[Show abstract][Hide abstract]ABSTRACT: Although caffeinol (a combination of a low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action.
We used an in vivo excitotoxicity model based on intracortical infusion of N-methyl-D-aspartate (NMDA) and a model of reversible focal ischemia to demonstrate NMDA receptor inhibition as a potential mechanism of caffeinol anti-ischemic activity.
Caffeinol reduced the size of excitotoxic lesion, and substitution of ethanol in caffeinol with the NMDA antagonists CNS-1102 and MK-801 but not with MgSO(4) produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as caffeinol. This NMDA receptor antagonist and caffeine combination demonstrated a long window of opportunity, activity in spontaneously hypertensive rats, and, unlike caffeinol, was fully effective in animals chronically pretreated with ethanol.
Our study suggests that antiexcitotoxic properties may underlie some of the anti-ischemic effect of caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new use of NMDA-based pharmacology in the treatment of stroke.
[Show abstract][Hide abstract]ABSTRACT: Up to 40% of primary intracerebral hemorrhages (ICHs) expand within the first 24 hours (natural history). The authors aimed to study the safety and preliminary efficacy of epsilon-aminocaproic acid (EACA) in halting ICH enlargement.
Consecutive patients with hematoma volumes ranging from 5 to 80 mL were recruited within 12 hours of ICH onset. A total of 5 g EACA was infused during 1 hour and then 1 g/hour for 23 hours. Hematoma volume was compared on baseline, and 24-48-hour brain imaging. Consecutive untreated patients underwent the same imaging protocol.
Three of the first five patients treated had HE>33% of their baseline volume. HE occurred in two of the nine untreated patients. The 80% confidence interval for HE in the treated patients was 32-88%. No thrombotic or other serious adverse events were attributed to EACA.
It is unlikely that the rate of HE in patients given EACA within 12 hours of ICH is less than the natural history rate, although this treatment appears to be safe.
No preview · Article · Mar 2004 · Neurocritical Care
[Show abstract][Hide abstract]ABSTRACT: In animal models, the combination of caffeine and ethanol (caffeinol) provides robust neuroprotection at blood levels that should be easily and safely achieved in humans. This study was designed to determine the safety and tolerability of ascending doses of this combination in stroke patients.
This Food and Drug Administration-approved open-label, single-arm, dose-escalation study had 3 original dose groups: group 1, caffeine 6 mg/kg plus ethanol 0.2 g/kg; groups 2 and 3, incremental increases of caffeine and ethanol by 2 mg/kg and 0.2 g/kg, respectively. Intravenous thrombolysis was encouraged if patients qualified. Drug was started within 6 hours of stroke onset, and blood levels of caffeine and ethanol were drawn at baseline and end of infusion. The target blood caffeine and ethanol ranges were 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. Clinical outcome measurements included the National Institutes of Health Stroke Scale at the end of infusion, at 24 hours, and at discharge. Potential complications from caffeine and ethanol were recorded. Cases were reviewed by an independent stroke neurologist for safety.
A total of 23 patients were recruited. Target blood caffeine and ethanol levels were reached in 0 of the 4 patients in the first group. The second dose group (caffeine 8 mg/kg plus ethanol 0.4 g/kg) included 8 patients. The median end-of-infusion caffeine and ethanol levels were within the desired target ranges. Two days after infusion, 1 patient in this group with preexisting cardiac disease and end-of-infusion caffeine and ethanol levels of 10.7 microg/mL and 69 mg/dL developed reversible congestive heart failure and required transfer to an intensive care unit. The original third dose group was canceled given achievement of target blood caffeine and ethanol levels in group 2. However, 3 new dose groups were created in an attempt to minimize the dose of ethanol. Although blood levels were proportional to dose, none of these new dose groups provided optimal blood levels. Congestive heart failure occurred in 1 other patient with previously asymptomatic cardiomyopathy. No other side effects were noted. Concomitant thrombolytic therapy was given in 8 patients, 1 of whom died of intracerebral hemorrhage.
Caffeinol alone or combined with intravenous tissue plasminogen activator can be administered safely. Caffeine 8 mg/kg plus ethanol 0.4 g/kg produces target caffeine and ethanol levels of 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination.
[Show abstract][Hide abstract]ABSTRACT: To provide a scientific rationale for choosing an optimal stroke surveillance method, the authors compared active surveillance with passive surveillance. The methods involved ascertaining cerebrovascular events that occurred in Nueces County, Texas, during calendar year 2000. Active methods utilized screening of hospital and emergency department logs and routine visiting of hospital wards and out-of-hospital sources. Passive means relied on International Classification of Diseases, Ninth Revision (ICD-9), discharge codes for case ascertainment. Cases were validated by fellowship-trained stroke neurologists on the basis of published criteria. The results showed that, of the 6,236 events identified through both active and passive surveillance, 802 were validated to be cerebrovascular events. When passive surveillance alone was used, 209 (26.1%) cases were missed, including 73 (9.1%) cases involving hospital admission and 136 (17.0%) out-of-hospital strokes. Through active surveillance alone, 57 (7.1%) cases were missed. The positive predictive value of active surveillance was 12.2%. Among the 2,099 patients admitted to a hospital, passive surveillance using ICD-9 codes missed 73 cases of cerebrovascular disease and mistakenly included 222 noncases. There were 57 admitted hospital cases missed by active surveillance, including 13 not recognized because of human error. This study provided a quantitative means of assessing the utility of active and passive surveillance for cerebrovascular disease. More uniform surveillance methods would allow comparisons across studies and communities.
No preview · Article · Jan 2003 · American Journal of Epidemiology
[Show abstract][Hide abstract]ABSTRACT: Mild alterations in temperature have prominent effects on ischemic cell injury and stroke outcome. Elevated core body temperature (CBT), even if mild, may exacerbate neuronal injury and worsen outcome, whereas hypothermia is potentially neuroprotective. The antipyretic effects of acetaminophen were hypothesized to reduce CBT.
This was a randomized, controlled clinical trial at 2 university hospitals. Patients were included if they had stroke within 24 hours of onset of symptoms, National Institutes of Health Stroke Scale (NIHSS) score > or =5, initial CBT <3 8.5 degrees C, and white blood cell count < 12 600 cells/mm(3); they were excluded if they had signs of infection, severe medical illness, or contraindication to acetaminophen. CBT was measured every 30 minutes. Patients were randomized to receive acetaminophen 650 mg or placebo every 4 hours for 24 hours. The primary outcome measure was mean CBT during the 24-hour study period; the secondary outcome measure was the change in NIHSS.
Thirty-nine patients were randomized. Baseline CBT was the same: 36.96 degrees C for acetaminophen versus 36.95 degrees C for placebo (P=0.96). During the study period, CBT tended to be lower in the acetaminophen group (37.13 degrees C versus 37.35 degrees C), a difference of 0.22 degrees C (95% CI, -0.08 degrees C to 0.51 degrees C; P=0.14). Patients given acetaminophen tended to be more often hypothermic <36.5 degrees C (OR, 3.4; 95% CI, 0.83 to 14.2; P=0.09) and less often hyperthermic >37.5 degrees C (OR, 0.52; 95% CI, 0.19 to 1.44; P=0.22). The change in NIHSS scores from baseline to 48 hours did not differ between the groups (P=0.93).
Early administration of acetaminophen (3900 mg/d) to afebrile patients with acute stroke may result in a small reduction in CBT. Acetaminophen may also modestly promote hypothermia <36.5 degrees C or prevent hyperthermia >37.5 degrees C. These effects are unlikely to have robust clinical impact, and alternative or additional methods are needed to achieve effective thermoregulation in stroke patients.