Efficacy of Methylene Blue in an Experimental Model of Calcium Channel Blocker–Induced Shock

Abstract

BACKGROUND Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. While supportive care is the mainstay of treatment, experimental therapies such as high dose insulin-euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. Methylene blue acts as both a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cGMP. Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study was to determine the efficacy of methylene blue in an animal model of amlodipine-induced shock. METHODS Sprague-Dawley rats were anesthetized, ventilated and instrumented for continuous blood pressure and heart rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg/hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline (NS) with 15 rats in each group. Rats received methylene blue at 2 mg/kg over 5 mins or an equivalent amount of NS in three intervals from the start of the protocol: Minute 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed using Fisher’s exact test and Kaplan Meier survival analysis with the log rank test. RESULTS Overall, 1/15 (7%) rats in the saline-treated group survived to 120 minutes compared with 5/15 (33%) rats in the methylene blue-treated group (difference −26%, 95% CI –54%, 0.3%). The median survival time for the NS group was 42 min (95% CI, 28.1,55.9) and the methylene blue group was 109 min (95% CI, 93.9,124.1). Heart rate and MAP differences between groups were analyzed until 60 minutes. Heart rate was significantly higher in the methylene blue-treated group starting 25 min after the start of the amlodipine infusion (95% CI, 30–113) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 min after the amlodipine infusion (95% CI, 2–30) that was analyzed up until 60 minutes. CONCLUSIONS Methylene blue did not result in a significant difference in mortality risk. There was an increase heart rate, MAP and median survival time in the methylene blue group.

Past, Present, and Future of Lipid Resuscitation Therapy

“…However, there does not seem to be a contraindication to giving them concurrently as insulin has shown benefit in some circumstances, 141 and LRT has been shown better in others 63 , 196 . Another alternative is methylene blue, which will increase the median survival time for calcium channel blocker toxicity by increasing pulse rate and mean arterial pressure 197 . Other reviews have covered the topic well, with the conclusion that 1–2 mg/kg of 1% methylene blue can be beneficial in toxin‐induced shock as an adjuvant to vasopressors 198 …”

Improvement in Hemodynamics After Methylene Blue Administration in Drug-Induced Vasodilatory Shock: A Case Report

“…The human reports primarily describe the successful use of methylene blue in vasodilatory shock caused by dihydropyridine calcium channel blockers, though successful treatment of shock from quetiapine [9] and valsartan [12] with methylene blue has also been described. A recently published animal study found significant increases in pulse, mean arterial pressure, and median survival time after administration of methylene blue in an experimental model of amlodipine-induced shock in rats [11]. Upon review of the human cases, however, we find no cases where hemodynamic data from invasive monitoring was available during the administration of methylene blue to more accurately describe its physiologic effects in humans with drug-induced vasodilatory shock.…”

“…Increases in systemic vascular resistance and mean arterial pressure have been consistently described following methylene blue administration for shock due to non-poisoning causes, including vasoplegic syndrome after coronary artery bypass surgery [4] and sepsis [5][6][7]. Methylene blue, from a mechanistic standpoint, is an attractive therapy for drug-induced vasodilatory shock, though published literature includes only a small number of human case reports and animal studies [8][9][10][11]. The human reports primarily describe the successful use of methylene blue in vasodilatory shock caused by dihydropyridine calcium channel blockers, though successful treatment of shock from quetiapine [9] and valsartan [12] with methylene blue has also been described.…”

Therapeutic Approach to the Critically Poisoned Patient

“…Limited evidence also supports the use of methylene blue in the treatment of shock from calcium channel antagonists [124,125]. In a single case report, methylene blue was successfully used in a mixed atenolol and amlodipine ingestion [126].…”