Etiology of cerebral hemorrhage
1. The two main causes of primary ICH are hypertension and amyloidosis, which mainly involves the intima and ependyma of the arteries and results in amyloid deposits, leading to fibrinoid necrosis;
2. Hypertensive cerebral hemorrhage is mainly located in deep brain nuclei such as the basal ganglia and thalamus, while amyloidosis is mainly located in the cerebral lobes;
3. The clinical manifestations of ICH vary depending on the location and volume of bleeding; larger hematomas (>150 ml) can lead to sudden changes in intracranial pressure (ICP) and compression of brain tissue, resulting in death;
4. Other common clinical manifestations include sudden changes in consciousness, nausea, vomiting, new neurological deficits, mild numbness, tingling, etc.; cerebellar hemorrhage may present with ataxia, poor distance discrimination and nystagmus, and may be accompanied by epilepsy in 7% of patients;
5. The ICH clinical risk stratification score is shown in Table 1. The ICH score is significantly associated with mortality, which can reach 100% with a score of 6.
Pathophysiology
The pathophysiology of cerebral hemorrhage is currently considered to be a cascade of waterfall responses: first, the initial hemorrhagic injury, the size of the initial hemorrhage volume is significantly associated with both the level of consciousness and mortality; 30% of patients subsequently experience hematoma enlargement, which is not only associated with death, but also significantly reduces the likelihood that the patient will regain functional independence; and finally the extent of perihematomal brain edema is also associated with further neurological injury and mortality.
1. Initial hemorrhage
Treatment options for this stage are limited; surgical removal of the hematoma may help to reduce ICP as well as limit the expansion of the hematoma and perihematomal edema. Whether patients are treated surgically depends on the site and size of the hematoma, and a meta-analysis showed an overall benefit of surgical treatment compared with conservative treatment; however, patients with deep brain and ventricular hemorrhage had a poor prognosis for early surgery, whereas those with superficial cortical hemorrhage (<1 cm) had a better prognosis for surgery.
Surgery is recommended for patients with cerebellar hemorrhage with large hematoma size (>3 cm), persistent worsening of symptoms, or brainstem compression or hydrocephalus. Debulking decompression can be used in patients with malignant cranial hypertension and hydrocephalus, but prospective studies have not been performed to confirm this, and the two studies that have been performed have had mixed results. Because initial bleeding volume is strongly associated with hematoma enlargement and the development of perihematomal edema, some authors believe that early hematoma debridement may reduce the damage of the 2 subsequent processes.
Ventricular hemorrhage (IVH), usually secondary to basal ganglia or thalamic hemorrhage, may occur in 45% of patients with ICH; IVH is an independent risk factor for poorer prognosis in patients with ICH, regardless of whether cerebral edema is present. mortality in patients with IVH ranges from 50% to 90%.
2. Hematoma enlargement
Hematoma enlargement usually occurs within 24 hours of the initial bleeding, with an incidence of up to 30%. Risk factors for hematoma enlargement include the volume of the initial bleed, early symptoms, use of antithrombotic and antiplatelet agents, and the presence of the “dot sign” (a marker of persistent bleeding on CTA), see Figure 1.
Clinical studies aimed at reducing hematoma expansion have focused on the use of recombinant factor VIIa (rFVIIa) or lowering arterial pressure. Phase II clinical studies on rFVIIa treatment showed a reduction in hematoma volume and mortality, but phase III clinical studies ended in failure. Therefore, rFVIIa therapy is not currently recommended for patients with ICH without a history of anticoagulant use.
Blood pressure management
Several clinical studies have attempted to reduce hematoma volume by lowering arterial pressure. the INTERACT2 study, which evaluated the efficacy of reducing blood pressure to <140 mmHg with intravenous medication within 1 hour of randomization, did not meet the primary endpoint, but patients in the treatment group with "no disability" or "mild disability" were treated. A higher proportion of patients in the treatment group had "no disability" or "mild disability. Weighing the benefits and risks to patients, it is recommended that blood pressure in ICH patients not fluctuate too much.
The ongoing ATACH2 study used a single drug, nicardipine, to rapidly reduce arterial pressure to between 110-140 mmHg within 4 hours, and preliminary analysis showed a reduction in hematoma volume and mortality. the INTERACT2 study did not meet the primary endpoint, and the ATACH2 study has not yet been completed. these results suggest that rapid BP reduction may be beneficial in patients with ICH.
Perihematoma edema
Reducing secondary injury due to perihematomal edema is another goal of clinical management of ICH. Edema can appear within 3 hours of the onset of bleeding and peaks about 10-20 days after the initial bleed.
Early glucocorticoid treatment studies have not shown clinical benefit but rather increased the risk of complications. Two retrospective case-control studies suggest that hypothermia may help limit the development of perihematomal edema in patients with ICH, so a prospective phase II RCT study is underway. In addition, a small clinical study of fingolimod treatment showed a reduction in edema volume and improvement in NIHSS scores in patients who used the drug within 72 hours of ICH onset.
Cerebral hemorrhage associated with anticoagulant use
The use of anticoagulants in secondary prevention of ischemic stroke increases the incidence and severity of ICH. The incidence of anticoagulant-associated cerebral hemorrhage (AAICH) has increased from 0.8/100,000 in 1988 to 45.9/100,000 in 1999, and the proportion of AAICH in ICH has increased from 5% to 17%.
1.Antithrombotic drugs
Warfarin use led to a 7-fold increase in the risk of cerebral hemorrhage and a 60% increase in mortality, which may be associated with an increase in initial bleeding volume. A meta-analysis showed that warfarin resulted in 12 additional cases of ICH per 10,000 population, but also reduced ischemic stroke patients by 39. 54% of AAICH patients develop hematoma enlargement, which is twice the rate of patients with no history of anticoagulant use, and the mean time to hematoma enlargement is 21 hours. Therefore, urgent reversal of the efficacy of anticoagulants is essential and has been recommended in different guidelines.
2. Guideline recommendations for reversal of oral anticoagulants
Studies have shown that newer anticoagulants are equally effective in preventing thromboembolic events in patients with atrial fibrillation. A meta-analysis showed a significant reduction in the incidence of ICH in patients treated with new anticoagulants compared with warfarin therapy. One study showed that dabigatran increased the incidence of stroke and MI in patients with mechanical valves, so warfarin therapy is still recommended for this group of patients.
3. Dual antiplatelet therapy
Dual antiplatelet therapy (DAPT) is associated with an increased incidence of ICH. When using DAPT therapy, its efficacy in preventing stent thrombosis and minimizing the risk of bleeding complications needs to be evaluated. Although the absolute incidence of cerebral hemorrhage due to DAPT treatment is not high, the mortality rate is very high (55%). Therefore, a quantitative assessment of the platelet inhibitory effects caused by the combination of P2Y12 inhibitors and aspirin could help guide treatment.