Administration of t-PA (Activase)

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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.
09/0709/08R
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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

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Thrombolysis in Acute Stroke

• Rationale
• 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

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Thrombolytic Agents

• 1st generation
• Streptokinase
• Urokinase
• Anistreplase
• 2nd generation
• Pro-urokinase
• Alteplase (recombinant tissue plasminogen
  activator rtPA)

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Thrombolytic Agents

• 3rd generation
• Reteplase
• Lanoteplase
• Tenecteplase (TNK)
• Desmoteplase (in phase 3 trials)
• Ancrod (defibrinogenating enzyme)

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rt-PA (Activase) Clinical Trial

• NINDS Study (1995)
• Double-blind, placebo-cont., randomized
• 624 patients
• IV tPA (0.9 mg/kg) given lt3 hrs stroke onset
• 10 bolus then 90 infusion over 1 h
• Favorable outcomes
• 31-51 rtPA treated group
• 20-38 placebo group

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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 (Plt.001)
• Mortality by 3 months
• 17 tPA,
• 21 placebo

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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

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Minutes Stroke Onset To Start of Treatment
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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 (N2776) Pooled Analysis NINDS tPA,
ATLANTIS, ECASS-I, ECASS-II
Courtesy Brott T et al
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BRAIN ATTACKTIME IS BRAIN!

• Get drug in fast!
• 1.9 million neurons are destroyed each minute
  treatment is delayed
• Goal - door to drug lt 30 min

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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.
• gt50 cleared within 5 min after infusion
• 80 cleared within 10 min

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Pathophysiology and tPA

• Reperfusion - thrombolytic
• (intravenous tPA)

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Indications for tPA therapy

• Patients presenting within 3hrs of an acute
  ischemic stroke who meet the inclusion criteria
  for thrombolysis
• To be given lt 3 hours after stroke symptom onset
• May be given lt 6hrs only under care of Stroke
  Neurologist

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Onset Time

• Onset Time Time when patient was last seen well
• Requires detective skills

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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 gt1/3 MCA territory
• No midline shift (mass effect)
• No evidence tumor, aneurysm
• or AVM

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Exclusion Criteria

• Decreased level of consciousness
• Symptom onset gt3 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

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Exclusion Criteria(Continued)

• Previous CNS bleeding
• Hx of GI/GU hemorrhage lt21 days
• Major trauma/surgery lt14 days
• Hematological abnormality or coagulopathy, INR
  gt1.7
• Arterial puncture at a non-compressible site in
  the last 7 days

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Exclusion Criteria (Continued)

• HTN (BP gt185/110 not responding to
  antihypertensive tx)
• Pericarditis lt3 months
• Serious underlying medical illness where the
  benefit of tPA is doubtful and the risks high

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Prior to Infusion of tPA

• EMS / Bypass, ER protocols
• Early arrival to ER (best if within 2 hours)
• Rapid Assessment - ABCs, LOC
• Ensure Bloodwork is drawn
• CBC (Plts), Lytes, BUN, Glucose, Troponin, INR,
  PTT,
• Determine eligibility for tPA based on the
  inclusion/exclusion criteria.
• TIME of ONSET is CRITICAL!
• CT ASAP

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Prior to Infusion of tPA

• IV Access start 2 IVs
• 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 lt 185 mmHg /or DBP lt 110 mmHg
• Patient / family education

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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
• TIME IS BRAIN!

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Preparing tPA (continued)

• Holding Activase vial upside down, insert other
  end of transfer device into center of the stopper
• Invert vials

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Preparing tPA (continued)

• DO NOT SHAKE THE VIAL AS IT WILL DENATURE THE
  PROTEIN STRANDS
• Allow vials to sit undisturbed till foam subsides
  (takes only seconds)
• Remove transfer device once the drug is
  reconstituted.

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Preparing tPA (continued)

• Infusion Chart Look up patients 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 patients 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 patients weight
• 0.9 mg/kg given over 60 minutes
• tPA Must be given with an INFUSION PUMP!!

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Precautions!!

• 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

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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

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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 gt180mmHg /or DBP gt105mmHg 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

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Nursing Care during tPA

• Avoid taking BP in arm with IVs 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

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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

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APSS Recommended tPA Protocol

• Diet
• NPO pending swallow screen
• Complete swallow screen prior to any oral intake
• If fails, keep NPO then reassess
• Glucose
• Monitor capillary glucose as follows
• If diabetic or lab glucose gt10 mmol/L
• q4h x 24hr then reassess
• If non-diabetic or lab glucose lt 10 mmol/L
• qid x 48 hr then reassess
• If glucose elevated recommend insulin sliding
  scale (sc or IV)

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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

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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

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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 lt 100 ml

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Adverse Effects of tPA

• Bleeding
• 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 STOP tPA and
  notify physician.

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Adverse Effects of tPA

• Angioedema
• 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

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Adverse Effects of tPA

• Nausea Vomiting
• 25 of patients
• Allergy/Anaphylaxis
• lt0.02 of patients
• Observe for skin eruptions, airway tightening
• Unexplained hypotension may occur as an immune
  reaction

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Patient/Family Education

• Educate patients and family regarding
• Purpose of therapy
• Potential side effects

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Follow-Up

• Repeat CT scan or MRI scan at 12-36 hrs (approx
  24 hrs) post tPA
• Daily Neuro assessments after first 24 hours

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Successful OutcomeOn the table responders

Lazarus effect 1 in 4-5 tPA patients
versus 1 in 30 placebo patients
NIHSS
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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

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• THROMBOLYTICS
• Beyond the 3 hr Time Window

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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

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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 lt2 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

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Thrombolytics Beyond the 3 hr Time Window

• Imaging
• 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

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MRI-Mismatch Concept
DWI-Core of Infarct
MRA Vessel Occlusion
Tissue at Risk
Impaired Perfusion PWI
T2 Rule out ICH
Jansen ea, Lancet 1999
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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

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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
• lt 6 hours from stroke symptom onset
• Results
• 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

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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

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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 gt 10
• Presents between 3-6 hours
• Recent history of surgical procedure
• Occlusion of major cervical and/or intracranial
  vessels

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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.

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Intra-Arterial Thrombolysis Beyond the 3 hr
Time Window

• Recommendations
• IA thrombolysis is an option in selected
  patients
• Presents lt 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

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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

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Administration of t-PA (Activase) in  ACUTE
ISCHEMIC STROKE

• Prepared by
• Carolyn Walker, RN, BN
• Education Coordinator
• Alberta Provincial Stroke Strategy
• September 2007
• Reviewers
• 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