Cerebral Hemorrhage: Drug Therapy

Therapeutic Targets

  • Prevention of hematoma progression (progression of bleeding; synonyms: hematoma growth; hematoma expansion) by:
    • Blood pressure reduction
    • Hemostatic procedures (measures to stop bleeding).
    • If necessary, hematomevacuation (neurosurgical procedure to clear out hematoma).
  • Avoidance of complications
  • Securing or stabilizing the vital functions

Therapy recommendations

Treatment recommendations depend on the size of the intracerebral hemorrhage and the clinical presentation of the patient, among other factors:

  • Measures for small intracerebral hemorrhage:
    • Stroke unit treatment (see under “Further therapy“).
    • Blood pressure management
    • Prevention of hematoma progression (progression of bleeding; synonyms: hematoma growth; hematoma expansion).
  • Measures for large intracerebral hemorrhage:
    • Airway management (see under “Further therapy“).
    • In acute occlusive hydrocephalus (hydrocephalus occlusus; pathologic/diseased dilation of the fluid-filled fluid spaces (cerebral ventricles) of the brain): Installation of an external ventricular drainage (EVD).
    • Clot balancing
    • If necessary, hematomevakuation (hematoma evacuation).
    • Intracranial pressure-lowering strategies

Prevention of hematoma progression by blood pressure lowering and hemostatic procedures

Hematoma progression occurs in approximately 30% of cases and is associated with worsening of the patient’s clinical condition and poorer survival. This may be caused by a lack of self-tamponade. Furthermore, individual rebleeding may occur, which is favored by uncontrolled blood pressure or a coagulopathic diathesis (increased bleeding tendency). Blood pressure management

In acute therapy, systolic blood pressure should be lowered to below 140 mmHg. This reduces bleeding progression as well as the risk of rebleeding – increasing the chances of survival. Note: Systolic blood pressure < 120 mmHg results in an increased rate of acute cerebral ischemia (impaired blood flow to the brain with impending neuronal cell death) outside the ICB localization. Patients with intracerebral hemorrhage and systolic values ≥ 220 mmHg: According to a post-hoc analysis of the ATACH II trial, intensive therapy (target 110-139 mmHg) resulted in neurological deterioration within 24 hours twice as often as standard therapy (140-179 mmHg). Furthermore, renal dysfunction occurred three times as often. Successful blood pressure lowering in the first four hours can reduce the risk of bleeding progression, especially with therapy with direct oral anticoagulants/anticoagulants (DOAK; synonym: new oral anticoagulants (NOAK)). Hemostatic procedures (measures to stop bleeding).

The goal is to normalize blood clotting as quickly and completely as possible.

  • Secondary intracerebral hemorrhage during anticoagulant/anticoagulant therapy (vitamin K antagonists (VKA) or direct oral anticoagulants (DOAK; synonym: new oral anticoagulants (NOAK)).
    • For vitamin K antagonist-induced intracerebral hemorrhage, it is recommended to antagonize with prothrombin complex preparations (PPSB; 30 IU/kg bw) and vitamin K or fresh plasma or recombinant factor VIIa.
      • A target International Normalized Ratio (INR) of at least 1.3 or 1.2 should be achieved within 4 hours.
      • A one- to two-week VKA break is recommended.
    • In the context of therapy with dabigatran (factor IIa inhibitors), the medication must be stopped immediately! Idarucizumab (5 g) is administered as an antidote.
    • For bleeding under factor Xa inhibitors, e.g. apixaban, edoxaban, rivaroxaban, high-dose prothrombin complex preparations (PPSB; 50 IU/kg bw), vitamin K, platelet concentrates, fresh plasma, tranexamic acid are used. For the factor Xa inhibitors (apixaban, edoxaban, rivaroxaban), the recombinant protein andexanet alfa, given intravenously, is in phase III clinical testing. The compound binds with high affinity and competitively to human FXa factor Xa inhibitors present in blood. and both direct factor Xa inhibitors and indirect factor Xa inhibitors such as enoxaparin.
    • For bleeding during therapy with heparinoids, protamine sulfate (50 mg) is administered for antagonism.
  • In adults with acute spontaneous intracerebral hemorrhage, administration of hemostatic drugs is not recommended.

Hematomevacuation (hematoma clearance)

(See under “Surgical Therapy”)

Therapy recommendations for complications:

Edema- or intracranial pressure-lowering therapy (peri-hemorrhagic edema).

In most cases, major hemorrhage leads to an increase in intracranial pressure (ICP). In addition, peri-hemorrhagic (perifocal) edema often develops in the course, which also increases ICP. The edema reaches its maximum after approximately 10-14 days. Initially, osmodiuretics are used therapeutically. If this does not control the intracranial pressure or if the edema continues to progress, endovascular hypothermia (34-35°) can be given for 72 hours in addition to normothermia.

  • Intracranial pressure lowering measures (if ICP > 20 mmHg) – intracranial pressure (ICP) must be monitored:
    • Osmodiuretics (drugs with a dehydrating effect) – (No controlled analyses of the risk-benefit ratio are available).
      • Mannitoline infusions
        • 20%, maximum 6 x 250 ml/day.
        • Target serum osmolality: 320 mosmol/l
      • Hypertonic saline solutions (NaCl infusion; 3% or 10%, titrations to serum sodium levels between 145-155 mmol/l).
    • Basic management
      • Analgesia (drug-induced analgesia) to deep anesthesia.
      • Arterial oxygenation (oxygenation of the blood).
      • Hypothermia (lowering of body temperature).
      • Normoglycemia (normalization of blood glucose levels).
      • Normovolemia (normal blood volume).
      • Upper body elevation (30°)
      • Normocapnia (normal partial pressure of carbon dioxide in arterial blood).
    • Other therapeutic measures to be considered:
      • Hematome evacuation (hematoma removal) (see under “Surgical Therapy”) – to remove the hematoma (bruise) in the presence of severe intracranial pressure elevation.
      • For occlusive hydrocephalus: external ventricular drainage (EVD).

Intraventricular hemorrhage (IVB) – hemorrhage collapse into the ventricular system.

In up to 40% of intracerebral hemorrhages, the hemorrhage breaks into the ventricular system (cavity system in the brain), which is an independent risk factor. Compared with intracerebral hemorrhage without ventricular collapse, the mortality rate is increased 2- to 3-fold. In addition, occlusive hydrocephalus (hydrocephalus occlusus; pathological/diseased dilatation of the fluid-filled fluid spaces (cerebral ventricles) of the brain) is often present, which necessitates the placement of an external ventricular drain (EVD) in the acute phase. Furthermore, intraventricular fibrinolysis (IVF; lysis therapy) may be considered for the treatment of IVB. In this procedure, recombinant tissue plasminogen (rtPA) is introduced into the ventricular space via the existing external ventricular drainage. This achieves rapid reabsorption of ventricular blood. Dosage: 1 mg rtPA every 8 hours (daily CT cristula).

Other therapy recommendations

  • Epileptic seizures occur in up to 24% of patients with ICB. When epilepsy-type potentials are detected after intracerebral hemorrhage:
  • For prophylaxis of thromboembolic complications:
    • Low molecular weight heparin (24 hours after intracerebral hemorrhage – rebleeding must be ruled out by cCT/MRI!).
  • Low-dose (75-300 mg/day) continuous medication with acetylsalicylic acid (ASA; antiplatelet agent), as prescribed in primary and secondary prevention of vascular events, does not increase the risk of intracranial hemorrhage.

Therapeutic anticoagulation (TA) after cerebral hemorrhage in patients with mechanical heart valves

  • If started before day 6: more major bleeding and more thromboembolic complications than without TA.
  • At onset before day 14: more severe bleeding than without TA.
  • CONCLUSION: Only patients at high risk of thromboembolism should receive TA no earlier than day 6.

Resumption of antiplatelet therapy after cerebral hemorrhage

Resumption of antiplatelet therapy after hemorrhagic stroke (stroke with a cerebral hemorrhage) was shown to be safe in a randomized clinical trial: 2 years after resumption of therapy, only 12 (4%) suffered a new cerebral hemorrhage after a median of 2.0 years, compared with 23 of 268 patients (9%) in the control group. Immediately, the number of serious vascular events (myocardial infarction (heart attack), apoplexy (stroke), or cardiovascular death) was significantly reduced by 35% (hazard ratio 0.65; 0.44-0.95).