To present a fatal intoxication involving Ivabradine.

A 61-year-old woman was admitted to hospital for voluntary intoxication. At admission, the patient presented drowsiness. Few hours later she suffered a cardiac arrest followed by a successful resuscitation but she died 10hours after admission. Autopsy and reference toxicological analysis were performed.

HPLC-DAD, GC-MS and LC-MS/MS screening were performed. Quantification was achieved by LC-MS/MS (TSQ Vantage ThermoFischer^®), after a double liquid/liquid extraction under alkaline condition [hexane/ethyl acetate (1/1, v/v) followed by Chloroform/Isopropanol (80/20, v/v)]. Chromatographic separation was achieved using a Hypersyl gold PFP column and a classic acetonitrile/formiate2mM, 0.1% formic acid buffer gradient. IS used was morphine D3.

The method was fully validated in whole blood. Calibration curves were linear from 5 to 500ng/mL. The LOQ was 5ng/mL and the intra- and inter-assays bias were all acceptable (<15%). Ivabradine was found and quantified in every matrix. Results are listed in the Table 1. Due to high concentrations, samples were diluted 1:2 and 1:10. Midazolam, atropine and atracurium metabolite (laudanosine) were identified at therapeutic concentrations. Pregabalin, zopiclone and N-desmethylzopiclone were found at 50μg/mL (therapeutic range: 2–8μg/mL), 206ng/mL (therapeutic range: 10–50ng/mL) and 400ng/mL.

Midazolam, atropine and atracurium were administered during hospitalization, while ivabradine, zopiclone and pregabalin were part of her chronic treatment. Ivabradine is indicated in the management of stable angina pectoralis and symptomatic chronic heart failure. It selectively and specifically inhibits the pacemaker current I(f) thereby slowing heart rates with a dose dependent activity. There are few data about therapeutic concentrations; they appear to be around 10ng/mL, with a Cmax of 22ng/mL. Three non-fatal Ivabradine intoxications were reported in which peripheral blood concentrations were 119ng/mL [1Soichot M., e al. Acute ivabradine intoxication management in a critical care unit: need for constant interaction between biological and clinical wards to follow new drug intoxication cases Toxicol Anal Clin 2014 ;  26 : S53-S54 [inter-ref]

Cliccare qui per andare alla sezione Riferimenti], 375ng/mL [2Mathiaux F., e al. Case report of ivabradine intoxication J Anal Toxicol 2014 ;  35 : 231-232 [cross-ref]

Cliccare qui per andare alla sezione Riferimenti] and 525ng/mL [3Maskell K., e al. Acute on chronic ivabradine overdose: a case report J Med Toxicol 2016 ;  12 : 189-191 [cross-ref]

Cliccare qui per andare alla sezione Riferimenti]. The concentration in our case is much higher and probably played a major role in the occurrence of the death.

We describe here the first case of a fatal intoxication involving Ivabradine; we furthermore provide postmortem concentrations in organs.