Background: Mediastinal mass syndrome represents a major threat to respiratory and cardiovascular integrity, with difficult evidence-based risk stratification for interdisciplinary management. Methods: We conducted a narrative review concerning risk stratification and difficult airway management of patients presenting with a large mediastinal mass. This is supplemented by a case report illustrating our individual approach for a patient presenting with a subtotal tracheal stenosis due to a large cyst of the thyroid gland. Results: We identified numerous risk stratification grading systems and only a few case reports of regional anesthesia techniques for extracorporeal membrane oxygenation patients. Clinical Case: After consultation with his general physician because of exertional dyspnea and stridor, a 78-year-old patient with no history of heart failure was advised to present to a cardiology department under the suspicion of decompensated heart failure. Computed tomography imaging showed a large mediastinal mass that most likely originated from the left thyroid lobe, with subtotal obstruction of the trachea. Prior medical history included the implantation of a dual-chamber pacemaker because of a complete heart block in 2022, non-insulin-dependent diabetes mellitus type II, preterminal chronic renal failure with normal diuresis, arterial hypertension, and low-grade aortic insufficiency. After referral to our hospital, an interdisciplinary consultation including experienced cardiac anesthesiologists, thoracic surgeons, general surgeons, and cardiac surgeons decided on completing the resection via median sternotomy after awake cannulation for veno-venous extracorporeal membrane oxygenation via the right internal jugular and the femoral vein under regional anesthesia. An intermediate cervical plexus block and a suprainguinal fascia iliaca compartment block were performed, followed by anesthesia induction with bronchoscopy-guided placement of the endotracheal tube over the stenosed part of the trachea. The resection was performed with minimal blood loss. After the resection, an exit blockade of the dual chamber pacemaker prompted emergency surgical revision. The veno-venous extracorporeal membrane oxygenation was explanted after the operation in the operating room. The postoperative course was uneventful, and the patient was released home in stable condition. Conclusions: Awake veno-venous extracorporeal membrane oxygenation placed under local anesthetic infiltration with regional anesthesia techniques is a feasible individualized approach for patients with high risk of airway collapse, especially if the mediastinal mass critically alters tracheal anatomy. Compressible cysts may represent a subgroup with easy passage of an endotracheal tube. Interdisciplinary collaboration during the planning stage is essential for maximum patient safety. Prospective data regarding risk stratification for veno-venous extracorporeal membrane oxygenation cannulation and effectiveness of regional anesthesia is needed.