The influence of bolus to infusion delays on plasma Tissue Plasminogen Activator levels.

BACKGROUND: Estimates of neuronal loss in acute ischemic stroke show that the typical patient may lose 1·9 million neurons each minute that treatment is delayed. Consequently, significant emphasis has been placed on early evaluation and thrombolysis with tissue plasminogen activator (TPA), the only approved thrombolytic therapy. TPA should be administered as a bolus followed by an immediate infusion because of its short half life. However, in the real life clinical situation, delays in starting the infusion after the bolus can occur. Similarly, once infusion has started, interruptions in the infusion of TPA can also occur. These scenarios may result in lower serum concentrations which could decrease the effectiveness of thrombolysis. We sought to simulate, the influence of bolus infusion delays and also the influence of different intervals of interruptions in the infusion of TPA on serum TPA concentrations. METHODS: We simulated the effect of multiple intervals of delay after the bolus on serum TPA concentrations using known pharmacokinetics parameters of TPA. The effect of different intervals of interruptions in the infusion of TPA was also determined. The effect of rebolusing with TPA on serum concentrations in the event of significant bolus to infusion delays or significant infusion interruption was also simulated. RESULTS: Our data show that delays in starting the infusion may have significant effects on serum TPA concentrations. After the initial bolus, there is a rapid decrease in serum TPA concentrations unless the infusion is started immediately. Greater than 5 min delays in starting the infusion results in a slow gradual increase in serum TPA levels and levels stay well below the target concentrations for significant periods of time. Similarly, interruptions in the infusion of TPA lasting longer than 5 min can also significantly influence TPA levels. Rebolusing with TPA in these scenarios rapidly restores TPA levels to target concentrations. CONCLUSION: Because of its short half life, TPA should be administered as a bolus followed by an immediate infusion. Bolus to infusion delays or interruptions in the infusion of TPA after the bolus may significantly impact serum TPA levels and may reduce the efficacy of thrombolysis. Protocols or administration regimens should be employed to prevent delays or interruptions in the infusion. When delays do occur, rebolusing of TPA may be needed to rapidly restore TPA to target levels.

Does inflammation predispose to recurrent vascular events after recent transient ischaemic attack and minor stroke? The North West of England transient ischaemic attack and minor stroke (NORTHSTAR) study.

BACKGROUND AND HYPOTHESIS: Inflammation is implicated in the pathogenesis and outcome of ischaemic injury. Poststroke inflammation is associated with outcome but it remains unclear whether such inflammation precedes or results from ischaemic injury. We hypothesised that inflammatory markers are associated with an increased risk of recurrent vascular events soon after transient ischaemic attack and minor stroke. METHODS: This was a multicentre, prospective, nested case-control study. Plasma concentrations of C-reactive protein, interleukin-6, interleukin-1-receptor antagonist and fibrinogen, leucocyte counts, erythrocyte sedimentation rate and inflammatory gene allele frequencies were analysed in 711 patients with recent transient ischaemic attack or minor stroke. Cases were defined by the incidence of one or more recurrent vascular events during the three-month follow-up. Association of inflammatory markers with case-status was determined using conditional logistic regression. RESULTS: Plasma concentrations of C-reactive protein, interleukin-1-receptor antagonist and interleukin-6 were not associated with case-status. In secondary analyses, only erythrocyte sedimentation rate was significantly associated with case-status (odds ratio 1·39, 95% confidence interval 1·03-1·85; P=0·03), but this effect did not persist after adjustment for smoking and past history of transient ischaemic attack or stroke. Single nucleotide polymorphisms in four inflammatory genes (interleukin-6, fibrinogen, P-selectin and vascular cell adhesion molecule-1) were nominally associated with case-status. CONCLUSIONS: Circulating inflammatory markers were not associated with recurrent vascular events. Nominally significant associations between genetic markers and case-status will require replication. These data provide little evidence for an inflammatory state predisposing to stroke and other vascular events in a susceptible population.