title: The influence of bolus to infusion delays on plasma Tissue Plasminogen Activator levels.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sparrow Health System, Lansing, MI, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Smith
authors.forename: Yusur
authors.initials: Y
authors.lastname: Al-Nuaimi
authors.forename: Jane
authors.initials: J
authors.lastname: Wainwright
authors.forename: Charles
authors.initials: C
authors.lastname: Sherrington
authors.forename: Arun
authors.initials: A
authors.lastname: Singh
authors.forename: Jouher
authors.initials: J
authors.lastname: Kallingal
authors.forename: Christopher
authors.initials: C
authors.lastname: Douglass
authors.forename: Adrian
authors.initials: A
authors.lastname: Parry-Jones
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.forename: Anand
authors.initials: A
authors.lastname: Dixit
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
mesh_terms: D003198:Computer Simulation; D005343:Fibrinolytic Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D020521:Stroke / Q000097:blood / Q000188:drug therapy; D015912:Thrombolytic Therapy / Q000379:methods*; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator