A 19-year-old female, with a past medical history of borderline personality with multiple suicide attempts, and currently treated with ivabradine, bisoprolol, amitriptyline and oxcarbazepine, voluntarily ingested 28 pills of ivabradine (Procoralan^®, 7.5mg) during a consultation with her psychiatrist. The emergency medical services were alerted by the psychiatric hospital staff, after the patient started to be bradycardic at 36 beats per minutes, and arrived 75 minutes after ingestion. At first examination the patient was found bradycardic with conserved hemodynamics (blood pressure 94/58mmHg) and no evidence of shock, and an otherwise normal clinical examination. The patient was admitted in Critical Care 2.5 hours after ingestion. Upon arrival urine and blood were sampled and sent to the toxicological laboratory for further analyses.

Blood and urine toxicological screenings were not able to detect any drugs. A complementary GC-MS urinary screening enabled to detect patient's medication (oxcarbazepine, amitryptiline metabolite) as well as atropine. Ivabradine being ingested without any doubt, an assay was developed to monitor concentration of ivabradine and its major metabolite in plasma and urine, coupling liquid chromatography to mass spectrometry (LCMS/ MS). LC separation was achieved on a 50×3mm 3μm Hypersil Gold analytical column using a gradient mode. MS detection was performed in positive electrospray on a Quantum Ultra triple-quadrupole (Thermo, USA) in Multiple Reaction Monitoring (MRM) mode. Analytes co-eluted at 3.3min with a total analysis time of 11.5min.

After a rapid method development and partial validation that fulfilled bioanalytical validation parameters criteria, ivabradine and its metabolite were quantified in plasma and urine samples by LC-MS/MS. For both analytes, a linear response was obtained between 2.5 and 500ng/mL. At admission, concentration of ivabradine and its metabolite in patient's plasma were of 119.2 and 78.9μng/mL respectively, which confirmed the intoxication. Ivabradine was rapidly eliminated from the body, as its plasma level was undetectable 11.5 hours after ingestion. Decrease of plasma concentration was slightly slower for the metabolite which was found at 3.8μng/mL 23.5 hours after ingestion.

Untargeted screening could be limited for identifying drugs unregistered in library database, thus targeted assays such as LC-MS/MS are relevant for answering clinician's needs. Ivabradine and its metabolite were quantified by LC-MS/MS 3.5 hours after ingestion of 210mg of Procoralan^®, and during 21 hours following intoxication. For the authors, it is the first case of acute intoxication of this new specific bradycardic agent proposed as an alternative medication to beta-blockers. The patient answered well to isoprenaline which was administered approximately 7 hours after ingestion. Drugs levels decreased rapidly and werecorrelated to the lack of any other secondary effect, enabling a transfer to the psychiatric ward 48 hours after admission. This example clearly illustrates the need for continuous dialog between laboratory and clinical wards to match new drugs intoxication cases, which would improve therapeutic management of patients in Medical Care unit.