Thrombolysis

PROTCOL

Inclusion criteria

· Onset of ischaemic stroke within the preceding 4.5 hours

· Measurable and clinically significant neurological deficit on National Institute of Health Stroke scale examination (as a guide, NIHSS >4, dysphasia, visual field defects)

· Patient’s head CT scan does not show haemorrhage or non-vascular cause of stroke symptoms

· Patient’s age is >18 years

Exclusion criteria

ABSOLUTE – DO NOT administer alteplase if any of the following statements are true:

· Uncertainty about time of stroke onset (e.g. patients awaking from sleep)

· Coma or severe obtundation with fixed eye deviation and complete hemiplegia

· Only minor stroke deficit which is rapidly improving

· Seizure observed or known to have occurred at onset of stroke

· Hypertension: ≥185/>110 mmHg on repeated measures (unresponsive to single dose IV treatment)

· Clinical presentation suggestive of SAH even if the CT scan is normal

· Presumed septic embolus

· Patient having received heparin within the last 48 hours and has elevated APTT or has a known hereditary or acquired haemorrhagic diathesis (e.g. PT or APTT greater than normal)**

· INR >1.7**

· Serum glucose <2.8 mmol/L or >22.0 mmol/L (hypo and hyperglycaemia may cause symptoms mimicking stroke).

ABSOLUTE contra-indications for between 3 and 4.5 hours after stroke onset

(as patients with these features were excluded from the ECASS3 study)

o age >80 years

o Oral anticoagulant treatment

o Combination of previous stroke and diabetes mellitus

o Severe stroke as assessed clinically (NIHSS >25) or with brain imaging findings indicating involvement of >1/3 of the middle cerebral artery territory

RELATIVE CONTRAINDICATIONS

· Severe neurological impairment with National Institute of Health Stroke Scale score >22

· CT evidence of extensive middle cerebral artery territory infarction (sulcal effacement or blurring of grey-white junction in >1/3 of middle cerebral territory)

· Stroke or serious head trauma within the past 3 months where the risks of bleeding are considered to outweigh the benefits of therapy

· Platelets less than 100

· Major surgery within the last 14 days

· Known history of intracranial haemorrhage, SAH, intracranial AVM or previously known intracranial neoplasm that, in the opinion of the clinician, the increased risk of intracranial bleeding would outweigh the potential benefits of treatment.

· Suspected recent (within 30 days) myocardial infarction

· Recent (within 30 days) biopsy of a parenchymal organ or surgery that, in the opinion of the responsible clinician, would increase the risk of unmanageable (e.g. uncontrolled by local pressure) bleeding.

· Recent (within 30 days) trauma with internal injuries or ulcerative wounds

· Gastrointestinal or urinary tract haemorrhage within the last 30 days or any active or recent haemorrhage that, in the opinion of the responsible clinician, would increase the risk of unmanageable bleeding.

· Arterial puncture at a non-compressible site within the last 7 days

· Pregnancy

· Concomitant serious, advanced or terminal illness or any other condition that, in the opinion of the responsible clinician would pose a significant hazard, or where prognosis of co-morbidities would overshadow potential benefits of thrombolysis

Note, the following ARE NOT contra-indications to rtPA:

· Recent TIAs (deficits fully resolved)

· Prior aspirin or clopidogrel use

Process

HTN

If HTN to start with try:

· Metoprolol 2.5mg IV

· Hydralazine 5mg IV

· GTN patch 5mg

Alteplase

Dose is 0.9mg/kg (maximum dose 90mg) given as:

· 10% of total dose given as a bolus over 1 minute

· the remaining 90% as an infusion over 60 minutes

· hang 100 mls of normal saline at end of dose to ensure the full dose of alteplase is administered

Post-lysis management

· No antiplatelet or anticoagulant agents to be given for 24 hours after treatment

· Placement of NG tubes, urinary catheters, venepuncture or other invasive procedures should be avoided.

· Obtain blood from IV bung if possible. If venepuncture is required, apply direct pressure for 20 minutes

· BP should be maintained at <185 systolic and <110 diastolic for 36 hours following alteplase treatment

Pathophysiology

· Every 10min, 20million neurones will die in a typical infarct in the MCA territory (Lancet 2010, 375:1667)

Outcomes

Benefits

Time (min)	OR	ARR	NNT
0-90	2.81	12%	8.3
91-180	1.55	13%	7.6
180-270	1.4	6%	16.7

From Lancet 2010 combined results:

Modified Rankin 0-1 at 90days

Time (min)	OR	ARR	NNT
0-90	2.55		4.5
91-180	1.64		9.0
180-270	1.34		14.1
271-360 (not signif)	1.22		21.4
0-360	1.4		12.6

Risks

Intra-Cranial Haemorrhage

· Fatal ICH OR 3.6

o Base line ~1% increased to 4% (i.e. 33 extra per 1000 treated)

· Definition differs in terms of ‘symptomatic haemorrhage’ (Australian data presented below)

o SITS-MOST – large (type 2) infarct related haemorrhage or remote haemorrhage with decrease of 4 points in NIHSS

§ 1.3%

o ECASS – any haemorrhage and decrease of 4 points in NIHSS

§ 6.6%

o RCTs – Any haemorrhage and decrease of 1 point in NIHSS

§ 8.3%

o

· Overall in metanalysis - Symptomatic ICH OR 3.13

· In combined NINDS/ECASS analysis:

o Type 2 haemorrage seen in 5.9% vs 1.1%

· Factors associated with risk of haemorrhage include:

o Age

o Established infarct on initial CT

o Treatment delay and premorbid function of borderline significance

Mortality

· Overall data OR 1.17 (NS)

· Australian data OR1.04 (NS)

· May be a higher death rate in first two weeks which is balanced out with better survival in remainder such that by 3 months roughly equal.

Cochrane meta-analysis

· OR for death or disability 0.8

· Equivalent to 55/1000 additional independent survivors

Special Groups

· Old

Young

· More likely to do well:

· Toni D et al. Intravenous thrombolysis in young stroke patients: Results from the SITS-ISTR. Neurology 2012 Mar 20; 78:880