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Anesthetic and surgical considerations for awake craniotomy (AC) include airway patency, patient comfort, and optimization of real-time brain mapping. The purpose of this study is to report our experience of using dexmedetomidine and scalp blocks, without airway intervention, as a means to facilitate and optimize intraoperative brain mapping and brain tumour resection during AC. We conducted a retrospective cohort study of 55 patients who underwent AC from March 2012 to September 2016. The incidence of critical airway outcomes, perioperative complications, and successful intraoperative mapping was determined. The primary outcome was the incidence of a failed AC anesthetic technique as defined by the need to convert to general anesthesia with a secured airway prior to (or during) brain mapping and brain tumour resection. Secondary outcomes were the intraoperative incidence of: 1) altered surgical management due to information acquired through real-time brain mapping, 2) interventions to restore airway patency or rescue the airway, 3) hemodynamic instability (> 20% from baseline), 4) nausea and vomiting, 5) new onset neurologic deficits, and 6) seizure activity. There were no anesthesia-related critical events and no patients required airway manipulation or conversion to a general anesthetic. Multimodal language, motor, and sensory assessment with direct cortical electrical stimulation was successfully performed in 100% of cases. In 24% (13/55) of patients, data acquired during intraoperative brain mapping influenced surgical decision-making regarding the extent of tumour resection. Nine (16%) patients had intraoperative seizures. Dexmedetomidine-based anesthesia and scalp block facilitated AC surgery without any requirement for urgent airway intervention or unplanned conversion to a full general anesthetic. This approach can enable physiologic testing before and during tumour resection facilitating real-time surgical decision-making based on intraoperative brain mapping with patients awake thereby minimizing the risk of neurologic deficit and increasing the opportunity for optimal surgical resection.