Effect of Methylene Blue on a Porcine Model of Amlodipine Toxicity.

INTRODUCTION: Calcium channel blocker (CCB) overdoses cause significant morbidity and mortality. Dihydropyridine CCBs cause peripheral vascular dilation and at high doses cardiac dysfunction. Amlodipine, a dihydropyridine, causes peripheral vasodilation from release of nitric oxide (NO) in addition to calcium channel blockade; NO scavenging is a potential treatment. Methylene blue (MB) inhibits NO directly and inhibits NO production. We compared the effects of MB versus norepinephrine (NE), with time to death as the primary outcome, in a porcine amlodipine toxicity model. METHODS: Animals were anesthetized and instrumented, and an amlodipine infusion was administered to mimic oral overdose. After 70 minutes, each group was resuscitated with normal saline. Animals in each group were then randomized to receive either MB or NE. Hemodynamic parameters, including mean arterial pressure and cardiac output, were recorded every 10 minutes. The primary outcome was survival time (Kaplan-Meier analysis and log-rank test). RESULTS: Interim analysis after 15 animals (7 MB, 8 NE) revealed that MB was clearly not superior to NE. Overall, 1 of 7 animals in the MB group survived to 300 minutes compared with 2 of 8 animals in the NE group. The median survival time was 100 minutes for the MB group and 177 minutes for the NE group. Survival time did not differ by group (log-rank test p = 0.29). CONCLUSION: In this porcine model of amlodipine toxicity, methylene blue did not improve survival time compared with norepinephrine. Whether methylene blue is beneficial in combatting distributive shock in amlodipine toxicity remains unclear and requires further study.

Development and Feasibility of a Porcine Model of Amlodipine Toxicity.

INTRODUCTION: Toxicity related to calcium-channel blockers remains a significant cause of morbidity and mortality. Amlodipine-induced shock is unique in that its mechanism of action is thought to occur in part via the release of nitric oxide (NO) in the peripheral vasculature. Specific therapeutic interventions, including methylene blue (an NO scavenger), have been suggested, but efficacy studies are severely limited. To facilitate a larger porcine study into the effect of various interventions on amlodipine toxicity, we undertook this model development and feasibility study. METHODS: Intravenous amlodipine was prepared by dissolving commercially obtained amlodipine tablets in dimethylsulfoxide. The concentration of the drug was verified using ultraviolet spectroscopy. We administered this solution to three animals in order to determine a toxic dose, capable of facilitating a two-arm study of amlodipine toxicity. RESULTS: The first pig died rapidly after the bolus infusion. The second pig developed mild toxicity, but the dissolution of the plastic tubing by the solvent and subsequent leakage limited the interpretability of the result. The third animal developed expected toxicity with an infusion rate between 2.0  and 5.5 mg/kg/h. CONCLUSION: This study demonstrates a potentially repeatable model of amlodipine-induced toxic shock using intravenous administration of amlodipine and several methodological considerations for researchers undertaking similar work.

Ten Years of Robotripping: Evidence of Tolerance to Dextromethorphan Hydrobromide in a Long-Term User.

INTRODUCTION: Dextromethorphan hydrobromide is widely available as an over-the-counter cough suppressant. A semi-synthetic opioid displaying N-methyl-D-aspartate receptor antagonism, it is commonly abused for recreational purposes. Spuriously elevated serum chloride concentrations are a well-described phenomenon in the setting of dextromethorphan hydrobromide toxicity, but evidence to suggest the development of tolerance is limited to case reports. CASE: A 32-year-old male known to chronically ingest dextromethorphan hydrobromide for recreational purposes presented to regional hospitals on 179 occasions over 110 months and was treated for dextromethorphan toxicity on 163/174 (93.7%) of these visits. He reported a subjective need to increase his dosing over time to achieve the same degree of intoxication. Measured serum chloride over this period (n = 217) ranged from 98 to 138 mEq/L (median 115 mEq/L, IQR 110-123 mEq/L). Measured concentrations over the 110-month period progressively rose, with a fitted plot of 111.15 + 0.00232x describing the rise in measured chloride. Though not formally assessed, anion gaps tended to become progressively more negative over the observed period. DISCUSSION: We report a patient with persistent dextromethorphan hydrobromide abuse at escalating doses whose mean serum chloride concentration increased, on average, by 0.00232 mEq/L every day over a 110-month period. This case demonstrates progressive spurious hyperchloremia secondary to bromide interference in hospital-based chloride assays, supporting the patient's reported need to dose escalate to the same desired effect. Although this artefactual laboratory finding is a well-documented result of bromide ingestion, it may be useful in identifying patterns of dextromethorphan hydrobromide use that suggest tolerance.

A randomized controlled study comparing high-dose insulin to vasopressors or combination therapy in a porcine model of refractory propranolol-induced cardiogenic shock.

Context: Although cerebral perfusion (CP) is preserved across a wide range of mean arterial pressures (MAP) through cerebral-vascular autoregulation, the relationship between MAP and CP in refractory poison-induced cardiogenic shock (PICS) has never been studied. We compared the effects of therapies used in PICS: high-dose insulin (HDI), HDI plus norepinephrine (NE), and vasopressors alone (NE plus epinephrine (Epi)) on cerebral tissue oxygenation (PtO2). Methods: Fifteen swine were randomized to either HDI, HDI + NE, or NE + Epi. All animals received a propranolol infusion using an established model of toxicity. At primary toxicity (P1), defined as a 25% reduction in heart rate (HR) multiplied by MAP, the HDI and HDI + NE groups received HDI and the NE + Epi group received NE. Once a sustained MAP < 55 mmHg was reached (P2), the HDI group received saline (NS), the HDI + NE group received NE and the NE + Epi group received Epi until death or censoring. PtO2 and hemodynamic parameters including MAP, cardiac output (CO) and central venous pressure (CVP) were measured every 10 minutes. Glucose and potassium were measured at predetermined intervals. Results: Animals treated with HDI + NE maintained PtO2 over time more than the HDI-alone group. Due to rapid hemodynamic collapse, we were unable to analyze PtO2 data in the vasopressor only animals. Mean survival time was 1.9, 2.9 and 0.1 hours for the HDI, HDI + NE and NE + Epi groups, respectively. Survival time from P2 (sustained MAP <55 mmHg) to death or censoring was not different between HDI and HDI + NE groups. Conclusions: HDI + NE treatment was superior to HDI-alone at preserving PtO2 when MAP < 55 mmHg. We were unable to compare the PtO2 between the NE + Epi to the HDI or HDI + NE due to rapid decline in CO and death. If MAP is sustained at < 55 mmHg after maximizing HDI, adjunctive treatment with NE should be considered to preserve PtO2.