Protocols for thrombolytic therapy

Created 05/09/2022, last revision 19/03/2023

Blood pressure management during and after thrombolysis

Maintain BP ≤ 180/105 mmHg before infusion and for the next 24 hours

adequate blood pressure is an important preventive measure to reduce the risk of intracranial hemorrhagic complications
antihypertensive drugs are allowed to achieve the target BP
if parenteral medication is used, avoid rapid blood pressure (BP) drops (hypoperfusion → failure of collateral supply)
do not attempt full BP correction in the first 48h (target BP is around 140-160/90-100mmHg)
- especially with large ischemia or significant stenosis, higher BP is required to ensure adequate CPP
first-line drugs: urapidil (EBRANTIL), enalapril (ENAP), and labetalol (TRANDATE)
BP monitoring during the first 24h:
- 0-2h: every 10-15 minutes, if BP is stable
  - in decompensated patients, check BP every 5 minutes until the dose of the antihypertensive drug and BP are stable; consider continuous monitoring (invasive x non-invasive)
- 2-24h: every 30 minutes
  - measure more frequently in decompensated hypertension and on parenteral antihypertensive therapy
minimize the duration of parenteral therapy
after 24 hours, (re)start oral medications (e.g., ACE-I, Ca-blockers, sartans, possibly in combination with diuretics) and gradually reduce parenteral medications → see here

urapidil (EBRANTIL, TACHYBEN): coarctation of the aorta, grade II and III AV blocks, aortic stenosis. Combination with metoprolol (Betaloc) may enhance the bradycardic effect
enalapril (ENAP): angioneurotic edema (history), porphyria
Isosorbide dinitrate (ISOKET): use of phosphodiesterase inhibitors (sildenafil), hypertrophic obstructive cardiomyopathy, constrictive pericarditis
metoprolol (BETALOC): bronchial asthma, grade II and III AV blocks, significant bradycardia (TF <60/min) before initiation of therapy, inadequately compensated heart failure, sick sinus syndrome
sodium nitroprusside (NIPRUSS): aortic coarctation, Leber optic atrophy, tobacco amblyopia, vitamin B12 deficiency, metabolic acidosis, hypothyroidism, intrapulmonary AV shunts, severe hepatic failure, sildenafil therapy, hypotension, severe stenotic valve defects, hypertrophic obstructive cardiomyopathy

SBP 180-229 mmHg / DBP 105-139 mmHg

urapidil (EBRANTIL, TACHYBEN), labetalol (TRANDATE), enalapril (ENAP), esmolol (BREVIBLOCK)

SBP > 230 mmHg / DBP > 140 mmHg

in combination with the antihypertensive drugs listed above
Isosorbide dinitrate (ISOKET 0.1%) or sodium nitroprusside (NIPRUSS)
- the effect of both drugs is immediate
FUROSEMIDE
- onset of action within 30 minutes

usually, there is only a small decrease in the levels of fibrinogen and other clotting factors in the blood; it allows emergency surgery to be performed shortly after completion of IVT
in hypofibrinogenemia, there is little correlation between low fibrinogen levels (normal 1.8-4g/L) and the risk of ICH
- increased bleeding risk usually occurs at levels < 1 g/L
spontaneous correction of hypofibrinogenemia within 24-48h is common

in case of bleeding or persistent low levels (< 1 g/L), substitution is required:
HAEMOCOMPLETTAN P/HS (1amp=1g)
- fibrinogen content: 900-1300mg /1g; dissolve the product (1g /50mL of aqua for injection) and warm to room or body temperature before administration
- initial dose 1-2 g, the IV infusion must be slow (~5 mL/min)
Fresh Frozen Plasma (FFP)
- fibrinogen content: 2mg/mL
- administer 200-400 mL initially, then proceed according to the patient condition

patients treated with IVT should be monitored for bleeding at the injection site, from the gingiva, the GIT, UGT, etc.
minor bleeding (e.g., gingival bleeding) does not require discontinuation of IVT
if bleeding progresses, check hemocoagulation and platelet count and proceed to the next section
to assess whether the thrombolytic effect persists, check:
- thrombin time (TT) and plasma fibrinogen levels
- fibrin degradation product (FDP) levels
- euglobulin fibrinolysis (time-consuming test, short version takes approx. 60 minutes)

immediately discontinue the tPA infusion
check blood samples (CBC, coagulation, fibrinogen)
perform CT of the brain
- hemorrhagic infarction → classification of IC bleeding after TL
- SAH
- SDH or EDH
substitution of clotting factors is usually not necessary (thanks to the short biological half-life of tPA)
the following drugs may be administered if needed:

Fresh Frozen Plasma (FFP)
- start with 200-400 mL and titrate according to the clinical course
- up to a dose of 20 mL/kg
PROTHROMPLEX (amp/600IU/20mL)
- 4F–PCC concentrate
- dose: 25 IU/kg IV, infusion rate: 60j (2mL) /min (600jj=20mL)
with severe hypofibrinogenemia, use HAEMOCOMPLETTAN P/HS (1amp=1g)

tranexamic acid (EXACYL) inj. IV during 10 min – 10mL (=2 amp/1000 mg) every 8 hours
- reduce dose in patients with nephropathy!
aminocaproic acid
aprotinin (ANTILYSIN SPOFA) inj. (10 000 trypsin inhibitory units in 1 mL)
- a bolus of 100 000 TIJ (10 mL) IV + infusion 200-300 000 TIJ (diluted in 5% glucose) within 3-4 h

angioedema (incidence ~1-5%) is more common in patients taking ACEIs (RR 13.6!) and in patients with frontal lobe and operculo-insular lesions (RR 9) [Hill, 2003] [Fröhlich, 2019]
often only half of the tongue (contralateral to the lesion) or only the lip is affected
it is likely to be an anaphylactoid (not anaphylactic) reaction – caused by the activation of the complement system and the kinin cascade by plasmin
- complement activation causes mast cells degranulation with histamine release ⇒ vasodilation
- activation of the kinin cascade leads to increased levels of bradykinin, which causes vasodilation (the higher prevalence in patients taking ACEIs may be due to the inhibition of plasma kinases responsible for removing bradykinin) [Gauberti, 2018
- bradykinin is also associated with adverse effects of tPA on the CNS (↑ risk of ICH, greater edema)

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Therapy

stop tPA infusion
administer IV:
- promethazine (PROTHAZIN)1 amp/25mg IV or bisulepin (DITHIADEN) 1 amp/1mg IV
- famotidine (QUAMATEL) 20 mg IV inj.
- methylprednisolone (SOLU-MEDROL) 125 mg/2mL IV (repeat bolus if needed)
- or ADRENALIN IM/SC 0.3-0.5 mL

for angioedema associated with ACE-I, a selective bradykinin B2 receptor antagonist icatibant (FIRAZYR) may be used
- dose: 30 mg/3mL SC in the abdominal area; it can be repeated in 6 and 12 h
orotracheal intubation (OTI) if conservative treatment fails
- edema extending to the larynx and pharynx increases the risk of severe respiratory distress

→ management of anaphylactic reaction