Background: High-dose insulin (HDI) treatment for beta-blocker toxicity is a standard therapy, but needs further study, especially cases of persistent hypotension despite active HDI. Purpose: The objective was to develop a swine model of propranolol (P) toxicity with persistent hypotension despite treatment with HDI and to develop means to measure cerebral oxygen tension (PbrO2). Methods: Eight anesthetized adult Yorkshire pigs were instrumented with a tracheostomy, Swanz–Ganz catheter, arterial catheter, and intra-cerebral pressure and oxygen monitor. Two pigs had unique doses to derive the final protocol. A 0.5 mg/kg bolus of P was given, then a 0.25 mg/kg/min infusion (gtt) until the initial point of toxicity (POT), defined as 25 % reduction from baseline MAP×heart rate (HR). At the initial POT a 20 ml/kg normal saline bolus (NS) was given along with a 1 ml/kg/h NS gtt and a 10 units/kg/h insulin gtt. The P infusion was then set at 0.125 mg/kg/min for 60 min, then 0.1875 mg/kg/min for 30 min, and finally to 0.2188 mg/kg/min for the rest of the 240-min protocol. Group 2 pigs then received a norepinephrine (NE) gtt after a second POT, MAP <50 mmHg. NE was titrated from 0.1 to 0.3 mcg/kg/min to maintain subsequent MAPs >50 mmHg. Cardiac output, HR, MAP, PbrO2, and intracranial pressure were recorded every 5 min. Systemic vascular resistance, potassium, and glucose were also measured. Surviving pigs were euthanized. Results: One pig developed a tachyarrhythmia prior to protocol. Five pigs completed the protocol with three pigs in group 1 and two in group 2. Four pigs reached the second POT. The range of PbrO2 recordings for group 1 was 12.7–48.5 mmHg and 9.2–26.2 mmHg for group 2. Discussion: This model allowed serial physiologic measures including PbrO2. Limitations include a small sample size and a 240-min protocol. Conclusion: We report a swine model of P toxicity with hypotension despite HDI, in which serial measures including PbrO2 are achieved.