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Effect of glycerol treatment on the natural history of acute cerebral infarction
277 EFFECT
OF GLYCEROL
OF ACUTE
CEREBRAL
TREATMENT
ON THE NATURAL
HISTORY
INFARCTION
H. J. Gelmers*
SUMMARY
From a population of patients with acute cerebral infarction one hundred were selected and divided into two groups, with comparable neurological deficit and risk factors. To one group of patients glycerol was administered, the other group served as a control. Neurological deficit was scored on the day of admission and in the next 4 weeks. There was no noticeable beneficial effect of glycerol administration in acute cerebral infarction.
INTRODUCTION
cause of advanced morbidity in the very first days of acute cerebral infarction. Reduction of such edema might therefore be anticipated to reduce morbidity and mortality considerably in patients, who had an acute stroke. Many agents should reduce cerebral edema. Corticosteroid administration has shown to reduce cerebral edema in brain tumours (GALICICH and FRENCH, 1961), but the effects in patients with a stroke are at most conflicting (PATTEN, MENDELL, BRUUN, CURTIN and CARTER, 1972; BAUER and TELLER, 1973; NORRIS, 1975). Cerebral
edema
is a major
Hyperosmolar agents are short-lived in action and show a rebound phenomenon in intracranial pressure, while repeated administration is prohibited by increasingly severe side effects. Glycerol as a hyperosmolar agent not only reduces cerebral edema without rebound (CANTORE, GUIDETTI and VIRNO, 1964), but also improves cerebral bloodflow (MEYER, FUKUNCHI, SHIMAZU, OKUCHI and ERICSSON, 1972) and cerebral metabolism (MEYER et al., 1972; MEYER, ITAH, OKAMOKO, WELCH. MATHEW,OH,SAKAKI,NIYAKAWA,CHABI and ERICSSON, 1975). Because of favourable reports (MATHEW, MEYER, RIVERA, CHARNEY and HARTMANN, 1972; GILSANZ, REBOLLAR, BUENCUERPO and CHANTRES, 1975) the idea occurred to study the effect of glycerol-administration on the natural history of patients with acute cerebral infarction in the first 28 days, although recently LAWSON, MARINOVICH and BARBER (1976) failed to demonstrate any beneficial effect of this form of therapy.
:I’ Neurological Clin. Neural.
Department Neurosurg.
of Prinses Irene Ziekenhuis, 1975-4
Almelo, The Netherlands.
278 PATIENTS
AND METHODS
natural history of acute cerebral infarction is variable of nature and it is questioned whether therapeutic trials are reliable. However, we are convinced. that if groups of patients are selected, comparable in age, type of cerebral ischemia, severity of neurological deficit, associated risk factors, such as diabetes mellitus, hypertension, cardial and pulmonary disorders, scientific analysis is permitted and reliable results are obtained, when evaluation and scoring of the neurological deficit is done in the same manner. A population of patients with an acute stroke due to cerebral infarction underwent detailed physical and neurological examination. Determinations were taken of complete bloodcount, erythrocyte-sedimentation rate, blood ureanitrogen, serum creatinine, fasting blood-sugar, serum electrolytes, liver-function, thrombotest (Owren), urinanalysis, lumbar punction, electrocardiogram, chest X-ray, skull X-ray, echoencephalogram, electroencephalogram and brain scan and sometimes cerebral angiography. Patients with transient ischaemic episodes were excluded from the study. From this population 50 patients were selected at random and admitted to group I. A control group (II) of 50 patients was composed out of the stroke population, in such a manner, that both groups had comparable degrees and types of neurological deficit and similar riskfactors. Patients with associated potentially fatal conditions as massive myocardinfarction, cardiogenic shock, renal failure and severe systemic infections were excluded from the study. Patients were only admitted to the study, if treatment could be started within 12 hours after onset of the symptoms. 50 patients in group II were treated with oxygen application by nasal tube and aminophylline by rectal route. If necessary digoxine preparations, antihypertensive medication, or antibiotics were prescribed. In group I 50 patients were treated in the same way, but with additional glycerol administration. Glycerol was given during six days by intravenous route as a 100/o solution (in 5o/0 glucose or 0.90/o physiological saline) in a dose of 1,2 mgr. per kg. bodyweight. The whole glycerol dose was infused within 6 hours. Measurements of glycerol concentration and serum osmolality during administration were not undertaken. Patients of both groups received the same regimen of good nursing and medical care, with attention to hydration, bowel and bladderfunction, pulmonary condition, control of infection and physiotherapy in a comparable manner. Cerebral vasodilators and drugs which reduce cerebral edema such as corticosteroids, mannitol, urea and hypertonic glucose were withheld. All patients were scored on the basis of their neurological status, using actually the same patient evaluation sheet as MATHEW et al. (1972), which is illustrated in table 1. Scoring was performed on the day of admission and in the next 4 weeks. The
fABLE
279
1
Neurological evaluation for gIycero1 therapy in patients with acute stroke. _.__ Factor
---
score
Mentation Level of consciousness: Fully conscious Lethargic but mentally intact Obtunded stuporous Comatose orientation Oriented X 3 Oriented ’ 2 Oriented x 1 Disoriented Speech Schuell test Cranial nerves
Homonymous hemianopsia fntact Mild Moderate Severe Conjugate deviation of eyes
Intact Mild Moderate Severe Facial weakness Intact Mild Moderate Severe Motor power’ Normal strength Contracts against resistance Elevates against gravity Gravity eliminated Flicker No movements Performance or disability status scale Normal Mild impairment Moderate impairment Severe in~pairment Death Reflexes Normal Asymmetrical or pathologicat rdfexes Clonus No reflexes elicited Sensation Normal Mild sensory abnormality Sever sensory abnormality No response to pain No response to pain ‘Each limb separately.
O-23
3 2 I 0 3 2 I 0 3 2 1 0 5 4 3 2 1 0 28 21 14 7 0 3 2 I 0 3 2
I 0 II
280 The scoring system correlated condition.
well with any change in the patients’ neurological
RESULTS
patients completed the study; 44 in the control group and 42 in the glycerol treated group. Data and stroke scores for patients who died before compIetion of study are shown in table 2. 86
TABLE
2
Data and stroke scores for patients who died before completion of study.
Age
Sex
.~ Neurologic deficit (day) 1 7 14 21
Presumed cause of stroke
Cause of death
Day of death
cardiac arrhytmia cardiac arrhytmia MCAO ? ICAO ICAO embolic
7
51
pneumonia pulmonary embolus cerebral edema cardiac failure cardiac failure further embolia
21 11 7 12 11 9
47 59 18 39 49 53
53 50 56 18 39 48 55
? cardiac arrhytmia embolic MCAO ICAO embolic ICAO ICAO
pneumonia pulmonary embolus pneumonia pulmonary embofus further embolia cerebral edema cardiac failure cerebral edema
21
58 56 50 62 59 36 41 33
58 60 61 77 52 _ 41 _
28
Control-group 69 71 78 74 67 73 62
F M F F M M F
55 _. _ _
Glycerol-group 65 69 55 75 6X 78 68 64
F M F M M M M M
24 I1 21 8 2 13 4
58
56 _ 77 _.
ICAO signifies internal carotid artery occlusion. MCAO signifies middle cerebral artery occlusion. -
As indicated in table 3 the age in both groups did not si~ificantly differ according to the Student t test for independent groups. Similar analysis of neuroiogical deficit score on day of admission confirmed the impression, that the matching procedure was effective. Application of a two-tailed Fischer exact test indicated that total score response’; in the next 4 weeks by the glycerol administered group, were not significantly higher than that of the control group (p < 0.05). The same results were obtained if scoring items of both groups were compared, as was done for the disability status. The scoring results are compiled in table 3 and illustrated in the diagram.
281 TABLE
3
Mean scores of total neurological deficit score and disability status. Group II (Control)
Group 1 (glycerol)
66.2 t. 11.2
Age
65.8 h 10.2
Sex
M - 26
Day of scoring
Day 1 Day 7 n-50 n-48
M -- 28
F = 24
Total neurological 60.5 66.8 deficit score 1kl5.2 114.2
75.2 ztl3.6
78.7 77.8 k14.1 ztl3.6
Disability status
16.5 i6.9
18.1 sc7.0
10.8 i5.9
12.8 16.5
Day I n-50
Day 14 Day21 Day28 n-45 n-L-43 n--42
18.5 zr7.l
F = 22 Day 7 n--48
Day 14 Day 21 Day 28 n-44 n-43 n- 43
/ 6-1.4 68.0 t 14.3 rtl3.2
75. I 77.0 $ II.8 i-II.6
77.0
11.9 Lk5.5
16.1 ,cS.S
17.6 k6.2
II.8 +5.3
17.4 +6.2
+-II.6
‘-
total deficit
T I
I
I
I
I
t
I
scare
20.
:
1 I I I
I
I I
18. go16, 14
12 IO,
disablilty O --
0
I
7 GLYCEROL
IL GROUP
21
0
28 days ,------
CONTROL
7
11
scme 21
28 days
GROUP
DISCUSSION administration to patients with acute cerebral infarction is recommended to patients with acute cerebral infarction as a beneficial form of therapy (MATHEW et nl., 1972), because it reduces cerebral edema (MEYER et al., 1971) and improves cerebral bloodflow and cerebral metabolism {MEYER et a!., 1972, 1975). The aim in performing this trial was to determine whether any benificial effect couId be demonstrated by giving glycerol to patients, who present with clinical evidence oE stroke to a busy general hospital, without resorting to excessive invasive and expensive neurological investigation. Contrary to the above mentioned reports, Glycerol
282 this study
did not demonstrate
et al findings (1976). Since glycerol, referring ment,
any benefit
to neurological
of this procedure, deficit,
we do not feel that this form of therapy
produced
has any place
confirming no clinical
LARSON
improvc-
in the treatment
of
early strokes.
ACKNOWLEDGEMENT
wish to thank Ir. H. L. JournCe (Department Neurosurgery, State University Groningen) for his advice and helpful criticism in compiling the statistical results, as done in the Computer Centre of the State University.
I
REFERENCES
(1973). Dexamethason as treatment in cerebrovascular disease. 11. A controlled study in acute cerebral infarction. Stroke, 4, 541. CANTORE, G. GUIDETTI, B. and VJRNO, M. (1964). Oral glycerol for the reduction of intracranial pressure. J. Neurosurg. 21, 278. GALICICH, J. H. and FRENCH, L. A. (1961). Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brainsurgery. Amer. Practit. 12, 169. GILSANZ, v., REBOLLAR, J. L. BUENCUERPO, J. and CHANTRES, M. T. (1975). Controlled trial Of glycerol versus dexamethason in the treatment of cerebral edema in acute cerebral infarction. Lancet, I, 1049. LARSSON o., MARINOVICH, N. and BARBER, K. (1976). Double blind trial of glycerol therapy in BAUER, R. B. and TELLER, H.
early stroke. Lancet, I, 832. J. s., RIVERA, V.H., CHARNEY, J. 2. and HARTMANN, A. (1972) Double of glycerol therapy in acute cerebral infarction. Lancet, II, 1327. MEYER, J. s.,CHARNEY, J. z. RIVERA, v. M. and MATHEW, N. T. (1971). Treatment of cerebral edema due to acute cerebral infarction. Lancet, II, 993. MEYER, J. s., FIJKUNCHI, Y., SHIMAZU, K., OKUCHI, I. and ERICSSON, H. D. (1972). Effect of intravenous infusion of glycerol on hemispheric bloodflow and metabolism in patients with acute cerebral infarction. Stroke 3, 168.
MATHEW,
N. I.,MEYER,
blind evaluation
MEYER
J. S., ITAH, Y., OKAMOKO,
S., WELCH,
K. M. A., MATHEW,
N. T., OK, E. O., SAKAKI, S.
and ERICSSON, A. D. (1975). Circulatory and metabolic effects of glycerol infusion in patients with acute cerebral infarction. Circulation, 51, 701. PATTEN, B. M., MENDELL, J., BRUUN, B., CURTIN, w. and CARTER, s. (1972). Double-blind study of the effects of dexamethasone on acute stroke. Neurology (Minneap.) 22, 377.
NIYAKAWA,
Y., CHABI, E.
OF GLYCEROL
OF ACUTE
CEREBRAL
TREATMENT
ON THE NATURAL
HISTORY
INFARCTION
H. J. Gelmers*
SUMMARY
From a population of patients with acute cerebral infarction one hundred were selected and divided into two groups, with comparable neurological deficit and risk factors. To one group of patients glycerol was administered, the other group served as a control. Neurological deficit was scored on the day of admission and in the next 4 weeks. There was no noticeable beneficial effect of glycerol administration in acute cerebral infarction.
INTRODUCTION
cause of advanced morbidity in the very first days of acute cerebral infarction. Reduction of such edema might therefore be anticipated to reduce morbidity and mortality considerably in patients, who had an acute stroke. Many agents should reduce cerebral edema. Corticosteroid administration has shown to reduce cerebral edema in brain tumours (GALICICH and FRENCH, 1961), but the effects in patients with a stroke are at most conflicting (PATTEN, MENDELL, BRUUN, CURTIN and CARTER, 1972; BAUER and TELLER, 1973; NORRIS, 1975). Cerebral
edema
is a major
Hyperosmolar agents are short-lived in action and show a rebound phenomenon in intracranial pressure, while repeated administration is prohibited by increasingly severe side effects. Glycerol as a hyperosmolar agent not only reduces cerebral edema without rebound (CANTORE, GUIDETTI and VIRNO, 1964), but also improves cerebral bloodflow (MEYER, FUKUNCHI, SHIMAZU, OKUCHI and ERICSSON, 1972) and cerebral metabolism (MEYER et al., 1972; MEYER, ITAH, OKAMOKO, WELCH. MATHEW,OH,SAKAKI,NIYAKAWA,CHABI and ERICSSON, 1975). Because of favourable reports (MATHEW, MEYER, RIVERA, CHARNEY and HARTMANN, 1972; GILSANZ, REBOLLAR, BUENCUERPO and CHANTRES, 1975) the idea occurred to study the effect of glycerol-administration on the natural history of patients with acute cerebral infarction in the first 28 days, although recently LAWSON, MARINOVICH and BARBER (1976) failed to demonstrate any beneficial effect of this form of therapy.
:I’ Neurological Clin. Neural.
Department Neurosurg.
of Prinses Irene Ziekenhuis, 1975-4
Almelo, The Netherlands.
278 PATIENTS
AND METHODS
natural history of acute cerebral infarction is variable of nature and it is questioned whether therapeutic trials are reliable. However, we are convinced. that if groups of patients are selected, comparable in age, type of cerebral ischemia, severity of neurological deficit, associated risk factors, such as diabetes mellitus, hypertension, cardial and pulmonary disorders, scientific analysis is permitted and reliable results are obtained, when evaluation and scoring of the neurological deficit is done in the same manner. A population of patients with an acute stroke due to cerebral infarction underwent detailed physical and neurological examination. Determinations were taken of complete bloodcount, erythrocyte-sedimentation rate, blood ureanitrogen, serum creatinine, fasting blood-sugar, serum electrolytes, liver-function, thrombotest (Owren), urinanalysis, lumbar punction, electrocardiogram, chest X-ray, skull X-ray, echoencephalogram, electroencephalogram and brain scan and sometimes cerebral angiography. Patients with transient ischaemic episodes were excluded from the study. From this population 50 patients were selected at random and admitted to group I. A control group (II) of 50 patients was composed out of the stroke population, in such a manner, that both groups had comparable degrees and types of neurological deficit and similar riskfactors. Patients with associated potentially fatal conditions as massive myocardinfarction, cardiogenic shock, renal failure and severe systemic infections were excluded from the study. Patients were only admitted to the study, if treatment could be started within 12 hours after onset of the symptoms. 50 patients in group II were treated with oxygen application by nasal tube and aminophylline by rectal route. If necessary digoxine preparations, antihypertensive medication, or antibiotics were prescribed. In group I 50 patients were treated in the same way, but with additional glycerol administration. Glycerol was given during six days by intravenous route as a 100/o solution (in 5o/0 glucose or 0.90/o physiological saline) in a dose of 1,2 mgr. per kg. bodyweight. The whole glycerol dose was infused within 6 hours. Measurements of glycerol concentration and serum osmolality during administration were not undertaken. Patients of both groups received the same regimen of good nursing and medical care, with attention to hydration, bowel and bladderfunction, pulmonary condition, control of infection and physiotherapy in a comparable manner. Cerebral vasodilators and drugs which reduce cerebral edema such as corticosteroids, mannitol, urea and hypertonic glucose were withheld. All patients were scored on the basis of their neurological status, using actually the same patient evaluation sheet as MATHEW et al. (1972), which is illustrated in table 1. Scoring was performed on the day of admission and in the next 4 weeks. The
fABLE
279
1
Neurological evaluation for gIycero1 therapy in patients with acute stroke. _.__ Factor
---
score
Mentation Level of consciousness: Fully conscious Lethargic but mentally intact Obtunded stuporous Comatose orientation Oriented X 3 Oriented ’ 2 Oriented x 1 Disoriented Speech Schuell test Cranial nerves
Homonymous hemianopsia fntact Mild Moderate Severe Conjugate deviation of eyes
Intact Mild Moderate Severe Facial weakness Intact Mild Moderate Severe Motor power’ Normal strength Contracts against resistance Elevates against gravity Gravity eliminated Flicker No movements Performance or disability status scale Normal Mild impairment Moderate impairment Severe in~pairment Death Reflexes Normal Asymmetrical or pathologicat rdfexes Clonus No reflexes elicited Sensation Normal Mild sensory abnormality Sever sensory abnormality No response to pain No response to pain ‘Each limb separately.
O-23
3 2 I 0 3 2 I 0 3 2 1 0 5 4 3 2 1 0 28 21 14 7 0 3 2 I 0 3 2
I 0 II
280 The scoring system correlated condition.
well with any change in the patients’ neurological
RESULTS
patients completed the study; 44 in the control group and 42 in the glycerol treated group. Data and stroke scores for patients who died before compIetion of study are shown in table 2. 86
TABLE
2
Data and stroke scores for patients who died before completion of study.
Age
Sex
.~ Neurologic deficit (day) 1 7 14 21
Presumed cause of stroke
Cause of death
Day of death
cardiac arrhytmia cardiac arrhytmia MCAO ? ICAO ICAO embolic
7
51
pneumonia pulmonary embolus cerebral edema cardiac failure cardiac failure further embolia
21 11 7 12 11 9
47 59 18 39 49 53
53 50 56 18 39 48 55
? cardiac arrhytmia embolic MCAO ICAO embolic ICAO ICAO
pneumonia pulmonary embolus pneumonia pulmonary embofus further embolia cerebral edema cardiac failure cerebral edema
21
58 56 50 62 59 36 41 33
58 60 61 77 52 _ 41 _
28
Control-group 69 71 78 74 67 73 62
F M F F M M F
55 _. _ _
Glycerol-group 65 69 55 75 6X 78 68 64
F M F M M M M M
24 I1 21 8 2 13 4
58
56 _ 77 _.
ICAO signifies internal carotid artery occlusion. MCAO signifies middle cerebral artery occlusion. -
As indicated in table 3 the age in both groups did not si~ificantly differ according to the Student t test for independent groups. Similar analysis of neuroiogical deficit score on day of admission confirmed the impression, that the matching procedure was effective. Application of a two-tailed Fischer exact test indicated that total score response’; in the next 4 weeks by the glycerol administered group, were not significantly higher than that of the control group (p < 0.05). The same results were obtained if scoring items of both groups were compared, as was done for the disability status. The scoring results are compiled in table 3 and illustrated in the diagram.
281 TABLE
3
Mean scores of total neurological deficit score and disability status. Group II (Control)
Group 1 (glycerol)
66.2 t. 11.2
Age
65.8 h 10.2
Sex
M - 26
Day of scoring
Day 1 Day 7 n-50 n-48
M -- 28
F = 24
Total neurological 60.5 66.8 deficit score 1kl5.2 114.2
75.2 ztl3.6
78.7 77.8 k14.1 ztl3.6
Disability status
16.5 i6.9
18.1 sc7.0
10.8 i5.9
12.8 16.5
Day I n-50
Day 14 Day21 Day28 n-45 n-L-43 n--42
18.5 zr7.l
F = 22 Day 7 n--48
Day 14 Day 21 Day 28 n-44 n-43 n- 43
/ 6-1.4 68.0 t 14.3 rtl3.2
75. I 77.0 $ II.8 i-II.6
77.0
11.9 Lk5.5
16.1 ,cS.S
17.6 k6.2
II.8 +5.3
17.4 +6.2
+-II.6
‘-
total deficit
T I
I
I
I
I
t
I
scare
20.
:
1 I I I
I
I I
18. go16, 14
12 IO,
disablilty O --
0
I
7 GLYCEROL
IL GROUP
21
0
28 days ,------
CONTROL
7
11
scme 21
28 days
GROUP
DISCUSSION administration to patients with acute cerebral infarction is recommended to patients with acute cerebral infarction as a beneficial form of therapy (MATHEW et nl., 1972), because it reduces cerebral edema (MEYER et al., 1971) and improves cerebral bloodflow and cerebral metabolism {MEYER et a!., 1972, 1975). The aim in performing this trial was to determine whether any benificial effect couId be demonstrated by giving glycerol to patients, who present with clinical evidence oE stroke to a busy general hospital, without resorting to excessive invasive and expensive neurological investigation. Contrary to the above mentioned reports, Glycerol
282 this study
did not demonstrate
et al findings (1976). Since glycerol, referring ment,
any benefit
to neurological
of this procedure, deficit,
we do not feel that this form of therapy
produced
has any place
confirming no clinical
LARSON
improvc-
in the treatment
of
early strokes.
ACKNOWLEDGEMENT
wish to thank Ir. H. L. JournCe (Department Neurosurgery, State University Groningen) for his advice and helpful criticism in compiling the statistical results, as done in the Computer Centre of the State University.
I
REFERENCES
(1973). Dexamethason as treatment in cerebrovascular disease. 11. A controlled study in acute cerebral infarction. Stroke, 4, 541. CANTORE, G. GUIDETTI, B. and VJRNO, M. (1964). Oral glycerol for the reduction of intracranial pressure. J. Neurosurg. 21, 278. GALICICH, J. H. and FRENCH, L. A. (1961). Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brainsurgery. Amer. Practit. 12, 169. GILSANZ, v., REBOLLAR, J. L. BUENCUERPO, J. and CHANTRES, M. T. (1975). Controlled trial Of glycerol versus dexamethason in the treatment of cerebral edema in acute cerebral infarction. Lancet, I, 1049. LARSSON o., MARINOVICH, N. and BARBER, K. (1976). Double blind trial of glycerol therapy in BAUER, R. B. and TELLER, H.
early stroke. Lancet, I, 832. J. s., RIVERA, V.H., CHARNEY, J. 2. and HARTMANN, A. (1972) Double of glycerol therapy in acute cerebral infarction. Lancet, II, 1327. MEYER, J. s.,CHARNEY, J. z. RIVERA, v. M. and MATHEW, N. T. (1971). Treatment of cerebral edema due to acute cerebral infarction. Lancet, II, 993. MEYER, J. s., FIJKUNCHI, Y., SHIMAZU, K., OKUCHI, I. and ERICSSON, H. D. (1972). Effect of intravenous infusion of glycerol on hemispheric bloodflow and metabolism in patients with acute cerebral infarction. Stroke 3, 168.
MATHEW,
N. I.,MEYER,
blind evaluation
MEYER
J. S., ITAH, Y., OKAMOKO,
S., WELCH,
K. M. A., MATHEW,
N. T., OK, E. O., SAKAKI, S.
and ERICSSON, A. D. (1975). Circulatory and metabolic effects of glycerol infusion in patients with acute cerebral infarction. Circulation, 51, 701. PATTEN, B. M., MENDELL, J., BRUUN, B., CURTIN, w. and CARTER, s. (1972). Double-blind study of the effects of dexamethasone on acute stroke. Neurology (Minneap.) 22, 377.
NIYAKAWA,
Y., CHABI, E.