J Neurol (2002) 249 : 445–451 © Steinkopff Verlag 2002
Enrico Righetti Maria Grazia Celani Teresa Anna Cantisani Roberto Sterzi Gudrun Boysen Stefano Ricci
■ Abstract Brain oedema is a major cause of early death after stroke. Glycerol is a hyperosmolar agent that is claimed to reduce brain oedema. We sought to determine whether I. V. glycerol treatment in acute stroke, either ischaemic or haemorrhagic, influ-
Received: 17 May 2001 Received in revised form: 5 August 2001 Accepted: 27 August 2001 Dr. E. Righetti, MD () · M. G. Celani, MD · S. Ricci, MD Servizio Malattie Cerebrovascolari USL 2 Via Guerra 21 06127 Perugia, Italy Tel.: +39-75/5 05 55 26 Fax: +39-75/5 01 73 64 E-Mail:
[email protected] T. A. Cantisani, MD U.O Neurofisiopatologia Ospedale Silvestrini Perugia, Italy R. Sterzi, MD Divisione Neurologia Ospedale Civile Como, Italy G. Boysen, MD Dept. Neurology Bispebjerg Hospital Copenhagen, Denmark
ORIGINAL COMMUNICATION
Glycerol for acute stroke: a Cochrane systematic review
ences death rates and functional outcome in the short or long term and whether the treatment is safe. The Cochrane Stroke Group Trials Register was searched, conference proceedings were screened and some trialists were personally contacted. We considered all completed, controlled, published and unpublished comparisons, evaluating clinical outcome, in which intravenous glycerol treatment was initiated within the first days after stroke onset. Death from all causes, functional outcome and adverse effects were analysed. Analysis of short term death for acute ischaemic and/or haemorrhagic stroke was possible in ten trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (OR 0.78, 95 % Confidence Intervals 0.58–1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (odds ratio 0.65, 95 % CI 0.44–0.97). However, at the
end of the scheduled follow up period there was no significant difference in the odds of death (odds ratio 0.98, 95 % CI 0.73–1.31). Functional outcome was reported in only two studies and there was a non-significant positive effect on outcome at the end of scheduled follow up (odds ratio 0.73, 95 % CI 0.37–1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. This systematic review suggests a favourable effect of glycerol treatment on short term survival in probable or definite ischaemic stroke, but the magnitude of the treatment effect may be minimal (as low as a 3 % reduction in odds). Because of the relatively small number of patients and because the trials have been performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke. ■ Key words Acute stroke · Cerebral ischaemia · Osmotic antioedema treatment · Glycerol
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Introduction The thirty-day case fatality rate in prospective, community-based studies of patients with first-ever ischaemic stroke is 10 % and with first-ever haemorrhagic stroke about 52 % [1, 2]. Patients admitted to hospital with acute stroke are also at high risk of dying; the observed one month case fatality rate in trials with placebo treatment varies from 21 to 50 % [3]. Stroke-related oedema is maximal two to four days after stroke onset and is a major cause of early neurological deterioration and death [4]. Glycerol is a hyperosmolar agent that is claimed to reduce infarct-related oedema without rebound effect [5], to increase cerebral blood flow, and to improve cerebral metabolism by recoupling the uncoupled oxidative phosphorylation in the ischaemic brain tissue [6, 7]. Side effects of the treatment seem to be negligible [3]. A striking difference in the use of antioedema osmotic agents (OA) among the 36 countries which participated in the International Stroke Trial [8] has been described [9]. Subgroup analyses of the main study for Italian patients showed that OA, mainly glycerol, had been given to a high proportion of patients: 48.3 % (95 %CI 46.6–50) of 3437 Italian patients (in 77 centres) compared with 29.6 % (95 %CI 26.4–32.9) of 759 patients in Poland, and less than 2 % in the vast majority of the other countries where the remaining 15 239 patients were included. It was suggested that OA treatment did not change the prognosis, or even had a negative prognostic effect [10]. The differences in the therapeutical approach reflect a substantial uncertainty in the clinical use of such an inexpensive and relatively safe drug in severe stroke patients. The aim of this review is to determine the effectiveness and safety of early intravenous (I. V.) administration of glycerol in acute stroke. Since in the old studies, run in pre-CT era, definite diagnosis of ischaemic stroke was not possible, we decided to analyse data on both ischaemic and haemorrhagic stroke. The review seeks to test the following hypotheses: i. I. V. glycerol is effective in reducing case fatality in the acute phase of stroke. ii. I. V. glycerol is effective in reducing case fatality some months after stroke. iii. I. V. glycerol reduces the proportion of patients dead or dependent in activities of daily living some months after stroke. iv. I. V. glycerol treatment is safe.
Material and methods ■ Criteria for considering studies for this review We identified all completed, randomised and quasi-randomised (i. e., for the purpose of this review, those studies where allocation concealment was not clearly explained or, if it was, the randomisation procedure was not completely unbiased), controlled, unconfounded,
published and unpublished comparisons evaluating the clinical outcome of I. V. glycerol treatment initiated within the first two days from stroke onset. In only one study was glycerol treatment initiated within the first four days. The participants in the trials suffered from definite or presumed ischaemic strokes and /or definite haemorrhagic strokes. Cases of presumed ischaemic stroke reflect the fact that the majority of the studies were done before access to CT was routine. However, efforts were made in each trial to differentiate intracranial haemorrhage by lumbar puncture or arteriography. Patients with subarachnoid haemorrhage were excluded from the analyses. ■ Types of outcome measures The outcome measures were: i) the number of deaths in each group, from whatever cause, during the scheduled treatment period. ii) the number of deaths in each group, from whatever cause, by the end of trial follow up (within six months of the stroke onset). iii) disability evaluated among survivors by modified Rankin Scale (3 to5) or by Barthel Index (< 19/20), or comparable scales of activity of daily living by the end of trial follow up (within sixth months of the stroke onset). iv) poor prognosis in each group, by the end of trial follow up, considered as death or disability. v) any recorded adverse effect of the treatment according to the definitions given by the authors of each study. Wherever possible, results were determined by intention to treat analysis. ■ Search strategy for identification of studies This review has drawn on the search strategy developed for the Cochrane Stroke Review Group as a whole. [11]. Relevant trials were identified in the Group’s Specialised Register of Controlled Trials. The Register was last searched by the Review Group Coordinator for this review in December 1999. Further information was obtained from personal contacts with some authors. ■ Methods of the review Each trial was evaluated by two reviewers independently and a structured methodology and data collection form was completed for trials selected for inclusion. For trials reported in a language other than English, the form was sent by the Cochrane Stroke Review Group to a person familiar with the language for data extraction. Any disagreement between the two reviewers was cross-checked and solved by discussion among all the reviewers either by formal meeting or by electronic mail. The methodological quality of each trial has not been assessed by any scoring system, but the following details were noted: randomisation and type of allocation concealment, patient and assessor blinding, data evaluated with intention to treat analysis, number of patients who withdrew from treatment and/or were lost to follow up. The primary analysis included all trials independently of the method of randomisation, allocation concealment and intention to treat analysis. A sensitivity analysis was performed to compare the overall results of all trials with those of the truly randomised trials. As glycerol might have a different level of efficacy in patients with ischaemic and haemorrhagic stroke, or in patients with different levels of consciousness, specified subgroups had been identified as definite haemorrhagic stroke and probable and definite ischaemic stroke. Unconfounded trials comparing glycerol with control were subdivided by whether or not background anti oedema treatment (e. g. dexamethasone) had been given to both groups or not. The statistical analysis was performed using a standard fixed-effects model as described by Yusuf and Peto [12].
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Results We found 17 studies (13–30) in which glycerol had been used to treat acute stroke. Eleven (13–24) of these 17 trials fulfilled the entry criteria. Reason for exclusion are listed in Table 1. All the included trials were randomised, but only in six trials was allocation concealment definitely adequate; in three trials placebo was not used, and in one of these the assessment was blind. Eight of the 11 trials were evaluated according to an intention to treat analysis. The main characteristics of these studies are listed in Table 2. Further details are available in the Cochrane library [31]. Analysis of death within the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in ten trials where 482 glycerol-treated patients were compared with 463 control patients. Glycerol was associated with a non significant reduction in odds of death (OR 0.78), with wide confidence intervals (95 % Table 1 Characteristics of excluded studies Study
Reason for exclusion
Dekoninck 1978 [25] Comparison of vincamine + glycerol vs placebo + glycerol Gahlot 1982 [26] Glycerol compared to dexamethasone and not to placebo Gelmers 1975 [27] Non-randomised: control pts were “selected” to have comparable deficit to treated patients, assessors were not blind. Gilsanz 1975 [28] Glycerol compared to dexamethasone and not to placebo Kramer 1981 [29] Glycerol compared to dextran and not to placebo Gagliardi 1991 [30] Inclusion and exclusion criteria not clear; randomisation not stated
Fig. 1 All strokes: glycerol vs avoid glycerol. Death within the scheduled treatment period
Study Albizzati 1979 Azzimondi Bayer 1987 Frei 1987 Friedli 1979 Frithz 1975 Larsson 1976 Mathew 1972 Yu 1992 Yu 1993
CI 0.58 –1.06). There was no evidence of statistical heterogeneity between trials (Chi square= 11.89, df =9, p= 0.25). (Fig. 1) Excluding the trial using dexamethasone in both groups [13], given the possible negative interaction of the combination of glycerol with this drug, the results became marginally significant (OR 0.73, 95 % CI 0.53–1.00). Sensitivity analysis including only truly randomised trials with adequate concealment did not substantially alter the result (OR 0.69, 95 % CI 0.47–1.00). Among patients randomised with definite or probably ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (OR 0.65, 95 % CI 0.44–0.97) (Fig. 2). Among patients with haemorrhagic stroke no differences were evident between groups (OR 0.86, 95 % CI 0.48–1.53), but the number of patients was small (112 vs 112). Analysis of the effects of glycerol on death at the end of scheduled follow up was possible in eight trials where 412 glycerol treated patients were compared with 389 control patients. There was no evidence of any effect of glycerol on this outcome (OR 0.98, 95 % CI 0.73–1.31). Excluding the trial where dexamethasone was used in both groups [13], the results did not change (OR 0.95, 95 % CI 0.69–1.30). Similarly, the results were unaltered after sensitivity analysis including only truly randomised trials with adequate concealment (OR 0.89, 95 % CI 0.64–1.24) and in subgroup analyses of only definite or probable ischaemic stroke patients (OR 0.85, 95 % CI 0.59–1.24). Death at the end of scheduled follow up was not analysed in haemorrhagic stroke patients as only one relatively small study was available. Although many trials reported some results of functional outcome using disability scales, the functional Treatment n/N 12/46 14/42 10/85 1/18 8/32 14/50 4/12 5/34 28/107 12/56
Control n/N
Peto OR (95% CI Fixed)
Weight Peto OR % 895% Fixed)
9/47 9/19 26/88 0/20 5/24 23/56 5/15 3/28 33/109 9/57
9.8 7.5 17.1 0.6 6.0 14.5 3.7 4.2 26.3 10.3
Total (95% CI) 108/482 122/463 Test for heterogeneity chi-square = 11.89, df=9, p=0.22 Test for overall effect z=–1.59, p=0.11 0.1 0.2
Favours treatment
100.0
1
5
10
Favours control
1.48 (0.56, 3.89) 0.56 (0.18, 1.68) 0.34 (0.16, 0.71) 8.26 (0.16, 418.45) 1.26 (0.36, 4.36) 0.57 (0.26, 1.25) 1.00 (0.21, 4.86) 1.42 (0.32, 6.23) 0.82 (0.45, 1.48) 1.45 (0.56, 3.72) 0.78 (0.58, 1.06)
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Table 2 Characteristics of included studies Study
Methods
Participants
Interventions
Outcomes
Albizzati 1979 [13]
Not DB Not IT AL not stated
Any type of stroke within 24h; 93 pts analysed
Glycerol 10% (50 g) in 500 ml saline + Death and disability at 7 and 30 days dexamethasone for 7 days
Azzimondi [14]
Outcome assessment blind, IT, AL OK
First ischaemic, carotid artery territory stroke, with impairment of consciousness (pts with deep coma exluded), within 12 h; 67 pts included
Glycerol 10% (50 g) in 500 ml over 4 h vs glycerol 10% in 500 ml B. I. D. vs avoid glycerol
Death at 7 and 30 days, 6 and 12 months. Disability at 6 and 12 months, Side effects of treatment
Bayer 1987 [15]
DB, not IT AL OK
Probable ischaemic, carotid artery territory stroke with at least hemiparesis, within 48 h; 173 pts analysed
Glycerol 10% in 500 ml saline vs 500 ml saline over 4 h for 6 days
Death at 6 days, 3 months and 1 year. Rankin scale at 3 months and 1 year
Fawer 1978 [16]
DB, not IT AL OK
Probable ischaemic, middle cerebral artery territory stroke (lacunar cases excluded) within 48 h; 51 pts analysed
Glycerol 10% (25 g) in 250 ml of saline and glucose 5% or 250 ml of NaCl 9% and glucose 5% over 2 h, Q. I. D. for 6 days
Death at 4 months. Global performance score system at 7 days and 4 months. Side effects of treatment
Frei 1987 [17]
DB, IT AL not stated
Ischaemic stroke with hemiplegia (pts in coma excluded) within 48 h; 192 pts included
Glycerol 10% (50 g) in 500 ml followed by 500 ml placebo (glucose 2.5 % plus NaCl 0.45%) vs 500 ml placebo + 500 ml placebo for 7 days
Death at 7 days and 6 months; side effects of treatment
Friedli 1979 [18]
DB, IT? AL not stated
Probable ischaemic stroke within 24 h; 56 pts included
Glycerol 10% (50 g) in 500 ml vs 500 ml glucose 5% over 1 to 2 h, for 6 days
Death at 14 days and 6 months; side effects of treatment
Frithz 1975 [19]
Not DB, IT AL possibly biased
Probable ischaemic stroke within 24 h; 106 pts included
Glycerol 10% (50 g) in 500 ml glucose 5% in 25% saline over 6 h, for 6 days
Death at 6 days
Larsson 1976 [20]
DB, IT AL OK
Any type of stroke, within 6 h; 27 pts included
Glycerol 10% (50 g) in 500 ml solution Death at 10 days with dextrose 5% vs 500 ml solution dextrose 10% over 6 h, for 6 days
Mathew 1972 [21]
DB, IT AL not stated
Ischaemic stroke or intracerebral haemorrhage, within 4 days; 62 pts included
Glycerol 10% (50 g) in 500 ml of 5% Death at 14 days glucose in 25% saline vs 500 ml of 5% glucose in 25% saline for 4 to 6 days
Yu 1992 [22]
DB, IT AL OK
Spontaneous supratentorial Glycerol 10% (50 g) in 500 ml saline haemorrhage within 45 h; 216 pts included vs 500 ml saline over 4 h, for 6 days
Death at 6 days and 6 months. Disability at 6 months. Side effects of treatment
Yu 1993 [23, 24]
DB, IT AL OK
Ischaemic stroke within 48 h; 113 pts included
Death at 6 days and 6 months. Disability at 6 months. Side effects of treatment
Glycerol 10% (50 g) in 500 ml saline vs 500 ml saline over 4 h, for 6 days
DB double blind, IT intention to treat, AL allocation concealment
outcome was only comparable in two studies [14, 15], with data expressed as dichotomous variables (modified Rankin Scale). The odds of being alive but disabled at the end of scheduled follow up were non-significantly higher among patients allocated glycerol (OR 1.27, 95 % CI 0.73–2.20). However, glycerol was associated with a non significant reduction in the odds of being dead or dependent at the end of scheduled follow up (OR 0.73, 95 % CI 0.37–1.42) but these comparisons must be interpreted with caution owing to the limited number of patients (127 vs 107). Side effects of the active treatment were considered
in six trials and not reported in five. One trial [14] reported macro haematuria among 15 of 44 (34 %) patients in the treated group (7/20 in low dose group and 8/24 in high dose group) and only one case of heart failure, in the high dose group (see Table 1 for doses). No adverse events were reported in the control group. Fawer et al [16] reported a mean 5 mm Hg increase in systolic blood pressure during glycerol infusion. No changes were recorded in the control group. Frei et al [17] found biochemical, subclinical signs of haemolysis in 98 % of the glycerol treated patients with a mean drop of 1.7 g% in haemoglobin during the trial for both glycerol and
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Fig. 2 Probable and definite ischaemic strokes: glycerol vs avoid glycerol. Death within the scheduled treatment period
Study
Treatment n/N
Control n/N
Peto OR (95% CI Fixed)
Weight Peto OR % 895% Fixed)
Azzimondi
14/42
9/19
12.8
0.56, (0.18, 1.68)
Bayer 1987
10/85
26/88
29.4
0.34 (0.16, 0.71)
Frei 1987
1/18
0/20
1.0
Friedli 1979
8/32
5/24
10.2
1.26 (0.36, 4.36)
Frithz 1975
14/50
23/56
24.9
0.57 (0.26, 1.25)
2/29
2/25
3.9
0.85 (0.11, 6.46)
Yu 1993
12/56
9/57
17.7
1.45 (0.56, 3.72)
Total (95% CI)
61/312
74/289
100.0
0.65 (0.44, 0.97)
Mathew 1972
8.26 (0.16, 415.45)
Test for heterogeneity chi-square = 8.67, df=6, p=0.19 Test for overall effect z=–2.12, p=0.03 0.1 0.2 1 5 10 Favours treatment Favours control
glycerol plus dextran treated patients. No adverse effects were reported in the control group. Friedli et al [18] did not find adverse effects. Yu [22] observed gross haemoglobinuria leading to discontinuation of the glycerol among 9 of 107 treated patients (8 %) and 2 of 109 of control patients (1.8 %) (OR 4.9, 95 % CI 0.98–47.5), and [23] found haemoglobinuria among 8 of 56 (14.3 %) treated patients, but in none of the 57 controls.
Discussion If we compare this review with the previous one [3], 3 further studies were considered, but still the number of identified trials of glycerol treatment for acute stroke and the total number of patients included were low. The method of randomisation and concealment were adequate in less than half of the trials. Few patients had their stroke confirmed by CT, and therefore the diagnosis of haemorrhagic and of ischaemic stroke was not reliable in most of the studies. Furthermore, lacunar stroke patients (by definition a group at negligible risk of cerebral oedema) were overtly excluded only in three studies [14, 16, 23] but their clinical definition of lacunar stroke was not reported. In only one study [14] was the clinical suspicion of cerebral oedema considered in the list of inclusion criteria. In six of the trials glucose was used as control, which may not be completely inert. In one study all patients were treated with steroids. To verify any possible interference of dexamethasone treatment we repeated the analysis without this study, but the results remained the same. The results of the statistical review must be interpreted with circumspection. The analysis of the review indicated a decrease in case fatality rate in the acute
phase of the disease. This effect was statistically significant when only patients with probable or definite ischaemic stroke were considered. Furthermore, the only trial with a statistically significant favourable effect on death within the scheduled treatment period [15] did not undertake an intention to treat analysis. There was no apparent benefit from glycerol in definite haemorrhagic stroke patients, but the low number of cases does not allow for reliable conclusions. Case fatality at the end of scheduled follow up was virtually the same in the two groups. Data on long-term disability were comparable only in two studies. There was a suggestion that more patients in the glycerol group survived with a long term disability. Hence, glycerol may only temporarily delay death among patients with serious physical and mental handicaps. The only side effect reported in a small proportion of patients in the group treated with glycerol was haematuria, though this effect was not explicitly recorded in all studies. To summarise, this systematic review suggests that glycerol treatment has an effect on short-term survival in a subgroup of patients with probable or definite ischaemic stroke. Because of the relatively small number of patients and the fact that most of the trials were performed in the pre-CT era, the results must be interpreted cautiously. Furthermore, most patients included in the studies did not have impairment of consciousness. The lack of statistical significance of the long term effect does not support the wide use of glycerol treatment in acute stroke. Moreover, this review does not provide reliable evidence of the efficacy of the glycerol treatment in patients with established cerebral oedema and/or decreased consciousness. However, glycerol treatment is inexpensive and appears to be quite safe. This review
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suggests that it may be associated with the reduction in the number of patients dying within the first few days of stroke onset, but possibly at the price of more patients surviving with disability. Before its use can be recommended, the treatment should now be tested in a much larger randomised controlled trial comparing glycerol with non glycerol treatment, perhaps restricted to pa-
tients who have clinical evidence of cerebral oedema, in which the long term effects of treatment on disability, handicap and quality of life are reliably assessed. ■ Acknowledgments We thank the Cochrane Stroke Group for their collaboration and assistance. We also acknowledge the help of Dr G. Azzimondi, Dr M. Casmiro and Dr R. D’Alessandro for sending us their data and comments.
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