressure which can indirectly improve brain circulation.
Those used in recent years include mannitol,3"7 corticosteroids,2- *•5-"~21 and Hydergine,3'22~32 each with conflicting reports of clinical effectiveness. We have studied
these 3 therapies using 1) a large number of patients; 2) random selection for treatment; 3) each drug alone; 4) results
from reliable clinical parameters; 5) data evaluated by a correctly designed statistical program.
mean age for the whole group was 71 years. There were 110
men (mean age 69) and 190 women (mean age 73). Of these
241 were diagnosed as having an ischemic stroke, 189 in the
carotid artery territory, 40 in the vertebrobasilar territory.
In 12 the classification was uncertain. At hospitalization,
each patient was assigned randomly to one of the following 4
treatment groups:
Group A. These patients received adequate water and
electrolyte replenishment by intravenous infusion for the
first 48-72 hours, and then a suitable caloric intake, in the
form of a special standard diet if necessary, administered by
stomach tube. These patients also received suitable antibiotics and additional treatments, such as digitalis,
diuretics, tracheal aspiration and instillation of mucolytic
agents, and bedsore prevention.
Group B. These patients received the same treatment as
those in group A, plus a proprietary mixture of
dihydroergocornine, dihydroergocristine and dihydroergocriptine, 0.3 mg each (Hydergine) in a daily dosage of 6 ampoules representing 1.8 mg of each alkaloid in the mixture.
Group C. Patients in group C received the same treatment
as group A plus dexamethasone 24 mg daily, given in
divided doses.
Group D. Patients received the same treatment as group
A plus a solution of 20% hypertonic mannitol given i.v.
0.8-0.9 g/kg daily.
In all groups treatment was instituted between 3 and 24
hours after onset of symptoms. The period of observation
was 10 days for all 4 groups.
Materials and Methods
We studied 300 patients with a diagnosis of stroke,
hospitalized in the Emergency Medicine Division of the
Polyclinic Hospital in Milan, during 1974 and 1975. The
From the Emergency Medical Division, Ospedale Maggiore Policlinico,
Via Francesco Sforza 35, Milan, Italy 20122.
Reprint requests to Dr. Santambrogio, O.M. Policlinico, Milan, Italy.
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COMPARISON OF STROKE TREATMEUTS/Santambrogio et al.
Patient Classification
In accordance with Locksley33 and Derouesne,1 we
classified each patient as a case of hemorrhagic or ischemic
stroke by the behavior of the following parameters. Cerebrovascular accidents were thought to be due to hemorrhage
when the period of onset was less than 2 hours, impairment
of consciousness progressing steadily to coma and a very recent history of headache and vomiting. Patients with
cerebral hemorrhage generally had hypertension and bloody
spinal fluid. Ischemic strokes had a longer period of onset,
no history of headache or vomiting and clear spinal fluid.
Overt hypertension indicated an ischemic or hemorrhagic
stroke with indifferent probability, but a normal or low
blood pressure was more suggestive of an ischemic than a
hemorrhagic stroke.1' 33~38
We further divided patients with ischemic stroke into two
groups; transient stroke (prompt resolution of the stroke
episode with complete recovery in less than 24 hours) and
completed stroke (persistent stable neurologic impairment
during the first few days after onset).37
Our clinical material also included 4 patients with a
diagnosis of cerebral embolism made on the strength of
young age, extant mitral valve disease, a history of previous
embolization elsewhere in the body, and sudden onset.1-36-38
Patients were classified in terms of clinical evolution using
a scoring system similar to that of Bauer and Tellez:8-21 (A)
stroke in evolution in which both neurologic damage and impairment of consciousness changed during the observation
period; and (B) established or stationary strokes, in which
such changes did not occur.
Assessment of improvement or worsening was made by
the following parameters: (1) state of consciousness at time
of admission was classified at 4 levels, namely, wakefulness,
somnolence, stupor, and coma;39 (all shifts from one level to
another were recorded during the 10-day observation
period); (2) neurologic signs of motor or sensory impairment
with any change during the observation period, such as increasing or decreasing weakness or sensory impairment,
were recorded.
Each patient was evaluated at 1, 2, 4, 7 and 10 days after
hospitalization. Each evaluation required scoring the level of
consciousness, language function, motor function and sensory function. Total numerical scores were obtained based
on the presence or absence of 30 specific points. An increasing score was associated with worsening; a declining score
with improvement.
The observation period was restricted to the first 10 days
after the stroke. It was found that changes of focal motor
and speech abnormalities were less reliable as a criterion for
determining whether a stroke was improving or worsening
during the first 10 days than was the state of consciousness.1
Results
On reviewing our results we excluded patients with transient cerebral ischemia because the prompt abatement of
symptoms and signs (within 24 hours by definition) made it
impossible to judge effectiveness of treatment. Patients with
cerebral embolism were excluded because of the small
number of cases. Patients with cerebral hemorrhage were
excluded because an early mortality of 84%, regardless of
the treatment, made analysis impossible.
131
TABLE 1 Two-by-Three Contingency Tabulation by Treatment Groups in Patients with Ischemic Cerebral Stroke (ICS)
Treatment
groups
Group A
Improved
Unchanged
Worsened
Ischemic cerebral stroke (ICS)
Evolutive Established
Total
14
0
18
0
9
0
14
9
18
32
9
41
Improved
Unchanged
Worsened
15
0
18
0
8
0
15
8
18
Total
33
8
41
Improved
Unchanged
Worsened
15
0
19
0
14
0
15
14
19
Total
34
14
48
12
0
16
0
8
0
12
8
16
28
8
36
Total
Group B
Group C
Group D
Improved
Unchanged
Worsened
Total
Group A, control; Group B, Hydergine; Group C, dexamethasone; Group
D, mannitol.
The therapeutic results obtained in patients with ischemic
stroke were used for statistical evaluation. The results are
shown in tables 1 and 2. No significant differences were
observed for any of the treatments given. Nor were there
significant differences in outcome when strokes were divided
into evolving and established stroke. Patients who were not
in coma at the beginning of treatment did better than those
with severely impaired consciousness. Older patients, in
general, did worse than younger patients.
The three modes of treatment failed to show difference in
outcome between treatment groups or between these and the
reference group. A comparison with the reference group
showed clearly that evaluation of an ischemic stroke was
wholly independent of these treatments.
This finding could be interpreted to mean that treatment
really has no effect in determining the course of a stroke,
whether the wrong treatment was used or whether the wrong
parameters of change were evaluated. To test the last
hypothesis, we evaluated two possible sources of error: coma
at the outset of stroke and age.
The role of coma as a major source of error was suggested
by the very high mortality rate (86%) associated with coma
TABLE 2 Statistical Comparison Between Control Group (A)
and Three Treatment Groups (B, C, D) in Patients with Ischemic
Cerebral Stroke (ICS)
Interactions
ICS (A) X ICS (B)
ICS (A) X ICS (C)
ICS (A) X ICS (D)
x1
P
1
0
1
0.04
0.028
N.S.
N.S.
N.S.
Degrees of
freedom
1
X = cbi-equare corrected for continuity; P = statistical significance;
(other symbols same as in table 1).
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132
STROKE
in all 3 treatment groups as well as in the control group.
Coma at onset of symptoms suggests so severe an
anatomical injury as to make any drug treatment futile.
When we recalculated the corrected chi-square values after
eliminating patients with coma from the group, we found
some evidence of effectiveness of dexamethasone and
Hydergine treatment groups, but this did not reach
statistical significance.
Age had no effect in determining outcome in the control
group or in the groups treated with mannitol, Hydergine and
dexamethasone. The mean age of patients who improved
was less than 64.9 ± 2.08 and for those who became worse it
was more than 64.9. Confining our statistical comparison to
patients under this age limit and comparing them to their
age mates in the control group, differences in outcome are
below the minimum level of significance.
In conclusion, we were unable to demonstrate that any of
the given treatments, in the dosages used in these trials, had
a real influence on the clinical course of ischemic cerebral
stroke, during the first 10 days after onset.
15.
16.
17.
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