Multiphase adjuvant neuroprotection: A novel paradigm for improving acute ischemic stroke outcomes

Abstract

While several large pivotal clinical trials recently revealed a substantial benefit of endovascular thrombectomy for acute ischemic stroke (AIS) caused by large-vessel occlusion, many patients still experience mediocre prognosis. Enlargement of the ischemic core, failed revascularization, incomplete reperfusion, distal embolization, and secondary reperfusion injury substantially impact the salvaging of brain tissue and the functional outcomes of AIS. Here, we propose novel concept of "Multiphase Adjuvant Neuroprotection" as a new paradigm that may help guide our search for adjunctive treatments to be used together with thrombectomy. The premise of multiphase adjuvant neuroprotection is based on the diverse and potentially nonoverlapping pathophysiologic mechanisms that are triggered before, during, and after thrombectomy therapies. Before thrombectomy, strategies should focus on preventing the growth of the ischemic core; during thrombectomy, improving recanalization while reducing distal embolization and maximizing reperfusion are of significant importance; after reperfusion, strategies should focus on seeking targets to reduce secondary reperfusion injury. The concept of multiphase adjuvant neuroprotection, wherein different strategies are employed throughout the various phases of clinical care, might provide a paradigm to minimize the final infarct size and improve functional outcome in AIS patients treated with thrombectomy. With the success of thrombectomy in selected AIS patients, there is now an opportunity to revisit stroke neuroprotection. Notably, if the underlying mechanisms of these neuroprotective strategies are identified, their role in the distinct phases will provide further avenues to improve patient outcomes of AIS.

The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke

“…that edema-corrected infarct progression could be caused by other factors such as unsuccessful recanalization, no-reflow phenomenon, thrombus fragmentation, and/or formation of microvascular emboli (6). This could be supported by our finding that the 24-h lesion characteristics only showed a similar trend in the sub-population of unsuccessful recanalization.…”

“…In patients with unsuccessful or incomplete recanalization, the evolving lesion is expected to predominantly consist of increasing infarct volume, possibly due to the expansion of infarct into the downstream territory caused by persistently reduced blood flow (2). Conversely, in patients with successful recanalization, the evolving lesions may consist of more edematous volume growth as a result of reperfusion injury and status of the microvasculature (6). Distinguishing between infarct and edema volumes (EV) may provide insight on the constituents of subacute lesion growth and help to understand the influence of subacute lesion progression on unfavorable outcome to better target secondary treatments.…”

Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-Like Effect in Stroke: Rationale, Design, and Protocol for a Prospective Randomized Controlled Trial

“…At present, the effective methods of revascularization are thrombolysis and thrombectomy. However, the clinical efficacy of these therapies is limited by the narrow time window, potential complications and reperfusion injuries such as hemorrhagic transformation and brain edema ( 3 , 27 – 29 ). Exploring fast and effective neuroprotective strategies to earn time for vascular recanalization and reduce reperfusion injuries has become an essential desire in AIS treatment.…”

Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) After Stroke: Rationale, Design and Protocol for a Prospective Randomized Controlled Trial

“…One general conclusion would be that there is a low likelihood of success in targeting one pathway or one selective mechanism within a rather heterogeneous, nongenetically determined condition operative over many years (44). Ischemic stroke-induced brain injury results from the interaction of complex pathophysiological processes such as excitotoxicity, oxidative stress, inflammation, and apoptosis (9, [45][46][47]. The post-ischemic cascade is a complex, multipathway, multifactorial process involving a variety of pathological mechanisms; therefore, multiple targets of neuroprotection drugs may be more effective.…”