INTRODUCTION: High-dose insulin (HDI) therapy has been used successfully for beta-blocker toxicity, but needs further study when hypotension persists despite HDI. The objective was to develop a model of propranolol toxicity with persistent hypotension despite HDI and to develop means to measure cerebral oxygen tension (PbrO2). METHODS: Eight anesthetized Yorkshire pigs were instrumented with a tracheostomy, Swan-Ganz catheter, arterial catheter, and intra-cerebral pressure and oxygen monitor. Intravenous propranolol was given until the initial point of toxicity (POT); 25% reduction from baseline mean arterial pressure (MAP) x heart rate (HR). At the initial POT, normal saline (NS) bolus and infusion along with HDI infusion were started. The propranolol infusion was titrated up slowly to induce hypotension. Group 2 pigs received a norepinephrine (NE) infusion after a secondary POT defined as a MAP < 50 mmHg. NE was titrated to maintain subsequent MAPs > 50 mmHg. Cardiac output, HR, MAP, PbrO2, and intracranial pressure were then recorded every 5 min until death or 4 h. Systemic vascular resistance, potassium, and glucose were also measured. Surviving pigs were euthanized. RESULTS: Two pigs received unique doses for protocol development. One pig developed a tachyarrhythmia prior to protocol, one failed to reach secondary POT, leaving 2 pigs in each group reaching secondary POT. The range of PbrO2 recordings for group 1 was 12.7-48.5 mmHg and 9.2-26.2 mmHg for group 2. CONCLUSION: We report a pilot study swine model of propranolol toxicity with hypotension despite HDI, in which physiologic measures including PbrO2 are achieved. Our toxicity model can be used in the future, and the hemodynamic and brain monitoring model may prove important for subsequent research in various contexts.