(Stroke. 2000;31:1250.)
© 2000 American Heart Association, Inc.
Original Contributions |
Effect of Intravenous Nimodipine on Blood Pressure and Outcome After Acute Stroke
From the Karolinska Hospital (N.A., N.G.W.), Stroke Research Unit, Department of Neurology, Stockholm, Sweden; and Royal Institute of Technology (P.N.), Center for Safety Research, Teknikringen, Stockholm, Sweden.
Correspondence to Dr Niaz Ahmed, Karolinska Hospital, Stroke Research Unit, 3 tr, Department of Neurology, S-171 76 Stockholm, Sweden. E-mail niaz.ahmed{at}neuro.ks.se
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose—The Intravenous Nimodipine West European Stroke Trial (INWEST) found a correlation between nimodipine-induced reduction in blood pressure (BP) and an unfavorable outcome in acute stroke. We sought to confirm this correlation with and without adjustment for prognostic variables and to investigate outcome in subgroups with increasing levels of BP reduction.
Methods—Patients with a clinical diagnosis of ischemic stroke (within 24 hours) were consecutively allocated to receive placebo (n=100), 1 mg/h (low-dose) nimodipine (n=101), or 2 mg/h (high-dose) nimodipine (n=94). The correlation between average BP change during the first 2 days and the outcome at day 21 was analyzed.
Results—Two hundred sixty-five patients were included in this
analysis (n=92, 93, and 80 for placebo, low dose, and high
dose, respectively). Nimodipine treatment resulted in a statistically
significant reduction in systolic BP (SBP) and
diastolic BP (DBP) from baseline compared with placebo
during the first few days. In multivariate
analysis, a significant correlation between DBP reduction and
worsening of the neurological score was found for the high-dose group
(ß=0.49, P=0.048). Patients with a DBP reduction of
20% in the high-dose group had a significantly increased adjusted OR
for the compound outcome variable death or dependency (Barthel
Index <60) (n/N=25/26, OR 10.16, 95% CI 1.02 to 101.74) and death
alone (n/N=9/26, OR 4.336, 95% CI 1.131 16.619) compared with all
placebo patients (n/N=62/92 and 14/92, respectively). There was no
correlation between SBP change and outcome.
Conclusions—DBP, but not SBP, reduction was associated with neurological worsening after the intravenous administration of high-dose nimodipine after acute stroke. For low-dose nimodipine, the results were not conclusive. These results do not confirm or exclude a neuroprotective property of nimodipine.
Key Words: blood pressure • cerebral ischemia • nimodipine • stroke, acute
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
An elevated blood pressure (BP) in patients with acute stroke on admission to the hospital is a frequent observation that has been attributed to a multitude of factors. This increased BP usually declines during the first few days.1 2 3 4 5 6 Although the general recommendation is to not treat a moderate elevation in BP during the first few days,7 8 the issue is not entirely clarified.9 10 In a feline middle cerebral artery occlusion model, pharmacologically induced reduction in mean arterial BP (MAP) causes a parallel change of the regional cerebral blood flow (CBF) in the ischemic portion of the brain.11 In subhuman primates, CBF decreases due to rapidly induced hypotension and hypertensives are more susceptible to cerebral ischemia than are hypotensives.12 In humans, it is suggested that sudden lowering of the BP in the acute stage of occlusive stroke may reduce the cerebral perfusion pressure in the ischemic portion of the brain and increase the chance of irreversible damage,9 although evidence from randomized clinical trials is lacking. Other problems related to BP variations in acute stroke are altered autoregulation of CBF and watershed infarctions after hypotensive therapy.9 13
The Intravenous Nimodipine West European Stroke Trial (INWEST) was conducted to evaluate whether intravenously administered nimodipine, an L-type calcium channel antagonist, improved neurological and functional outcome in acute stroke. The study was terminated after inclusion of about half (n=295) of the planned number (n=600) of patients with acute ischemic stroke patients of indications of neurological worsening after intravenous infusion of nimodipine (1 or 2 mg/h).14 The authors found a correlation between nimodipine-induced reduction in BP and unfavorable outcome. The trial design of INWEST was based on the early positive results of oral nimodipine in acute ischemic stroke15 16 and a positron emission tomography study17 of intravenously administered nimodipine, which indicated a statistically significant beneficial effect on long-term recovery in patients with acute ischemic stroke. Like other calcium channel blockers, nimodipine has an antihypertensive property, and one of its main mechanisms of action is vasodilatation, causing decreased peripheral vascular resistance.18 In previous studies of intravenous nimodipine in patients with acute stroke, it was noted that the drug produces hypotension, although no analysis was performed in relation to outcome.19 20 The aim of the present study was to confirm the association between nimodipine-induced lowering of BP and outcome after acute stroke with and without adjustment for several prognostic variables and to investigate the outcome in subgroups of patients with increasing levels of BP reduction.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A complete description of the subjects and methods is given elsewhere14 ; a short summary is given here. A total of 295 patients were enrolled. Ethics committee approval was obtained at each study center, and all patients or their representatives gave informed consent. Patients with a clinical diagnosis of a recent (within 24 hours) ischemic stroke in the carotid artery territory were eligible for inclusion in the trial if they were
40
years old and functionally independent before the stroke.
Treatment Regimens
Patients received intravenous treatment for 5 days,
followed by oral treatment for an additional 16 days. The treatment
alternatives were 1 or 2 mg/h nimodipine IV or placebo, followed by an
oral dose of 30 mg nimodipine QID or placebo. Patients were
consecutively allocated to 1 of the 3 treatments in a double-blind
manner.
Definitions
"Average BP" (mm Hg) was defined as the mean value of BP
measurements for each day. BP was measured every hour for the first 4
hours, every 4 hours for the next 44 hours, twice daily (morning and
evening) for the next 7 days, and then daily while the subject remained
in the hospital. "Baseline BP" was defined by BP value just before
entering into the study.
BP changes, including systolic BP (SBP) and diastolic BP (DBP) changes, were calculated according to the formula [(average BP for each day-baseline BP)/baseline BPx100].17
Orgogozo scores21 and Barthel Index scores22 were transformed to adjust for the baseline differences, according to a procedure that is described elsewhere.15 The transformed score ranged from -100 (maximal worsening) to +100 (maximal improvements). Patients who died were given a score of -110.
"Death or dependency" was defined by Barthel Index score of <60.23
"MAP" was defined as DBP+1/3(SBP-DBP).
"Pulsatility" was defined by (SBP-DBP)/MAP.
"New cardiac manifestation" was defined by new ECG abnormality compared with baseline or any cardiac adverse event or cardiac cause of death (clinical or autopsy) during the treatment period.
Statistical Methods
In accordance with the INWEST study protocol, the primary
outcome measure was the transformed Orgogozo Score and the transformed
Barthel Index score on the follow-up at day 21. The results at week 24
were defined as the secondary outcome. For patients who could not be
followed up for any reason, the last available score was carried
forward. Statistical comparison to test differences between groups were
performed with ANOVA, after validation for normal distribution by use
of the Shapiro-Wilk W tests.24 The
procedure proposed by Bonferroni was used to control
multiplicity.24 To evaluate the hypothesis of
variables in contingency tables, the 
2
test was used or, in the case of small-expected frequencies, Fisher’s
exact test. The Spearman rank order correlation coefficient was used to
test the hypothesis of independence of variables. In addition to
that, descriptive statistical and graphic methods were used to
characterize the data. The significance level for statistical testing
was taken as P<0.05. Probability value should be regarded
as descriptive. The study used multiple hypotheses testing, in which
each hypothesis was analyzed separately and the existence of
patterns in and the consistency of the results were
considered in the analysis. Repeated measurement
analysis was used to analyze time-dependent data, and
the prognostic power of the different variables was compared with
multiple regression analysis. Peto methods25
were used to calculate the OR and 95% CI for unadjusted data, and
multiple logistic regression analysis were performed to adjust
for other prognostic factors. Analyses were carried out by use
of SAS and Statistica software.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Recruitment and Baseline Characteristics
Of the 295 patients recruited for the INWEST, 100 were allocated to receive placebo, 101 to receive 1 mg/h nimodipine (low dose), and 94 to receive 2 mg/h nimodipine (high dose). For evaluation of efficacy, 228 patients who fulfilled the validation criteria were included. In this follow-up analysis, 265 patients were eligible for evaluation of the effect of intravenous nimodipine on BP and outcome (92, 93, and 80 in placebo, low-dose, and high-dose groups, respectively). Patients with cerebral hemorrhage (n=15), serious infection or other life-threatening concurrent illness (n=6), no CT scan or no autopsy performed (n=6), BP value overdue (n=2), and delayed inclusion (n=1) were excluded. Some additional patients were accepted for the present but not for the efficacy analysis; these were patients who discontinued treatment for reasons other than death, earlier than 14 days, or temporarily for >1 day, because most of these treatment interruptions were caused by hypotension. There were no statistically significant differences in baseline characteristics and stroke severity between treatment groups.
Nimodipine Titration Rate and Concomitant Hypotensive
Medications
Patients in the low-dose group received an average of 0.957 mg/h
nimodipine (95% CI 0.935 to 0.979), and those in the high-dose group
received an average of 1.82 mg/h nimodipine (95% CI 1.747 to 1.897).
The median number of titration rate changes (median 2) was equal in all
treatment groups. One hundred seven (40.4%) patients received some
kind of antihypertensive medication before randomization (before and
after hospital admission). There were 38 (41.3%) patients in the
placebo group and 37 (39.8%) and 32 (40%) patients in the low- and
high-dose groups, respectively. One hundred twenty-seven patients
(47.9%) received at least 1 dose of antihypertensive medication before
or after randomization until the end of intravenous
treatment period. The distribution was 49 (53.3%) in the placebo and
41 (44.1%) and 37 (46.3%) in the low- and high-dose groups,
respectively. The difference between the treatment groups was not
statistically significant.
Effect of Nimodipine on BP
The BP course (in mm Hg) and the BP change (%) pattern from
baseline are illustrated in Figures 1A
and 1B, respectively. Average SBP during the first 2 days (48
hours) was reduced by 2.1% from baseline with placebo, 6.6% with the
low-dose (P=0.008 versus placebo), and 11.4% with the
high-dose nimodipine treatment (P<0.001 versus placebo).
Average DBP during the first 2 days (48 hours) was reduced by 1.7%
with placebo, 7.7% with the low-dose (P=0.005 versus
placebo), and 14.1% with the high-dose nimodipine treatment
(P<0.001 versus placebo). The average pulsatility during
the first 48 hours was significantly higher in the low-dose
(pulsatility 0.221, P<0.001) and the high-dose (pulsatility
0.224, P<0.001) groups compared with the placebo group
(pulsatility 0.201).
|
Correlation Between BP Change and Outcome
In Spearman’s correlation analyses, average DBP change
from baseline (%) during the first 2 days was significantly correlated
to transformed Orgogozo score for all patients at the day 21
(r=0.14, P=0.02) and the week 24
(r=0.13, P=0.04) follow-ups. In groupwise
analyses, a significant correlation between these variables
was found for the high-dose group at day 21 (r=0.34,
P=0.002) and at week 24 (r=0.23,
P=0.04). There was no significant correlation for all
patients or in any treatment group between DBP change and transformed
Barthel index score at any follow-up except in the high-dose group at
week 24 (r=0.26, P=0.02).
Multiple regression analyses were performed to confirm the
findings in Spearman’s correlation analyses. Items included in
the analysis were age, sex, history of hypertension, diabetes
mellitus or ischemic heart disease (IHD), baseline severity of
stroke, baseline BP, SBP and DBP changes during the first 2 days, DBP
drop at least once down to 
60 mm Hg during
intravenous treatment, concomitant antihypertensive
medications (before or after randomization until the end of
intravenous treatment period), and new cardiac
manifestations after start of the treatment. For all groups of patients
combined, the association between DBP change and transformed Orgogozo
score was no longer significant in any follow-up. In groupwise
multivariate analysis, a significant
correlation between DBP change and outcome at day 21 was found for the
high-dose group in terms of both transformed Orgogozo score
(standardized ß=0.49, P=0.048) and transformed Barthel
index score (standardized ß=0.27, P=0.033). There was no
significant correlation between DBP change and outcome in the placebo
or low-dose groups or between SBP change and outcome in any group. DBP
change was not significantly associated with any outcome measurement at
week 24 in multiple regression models. Baseline severity, age, and
history of diabetes were findings related to outcome in some
analyses. DBP drop down at least once to 60 mm Hg was
significantly associated with both outcome measures at day 21 in the
low-dose group. One hundred thirty-eight (52.1%) patients had
experienced DBP drop down to 60 mm Hg at least once during the
intravenous treatment period. The distribution was 35
(38%), 55 (59.1%), and 48 (60%) in the placebo, low-dose, and
high-dose groups, respectively. The difference between the groups was
statistically significant (P=0.004). Concomitant medication
with hypotensive drugs or history of IHD was not significantly
associated with outcome.
Outcome in Different Subgroup of Patients According to the Degree
of DBP Change
Based on the correlation evidence between DBP change and outcome,
DBP change rather than SBP change was selected for the further
analysis. The patients were divided into 4 subgroups according
to the amplitude of DBP change: subgroup 1, no change or increased DBP
from baseline; subgroup 2; DBP reduction to <10% from baseline;
subgroup 3; DBP reduction in 10% to <20% from baseline; and
subgroup 4, DBP reduction in 20% from baseline. The unadjusted OR
values for death or dependency at day 21 for the nimodipine groups and
for each nimodipine-treated subgroups compared with all placebo
patients are illustrated in Figure 2.
Multiple logistic regression analysis was performed to adjust
for age, sex, baseline severity, concomitant antihypertensive agents
(including prehospital antihypertensive agents), SBP changes, new
cardiac manifestations, and history of hypertension, diabetes, or IHD.
The only significant higher OR for death or dependency occurred in the
high-dose group with a DBP reduction of 20% (OR 10.158, 95% CI 1.02
to 101.735). Case series analysis of the neurological outcome
on day 3 in the high-dose nimodipine group revealed a higher incidence
of neurological deterioration if average DBP was reduced 20%
(occurring in 18 of 26 patients) during the first 2 days than in those
with a lower degree of DBP reduction (occurring in 18 of 54 patients,
P=0.005).
|
Death was analyzed separately. A total of 50 (18.9%) patients
were dead at day 21. The distribution was 14 (15.2%) in the placebo
group and 20 (21.5%) and 16 (20%) in the low- and high-dose groups,
respectively. The difference and adjusted OR between treatment groups
was not statistically significant. However, high-dose
nimodipine–treated patients with a 20% DBP reduction had a
mortality rate of 34.6% (9 of 26) and the adjusted OR (4.336, 95% CI
1.131 16.619) was significantly higher compared with placebo at day 21.
A comparison of the baseline and demographic data between the subgroups
shows no significant difference within the groups, except for age in
the high-dose nimodipine group.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This follow-up analysis confirmed an association between DBP reduction with high-dose intravenous nimodipine and neurological and functional outcome at 21 days after adjustment for several prognostic variables. Unadjusted subgroup analyses indicated that an increase in the OR for death or dependency in the high-dose nimodipine group at day 21 occurred for the moderate-to-profound DBP reduction subgroups (
10% reduction). After
adjustment for other prognostic factors, the OR for the compound
outcome variable death or dependency and for death alone increased
significantly for the profound DBP reduction subgroup (20%
reduction) treated with high-dose nimodipine. The relationship between
DBP reduction and outcome persisted even after adjustment for
concomitant antihypertensive medications (including prehospital
treatments).
A decrease in BP during the first days after entry occurred in all
treatment groups, but the pattern of reduction differed between the
placebo group and the 2 nimodipine groups. The gradual decline in BP in
the placebo group is known from previous studies and has been
attributed to recovery from mental stress due to the emergency and
other mechanisms.1 2 3 4 5 6 There were no significant
differences in BP between the treatment groups during the oral phase of
the treatment period as reported previously.14 The higher
BP reduction in the nimodipine-treated patients compared with the
placebo group in this analysis is consistent with
previous intravenous and high-dose oral (240 mg/d)
nimodipine studies19 20 26 but not with lower-dose oral
(120 mg/d) nimodipine studies.26 27 28 The difference in
BP reduction between the nimodipine groups and the placebo group was
more pronounced during the first few days of the
intravenous period; thereafter, the difference became
successively smaller. This might be due to stabilization of the BP
reduction sensitivity by nimodipine with time and continuous decline in
the placebo. A reduction in the nimodipine infusion rate in response to
hypotensive reactions may contribute to a smaller difference at the end
of the intravenous period. Differences in BP between the
treatment groups were unintended, and investigators were instructed to
reduce the titration rate if the DBP dropped below 50 mm Hg.
While examining the relationship between BP reduction and outcome, we found that DBP reduction was related to outcome in the high-dose nimodipine group but not in the placebo or low-dose group or for SBP in any group. Because both SBP and DBP were reduced in all 3 groups, the relative effect of nimodipine on DBP and SBP can be illustrated by observing the pulsatility of BP, as defined in Methods. A higher pulsatility from the baseline value in the nimodipine-treated groups indicated a greater reducing effect of nimodipine on DBP compared with SBP. The interpretation is that the impact of nimodipine was greater on DBP than on SBP, suggesting a lowering of peripheral resistance,18 which is a phenomenon related to DBP reduction. Placebo- and nimodipine-treated patients consequently seemed to differ in the BP decrease pattern. In contrast, BP reduction after the relief of mental stress does not seem to be associated with neurological worsening. In the entire group of patients, the correlation between DBP reduction and neurological deterioration thus may be less prominent after adjustment for prognostic variables than in the nimodipine-treatment groups considered separately.
When the regression analysis was repeated after adjustment for other prognostic variables at 24 weeks, the results were no longer statistically significant, even in the high-dose group. The likely explanation is that the relative effect of BP reduction was more profound early after the stroke and that with time, other unknown factors that were not considered in the study protocol added to both neurological and functional outcome. To prove an association between DBP reduction and outcome even at the late follow-up, a large sample size might be necessary.
In ischemic stroke, the development of infarction and,
consequently, outcome is critically correlated to residual perfusion
and oxygen availability.29 Regional CBF is more directly
related to systemic BP during the first few weeks after stroke due to
the failure of cerebral autoregulation.30 A reduction in
the systemic BP in acute occlusive stroke may risk depriving the
patient of the compensatory blood flow through collateral
arterial pathways over the surface of brain. Profound
hypotension in patients with acute stroke with altered autoregulation
may cause a further reduction in cerebral perfusion pressure and a
decrease in regional CBF below the lethal thresholds in the penumbra.
It is likely that the nimodipine-induced reduction in the BP resulted
in deterioration of this collateral supply and may have led to
irreversible cell damage.31 32 The results of 2 small
studies with calcium channel blockers in patients with acute stroke
support our hypothesis and show that calcium channel blockers can cause
an excessive fall of BP and impair CBF.33 34 Cardiac
perfusion is determined by DBP, and a very low DBP may induce cardiac
ischemia. A potential mechanism for the clinical deterioration
with nimodipine in the present study might have been that a low
DBP, which is more frequent after nimodipine treatment, resulted in an
increased risk for cardiac ischemia. Our results did not
support this hypothesis. However, a DBP drop to 60 mm Hg was
associated with a bad outcome in the low-dose group.
The first 2 days of average BP change were selected for analysis of neurological and functional outcome because the BP difference between the treatment groups was profound in this period. It was also a reasonable decision from a pathophysiological aspect, because ischemia is reversible only for a few hours up to about 24 hours.31 32 After 48 hours, reversible ischemia is not likely to occur. In the subgroup analysis of DBP change, all placebo-treated patients were considered as the control group because the placebo group consisted of patients with a natural decline in BP. The baseline characteristics and mechanism of BP reduction in placebo-treated subgroups were not comparable to the corresponding nimodipine-treated subgroups. A higher susceptibility for BP reductions among the elderly patients could be one of the explanations for the imbalance in age between subgroups.
In conclusion, DBP, but not SBP, reduction was associated with
neurological and functional worsening on high-dose nimodipine after
acute stroke. A profound initial DBP reduction (20%) by high-dose
nimodipine was associated with increased odds for the compound outcome
of death or dependency and of death alone. For slight-to-moderate DBP
reduction (<20%) by high-dose nimodipine and for any DBP reduction by
low-dose nimodipine, the results were not conclusive. On the basis of
this analysis, we were unable to reject or confirm whether
nimodipine has a neuroprotective effect in general in patient with
acute stroke; we could only determine that in patients treated with
high-dose intravenous nimodipine leading to a profound DBP
reduction, any neuroprotective effect seemed to be outweighed by the
hemodynamic effect. For a final evaluation of a
neuroprotective effect of nimodipine in acute stroke, a large study
would be necessary; such a trial should exclude the administration of
high-dose intravenous nimodipine leading to sudden DBP
reduction in 20% or even 10% or more during treatment. A combined
treatment with a plasma-expanding drug could be one way to reduce the
risk of sudden initial BP reactions.
|
Acknowledgments |
|---|
We are grateful to the investigators of the INWEST, who are listed in the original INWEST publication.14 INWEST was supported by Bayer AG.
Received January 10, 2000; revision received February 8, 2000; accepted February 25, 2000.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
- Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246:2177–2180.[Abstract]
-
Britton M, Carlsson A, Faire UD. Blood pressure course
in patients with acute stroke and matched controls. Stroke. 1986;17:861–864.
[Abstract/Free Full Text] - Jansen PAF, Schulte BPM, Poels EFJ, Gribnau FWJ. Course of blood pressure after cerebral infarction and transient ischemic attack. Clin Neurol Neurosurg. 1987;89:243–246.[Medline] [Order article via Infotrieve]
-
Morfis L, Schwartz RS, Poulos R, Howes LG. Blood
pressure changes in acute cerebral infarction and hemorrhage.
Stroke. 1997;28:1401–1405.
[Abstract/Free Full Text] - Carlberg B, Asplund K, Hägg E. High blood pressure in acute stroke: is it white coat hypertension? J Intern Med. 1990;228:291–292.
- Carlberg B, Asplund K, Hägg E. Course of blood pressure in different subsets of patients after acute stroke. Cerebrovasc Dis. 1991;1:281–287.
- Yatsu FM, Zivin J. Hypertension in acute ischemic strokes: not to treat. Arch Neurol. 1985;42:999–1000.[Medline] [Order article via Infotrieve]
- Lavin P. Management of hypertension in patients with acute stroke. Arch Intern Med. 1986;146:66–68.[Abstract]
- Spence JD, Del Maestro RF. Hypertension in acute ischemic strokes: treat. Arch Neurol. 1985;42:1000–1002.[Medline] [Order article via Infotrieve]
-
Chamorro A, Vila N, Ascaso C, Elices E, Schonewille W,
Blanc R. Blood pressure and functional recovery in acute
ischemic stroke. Stroke. 1998;29:1850–1853.
[Abstract/Free Full Text] -
Waltz AG. Effect of blood pressure on blood flow in
ischemic and in non-ischemic cerebral cortex.
Neurology. 1968;18:613–621.
[Free Full Text] - Graham DI. Ischemic brain damage following emergency blood pressuring lowering in hypertensive patients. Acta Med Scand. 1982;678(suppl):61–69.
-
Heiss WD, Hayakawa T, Waltz AG. Patterns of changes of
blood flow and relationships to infarction in experimental cerebral
ischemia. Stroke. 1976;7:454–459.
[Abstract/Free Full Text] - Wahlgren NG, MacMahon DG, De Keyser J, Indredavik B, Ryman T, for the INWEST Study Group. The Intravenous Nimodipine West European Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis. 1994;4:204–210.
- Gelmers HG, Gorter K, de Weerdt CJ, Wiezer HJA. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988;318:203–207.[Abstract]
- Paci A, Ottaviano P, Trenta A, Iannone G, De Santis L, Lancia G, Moschini E, Carosi M, Amigoni S, Caresia L. Nimodipine in acute ischemic stroke: a double blind controlled study. Acta Neurol Scand. 1989;80:282–286.[Medline] [Order article via Infotrieve]
- Holthoff V, Beil C, Hartmann-Klosterkotter, Neveling M, Pawlik G, Herholz K, Heiss W-D. Effect of nimodipine on glucose metabolism in the course of ischemic stroke. Stroke. 1990;21(suppl IV):IV-95–IV-97.
- Langley MS. Sorkin EM. Nimodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs. 1989;37:669–699.[Medline] [Order article via Infotrieve]
- Heiss WD, Holthoff V, Pawlik G, Neveling M. Effect of nimodipine on regional cerebral glucose metabolism in patients with acute ischemic stroke as measured by positron emission tomography. J Cereb Blood Flow Metab.. 1990;10:127–132.[Medline] [Order article via Infotrieve]
- Norris JW, LeBrun LH, Anderson BA, the Canwin Study Group. Intravenous nimodipine in acute stroke patients. Cerebrovasc Dis. 1994;4:194–196.
- Orgogozo JM, Dartigues JF. Clinical trials in acute brain infarction: the question of assessment criteria. In: Battistini B, Fioriani P, Courbier R, Plum F, Fieschi C, eds. Acute Brain Ischemia: Medical and Surgical Therapy. New York, NY: Raven Press; 1986.
- Mahoney FI, Barthel DW. Functional evaluation: Barthel Index. Md State Med J. 1965;14:61–65.[Medline] [Order article via Infotrieve]
-
Sulter G, Steen C, De Keyser J. Use of the Barthel
Index and Modified Rankin Scale in acute stroke trials.
Stroke. 1999;30:1538–1541.
[Abstract/Free Full Text] - Douglas C, Montgomery W. Design and Analysis of Experiments, ed 3. New York, NY: John Wiley & Sons; 1991.
- Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–371.[Medline] [Order article via Infotrieve]
-
Fagan SC, Gengo FM, Bates V, Levine SR, Kinkel WR.
Effect of nimodipine on blood pressure in acute ischemic stroke
in humans. Stroke. 1988;19:401–402.
[Abstract/Free Full Text] -
The American Nimodipine Study Group. Clinical trial of
nimodipine in acute ischemic stroke. Stroke. 1992;23:3–8.
[Abstract/Free Full Text] - Mohr JP, Orgogozo JM, Harrison MJG, Hennerici M, Wahlgren NG, Gelmers JH, Martinez-Vila E, Dycka J, Tettenborn D. Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis. 1994;4:197–203.
- Meyer JS, Fang HC, Brown D. Polarographic study of cerebral collateral circulation. Arch Neurol Psychiatry. 1954;72:296–312.
- Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol. 1991;29:231–240.[Medline] [Order article via Infotrieve]
-
Astrup J, Siesjo BK, Symon L. Threshold in cerebral
ischemia: the ischemic penumbra. Stroke. 1981;12:723–725.
[Free Full Text] -
Heiss WD. Flow thresholds of functional and
morphological damage of brain tissue. Stroke. 1983;14:329–331.
[Free Full Text] - Lisk DR, Grotta JC, Lamki LM, Tran HD, Taylor JW, Molony DA, Barron BJ. Should hypertension be treated after acute stroke? Arch Neurol. 1993;50:855–862.[Abstract]
- Vorstrup S, Andersen A, Blegvad N, Paulson OB. Calcium antagonist (PY108-086) treatment may further decrease flow in ischemic areas in acute stroke. J Cereb Blood Flow Metab. 1986;6:222–229.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. I. Qureshi Acute Hypertensive Response in Patients With Stroke: Pathophysiology and Management Circulation, July 8, 2008; 118(2): 176 - 187. [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Shin, M. Nishimura, P. B. Jones, H. Ay, D. A. Boas, M. A. Moskowitz, and C. Ayata Mild Induced Hypertension Improves Blood Flow and Oxygen Metabolism in Transient Focal Cerebral Ischemia Stroke, May 1, 2008; 39(5): 1548 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Goldstein Acute Ischemic Stroke Treatment in 2007 Circulation, September 25, 2007; 116(13): 1504 - 1514. [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Marik and J. Varon Hypertensive Crises: Challenges and Management Chest, June 1, 2007; 131(6): 1949 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Mattle, L. Kappeler, M. Arnold, U. Fischer, K. Nedeltchev, L. Remonda, S. M. Jakob, and G. Schroth Blood Pressure and Vessel Recanalization in the First Hours After Ischemic Stroke Stroke, February 1, 2005; 36(2): 264 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Lindsberg Editorial Comment--High Blood Pressure After Acute Cerebrovascular Occlusion: Risk or Risk Marker? Stroke, February 1, 2005; 36(2): 268 - 269. [Full Text] [PDF]
|
|
|
|
|
|
S. Aslanyan, C. J. Weir, K. R. Lees, and for the GAIN International Steering Committee and Elevated Pulse Pressure During the Acute Period of Ischemic Stroke Is Associated With Poor Stroke Outcome Stroke, June 1, 2004; 35(6): e153 - e155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Castillo, R. Leira, M. M. Garcia, J. Serena, M. Blanco, and A. Davalos Blood Pressure Decrease During the Acute Phase of Ischemic Stroke Is Associated With Brain Injury and Poor Stroke Outcome Stroke, February 1, 2004; 35(2): 520 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Goldstein Blood Pressure Management in Patients With Acute Ischemic Stroke Hypertension, February 1, 2004; 43(2): 137 - 141. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Oliveira-Filho, S.C.S. Silva, C.C. Trabuco, B.B. Pedreira, E.U. Sousa, and A. Bacellar Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset Neurology, October 28, 2003; 61(8): 1047 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Lindsberg, L. Soinne, R. O. Roine, O. Salonen, T. Tatlisumak, M. Kallela, O. Happola, M. Tiainen, E. Haapaniemi, M. Kuisma, et al. Community-Based Thrombolytic Therapy of Acute Ischemic Stroke in Helsinki Stroke, June 1, 2003; 34(6): 1443 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Martinsson and N. G. Wahlgren Safety of Dexamphetamine in Acute Ischemic Stroke: A Randomized, Double-Blind, Controlled Dose-Escalation Trial Stroke, February 1, 2003; 34(2): 475 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Leonardi-Bee, P. M.W. Bath, S. J. Phillips, and P. A.G. Sandercock Blood Pressure and Clinical Outcomes in the International Stroke Trial Stroke, May 1, 2002; 33(5): 1315 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Spedding Letters to the Editor: Reasons Why Stroke Trials Underestimate the Neuroprotective Effects of Drugs Stroke, January 1, 2002; 33(1): 324 - 325. [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Cano-Abad, M. Villarroya, A. G. Garcia, N. H. Gabilan, and M. G. Lopez Calcium Entry through L-type Calcium Channels Causes Mitochondrial Disruption and Chromaffin Cell Death J. Biol. Chem., October 19, 2001; 276(43): 39695 - 39704. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||