Pregabalin Poisoning: Evaluation of Dose-Toxicity Relationship

Context: Pregabalin poisoning is mostly benign, although coma and convulsions occasionally occur. Aim: To determine the dose-toxicity relationship of pregabalin. Methods: Dose-toxicity data of isolated pregabalin poisonings were collected from (1) a prospective study performed by the Dutch Poisons Information Centre (4 April 2014 to 4 October 2016) and from (2) case reports and case series reported in literature. Poisonings were graded using the Poisoning Severity Score (PSS) and the relationship between dose (mg kg −1) and PSS was evaluated. Results: In our study (n = 21 patients), the most commonly observed symptoms were drowsiness (62%), confusion (29%) and apathy (24%). PSS was none in three (14%), minor in 15 (71%), and moderate in three patients (14%). Most case series also reported a PSS of none to minor in the majority of poisonings (69-100%). For 34 individual patients (21 from our study and 13 from literature), detailed data on dose and clinical course were available to examine the dose-toxicity relationship. The median dose was significantly lower in the PSS none-minor group (“benign”) (8.6 mg kg −1, interquartile range (IQ25-75) 5.0-17.6 mg kg −1) than in the PSS moderate-severe group (“significant toxicity”) (46.7 mg kg −1, IQ25-75 21.3-64.3 mg kg −1); estimate of the median difference = 27.3 mg kg −1 (95% confidence interval (CI): 10-48.6). Conclusions: In general, higher pregabalin doses result in more severe poisonings. Below 20 mg kg −1 the majority of patients (83%) only suffer from mild poisoning. However, large interindividual differences exist in pregabalin-induced toxicity. Therefore, pre-hospital triage should not only include pregabalin dose, but also underlying illnesses, co-exposures and reported symptoms

Case report: Successful treatment of a thallium sulfate intoxication in a dog with use of Prussian blue

Soluble thallium salts are highly toxic, with mortality rates exceeding 70% in animals compared to 6%-15% in humans. Early identification of thallium intoxicated patients and decreasing the toxic load by targeted treatment using Prussian Blue are associated with a better outcome in humans. Prussian blue, however, is rarely available or used in veterinary settings. Here we present a rare report of the successful use of Prussian Blue in the management of a dog with a thallium intoxication. A 5-year-old miniature Schnauzer, ingested a thallium sulfate based rodenticide leading to lethargy, anorexia, regurgitation, abdominal pain, borborygmi, constipation, ataxia, dermatitis and progressive alopecia. Intervention involved supportive care with subcutaneous fluids, carprofen, butylscopolamine and dexamethasone in combination with targeted treatment using the chelating agent Prussian blue (15 days) followed by activated charcoal (4 days). The serum thallium concentration on the 5th day of the Prussian Blue treatment was 196 mcg/L confirming thallium intoxication. The serum thallium concentrations were 20.7 mcg/L and 21.5 mcg/L on days 14 and 34 of treatment, respectively. The calculated elimination half-life during the during PB treatment was 2.8 days. The patient showed gradual improvement over several weeks, achieving full recovery at 11 weeks. This case emphasizes the importance of a timely diagnosis and the early start of targeted therapy using Prussian blue, in the management of thallium intoxication in veterinary patients

Significant Increase in Deliberate Self-Poisonings Among Adolescents During the Second Year of the COVID-19 Pandemic

PURPOSE: The COVID-19 pandemic has been associated with a decline in mental health of adolescents. The aim of this study was to analyze the rate of deliberate self-poisonings (DSPs) among adolescents reported to the Dutch Poisons Information Center before and during the COVID-19 pandemic. METHODS: A retrospective study from 2016 until 2021 was performed to characterize DSPs among adolescents, and to analyze trends in the number of DSPs. All DSPs among adolescents with the age of 13 up to and including 17 years were included. DSP characteristics included: age, gender, bodyweight, used substance, dose, and treatment advice. Trends in the number of DSPs were analyzed using time series decomposition and Seasonal Autoregressive Integrated Moving Average models. RESULTS: Six thousand nine hundred fifteen DSPs in adolescents were recorded from January first 2016 until December 31st 2021. Females were involved in 84% of adolescent DSPs. A strong increase in the number of DSPs was observed in 2021 (45% increase compared to 2020), which deviated from the predicted trend based on previous years. This increase was most prominent in 13-, 14-, and 15-year-old female adolescents. Commonly involved drugs were paracetamol, ibuprofen, methylphenidate, fluoxetine, and quetiapine. The contribution of paracetamol rose from 33% in 2019 to 40% in 2021. DISCUSSION: The strong increase in the number of DSPs during the second year of the COVID-19 pandemic suggests that long-term containment measures such as quarantines, lockdowns, and school closures may enhance self-harm behavior among adolescents, especially among younger females (13-15 years of age), with a preference for paracetamol as DSP substance

The INTOXICATE study:methodology and preliminary results of a prospective observational study

Background: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients.Methods: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, ‘eventful admission’, was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 &gt; 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (&gt; 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital.Results: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273).Conclusions: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. Trial registration: OSF registration ID: osf.io/7e5uy.</p

Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Abstract: Therapeutic drug monitoring of tacrolimus whole-blood concentrations is standard care in thoracic organ transplantation. Nevertheless, toxicity may appear with alleged therapeutic concentrations possibly related to variability in unbound concentrations. However, pharmacokinetic data on unbound concentrations are not available. The objective of this study was to quantify the pharmacokinetics of whole-blood, total, and unbound plasma tacrolimus in patients early after heart and lung transplantation. Methods: Twelve-hour tacrolimus whole-blood, total, and unbound plasma concentrations of 30 thoracic organ recipients were analyzed with high-performance liquid chromatography–tandem mass spectrometry directly after transplantation. Pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Results: Plasma concentration was < 1% of the whole-blood concentration. Maximum binding capacity of erythrocytes was directly proportional to hematocrit and estimated at 2700 pg/mL (95% confidence interval 1750–3835) with a dissociation constant of 0.142 pg/mL (95% confidence interval 0.087–0.195). The inter-individual variability in the binding constants was considerable (27% maximum binding capacity, and 29% for the linear binding constant of plasma). Conclusions: Tacrolimus association with erythrocytes was high and suggested a non-linear distribution at high concentrations. Monitoring hematocrit-corrected whole-blood tacrolimus concentrations might improve clinical outcomes in clinically unstable thoracic organ transplants. Clinical Trial Registration: NTR 3912/EudraCT 2012-001909-24

The INTOXICATE study: methodology and preliminary results of a prospective observational study

Background There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients. Methods Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, ‘eventful admission’, was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital. Results Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273). Conclusions The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. Trial registration: OSF registration ID: osf.io/7e5uy

Predicting the outcome in poisoned patients: look at the past!

INTRODUCTION: When predicting future events, we often rely on analyzing past occurrences and projecting them forward. This methodology is crucial in various fields, including toxicology, in which predicting outcomes in poisoned patients plays a vital role in guiding treatment decisions and improving patient care. IMPORTANCE OF PREDICTING OUTCOMES IN POISONED PATIENTS: In cases of poisoning, understanding a patient's medical history, current physiological status, and the toxicokinetics of the ingested substance is essential for predicting potential outcomes and determining appropriate interventions. WHAT TO PREDICT?: Predicting whether an intoxicated patient needs (further) treatment or even admission to the hospital is one of the most difficult decisions a clinician needs to make. The prediction of the course of an intoxication often lacks crucial information, leaving physicians with a sense of uncertainty in treating and advising patients. A significant source of this uncertainty stems from patients' limited awareness of the specific chemical(s) causing their symptoms, making a targeted approach challenging. Adding to the complexity, both patients and physicians frequently lack knowledge of the exposure dose, onset time, and potential interactions, further complicating the prediction of symptom progression. Patients are commonly placed in observation wards until the pharmacodynamic effects have diminished, leading to extended observation periods and unnecessary healthcare utilization and costs. Therefore, a key objective of a predictive model is to determine the necessity for intensive care unit admission. PREDICTING THE REQUIREMENT FOR ADMISSION TO AN INTENSIVE CARE UNIT: Factors such as age, Glasgow Coma Scale, and specific comorbidities like dysrhythmias and chronic respiratory insufficiency significantly influence the likelihood of intensive care unit admission. By examining a patient's trajectory based on past medical history and organ function deterioration, clinicians can better anticipate the need for critical care support. ENHANCING PREDICTION MODELS FOR IMPROVED PATIENT CARE: To enhance prediction models, leveraging modern methodologies like machine learning on large datasets (big data) are crucial. These advanced techniques can uncover previously unknown patient groups with similar outcomes or treatment responses, leading to more personalized and effective interventions. Regular updates to clustering, discrimination, and calibration processes ensure that predictive models remain accurate and relevant as new data emerges. CONCLUSIONS: The field of clinical toxicology stands to benefit greatly from the creation and integration of large datasets to advance toxicological prognostication. By embracing innovative approaches and incorporating diverse data sources, clinicians can enhance their ability to predict outcomes in poisoned patients and improve overall patient management strategies

Evaluation of semi-generic PBTK modeling for emergency risk assessment after acute inhalation exposure to volatile hazardous chemicals

BACKGROUND: Physiologically Based Toxicokinetic Models (PBTK) may facilitate emergency risk assessment after chemical incidents with inhalation exposure, but they are rarely used due to their relative complexity and skill requirements. We aimed to tackle this problem by evaluating a semi-generic PBTK model built in MS Excel for nine chemicals that are widely-used and often released in a chemical incident. MATERIAL & METHODS: The semi-generic PBTK model was used to predict blood concentration-time curves using inhalation exposure scenarios from human volunteer studies, case reports and hypothetical exposures at Emergency Response Planning Guideline, Level 3 (ERPG-3) levels.(2) Predictions using this model were compared with measured blood concentrations from volunteer studies or case reports, as well as blood concentrations predicted by chemical-specific models. The performances of the semi-generic model were evaluated on biological rationale, accuracy, and ease of use and range of application. RESULTS: Our results indicate that the semi-generic model can be easily used to predict blood levels for eight out of nine parent chemicals (dichloromethane, benzene, xylene, styrene, toluene, isopropanol trichloroethylene and tetrachloroethylene). However, for methanol, 2-propanol and dichloromethane the semi-generic model could not cope with the endogenous production of methanol and of acetone (being a metabolite of 2-propanol) nor could it simulate the formation of HbCO, which is one of the toxic end-points of dichloromethane. The model is easy and intuitive to use by people who are not so familiar with toxicokinetic models. CONCLUSION: A semi-generic PBTK modeling approach can be used as a 'quick-and-dirty' method to get a crude estimate of the exposure dose