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Endovascular mechanical thrombectomy is a new standard of care for acute ischemic stroke (AIS). The majority of these patients receive mechanical ventilation (MV), which has been associated with poor outcomes. The implication of this is significant, as most neurointerventionalists prefer general compared to local anesthesia during the procedure. Consequences of hemodynamic and respiratory perturbations during general anesthesia and MV are thought to contribute significantly to the poor outcomes that are encountered. In this review, we first describe the unique risks associated with MV in the specific context of AIS and then discuss evidence of brain goal-directed approaches that may mitigate these risks. These strategies include an individualized approach to hemodynamic parameters (eg, adherence to a minimum blood pressure goal and adequate volume resuscitation), respiratory parameters (eg, arterial carbon dioxide optimization), and the use of ventilator settings that optimize neurological outcomes (eg, arterial oxygen optimization).