Stroke is the second leading cause of death worldwide after ischemic heart disease and is caused by cerebral hemorrhage (ICH), which is divided into primary ICH and secondary ICH. primary ICH accounts for 85% of all ICH and is mainly caused by hypertension (60%) and cerebral amyloidosis (30%), while secondary ICH causes include trauma, aneurysm, vascular malformation, vasculitis, infarct hemorrhagic transformation, and substance abuse. Secondary causes of ICH include trauma, aneurysm, vascular malformation, vasculitis, infarct hemorrhagic transformation and substance abuse.
Despite recent advances in the treatment of stroke, the optimal management of patients with cerebral hemorrhage, including blood pressure management, surgical treatment, prevention of hematoma expansion, and management of various complications, remains a challenge for neurologists and surgeons. A recent review published in updates the latest advances in the treatment of cerebral hemorrhage from an anesthesiology perspective, advocating optimal treatment of patients with cerebral hemorrhage and improved patient prognosis.
Etiology of cerebral hemorrhage
1. The two main causes of primary ICH are hypertension and amyloidosis, which mainly involves the intima and the outer membrane of the artery 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, and the ICH score is significantly associated with mortality, which can reach 100% with a score of 6.
Table 1. cerebral hemorrhage scores
Pathophysiology
The pathophysiological course of cerebral hemorrhage is currently considered to be a cascade of waterfall responses: first there is the initial hemorrhagic injury, and the size of the initial hemorrhage volume is significantly correlated 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 patient’s likelihood of regaining 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 in CTA), see Figure 1.
Figure 1. “Dot sign” and hematoma enlargement in ICH. (A) CT shows a cerebral hemorrhage volume of approximately 18 ml; (B) CTA shows a large “spot sign” in the arterial area of the hemorrhage; (C) CT 7 hours after onset shows an enlarged hematoma of 119 ml.
Clinical studies aimed at reducing hematoma enlargement 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, with preliminary analysis showing a reduction in hematoma volume and mortality. The study did not meet the primary endpoint and the ATACH2 study has not yet been completed. These results suggest that in patients with ICH, rapid BP reduction may be beneficial.
Perihematomal 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) increased from 0.8 per 100,000 in 1988 to 45.9 per 100,000 in 1999, and the proportion of AAICH in ICH increased from 5% to 17%.
1. Antithrombotic drugs
Warfarin use resulted in 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 people, but also reduced ischemic stroke by 39 patients. 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 anticoagulant efficacy is essential and has been recommended by different guidelines (see Table 2).
Table 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 (Figure 2). A meta-analysis showed a significant reduction in the incidence of ICH in patients treated with newer anticoagulants compared with warfarin therapy. One study showed an increased incidence of stroke and MI with dabigatran in patients with mechanical valves, so warfarin therapy is still recommended for this group of patients.
Figure 2. Target of action of anticoagulant drugs
2. 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.
Treatment of cerebral hemorrhage
The AHA/ASA has developed recommended guidelines for the treatment of cerebral hemorrhage (see Table 3).
Table 3. Recommendations for the treatment of ICH from the AHA/ASA and European stroke organizations in the United States
1. Treatment of elevated ICP
Patients with ICH may present with an acute elevation of ICP, which requires urgent management. The use of external ventricular drainage (EVD) allows direct monitoring of ICP and possible drainage of cerebrospinal fluid to reduce ICP. if bleeding is associated with anticoagulant use, the effects of anticoagulants need to be reversed before EVD can be performed. The primary measures to reduce ICP include elevation of the head, administration of mannitol or hypertonic saline, sedation, and intubation or mechanical ventilation.
2. Blood pressure management
The risks associated with moderate blood pressure lowering in patients with ischemic stroke may not apply to patients with ICH because there is no obvious perihematomal semidark zone in ICH. Cerebral autoregulation is not impaired during the acute phase of ICH. Progressive impairment of autoregulation begins to occur 3-5 days after hemorrhage and is associated with a poor prognosis after 90 days.
3. Prevention of epilepsy
Less than 7% of patients with ICH develop seizures, yet studies have shown that prophylactic administration of antiepileptic drugs increases patient mortality. Therefore, antiepileptic drugs should be given only to patients with clinical or electroencephalographic seizures.
4. Glucose management
Hyperglycemia is an independent predictor of death within 28 days in patients with ICH. However, “too tight” glycemic control is associated with depletion of intracerebral blood glucose levels and increases mortality compared to conventional glycemic control (blood glucose reduction to <180 mg/dl). Therefore, the AHA/ASA guidelines recommend that a blood glucose of <180 mg/dl is sufficient.
Key summary
1. Brain hemorrhage needs to be treated promptly in order to maximize the functional prognosis;
2. Methods to reduce hematoma expansion and improve functional prognosis include the use of recombinant factor VIIa and arterial pressure reduction therapy;
3. In patients with ICH, reversal of anticoagulant therapy is becoming increasingly important;
4. Many ongoing multicenter studies are aimed at improving the management of these complex patients.