Effect of methylene blue on mortality in a porcine model of amlodipine toxicity [abstract]
- View All
Background: Cardiovascular medication overdose causes significant morbidity and mortality in the US. In 2015, the National Poison Data System responded to over 2.1 million exposures, 103,339 related to cardiovascular drugs. Cardiovascular drugs were the seventh most frequently involved substance and rated as the fourth category with the greatest rate of increase in exposure. Despite maximal supportive pharmacologic therapy (including vasopressor administration, high-dose insulin therapy, lipid emulsion therapy, and extracorporeal life support), there are still cases of refractory shock leading to death. In vitro studies on canine arteries exposed to amlodipine have shown that it stimulates release of nitric oxide (NO) leading to peripheral vasodilation. Amlodipine overdose could therefore be managed by scavenging NO. Methylene blue (MB) inhibits NO directly but also inhibits NO production by inhibiting guanylyl cyclase and endothelial NO synthase activity. We developed a porcine model of amlodipine toxicity and compared the effects of MB versus traditional vasopressor therapy with norepinephrine (NE), with time to death as the primary outcome. Methods: Animals were anesthetized and instrumented with monitoring devices according to previous protocols in our institution and a pilot study was first completed to establish a lethal model of amlodipine toxicity. Each of the two groups of animals received a toxic dose of amlodipine. A continuous infusion of amlodipine with accelerating doses was given to mimic overdose and continuing gastrointestinal absorption. After 70 min of amlodipine infusion, each group was resuscitated with 20 mL/kg of normal saline. Animals in each group were then randomized to receive either MB or NE therapy. Hemodynamic parameters, including mean arterial pressure, cardiac output, were measured every 10min. Results: The primary outcome was time to death. Survival times were compared using a Kaplan–Meier analysis, and the two groups were compared with the log-rank test. The study was powered at 80% to detect a hazard ratio of 0.2 (MB versus NE), assuming a two-sided log-rank test with alpha¼0.05. Nine animals per group were required for adequate power. An interim
analysis was conducted after 15 of the initially planned 18 animals were completed (seven MB and eight NE). This revealed that, for the primary outcome, MB was clearly not superior to NE. Furthermore, it would be impossible to achieve a statistically significant effect for the MB hazard ratio with the addition of three pigs, regardless of the outcome. Therefore, the study was ended prematurely. Overall, one of the seven (14%) animals in the MB group survived to 300 min compared with two of the eight animals (25%) in the NE group. Median survival time was 100min for the MB group and 177min for the NE group. Survival time did not differ by group (log-rank test, p¼.29) but there was a nonsignificant trend toward longer survival in the NE group. Conclusions: In this newly developed porcine model of amlodipine toxicity, MB did not lead to increased time to death as compared with NE poisoned animals. Whether MB is beneficial in combatting distributive shock in amlodipine toxicity remains unclear and requires further study.