Levosimendan does not improve survival time in a rat model of verapamil toxicity

Cardiovascular shock due to verapamil intoxication is often refractory to standard resuscitation methods. Recommended therapy includes prevention of further absorption of the drug, inotropic therapy, calcium gluconate, and hyperinsulinemia/euglycemia therapy. Often further measures are needed such as ventricular pacing or mechanical circulatory support. Still, mortality remains high. Levosimendan, an inotropic agent, that enhances myofilament response to calcium, increases myocardial contraction and could therefore be beneficial in verapamil intoxication. Here, we report the case of a 60-year-old patient with clinically severe verapamil poisoning who presented with shock, bradycardia, and sopor. Standard therapy including high-dose inotropes failed to ameliorate the signs of intoxication. But additional therapy with levosimendan led to rapid improvement. Based on this observation, the literature is reviewed focusing on utilization of levosimendan in the treatment of calcium channel blocker overdose. We suggest to consider levosimendan as additional treatment option in patients with cardiovascular shock due to verapamil intoxication that are refractory to standard management.

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“…This may be attributed to levosimendan ability to exacerbate the hypotension induced by verapamil intoxication [20]. …”

Section: Discussionmentioning

confidence: 99%

Levosimendan as Treatment Option in Severe Verapamil Intoxication: A Case Report and Review of the Literature

Osthoff

Bernsmeier

Marsch

et al. 2010

Case Reports in Medicine

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“…Adult Sprague-Dawley rats (300–400 grams) were chosen because they have been used in multiple studies of calcium blocker poisoning and shock. 20,27,28 The animal care and use committee of the institution approved this protocol and the care and handling of the animals were in accordance with National Institutes of Health guidelines. The animals were housed in plastic cages with 12-hour light and dark cycles and allowed free access to food and water.…”

Section: Methodsmentioning

confidence: 99%

“…17–19 Despite promising results from experimental models and case reports, there is still no consistently successful treatment for severe CCB poisoning, and deaths are still reported. 20–22 There is therefore important need for new therapy in the treatment of patients with severe CCB poisoning. One such therapy that has been used for other shock states such as sepsis and anaphylaxis is methylene blue.…”

Section: Introductionmentioning

confidence: 99%

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

Jang

Donovan

Nelson

et al. 2015

Annals of Emergency Medicine

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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.

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“…5 Third, the authors refer to a study by Graudins et al 6 and correctly stated that the levosimendan group had improved hemodynamics over placebo but omitted they did worse than those receiving calcium alone. 7 Levosimendan has not been demonstrated to be an effective therapy for CCB poisoning in animals and we question its use in human cases of CCB poisoning. 7 Levosimendan has not been demonstrated to be an effective therapy for CCB poisoning in animals and we question its use in human cases of CCB poisoning.…”

Section: Levosimendan For Calcium Channel Blocker Poisoning In Humansmentioning

confidence: 99%

Levosimendan for Calcium Channel Blocker Poisoning in Humans

Espinoza¹,

Mottram²,

Bryant³

2009

Anesthesia &Amp; Analgesia

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Levosimendan does not improve survival time in a rat model of verapamil toxicity

Cited by 19 publications

References 12 publications

Levosimendan as Treatment Option in Severe Verapamil Intoxication: A Case Report and Review of the Literature

Levosimendan as Treatment Option in Severe Verapamil Intoxication: A Case Report and Review of the Literature

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

Levosimendan for Calcium Channel Blocker Poisoning in Humans

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