Implementation and outcome of an electronic tool for detection of paracetamol overdose in a tertiary care hospital.

Background Paracetamol is a widely used analgesic and antipyretic drug in hospitals. The development and implementation of an electronic tool with algorithm-based alerts (e-agent) in a clinical information system could reduce the risk of overdose. Objective In this study, the performance of such an e-agent developed to detect paracetamol overdosing was analyzed. Setting Swiss tertiary care hospital. Method All patients ≥ 18 years old who had documented paracetamol administration in the used clinical information system during 2017 were retrospectively screened for an absolute and relative overdosing of paracetamol (> 4 g and > 60 mg/kg/24 h, respectively). This was compared with the patients for which the e-agent had, during the same period, prospectively made an alert for absolute or relative overdosing or for a dosing interval < 4 h (potentially leading to an absolute overdose). Main outcome measure E-agent performance defined as detection rate. Results of the 13,196 adult patients who received at least one dose of paracetamol, 2292 were exposed at least once to > 4 g/day (17.4%), 39 of these (0.3% of total) were given > 5 g paracetamol. None received more than 6 g. The e-agent detected 87.2% of cases with doses > 5 g. In most cases (87.9%), the cause of the absolute overdose was a switch from intravenous to oral paracetamol, resulting in an absolute overdose the day of the change. The maximal daily dose of 60 mg/kg was exceeded in 30.1% of patients weighing < 50 kg, as well as in 42.3% of patients weighing < 60 kg. The e-agent detected 73.4% and 75.5% of those cases. Multiple absolute overdoses were found in 204 patients. The e-agent detected 72.7% of those. 90 multiple overdoses occurred during the same hospital stay and 11 on consecutive days. Conclusion Paracetamol overdose is a common medication error in hospitalized patients, which may occur due to process failures such as wrong timing when changing administration route or when factors like comedication and low body weight are ignored. The e-agent detects cases of paracetamol overdose, and therefore, can help prevent this kind of medication error in the clinical setting.

Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone.

Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50 µM, respectively. The cellular ATP content started to decrease at 20 µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial ß-oxidation at 10 µM and amiodarone at 20 µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of ß-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.