Cerebral infarction venous thrombolysis, why is it limited to 4.5 hours? How can I save beyond the time window?

Various therapeutic measures (intravenous thrombolysis, mechanical thrombolysis, etc.) with vascular recanshitation as the core in the time window of the acute stage of cerebral infarction are mainly to rescue the nerve cells around the infarction foci that are abnormal due to ischemic injury but have not yet died, which helps to reduce the degree of functional damage in patients and promote the recovery of nerve function.

The nerve tissue around the infarction lesion, which still has a chance of treatment, is generally considered to be an ischemic penumbra.

The content of this article refers to the "Clinical Evaluation and Treatment of Acute Cerebral Infarction Ischemic Semi-dark Belts" Chinese Expert Consensus 2021, prepared by the Cerebrovascular Disease Group of the Neurologists Branch of the Chinese Medical Doctor Association.

1 What does ischemic semi-dark band refer to?

At present, it is believed that the semi-dark band of ischemia refers to the hypoperfusion area around the infarct foci in the same vascular blood supply area as the cerebral infarction core, where nerve cells have physiological and biochemical abnormalities due to ischemia and lead to dysfunction, but they have not yet died, and timely improvement of hypoperfusion can return to normal, otherwise it can worsen into an infarction foci and aggravate brain damage.

Normal blood-supplying brain tissue and ischemic brain tissue have traditionally been distinguished by the degree of reduction in cerebral blood flow (CBF), which can be divided into three areas: mild ischemia without dysfunction, ischemic semi-dark bands with dysfunction, and infarction lesions.

However, the study found that it was unreliable to judge ischemic semi-dark bands by the absolute cbF threshold alone. Studies have suggested that it is more accurate to distinguish ischemic tissues by a "mismatch" between neurocellular protein synthesis and adenosine triphosphate (ATP) production. However, based on the limitations of observation methods and conditions, the method determines that the ischemic semi-dark band has not been applied to the clinic.

2 Pathophysiological changes and clinical significance of ischemic semi-dark bands

The ischemic semi-dark band presents a series of dynamically varying cascades of ischemia and hypoxia. On the one hand, cell depolarization, oxygen radical damage, and excitatory amino acid toxicity occur within minutes after CBF is reduced, and it can last for several days, resulting in inhibition of protein synthesis;

If CBF is not effectively improved, ischemia-induced inflammation further causes disorders of cellular ATP synthesis leading to neuronal death, and ischemic semi-dark bands are converted into infarction foci. On the other hand, the body can develop protective mechanisms to delay ischemic damage.

Based on the above pathophysiological processes, the study found that the early stage of cerebral infarction, which is mainly based on the restoration of blood flow perfusion, such as intravenous thrombolysis or vascular thrombolysis, is the most effective treatment for the treatment of acute cerebral infarction.

3 Clinical prediction and influencing factors of ischemic semi-dark bands

Predicting ischemic semi-dark bands solely on changes in clinical signs and symptoms is inaccurate. Clinical/imaging "mismatch" within 6 hours of onset of acute cerebral infarction in the internal carotid artery blood supply area, i.e., severe neurological deficits (high NIHSS score) and small imaging infarction foci may indicate the presence of ischemic semi-dark bands.

The following factors affect the dynamics of ischemic semi-dark bands:

1) Ischemic semi-dark band time: ischemic semi-dark bands may still exist within 24 hours after cerebral infarction, but the recognized benefit time of intravenous thrombolysis to rescue is is within 4.5 hours of onset.

2) Compensatory lateral branch circulation: good collateral circulation helps to delay the transformation of ischemic semi-dark bands into infarction foci, and the infarction core is smaller.

3) Risk factors for cerebrovascular disease: advanced age, large fluctuations in blood pressure, hyperglycemia, hyperlipidemia, etc. can accelerate the transformation of ischemic semi-dark bands into infarction foci.

4) Associated diseases and stroke complications: infection, electrolyte disorders, gastrointestinal bleeding, etc., can accelerate the transformation of ischemic semi-dark bands into infarction foci.

5) Neuroprotective therapy: such as improving collateral circulation, reducing tissue metabolism, inhibiting cellular hypoxia depolarization, reducing inflammatory response, etc., can theoretically delay the progression of ischemic semi-dark bands into infarct foci.

Recommendations:

1) In the acute stage of aortic occlusive cerebral infarction, the loss of nerve function is mild, but when the early nerve function deteriorates or the neurological function loss is more severe but the imaging infarction foci are small, indicating that ischemic semi-dark bands may exist, clinical recognition should be strengthened (grade III recommendation, grade C evidence).

2) Factors such as ischemic duration, collateral circulation, risk factors for cerebrovascular disease, concomitant diseases and stroke complications affect the dynamic changes of ischemic semi-ductile bands, which should be paid attention to and actively intervene (grade II recommendation, grade C evidence).

4 Clinical imaging evaluation of ischemic semi-dark bands

At present, imaging "mismatch" or clinical symptoms and imaging "mismatch" are often used in clinical practice to replace the histologically defined ischemic semi-dark band to guide the treatment decision and prognosis assessment of acute cerebral infarction. PET is the gold standard for assessing ischemic semi-faint bands, but is clinically poorly operable. The technical methods of CT or MRI are often used.

01. Evaluation method based on imaging "mismatch"

1) CT mode

Multimodal CT includes CT plain scan, CT perfusion imaging (CT perfusion), and CT angiography (CT angiography, CTA), where CTP accurately reflects the degree of vascularization and perfusion of cerebral tissue by assessing changes in cerebral hemodynamics;

Its perfusion parameters include CBF, cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), time to maximum of the residual function (Tmax), etc.

The assessment of ischemic semi-dark bands is mostly based on CTP perfusion plots, and subjective evaluation of the "mismatch" between the infarct core and the abnormal perfusion area. CBF/CBV "mismatch" is the easiest and most practical way to quickly evaluate ischemic semi-dark bands in the current emergency department.

Many perfusion post-processing software adds the Tmax parameter as a sensitive parameter for quantitative evaluation of low perfusion zones and infarction cores, typically with Tmax > 6 seconds or a relative MTT (rMTT) value of > 145% as the threshold for ischemic semi-dark bands, relative to CBF (relative CBF, rCBF).

2) MRI mode

MR perfusion-weighted imaging (PWI)/DWI "mismatch" and FLAIR/DWI "mismatch" can efficiently complete the clinical assessment of ischemic semi-dark bands.

In MR mode, the DWI high signal is usually used as the core of the infarction, and the CBF/DWI "mismatch" is used to qualitatively evaluate the ischemic semi-dark band;

RCBF is measured in pWI Tmax > 6 seconds or rMTT > 145% as the threshold for ischemic semi-dark bands

FLAIR/DWI "mismatch" refers to the DWI high signal, and the signal in the corresponding area on flair does not change significantly. This method is not part of the imaging evaluation method of ischemic semi-dark bands, but it can effectively identify patients within 4.5 hours of onset in stroke patients with post-awakening stroke and unknown onset of onset, indirectly judging the presence of ischemic semi-dark bands.

02. Assessment methods for "mismatch" between clinical symptoms and imaging

In the absence of multimodal imaging assessment, the presence of ischemic semi-dark bands can be indirectly reflected by a "mismatch" of clinical symptoms at the core of infarction in conventional CT/MRI imaging.

If the NIHSS ≥ 6 and the ASPECTS score is ≥ 6, or the NIHSS ≥ 8 and the DWI high signal volume is ≤ 25 mL, there may be ischemic semi-dark bands.

03. AI-assisted assessment of ischemic semi-dark bands

AI-assisted analysis software such as RAPID, MIstar, eStroke, and F-Stroke can help clinicians quickly read images and accurately identify and calculate ischemic semi-dark bands and infarction core volumes, although the method is not yet widely available in mainland China.

04. Side branch cycle assessment

Collateral circulation capacity is an important factor in determining the volume of final infarction and the volume of ischemic semi-dark bands, and imaging assessment of acute cerebral infarction collateral circulation plays an important role.

1) For patients with proposed intravenous thrombolysis within 4.5 hours of onset, CT should be performed as soon as possible to exclude bleeding, and multimodal imaging is not recommended to evaluate ischemic semi-dark bands and delay the time of intravenous thrombolysis (grade I recommendation, grade A evidence).

2) For patients with an unknown onset or greater than 4.5 h from the last normal time, MRI may be considered to evaluate ischemic semi-ductile bands with FLAIR/DWI "mismatch" to screen patients who may benefit from intravenous thrombolysis (grade II recommendation, grade B evidence).

3) For patients with proposed endovascular embolism within 6 hours of onset, CTA or MRA examination should be performed to determine the vascular condition (Class I recommendation, Grade A evidence);

Based on clinical symptoms, ct scan, and CTA (or MRI and MRA), when NIHSS ≥ 6 and ASPECTS ≥ 6, or NIHSS ≥ 8 and DWI high signal volume ≤ 25 mL, endovascular embolization may be considered without the need for further imaging evaluations such as perfusion imaging for ischemic semi-dimmed bands (Class I recommendation, Grade B evidence).

4) For patients with onset time of 6 to 16 hours, the CBF/CBV "mismatch" in CT mode should be used to qualitatively evaluate ischemic semi-dark bands;

Or refer to dawn or DEFUSE-3 study criteria: patients suitable for thrombotic retrieval were screened with Tmax > 6 s and rCBF1.8, infarction core ≤ 70 mL, ischemic semi-dark band volume ≥ 15 mL (Class I recommendation, Class A evidence).

5) For patients with onset time 16 to 24 h or unknown onset, the CBF/CBV "mismatch" in CT mode should be used to qualitatively evaluate the ischemic semi-dark band, and patients suitable for thrombosis can be screened according to the DAWN study criteria (grade II recommendation, grade B evidence).

6) Ai-aided analysis software facilitates rapid, fully automated quantitative assessment of infarct core and ischemic semi-dark band volume (Grade II recommendation, Grade B evidence).

7) Assessment of collateral circulation helps determine outcome of ischemic semi-dark bands (grade II recommendation, grade B evidence).

5 Treatment of ischemic semi-dark bands

Vascular recantherapy such as thrombolysis or thrombolysis is the main means of rescuing ischemic semi-dark bands. At the same time, it is also necessary to actively control harmful factors such as hyperglycemia, treat pulmonary infections, cardiac insufficiency and other concomitant diseases, and take a variety of measures, including improving collateral circulation, to create conditions for reversing the semi-dark band of ischemia.

1) For acute cerebral infarction within 4.5 hours of onset, intravenous thrombolysis or, if necessary, bridging endovascular thrombolytic therapy (Class I recommendation, Grade A evidence); in cases with onset time more than 4.5 h or unknown onset time, there is a "mismatch" after multimodal imaging assessment, and intravenous thrombolytic therapy can be achieved (Grade II recommendation, Grade B evidence).

2) For acute anterior circulation large vessel occlusive cerebral infarction within 6 hours of onset, if there are indications and no surgical contraindications, endovascular embolism should be performed as soon as possible (Grade I recommendation, Grade A evidence);

For anterior circulating macrovascular occlusion of more than 6 h [6 to 16 h (grade I recommendation, grade A evidence), 16 to 24 h (grade II recommendation, grade B evidence)] or an unknown time of onset (grade II recommendation, grade B evidence), endovascular embolectomy can be performed after strict clinical and imaging assessment of the presence of ischemic semi-dark bands.

3) For patients who exceed the time window of thrombolysis or endovascular thrombosis or undergo unconditional vascular recanthesis, drugs such as euremiclin or butophthalein can be used early to promote the opening of collateral circulation to save ischemic semi-dark bands (grade II recommendation, grade B evidence).

4) Reasonable management of blood pressure, timely antiplatelet or anticoagulant therapy can help improve the perfusion of blood flow in the ischemic semi-dark band (Class I recommendation, Grade A evidence).

5) Actively control harmful factors such as hyperglycemia and hyperthermia, as well as various complications in the acute stage of cerebral infarction, which is conducive to the protection of ischemic semi-dark bands (grade II recommendation, grade B evidence).

6) The effect of neuroprotective agents on ischemic semi-dark bands is not clear. The protective effect of edarafen dexterol on ischemic semi-dark bands by blocking cerebral ischemia cascade with multiple targets is worth further clinical exploration (grade II recommendation, grade B evidence).

6 Outlook

Saving the semi-dark band of ischemia is the main purpose of acute cerebral infarction treatment, and its treatment focuses on the early opening of occluded blood vessels, protection and opening of collateral circulation, and protection of ischemic tissues.

In the future, with the advancement of diagnostic and treatment methods, there will be more rapid, accurate and effective methods to assess and rescue ischemic semi-dark bands and improve the prognosis of acute cerebral infarction.

bibliography:

"Clinical Evaluation and Treatment of Acute Cerebral Infarction Ischemic Semi-dark Belts Chinese Expert Consensus 2021", Cerebrovascular Disease Group of Neurologist Branch of the Chinese Medical Doctor Association

Planning | Time capsule

Caption | Stand cool Heero

This article was first published on Lilac Garden's professional platform: Nerve Time