Antifibrinolytic Agents in Current Anaesthetic Practice
Antifibrinolytic Agents in Current Anaesthetic Practice
In neurosurgical patients massive bleeding and transfusion, with the previously mentioned detrimental effect on the coagulation and fibrinolytic system, are a rare event. However, even small amounts of intracranial blood carry a high risk of morbidity and mortality. Managing the coagulation therefore is primarily focused on the prevention of any haemorrhage within the cranial cavity, and the therapeutic target is improvement of clot stability rather than pathological hyperfibrinolysis.
Antifibrinolytic agents have been used to prevent rebleeding in patients presenting with aneurysmal subarachnoid haemorrhage. The risk of rebleeding within the first 24 h after the initial insult have been reported to be as high as 9–17%, and are associated with a remarkable increase in mortality. The other major complication after subarachnoid haemorrhage is ischaemia because of cerebral arterial vasospasm. An additional thrombotic event, a possible side-effect of any procoagulant therapy, could be disastrous. Hence, the use of antifibrinolytics, before definitive surgical or interventional treatment of the aneurysm, remains controversial.
A Cochrane review on this topic included nine studies published between 1973 and 2000 and found that even though antifibrinolytic therapy reduced the rebleeding risk, there was an increase in poor outcome because of cerebral ischaemia. The authors concluded that there were no data to support the use of antifibrinolytics in subarachnoid haemorrhage. It is of interest that eight of those nine trials were published before 1990 and might not represent modern clinical practice. Specifically, the use of calcium antagonists and triple-H-therapy for the prophylaxis of vasospasm was not used, which might account for the higher number of ischaemic events. However, even the study using prophylaxis only showed a reduction in re-bleeding (RR 0.58; 95% CI, 0.42–0.80) with the same rate of ischaemic events but failed to demonstrate a beneficial effect on outcome measured on the Glasgow outcome scale (RR 1.10; 95% CI, 0.91–1.34).
More favourable for the use of antifibrinolytics in subarachnoid haemorrhage is a study conducted in three university hospitals in Sweden in the late 1990s, which was not included in the Cochrane review. Hillman and colleagues randomized 596 patients with verified subarachnoid haemorrhage to receive tranexamic acid (1 g every 6 h) or no treatment. The first dose was given in the referring hospital and therapy was discontinued after the aneurysm was secured. Prophylaxis was started early and only given for a short period of time, as 70% of aneurysms had been treated within 24 h of hospital admission. One limiting factor of this study is the unblinded design. In the tranexamic acid group, the number of patients who re-bled within the first 24 h was significantly lower (2.4 vs 10.8%, P=0.01). Interestingly, the vast majority of re-haemorrhages occurred within the first 8 h (30 of 33), which supports the strategy of early tranexamic acid prophylaxis. With respect to outcome, the study demonstrated only non-significant trends to a decrease in mortality (16.3 vs 12.9%) and an increase in favourable outcome (Glasgow outcome score 4 or 5: 70.5 vs 74.8%) in the tranexamic acid group. Larger patient cohorts are therefore necessary to confirm this in adequately powered trials. Notably, ischaemic events and clinical signs for vasospasm were not more prevalent in patients who received tranexamic acid.
The impact of the implementation of a similar protocol with É›-aminocaproic acid at Columbia University New York was analysed by Starke and colleagues. Starting in May 2003, all patients diagnosed with subarachnoid haemorrhage were supposed to receive a loading dose (4 g) followed by an infusion of 1 g h. The data of 248 patients were analysed, 73 of those received É›-aminocaproic acid. The rebleeding rate was significantly lower in treated patients (2.7 vs 11.4%, P=0.02) with a hazard ratio of 0.23 (P=0.05). Again, there was only a non-significant trend to increased favourable outcomes. The rate of cerebral ischaemic events was not altered but there was a notable 8-fold increase in lower extremity deep vein thrombosis (P=0.003).
Another cohort of 356 patients with subarachnoid haemorrhage, who were all treated with É›-aminocaproic acid on admission to the neuro-intensive care unit, were reviewed retrospectively by Harrigan and colleagues. The re-bleeding rate was even lower than in the treatment groups of the two above-mentioned studies. More importantly, the rate of ischaemic complications compared favourably to previous published data in similar patients and did not indicate a higher risk in patients treated with É›-aminocaproic acid.
In summary, the existing data suggest that there is a place for antifibrinolytic therapy as prophylaxis for early re-bleeding in subarachnoid haemorrhage with no increased risk of ischaemic events. A benefit for survival and favourable outcome is likely but not yet proved.
Neurosurgery
In neurosurgical patients massive bleeding and transfusion, with the previously mentioned detrimental effect on the coagulation and fibrinolytic system, are a rare event. However, even small amounts of intracranial blood carry a high risk of morbidity and mortality. Managing the coagulation therefore is primarily focused on the prevention of any haemorrhage within the cranial cavity, and the therapeutic target is improvement of clot stability rather than pathological hyperfibrinolysis.
Antifibrinolytic agents have been used to prevent rebleeding in patients presenting with aneurysmal subarachnoid haemorrhage. The risk of rebleeding within the first 24 h after the initial insult have been reported to be as high as 9–17%, and are associated with a remarkable increase in mortality. The other major complication after subarachnoid haemorrhage is ischaemia because of cerebral arterial vasospasm. An additional thrombotic event, a possible side-effect of any procoagulant therapy, could be disastrous. Hence, the use of antifibrinolytics, before definitive surgical or interventional treatment of the aneurysm, remains controversial.
A Cochrane review on this topic included nine studies published between 1973 and 2000 and found that even though antifibrinolytic therapy reduced the rebleeding risk, there was an increase in poor outcome because of cerebral ischaemia. The authors concluded that there were no data to support the use of antifibrinolytics in subarachnoid haemorrhage. It is of interest that eight of those nine trials were published before 1990 and might not represent modern clinical practice. Specifically, the use of calcium antagonists and triple-H-therapy for the prophylaxis of vasospasm was not used, which might account for the higher number of ischaemic events. However, even the study using prophylaxis only showed a reduction in re-bleeding (RR 0.58; 95% CI, 0.42–0.80) with the same rate of ischaemic events but failed to demonstrate a beneficial effect on outcome measured on the Glasgow outcome scale (RR 1.10; 95% CI, 0.91–1.34).
More favourable for the use of antifibrinolytics in subarachnoid haemorrhage is a study conducted in three university hospitals in Sweden in the late 1990s, which was not included in the Cochrane review. Hillman and colleagues randomized 596 patients with verified subarachnoid haemorrhage to receive tranexamic acid (1 g every 6 h) or no treatment. The first dose was given in the referring hospital and therapy was discontinued after the aneurysm was secured. Prophylaxis was started early and only given for a short period of time, as 70% of aneurysms had been treated within 24 h of hospital admission. One limiting factor of this study is the unblinded design. In the tranexamic acid group, the number of patients who re-bled within the first 24 h was significantly lower (2.4 vs 10.8%, P=0.01). Interestingly, the vast majority of re-haemorrhages occurred within the first 8 h (30 of 33), which supports the strategy of early tranexamic acid prophylaxis. With respect to outcome, the study demonstrated only non-significant trends to a decrease in mortality (16.3 vs 12.9%) and an increase in favourable outcome (Glasgow outcome score 4 or 5: 70.5 vs 74.8%) in the tranexamic acid group. Larger patient cohorts are therefore necessary to confirm this in adequately powered trials. Notably, ischaemic events and clinical signs for vasospasm were not more prevalent in patients who received tranexamic acid.
The impact of the implementation of a similar protocol with É›-aminocaproic acid at Columbia University New York was analysed by Starke and colleagues. Starting in May 2003, all patients diagnosed with subarachnoid haemorrhage were supposed to receive a loading dose (4 g) followed by an infusion of 1 g h. The data of 248 patients were analysed, 73 of those received É›-aminocaproic acid. The rebleeding rate was significantly lower in treated patients (2.7 vs 11.4%, P=0.02) with a hazard ratio of 0.23 (P=0.05). Again, there was only a non-significant trend to increased favourable outcomes. The rate of cerebral ischaemic events was not altered but there was a notable 8-fold increase in lower extremity deep vein thrombosis (P=0.003).
Another cohort of 356 patients with subarachnoid haemorrhage, who were all treated with É›-aminocaproic acid on admission to the neuro-intensive care unit, were reviewed retrospectively by Harrigan and colleagues. The re-bleeding rate was even lower than in the treatment groups of the two above-mentioned studies. More importantly, the rate of ischaemic complications compared favourably to previous published data in similar patients and did not indicate a higher risk in patients treated with É›-aminocaproic acid.
In summary, the existing data suggest that there is a place for antifibrinolytic therapy as prophylaxis for early re-bleeding in subarachnoid haemorrhage with no increased risk of ischaemic events. A benefit for survival and favourable outcome is likely but not yet proved.
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