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Administration of t-PA (Activase) in. ACUTE ISCHEMIC STROKE. August 2007. Information was produced and/or compiled by the Alberta Provincial Stroke Strategy and written permission is required prior to reprinting any of the material located within this document. 09/07:09/08[R].

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Administration of t-PA (Activase)



August 2007

Information was produced and/or compiled by the Alberta Provincial Stroke Strategy and written permission is required prior to reprinting any of the material located within this document.


administration of tpa activase in acute ischemic stroke
Administration of tPA (Activase) in Acute Ischemic Stroke

Learning Objectives:

Upon completion of this session, participants will be able to:

  • Describe the action of tPA in relation to acute ischemic stroke
  • Identify criteria necessary for the administration of tPA in acute ischemic stroke
  • Explain recommended preparation, administration, assessment and on-going care of tPA infusion
  • Identify possible adverse effects of tPA administration
thrombolysis in acute stroke
Thrombolysis in Acute Stroke


  • Limit size of infarct by dissolving clot & restoring blood flow to ischemic brain
  • Neuronal death & infarction evolve in a time dependent manner
  • Prompt treatment with a thrombolytic agent may promote reperfusion & improve functional outcomes
thrombolytic agents
Thrombolytic Agents

1st generation:

  • Streptokinase
  • Urokinase
  • Anistreplase

2nd generation:

  • Pro-urokinase
  • Alteplase (recombinant tissue plasminogen activator [rtPA])
thrombolytic agents5
Thrombolytic Agents

3rd generation:

  • Reteplase
  • Lanoteplase
  • Tenecteplase (TNK)
  • Desmoteplase (in phase 3 trials)

Ancrod (defibrinogenating enzyme)

rt pa activase clinical trial
rt-PA (Activase): Clinical Trial

NINDS Study (1995)

  • Double-blind, placebo-cont., randomized
  • 624 patients
  • IV tPA (0.9 mg/kg) given <3 hrs stroke onset

10% bolus then 90% infusion over 1 h

  • Favorable outcomes
    • 31%-51% rtPA treated group
    • 20%-38% placebo group
rt pa activase clinical trial7
rt-PA (Activase): Clinical Trial

NINDS Study (1995) cont:

  • 32% more tPA pts had minimal or no disability
    • Measured by Barthel Index
  • Symptomatic Intracranial hemorrhage by 36 h:
    • 6.4% tPA
    • 0.6% placebo (P<.001)
  • Mortality by 3 months:
    • 17% tPA,
    • 21% placebo
rt pa activase in acute ischemic stroke
rt-PA (Activase) in Acute Ischemic Stroke

Thrombolytic (clot buster) given IV for treatment for acute ischemic stroke:

  • Approved in US in 1996
  • Approval in Canada in 1999
  • CASES - 2002 (Canadian Study)
    • 1135 patients treated
    • Hemorrhage rate - 4.6%
    • Anaphylactic/angioedema reaction - 1.3%
    • Favorable outcomes at 3 months & 12 months

NINDS tPA Stroke Study:

Time to Treatment and Odds Ratio of Favorable Outcome





Odds Ratio

Favorable Outcome





Benefit for rt-PA



No Benefit for rt-PA
















Stroke Onset To Start of Treatment


Diminishing Returns over Time

Favorable Outcome (mRS 0-1, BI 95-100, NIHH 0-1) at Day 90 Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776)


Courtesy Brott T et al

brain attack time is brain
  • Get drug in fast!
  • 1.9 million neurons are destroyed each minute treatment is delayed
  • Goal - door to drug < 30 min
pathophysiology and tpa
Pathophysiology and tPA
  • Thrombus is formed during ischemic stroke.
  • Alteplase binds to fibrin in a thrombus:
    • converts plasminogen to plasmin
    • initiates local fibrinolysis with minimal systemic effects.
  • Cleared rapidly from circulating plasma by liver.
    • >50% cleared within 5 min after infusion
    • 80% cleared within 10 min
pathophysiology and tpa13
Pathophysiology and tPA
  • Reperfusion - thrombolytic

(intravenous tPA)

indications for tpa therapy
Indications for tPA therapy:
  • Patients presenting within 3hrsof an acute ischemic stroke who meet the inclusion criteria for thrombolysis
  • To be given < 3 hours after stroke symptom onset
  • May be given < 6hrs only under care of Stroke Neurologist
onset time
Onset Time
  • Onset Time = Time when patient was last seen well
  • Requires detective skills
inclusion criteria
Inclusion Criteria
  • Acute ischemic stroke presenting within 3 hours of onset of symptoms.
  • No hemorrhage on CT
  • No evidence of massive infarction or edema involving >1/3 MCA territory
  • No midline shift (mass effect)
  • No evidence tumor, aneurysm

or AVM

exclusion criteria
Exclusion Criteria:
  • Decreased level of consciousness
  • Symptom onset >3 hrs
  • SAH, aneurysm, AVM, ICH, mass effect, tumor on CT, or any major hypodensity representing well-evolved infarction
  • Stroke or serious head injury within 3 months
exclusion criteria continued
Exclusion Criteria(Continued):
  • Previous CNS bleeding
  • Hx of GI/GU hemorrhage <21 days
  • Major trauma/surgery <14 days
  • Hematological abnormality or coagulopathy, INR >1.7
  • Arterial puncture at a non-compressible site in the last 7 days
exclusion criteria continued19
Exclusion Criteria (Continued):
  • HTN (BP >185/110 not responding to antihypertensive tx)
  • Pericarditis <3 months
  • Serious underlying medical illness where the benefit of tPA is doubtful and the risks high
prior to infusion of tpa
Prior to Infusion of tPA:
  • EMS / Bypass, ER protocols
  • Early arrival to ER (best if within 2 hours)
  • Rapid Assessment - ABC’s, LOC
  • Ensure Bloodwork is drawn:
    • CBC (Plts), Lytes, BUN, Glucose, Troponin, INR, PTT,
  • Determine eligibility for tPA based on the inclusion/exclusion criteria.
prior to infusion of tpa21
Prior to Infusion of tPA:
  • IV Access: start 2 IV’s
    • #1: used only for tPA
        • Saline Lock post infusion, and use for blood drawing only
    • #2: ‘life line’
        • for IV drug access/fluid administration
  • Blood pressure management
    • Maintain SBP < 185 mmHg &/or DBP < 110 mmHg
  • Patient / family education
preparing tpa 100mg vial
Preparing tPA - 100mg Vial
  • Package Contains:
    • 100 mg vial of Activase
    • 100 ml vial of sterile H20
    • A double-sided sterile transfer device
  • Insert one end of transfer device into vial containing diluent


preparing tpa continued
Preparing tPA (continued)
  • Holding Activase vial upside down, insert other end of transfer device into center of the stopper
  • Invert vials
preparing tpa continued24
Preparing tPA (continued)
    • Allow vials to sit undisturbed till foam subsides (takes only seconds)
  • Remove transfer device once the drug is reconstituted.
preparing tpa continued25
Preparing tPA (continued)
  • Infusion Chart: Look up patient’s weight to determine bolus and infusion amounts
    • Spike reconstituted vial of tPA with infusion tubing, and prime line
    • Set infusion pump rate and volume limit for BOLUS as specified for patient’s weight
      • 10% of total dose given over 60 seconds
    • Once bolus infused, set infusion pump rate and volume limit for continuous infusion as specified for patient’s weight
      • 0.9 mg/kg given over 60 minutes

tPA Must be given with an INFUSION PUMP!!

  • Do not mix tPA with any other medications.
  • Do not use IV tubing with infusion filters.
  • All patients must be on a cardiac monitor
  • When infusion is complete, saline lock IV and flush with N/S
  • tPA must be used within 8 hours of mixing when stored at room temperature or within 24 hours if refrigerated
assessment during tpa vs
Assessment during tPA - VS
  • Assess NVS
    • q15min x 2 hrs then q30 min x 6 hrs, q1hr x 16 hrs and q4 hrs x 48 hrs
  • Assess NIHSS
    • Immediately after tPA bolus, repeat at 30min, 60min, 3hr, 6hr and 24hr post tPA initiation

If evidence of bleeding, neurological deterioration (change of 2+ points on NIHSS), new headache or nausea: - notify physician

- arrange CT scan

assessment during tpa vs28
Assessment during tPA - VS
  • Assess BP and Pulse
    • q15min x 2 hrs then q30 min x 6 hrs, q1hr x 16 hrs and q4 hrs x 48 hrs
    • If SBP >180mmHg &/or DBP >105mmHg notify physician and consider the following treatment:
      • Labetalol 10-20 mg IV over 1-2 min, repeat

q10-20 min (max 150 mg)

      • If Labetalol ineffective, alternates include:
        • Hydralazine 10 mg IV push over 1-2min, q10-20 min
        • Enalaprilat 1.25 mg IV push over 1 min, q6h
        • Sodium nitroprusside 0.5-10 ug/kg/min
nursing care during tpa
Nursing Care during tPA
  • Avoid taking BP in arm with IV’s or venipunctures.
    • BP should be taken manually
    • an NIBP will cause petechiae
  • Avoid unnecessary handling of the patient.
    • Bed rest x 12 hours then reassess
nursing care during tpa30
Nursing Care during tPA
  • No unnecessary venous or arterial punctures
    • Blood is drawn from IV saline lock if possible
  • Avoid invasive procedures
    • NG tubes, suction, or urinary catheterization
  • Apply pressure dressing to potential sources of bleeding
  • Assess all secretions and excretions for blood
apss recommended tpa protocol
APSS Recommended tPA Protocol


  • NPO pending swallow screen
    • Complete swallow screen prior to any oral intake
    • If fails, keep NPO then reassess


  • Monitor capillary glucose as follows:
    • If diabetic or lab glucose >10 mmol/L
      • q4h x 24hr then reassess
    • If non-diabetic or lab glucose < 10 mmol/L
      • qid x 48 hr then reassess

If glucose elevated: recommend insulin sliding scale (sc or IV)

apss recommended tpa protocol32
APSS Recommended tPA Protocol

Antiplatelet/Anticoagulant Therapy

  • No ASA, Clopidogrel, Aggrenox, Ticlopidine or other antiplatelet agents for 24 hours from start of tPA
  • No heparin, heparinoid or warfarin for 24 hours from start of tPA

CT or MRI must be completed and reviewed by physician to exclude intracranial hemorrhage prior to above therapy

apss recommended tpa protocol33
APSS Recommended tPA Protocol

DVT Prophylaxis

  • Assess patient daily for deep vein thrombosis
  • Intermittent pneumonic compression stockings while on bed rest, then reassess
  • After 24h, if CT/MR is negative for hemorrhage, consider the following when patient remains on bed rest due to significant lower limb hemiparesis/plegia:
    • Unfractionated heparin sc 5000u q12 h OR
    • Enoxaparin 40mg sc q24h
apss recommended tpa protocol34
APSS Recommended tPA Protocol

Bladder Management

  • If possible, catheterize before tPA admin
    • DO NOT DELAY tPA for this
  • Avoid catheterization 5-7 hrs post tPA infusion
  • If unable to void - bladder scanner and in/out catheterization q4-6hrs
  • If voiding - residuals daily until < 100 ml
adverse effects of tpa
Adverse Effects of tPA


  • Superficial: due to lysis of fibrin in the hemostatic plug
      • observe potential bleeding sites: venous & arterial puncture, lacerations, etc.
  • Internal:
    • GI tract, GU tract, Respiratory, Retroperitoneal or Intracerebral

ACTIONS: If clinically significant bleeding or deterioration of Neuro status: STOPtPA and notify physician.

adverse effects of tpa36
Adverse Effects of tPA


  • Assess patient for signs of

Angioedema of the tongue:

    • Swelling of tongue/lips
    • notify Physician immediately

if swelling seen

    • 1.3% of population
  • Assess at 30, 45, 60, 75 minutes after tPA bolus. Once the tPA infusion has finished the risk of angioedema falls off
  • Patients on ACEi are at higher risk of angioedema
adverse effects of tpa37
Adverse Effects of tPA

Nausea & Vomiting

  • 25% of patients


  • <0.02% of patients
  • Observe for skin eruptions, airway tightening
  • Unexplained hypotension may occur as an immune reaction
patient family education
Patient/Family Education

Educate patients and family regarding:

  • Purpose of therapy
  • Potential side effects
follow up
  • Repeat CT scan or MRI scan at 12-36 hrs (approx 24 hrs) post tPA
  • Daily Neuro assessments after first 24 hours
successful outcome on the table responders
Successful Outcome“On the table responders”

“Lazarus effect”

1 in 4-5 tPA patients

versus 1 in 30

placebo patients


successful outcome of iv tpa therapy
Successful Outcome of IV tPA therapy:
  • Thrombolysis of arterial occlusion
  • Reperfusion of viable tissue
  • Improvement in pt functioning/outcome
    • Improvement can be delayed
    • only uncommonly occurs in the first 24h
  • Rehabilitation and reintegration

Beyond the 3 hr Time Window

thrombolytics beyond the 3 hr time window
Thrombolytics: Beyond the 3 hr Time Window

Learning Objective:

Upon completion of this session, participants will be able to:

  • Describe circumstances in which tPA may be infused beyond the 3 hour time window
thrombolytics beyond the 3 hr time window45
Thrombolytics: Beyond the 3 hr Time Window
  • Meta-analysis of 6 randomized controlled trials of IV tPA
    • The sooner the tPA the greater the benefit
    • Best outcome if treated <2 hours
    • Some benefit out to 5 hours
  • Imaging might assist to select patients who would benefit with treatment beyond 3 hours:
    • MRI: Diffusion / Perfusion weighted imaging
    • CT based perfusion imaging
  • Intra-arterial thrombolytic administration is being studied
thrombolytics beyond the 3 hr time window46
Thrombolytics: Beyond the 3 hr Time Window


  • Magnetic Resonance Imaging (MRI)
    • Diffusion weighted imaging (DWI)
      • Evolving brain edema results in disturbed diffusion
      • Damaged brain tissue
      • Early detection of ischemic brain
    • Perfusion weighted imaging (PWI)
      • Obtained following injection of a contrast agent
      • Identifies areas of decreased perfusion
mri mismatch concept
MRI-Mismatch Concept

DWI-Core of Infarct


Vessel Occlusion

Tissue at Risk





Rule out


Jansen ea, Lancet 1999

intra arterial thrombolysis beyond the 3 hr time window
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window
  • Infuse thrombolytic agent at site of occlusion through microcatheter
    • Remains experimental
    • Not approved in Canada or US
    • May show some benefit in treatment of carefully selected patients
    • Hemorrhage remains substantial concern
intra arterial thrombolysis beyond the 3 hr time window49
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window
  • PROACT II study - Prolyse in Acute Cerebral Thrombolism
    • Prospective, randomized, placebo-controlled, phase III
    • Effectiveness of IA thrombolysis with Prourokinase
    • Patients with ischemic stroke secondary to occlusion of MCA
    • < 6 hours from stroke symptom onset


    • Rankin 0-2 at 90 day: 40% in treatment group (121 patients)

25% in control group (59 patients)

    • Recanalization of MCA: 66% treatment, 18% control
    • SICH within 24 hours: 10% treatment, 2% control

No difference in overall death rate

Not approved: Prourokinase not available for clinical use

intra arterial thrombolysis beyond the 3 hr time window50
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window
  • Results of PROACT II extrapolated to tPA and urokinase
  • IA promoted due to:
    • General consensus and case data
    • High concentration of drug delivered into thrombus
    • Clinicians observe higher recanalization rates with IA than IV tPA (uncontrolled)
  • Clinical benefit may be offset by delay to initiate IA treatment
intra arterial thrombolysis beyond the 3 hr time window51
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window
  • Popular clinical practice among stroke neurologists to give IA tPA if expect limited response to IV tPA: For example:
    • Severe NIHSS score > 10
    • Presents between 3-6 hours
    • Recent history of surgical procedure
    • Occlusion of major cervical and/or intracranial vessels
intra arterial thrombolysis beyond the 3 hr time window52
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window
  • Data suggests selection of patients for IA thrombolysis based on:
    • Angiogram
      • Identify site of occlusion and collateral supply
    • Radiological criteria
      • May benefit whether hyperdense artery sign is present or not
      • May benefit acute ischemic stroke secondary to MCA
      • IA Urokinase maybe useful if vertebral / basilar artery occlusion
      • May benefit embolic stroke involving anterior circulation within 4.5 hours.
intra arterial thrombolysis beyond the 3 hr time window53
Intra-Arterial Thrombolysis: Beyond the 3 hr Time Window


  • IA thrombolysis is an option in selected patients:
    • Presents < 6 hours from symptom onset
    • Due to occlusion of MCA
    • Not candidate for IV tPA
  • IA should not preclude IV administration of tPA
  • IA is reasonable if contraindications exist to use of IV tPA
  • Use only at experienced Stroke Centers
iv ia thrombolysis beyond the 3 hr time window
IV-IA Thrombolysis: Beyond the 3 hr Time Window
  • Combining IV and IA tPA is being studied:
    • Looks promising
    • quick availability of IV
    • recanalization of IA
  • Give slightly lower dose IV tPA (0.6 mg/kg) followed by additional tPA via microcatheter (IA)
    • may have better outcomes than treatment with IV tPA alone.
  • Requires complex infrastructure
    • only experienced interventionalists and stroke neurologists
administration of t pa activase in acute ischemic stroke
Administration of t-PA (Activase) inACUTE ISCHEMIC STROKE

Prepared by

Carolyn Walker, RN, BN

Education Coordinator

Alberta Provincial Stroke Strategy

September 2007


Dr. Michael Hill, MD, MSc, FRCPC

Assistant Professor, Department of Clinical Neurosciences at the University of Calgary

Director of the Calgary Stroke Unit and a member of the renowned stroke team at the University of Calgary Faculty of Medicine

Dr. Toni Winder, MD, FRCP

Stroke Neurologist

Chinook Health, Lethbridge, Alberta

Recognition of the Chinook, Capital and Calgary Health Regions for information utilized in the development of this presentation