Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register.

AIM: To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS: The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS: A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION: Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.

Comparison of caffeine-induced changes in cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle cerebral artery diameter.

Changes in cerebral blood flow (CBF) can be assessed directly with xenon clearance (XeC) or indirectly by measuring changes in middle cerebral artery blood velocity (Vmca) with transcranial Doppler (TCD). The aim of this study was to compare the changes in CBF and Vmca following caffeine ingestion. Nineteen patients (age 48-86, recovering from an acute stroke) and ten controls (age 52-85) were each studied twice. Bilateral measurements of CBF and Vmca were made before and after ingestion of 250 mg caffeine or matched placebo. The percentage change in CBF and Vmca after caffeine was calculated. Full results (CBF and Vmca) were obtained from 14 patients and 9 controls. There was no significant difference between patients and controls, so results were combined. Caffeine reduced CBF by 22% (95% confidence interval (CI) = 17% to 28%) and reduced Vmca by 13% (95% CI = 10% to 17%). The fall in Vmca was significantly less than that in CBF (p = 0.0016), showing that caffeine reduces mca diameter. Analysis based on Poiseuille flow in the arterioles suggests that caffeine reduced arteriole diameter by 5.9% (95% CI = 4.6% to 7.3%) and mca diameter by 4.3% (95% CI = 2.0% to 6.6%). TCD is being used as an alternative to XeC for assessing the effect of vasoconstrictors and vasodilators on CBF. This study has demonstrated that in mca diameter can be changed by the vasoactive agents, and that changes in Vmca do not necessarily reflect changes in CBF.

Transcranial Doppler blood velocity measurement--the effect of changes in velocity profile.

Transcranial Doppler (TCD) units measure blood velocity in the middle cerebral artery (MCA) and are used to examine the effects of pharmacological agents. The units actually measure the average of the maximum blood velocity envelope (aveV(max)) and it is assumed that changes in aveV(max) follow changes in the true mean velocity (aveV(mean)). This may not be true if there are changes in velocity profile. Results from previous TCD studies using acetazolamide (ACZ) and caffeine were examined for evidence for changes in velocity profile. ACZ increased aveV(max) by 21% (95% CI 13 to 29%) and aveV(mean) by 14% (95% CI 9 to 19%). Caffeine decreased aveV(max) by 8% (95% CI 4 to 12%) and aveV(mean) by 5% (95% CI 4% increase to 13% decrease). In both cases, the true change, measured using aveV(mean) was lower, indicating possible changes in velocity profile. We conclude that the possibility of changes in velocity profile must be considered when using TCD to quantify changes in blood velocity.

The role of the sodium pump during prolonged end-plate currents in guinea-pig diaphragm.

1. Depolarization caused by carbachol or decamethonium is followed by spontaneous recovery of membrane potential in the presence of the drug. The involvement of the Na pump in this recovery has been investigated in guinea-pig diaphragm at 37 degrees C. 2. Restoration of potassium ions (K+) to the bathing solution gives a rapid recovery of membrane potential which is compatible with a component of recovery of potential being attributable to an electrogenic ion pump and from which a Na pump current of over 60 nA has been estimated. 3. The maintenance of membrane potential in the presence of depolarizing drugs is interpreted in terms of a residual rate of channel opening at a time when the membrane potential is restored, balanced by Na pump action producing tubular depletion of K+. To account for these results a Na pump conductance has been added to a model circuit of drug action. 4. The peak end-plate current produced by carbachol (80 microM) is 100 nA (n = 11) as recorded by the voltage clamp technique; similar estimates may be obtained from measurements of input resistance which falls to 31% of the initial value (n = 5). In muscles desensitized by carbachol for 30 min the end-plate current is 11 nA. 5. In normal muscle removal of K+ from the bathing solution produces a reversible hyperpolarization. In muscles where the membrane potential has recovered in the continued presence of the drug, a hyperpolarization is also found on removal of K+. Withdrawal of K+ during the early stage of spontaneous recovery of potential produces a depolarization or an arrest of the spontaneous repolarization. These results are interpreted in terms of the Na pump producing different effects during the course of spontaneous repolarization. 6. Indirect evidence for K+ depletion in the transverse tubules by the Na pump is provided by an increased resistance to inward current following brief exposure to carbachol or decamethonium. A similar mechanism is used to interpret both the observed change in end-plate revérsal potential to a more negative value and the marked diminution in the amplitude of the action potential at the end-plate during drug action.