1. No category

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
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1978 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/9/2/130
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click Request
Permissions in the middle column of the Web page under Services. Further information about this process is
available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2014
STROKE
130
VOL 9, No 2, MARCH-APRIL 1978
and perfusion in brain and heart. J Nucl Med 17: 603-612, (July) 1976
19. Symon L, Dorsch NWC, Crockard HA: The production and clinical
features of a chronic stroke model in experimental primates. Stroke 6:
476^t81, (Sept-Oct) 1975
20. Pasztor E, Symon L, Dorsch NWC, Branston NM: The hydrogen
clearance method in assessment of blood flow in cortex, white matter, and
deep nuclei of baboons. Stroke 4: 556-567, (July-Aug) 1973
21. Zatz LM, Alvarey RE: An inaccuracy in computed tomography: The
dependence of CT values. Radiology 124: 91-97, (July) 1977
22. McCullough EC: Factors affecting the use of quantitative information
from a CT scanner. Radiology 124: 99-107, (July) 1977
15. Collins VJ: Pharmacology of inorganic gas anesthetics, pp. 1541-1542.
In Principles of Anesthesia, 2nd edition. Philadelphia, Lea and Febiger,
1976
16. Obrist WD, Thompson HK, Wang HS, Wilkinson WE: Regional
cerebral blood flow estimated by '"Xenon inhalation. Stroke 6: 245-256,
(May-June) 1975
17. Kuhl DE, Reivich M, Alavi A, Nyary I, Staum MM: Local cerebral
blood volume determined by three-dimensional reconstruction of radionuclide scan data. Circ Res 36: 610-619, (May) 1975
18. Phelps ME, Hoffman EJ, Coleman RE, Welch MJ, Raichle ME, Weiss
ES, Sobel BE, Ter-Pergossian MM: Tomographic images of blood pool
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.
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2014
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).
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2014
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.
18.
19.
20.
21.
22.
23.
24.
25.
26.
References
27.
1. Derouesne C: Le diagnostic des rammolisments recents. Rev Prat 9:
621-625, 1976
2. Dyken M, White PT: Evaluation of cortisone in the treatment of cerebral
infarction. JAMA 162: 1531-1534, 1956
3. Pratesi F, Corsi C, Nuti A, Tesi M: Terapia dell'infarto encefalico
arterio-sclerotico. Orientamenti attuali e prospettive. Giorn
Arteriosclerosi 2 - 3 : 147-156, 1972
4. Candelise L, Colombo A, Spinnler H: Therapy against brain swelling in
stroke patients. Stroke 6: 353-356, 1975
5. Hooshmand H, Quinn JC, Houff SA: Cerebrovascular fluid pressure
changes with chemotherapy for intracerebral hemorrhage. Neurology
(Minneap) 22: 56-61, 1972
6. Shenkin HA, Goluboff B, Haft H: Use of mannitol for reduction of intracranial pressure in intracranial surgery. J Neurosurg 19: 897-900, 1962
7. Wise BL, Chater N: Value of hypertonic mannitol solution in decreasing
brain mass and lowering cerebrospinal fluid pressure. J Neurosurg 19:
1038-1043, 1962
8. Bauer RB, Tellez H: Dexamethasone as treatment in cerebrovascular disease. II. A controlled study in acute cerebral infarction. Stroke 4:
547-555, 1973
9. Foley JM, Chambers RA, Adams RD: Effect of cortisone on the early
repair of brain wounds in Guinea pigs, (abstract). J Neuropathol Exp
Neurol 12: 101-104, 1953
10. Harrison MJG, Russel RWR: Effect of dexamethasone on experimental
cerebral infarction in the gerbil. J Neurol Neurosurg Psychiatry 35:
520-521, 1972
11. Hetzel BS, Lander H, Robson HN: Immediate treatment of apoplexy. Br
Med J 1: 1122, 1957
12. Kahn K, Pranzarone FG, Newman T: Dexamethasone treatment of experimental cerebral infarction (abstract). Neurology 22: 406-407, 1972
13. Lee MC, Mastri AR, Waztz AG, Loewenson RB: Ineffectiveness of dexamethasone for treatment of experimental cerebral infarction. Stroke 5:
216-218, 1974
14. Patten BM, Mendell J, Bruun B, Curtin W, Carter S: Double-blind study
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
VOL 9, No 2, MARCH-APRIL
1978
of the effects of dexamethasone on acute stroke. Neurology 22: 377-383,
1972
Plum F, Alvord EC Jr, Posner JB: Effect of steroids on experimental
cerebral infarction. Arch Neurol 9: 571-573, 1963
Prados M, Strowger B, Feindez WH: Studies on cerebral edema: I. Reaction of the brain to air exposure; pathologic changes. Arch Neurol
Psychiat 54: 163-174, 1945
Roberts HJ: Supportive adrenocortical steroid therapy in acute and subacute cerebro-vascular accidents with particular reference to brain stem
involvement. J Am Geriatr Soc 6: 686-702, 1958
Rubenstein MK: Influence of adrenocortical steroids on severe cerebrovascular accidents. J Nerv Ment Dis 141: 291-299, 1965
Russek HI, Russek AS, Zohman BL: Cortisone in immediate therapy of
apopletic stroke. JAMA 159: 102-105, 1955
Sheely RF: Effect of cortisone and hydrocortisone in hemiplegia after
cerebral infarction. JAMA 158: 803-806, 1955
Tellez H, Bauer RB: Dexamethasone as treatment in cerebrovascular disease. I. Controlled study in intracerebral hemorrhage. Stroke 4:541-546,
1973
Agnoli A: Drug action on regional cerebral blood flow in cases of acute
cerebrovascular involvement. Acta Neurol Scand (Suppl) 14: 143, 1965
Aradas A: II trattamento dei disturb! circolatori cerebrali con alcaloidi
diidrogenati della segale cornuta, per via endovenosa a dosi subentranti.
Giorn di Gerontol 8: 677-682, 1963
Berselli L, Ferracini R: Sul trattamento degli incidenti cerebrovascolari
acuti. La Clinica XXV: 68-75, 1965
Betti R: Rilievi clinici sul trattamento degli episodi di insufficienze
cerebrovascolari acuti. La Riforma Medica 13: 3-14, 1975
Emmenegger H, Meier-Ruge W: L'effetto dell'Hydergina a livello
cerebrale. Studio istochimico, circolatorio e neurofisiologico. Pharmacology 1: 65-78, 1968
Geraud J: Traitment des troubles chroniques de la circulation cerebrale.
In International Symposium on Cerebral Circulation. Paris, Sandoz, pp
305-317, 1965
Heyck H: Der einfluss der ausgangslage auf sympathikolytische effekte
am hirnkreislauf bei zerebralvaskularen erkrankungen. Arzneim Forsch
15: 243-251, 1961
Iwangoff P, Enz A: Influence of various dihydroergotamine analogues on
cyclicadenosine - 3' 5' - monophosphate phosphodiesterase in the grey
matter of cat brain in vitro. Agents Actions 2: 223-230, 1972
Pratesi F, Dabizzi RP, Caramelli L: Traitment intracarotidien et intraveineux vaso-moteur des maladies vasculaires cerebrales. In International Symposium on Cerebral Circulation. Paris, Sandoz, pp.
296-300, 1965
Taeschler M: Pharmacologie classique de I'Hydergine. Ann Anesthesiol
Fr VI: 97-104, 1965
Turon R: Le traitment medical des troubles vasculaires aigus du cerveau.
In International Symposium on Cerebral Circulation. Paris, Sandoz, pp.
327-329, 1965
Locksley HB: L'ictus emorragico. In Clinical Medicine North America,
Padova, (Italy) Piccin 1: 1302-1323, 1969
Agnoli A, Ruggieri S: II liquido cerebrospinale nelle vasculopatie
cerebrali. Gior Arteriosclerosi 2-3: 187-197, 1972
Fager CH A: Le sindromi endocraniche acuti. In Clinical Medicine
North America, Padova (Italy) Piccin 2: 885-892, 1970
Fieschi C: Problemi diagnostici dell'apoplessia cerebrale. Gior
Arteriosclerosi 2-3: 83-86, 1972
Hass W: Malattie cerebro-vascolari occlusive. In Clinical Medicine
North America, Padova, (Italy) Piccin, 5: 1244-1262, 1973
Lhermitte F, Mamo N: "Systeme nerveux et muscles." In Pathologic
Medicale, Paris, Flammarion, 1973
Hinterbuchner LP: La valutazione del paziente in stato di incoscienza. In
Clinical Medicine North America, Padova (Italy), Piccin, 6: 1519-1529,
1975
Lison L: Statistica Applicata alia Biologia Sperimentale, Milano, Ambrosiana, 1961
Downloaded from http://stroke.ahajournals.org/ by guest on September 9, 2014