Thrombolysis – What can I do when it goes wrong? Complications – recognition & management Dr L Sekaran Consultant Stroke Physician Clinical Lead, Beds, Herts & Milton Keynes Stroke Network This is an example of an opening slide. Please use other photos if you wish

1930 – discovery of antibiotics 1950 – double helix of DNA 1970 – an extremely aggressive cancer of melanoma Events above contributed to the development of thrombolytic agent CLOT BUSTERS!! - DISCOVERY OF THROMBOLYTIC THERAPY FOR HEART ATTACK & STROKE

Alteplase / recombinant tissue plasminogen activator, rtPA Useful Facts Selective localised fibrinolysis – fibrin dependant activation TPA within the clot. – minimal systemic effects Fibrinogen – levels decrease 60% at 4 hours, reverts to 80% at 24 hrs Plasminogen –levels decrease 70% at 4 hrs, reverts to 80% at 24 hrs Alpha antiplasmin – levels decerease 35% at 4 hrs and reverts to 80% at 24 hours Clearence of rtPA – 50% in 5 minutes, 80% in 10 mts, completely in 40 mts Antibody to rtPA - <0.5% patients transiently, NO sustained formation of antibodies rtPA readministartion in stroke – no data available

Thrombolysis - A lot can go wrong Intracranial bleeding – infarct, normal parenchyma Brain oedema ERIS – early recurrent Ischemic strokes Oro-lingual facial angio-neurotic oedema Anaphylaxis Fat / Cholesterol embolism Systemic bleeding – GI, urological, ENT etc Reperfusion arrhythmias

Symptomatic ICH StudiesPlacebortPAP-value NINDS3.5%7.9%0.006 ECASS II0.2%2.4%0.008 ECASS III2.2%5.3%0.023 SITS-MOST0.2%1.9%0.022 IST-31.0%7.0% ECASS III definition – Symptomatic cerebral haemorrhage was defined as any blood in the brain or intracranially associated with a clinical deterioration of ≥ 4 points of the NIHSS for which the haemorrhage has been identified as the dominating cause of the neurologic deterioration. ECASS II definition – Any intracranial bleed and 4 points or more worsening on the NIHSS score from baseline or the lowest value in the first 7 days, or any haemorrhage leading to death. NINDS definition – A haemorrhage was considered symptomatic if it was not seen on a previous CT scan and there had subsequently been either a suspicion of haemorrhage or any decline in neurologic status. To detect intracranial haemorrhage, CT scans were required at 24 hours and 7 to 10 days after the onset of stroke and when clinical finding suggested haemorrhage. SITS-MOST definition – Local or remote parenchymal haematoma type 2 on the 22- to 36-hour post-treatment imaging scan, combined with a neurologic deterioration of 4 points or more on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 hours, or leading to death. Intracranial bleeding – infarct, normal parenchyma Actilyse info leaflet from Boehringer-Ingelheim ltd,NSW, Australia 25/10/2012, IST-3 Lancet 2012;

CategoryDefinition HI 1Small petechiae along margins of infarct HI 2More confluent petechiae within infarct area but without space-occupying effect PH 1haematoma(s) < 30% of infarct area with some mild space- occupying effect PH 2Haematoma(s)> 30% of infarct area with significant space- occupying effect PHr 1Small or medium-sized clots located remote from actual infarct; mild space-occupying effect could be present PHr 2Large confluent dense blood clots in area remote from actual infarct; significant space-occupying effect may be present Intracranial bleeding – infarct, normal parenchyma J Vasc Interv Radiol 2013; 24:151–163

Intracranial bleeding – infarct, normal parenchyma Predictors of risk of haemorrhage  Hypertension  Chronic atrial fibrillation  Increasing age   Increased blood glucose  High NIHSS score  Overweight   Early ischaemic change on CT scan  Profound cerebral blood volume reduction   Large perfusion/diffusion abnormalities (diffusion volume ≥100ml)   Early blood-brain barrier disruption on FLAIR imaging sequences   Leukoaraiosis of the deep white matter

Intracranial bleeding – infarct, normal parenchyma Management; Stop the infusion – repeat CT, fibrinogen levels, bleeding profile Platelet infusion, FFP, Cryoprecipitate 1 unit / 10 kg ( replace fibrinogen ) Antifibrinolytic agent – trenexamic acid 5 gm bolus IV over mts

PH 1HT1HT2PH2

63 yr M pre and post TX scans with Lt side weakness & PHr 1

Brain Oedema Brain oedema after Thrombolysis; Forced Reperfusion injury of already damaged tissue Less common than after conventional treatment More severe Cerebrovasc Dis 1998;8:166–171

Brain Oedema Management; Discuss with Neurosurgery Hemicraniectomy Age - 60, time 15 Dexamethasone IV Hypertonic solutions – IV Mannitol, IV 3% Normal saline

Post -Thrombolysis Brain oedema

During admission: Day 2: noted to be drowsy, responding but keeping eyes shut Day 3: intermittently seems alert and drowsy Day 4: ‘very sleepy’ Day 5: GCS noted to be 10/15 by NS, 14/15 on Drs r/v. Rpt CT r/q Later in day 5: GCS 12/15 Discussed with RF hospital and transferred

During RF admission: Day 5: transferred Day 6: right decompressive craniectomy, taken to ITU post-op Day 7: extubated, GCS 11/15 Day 8: on ward, continuing dense left hemiplegia Day 14: transferred back to L&D, GCS /15

An early Assessment of a TIA case

Early Recurrent Ischemic Stroke Rare – 0.6% IST-3 – 1% Due to emboli from cardiac / aortic Usually within the first few hours Further deterioration after thrombolysis Neuro-observations / Neurocritical care Circulation. 2006;114: IST-3, Lancet ;May 23, 2012DOI: /S (12)

hrs weakness of all 4 limbs and GCS was E-1, M-1, V-1 Intubated & ventilated

MRI Brain scans

Oro-lingual angio-neurotic edema Rare 0.02% after Tx in MI 1-5% after Tx in Stroke Histamine, bradykinin mediated More common in those who are already on ACEI, less so on ARBs /hereditary complement deficiencies. Increases C3a, C4a, C5a, C2 Increases Bradykinin Unilateral angioedema - Insular cortex in sympathetic and parasymp. Regulation – autonomic dysregulation leading to angioedema on the hemiparetic side CMAJ,2000;162(9);

Oro-lingual angio edema Management; Stop infusion Stop ACEI / ARBs IV hydrocortisone mg IV diphenhydramine 50 mg IV Ranitidine 50 mg Other; Rash Urticaria Laryngeal edema - Respond to above treatment JNNP,2010;81;1079

Anaphylaxis Rare Anti alteplase antibodies Transient Not seen sustained levels Management; As for angioedema Early anaesthetic evaluation, intubation, tracheostomy Adrenaline avoided unless really required

Fat / Cholesterol embolism Uncommon after thrombolysis May be not recognised Petechial rash SoB, hypoxia Tachycardia Livedo reticularis J Emer Trauma shock; 2009; 2(1);29-33 MRI – imaging modality, T2WI Management; Supportive measures High flow O2 IV Albumin Ventilation if needed

Systemic Bleeding Pre Tx CT Post Tx CT, bleeding PRCaecal Ca

Reperfusion Arrhythmias Atrial fibrillation Ventricular arrhythmias Bradycardia / Heart Blocks Majority can be managed in Hyperacute Stroke Units

Alteplase – rtPA – useful facts Intracranial bleeding – infarct / normal parenchyma – devastating in some cases Brain oedema – fatal in some cases ERIS – early recurrent Ischemic strokes – rare % Oro-lingual facial angio-neurotic oedema – 1-5% Anaphylaxis – uncommon but be prepared Fat / Cholesterol embolism – unrecognised in this setting Systemic bleeding – GI, urological, ENT etc Reperfusion arrhythmias