How to manage thrombolysis interruptions in acute stroke?

Tissue plasminogen activator (t-PA) is the only approved thrombolytic therapy for the treatment of stroke patients. Its effectiveness is highly time dependent because of the sensitivity of brain tissue to ischemia. Because of the short half-life of t-PA, it should be administered as a bolus followed by an immediate infusion. However, in clinical practice, there are sometimes delays between the application of the bolus and the start of the infusion; in addition, interruptions of the infusion may occur. There are no recommendations regarding how to handle such situations.

We simulate the effects on serum t-PA concentrations of different delays in administering t-PA using its known pharmacokinetic parameters in a 2-compartment model.

Our results demonstrate that even short delays of only 1 minute between bolus and infusion severely affect serum t-PA concentrations. In addition, interruptions to the infusion that are over 1 minute in duration affect serum t-PA concentrations.

These results strongly suggest avoiding bolus-infusion delays by giving the bolus only when the infusion is ready. In case of a delayed start of the infusion, the possibilities are restricted to do nothing or to give a second bolus. We have estimated the dosing of the second bolus depending on the duration of the delay/interruption to allow for the achievement of appropriate serum t-PA concentrations. However, clinical safety data are needed to recommend the application of a second bolus.