Anticoagulant-associated ICH
While research is directed towards the discovery of treatments to improve the outcome of ICH, the use of anticoagulants for the prevention of thromboembolic stroke and coronary stent thrombosis has increased both the incidence and severity of ICH.
Atrial fibrillation is associated with 15–25% of ischaemic strokes, and warfarin therapy decreases the risk of ischaemic stroke in patients with atrial fibrillation by 62%. Unfortunately, as the prevalence of patients receiving anticoagulation and antiplatelet medications has increased, so has the incidence of anticoagulant-associated intracerebral haemorrhage (AAICH) (0.8/100 000 persons in 1988 to 45.9/100 000 in 1999). The incidence of AAICH as a percentage of ICH increased from 5% to 17%.
Antithrombotic Medication
Significant haemorrhage is the major complication of warfarin therapy. In fact, ICH causes 90% of bleeding-related deaths in patients on warfarin. Warfarin increases the risk of ICH seven-fold and is associated with a 60% mortality rate, perhaps because the use of anticoagulant medication is associated with larger initial haematoma size. A meta-analysis of aspirin use showed a statistically significant absolute risk increase of 12 ICH events per 10 000 patients; however, this was counterbalanced by an absolute risk reduction of 39 ischaemic strokes per 10 000 patients. Combining aspirin and warfarin in elderly patients doubles the risk of ICH compared with the use of warfarin alone. Of interest, almost all studies of anticoagulant safety and efficacy exclude patients at high risk for bleeding, such as the very elderly.
Haematoma expansion occurs in 54% of patients with AAICH, almost twice that of patients not on antithrombotic medication, with a median time of expansion occurring at 21 h. Thus, urgent reversal of antithrombotic effect is important in survival. Various professional societies have recommended protocols to reverse warfarin in the setting of ICH (Table 2). All recommendations include administration of prothrombin complex concentrate (PCC), pooled plasma products containing factors II, IX, and X. Four-factor PCC, which also includes factor VII, is preferred. Alternatively, fresh-frozen plasma (FFP) or three-factor PCC plus factor VII can be administered. The use of FFP as the sole reversal is less effective and is associated with a slower time to INR correction and large volume of administration, which might not be tolerated in some patients. Studies suggest that the PCC can achieve the target INR within 15 min in 89% of patients. There is a risk of a prothrombotic event (deep vein thrombosis, myocardial infarction) in as many as 1.5% of patients receiving PCC. Because the half-life of PCC can be as brief as 6 h, i.v. vitamin K (5–10 mg i.v. every 12 h up to 25 mg) should also be administered and should normalize the INR within 24 h. If the initial dose of PCC or FFP does not reduce the INR to 1.4 30 min after administration, consideration should be given to repeating the dose.
The newer oral anticoagulants, dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa inhibitors), have been shown to be as effective as warfarin in preventing thromboembolic events in patients with atrial fibrillation (Fig. 3). In a meta-analysis, the incidence of ICH was significantly less in patients treated with the newer agents compared with those treated with warfarin (RR 0.49, 95% CI 0.17–1.09). Although reversal agents currently are not available, a number of pre-clinical and clinical trials are ongoing. Neurologists, in response to a survey, indicated that if necessary to treat life-threatening haemorrhage, they would try to reverse the effects of dabigatran with FFP (53%), PCC (61%), factor VIIa (24%), or haemodialysis (24%).
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Figure 3.
Sites of action of antithrombotic medications. Reproduced from, with permission
Although increasingly used in patients with atrial fibrillation, the direct thrombin and factor Xa inhibitors are not used in patients with mechanical valves because the RE-ALIGN study found that patients given dabigatran had a higher incidence of stroke, MI, and valve thrombosis. Warfarin remains the standard oral anticoagulant in this population.
Dual Antiplatelet Therapy
The use of dual antiplatelet therapy (DAPT) after percutaneous coronary interventions with drug-eluting stents (DES) for the treatment of coronary artery disease is also associated with an increased incidence of ICH. Various drug combinations for DAPT have been evaluated for their effectiveness at preventing stent thrombosis while minimizing the risk of haemorrhagic complication, and have resulted in the combination of aspirin and P2Y12-ADP-receptor inhibitors as the mainstay of DES maintenance therapy. Commonly used P2Y12-ADP inhibitors include clopidogrel, prasugrel, and ticagrelor. Ticagrelor is unique in that it is not a pro-drug and has a relatively rapid onset and offset in inhibition of platelet activity. In the PLATO (PLATelet inhibition and patient Outcomes) trial, the incidence of ICH was 0.34% and 0.19% for ticagrelor- and clopidogrel-treated patients, respectively. Although the absolute incidence of ICH in patients on DAPT is low, the mortality is very high (55%). Accordingly, the management of a patient on DAPT in the setting of a ICH is guided by the patient's risk of neurological deterioration and permanent injury vs the risk of coronary stent thrombosis. Ideally, the patient should be cared for in the setting where there is both neurological critical care and interventional cardiology. Quantitative assessment of platelet inhibition due to P2Y12 inhibitor and aspirin is helpful in guiding therapy. In spite of a history of prior antiplatelet medication use in patients with ICH, only 9–21% demonstrated inhibition of platelet activity on assay evaluation. Naidech and colleagues reported better functional outcome in a very small study in patients receiving early platelet transfusion. American Heart Association/American Stroke Association Guidelines consider the evidence for platelet transfusion for ICH in patients taking antiplatelet medication to be Class IIB.
Management of ICH
The American Heart Association/American Stroke Association and European Stroke Organization have developed guidelines for the management of ICH (Table 3), many of which will occur in the operating theatre. Few of these recommendations are based on strong randomized clinical trial data, but rather represent the consensus opinion of experts in the field based upon the available evidence. Many of the recommendations, such as those regarding timing of surgical intervention and reversal of anticoagulant medications, are summarized above.
Management of Elevated ICP
ICP may be acutely increased in the setting of ICH, and emergent interventions to control elevated ICP should be undertaken when indicated. Placement of an external ventricular drain (EVD) allows direct monitoring of ICP and possible drainage of cerebrospinal fluid to reduce ICP. If ICH is associated with the use of antithrombotic or antiplatelet medications, those medications should be reversed before placement of the EVD. Initial interventions to decrease ICP include elevating the head of the bed, administration of mannitol or hypertonic saline, sedatives, and paralytics (intubation and mechanical ventilation). Mild hyperventilation can be useful; however, more significant levels of hyperventilation are not recommended without the guidance of jugular venous oxygen saturation or a cerebral oximeter to ensure adequate tissue oxygenation.
Control of Systemic Arterial Pressure
Maintenance of adequate cerebral perfusion pressure has long been a mainstay of appropriate anaesthetic management in patients with neurological disease; however, the risks of modest arterial pressure reduction in ischaemic stroke may not apply in ICH where there is no significant perihaematoma penumbra in the acute setting. Cerebral autoregulation is not usually impaired in acute ICH; however, progressive impairment of autoregulation beginning post-haemorrhage days 3–5 is associated with poor outcome at 90 days.
Seizure Prophylaxis
Fewer than 7% of ICH patients present with seizure. Although subclinical seizure activity may be seen in up to 25% of patients with ICH, this is not associated with an increase in morbidity or mortality. In fact, increased mortality was noted in patients receiving prophylactic antiepileptic medication, specifically, phenytoin. The use of antiseizure medication, therefore, should be reserved for those patients with clinical or EEG demonstrated seizure activity.
Blood Glucose
Hyperglycaemia is an independent predictor of mortality within the first 28 days of ICH; however, 'tight' glucose control has been found to be associated with depleted cerebral glucose level and also increased mortality when compared with conventional glucose control of a goal of <180 mg dl. Thus, the AHA/ASA recommendation is to avoid blood glucose >180 mg dl.