Cardiotoxicity After Synthetic Cathinone Use; Two Cases, A Case Series and Scoping Review.

The cardiotoxic effects of synthetic cathinones remain largely unknown. In this study, we present two cases, a case series and a scoping review, to explore synthetic cathinone associated cardiotoxicity. Case 1 involved a 28-year-old male with non-ST-elevation myocardial infarction after ingesting a substance containing 4-methylmethcathinone (4-MMC), 3-methylmethcathinon (3-MMC), and methcathinone. Case 2 involved a 49-year-old male with ventricular fibrillation after 4-methylmethcathinone ingestion, who was diagnosed with severe three-vessel disease. A retrospective analysis was performed on self-reported synthetic cathinone poisonings reported to the Dutch Poisons Information Centre from 2012 to 2022. A total of 222 mono-intoxications with cardiotoxicity were included, mostly involving 3-methylmethcathinon (63%). Often tachycardia, hypertension, palpitations, and chest pain were reported. A comprehensive literature search was performed on PubMed to identify the studies reporting cardiac arrest, myocardial infarction, cardiac inflammation, cardiomyopathy, and life-threatening arrhythmias following synthetic cathinone use. A total of 30 articles reporting 40 cases were included. The reported complications included cardiac arrest (n = 28), ventricular tachycardia (n = 4), supraventricular tachycardia (n = 1), ST-elevation myocardial infarction (n = 2), non-ST-elevation myocardial infarction (n = 2), cardiomyopathy (n = 1), and myocarditis (n = 2). A total of ten different associated synthetic cathinones were identified. Cardiac arrest, myocardial infarction, and ventricular arrhythmias have been reported following the use of synthetic cathinones, underscoring the importance of obtaining a detailed recreational drug use history from patients presenting with syncope, chest pain, or palpitations.

The association of amfetamines and cathinones with acute coronary syndrome - a systematic review.

BACKGROUND: It is well known that cocaine increases the risk of acute coronary syndrome. However, it is uncertain if the use of other stimulants, such as amfetamines and cathinones, is also related to acute coronary syndrome. OBJECTIVES: To identify all reported cases of acute coronary syndrome related to the use of amfetamines and cathinones, the type of acute coronary syndrome, the atherothrombotic aetiology, and the mortality rate. METHODS: A systematic literature search in PubMed, Embase database, Cochrane library, PsycInfo and Web of Science was performed from inception until 31 August 2022. All original articles in English or Dutch describing adult patients with acute coronary syndrome after the use of amfetamines or cathinones were included. The main outcome was the occurrence of acute coronary syndrome associated with amfetamine-type stimulants or cathinones. Data were collected and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 11,605 articles were identified, 56 of which met the inclusion criteria. A total of 160 patients presented with acute coronary syndrome after five different types of amfetamines, namely, amfetamine (n = 48), metamfetamine (n = 98), 3,4-methylenedioxymetamfetamine (n = 11), fenethylline (n = 2), and 4-fluoroamfetamine (n = 1). Khat chewing was associated with acute coronary syndrome (n = 4234), as were three different types of synthetic cathinones, namely, non-defined cathinones (n = 1), 4-methylmethcathinone (n = 1), and α-pyrrolidinopentiophenone (n = 1). In patients with a known acute coronary syndrome type (n = 157), ST-segment elevation myocardial infarction was diagnosed in 53 patients (75%) and non-ST-segment elevation myocardial infarction in 18 patients (25%). Of the ST-segment elevation myocardial infarction patients, 36% were diagnosed with significant coronary stenosis or thrombus. The mortality rate for khat-associated acute coronary syndrome, with more often male and older patients with fewer cardiovascular risk factors, was higher compared to non-khat-associated acute coronary syndrome. For amfetamine, metamfetamine, and 3,4-methylenedioxymetamfetamine, mortality associated with ST--segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction was 14% and 7%, respectively. Risk factors for acute coronary syndrome were infrequently reported, and risk stratification scores were not reported. CONCLUSION: There is evidence that amfetamine-type stimulants and cathinones are associated with the occurrence of acute coronary syndrome. Khat chewing appears to be a risk factor for acute coronary syndrome. Amfetamine, metamfetamine, 3,4-methylenedioxymetamfetamine, fenethylline, 4-fluoroamfetamine, and synthetic cathinones were also reported in relation to acute coronary syndrome. However, this evidence is limited, of low quality and with a low number of reported cases. Further prospective studies need to be conducted.

Complications in post-mortem GHB cut-off values in urine samples: A case report.

Gamma-hydroxybutyric acid (GHB) is a drug of abuse, that interplays with a GABAergic system, resulting in an euphoric state and increased mood and impulses. Two cases of fatal mixed intoxications including GHB intake are presented here. In both cases, GHB was used together with multiple other drugs. Interpretation of GHB cut-off values are complicated in post-mortem analysis, because GHB can be post-mortem formed. The post-mortem GHB formation is dependent of the post-mortem interval (PMI) and the storage conditions of the samples. The GHB concentrations in urine are more stable compared to blood samples, when the samples are stored at the correct way at - 20 °C. Therefore, urine is the recommended matrix to analyze in toxicological screenings, since it allows more specific determination of exposure to exogenous GHB. Different cut-off values are used for matrices from living and deceased people. A cut-off value of 30 mg/L is recommended to discriminate between endogenous concentrations and concentrations resulting from exogenous GHB exposure. Moreover, post-mortem GHB formation can take place before sampling. However, when the samples are immediately stored at cooled conditions, no in vitro formation of GHB will take place. Urinary screening of GHB may serve as an initial screening for estimation of exposure of GHB in the body. However, additional quantitative GHB analysis in blood is required to estimate GHB exposure at the time of death. Furthermore, to obtain more reliable results for the ante-mortem GHB exposure, it may be useful to measure other biomarkers, like some GHB metabolites, especially in blood.

Intralipid administration in case of a severe venlafaxine overdose in a patient with previous gastric bypass surgery.

This case describes a patient with a history of bariatric surgery who was admitted to our hospital with a severe venlafaxine intoxication. Due to the altered anatomy of the gastrointestinal tract, the use of oral activated charcoal and large volumes of laxatives to prevent further uptake of venlafaxine was hampered. This resulted in massive absorption and a severe serotonergic syndrome. The patient was successfully treated with intravenous lipid emulsion.

Nephrotoxicity of continuous amphotericin B in critically ill patients with abdominal sepsis: a retrospective analysis with propensity score matching.

BACKGROUND: Continuous infusion of conventional amphotericin B (CCAB) is used in ICUs for pre-emptive treatment of invasive fungal infections. Amphotericin B has previously been associated with nephrotoxicity. OBJECTIVES: To investigate if CCAB with therapeutic drug monitoring (TDM) results in renal impairment over time in critically ill patients with abdominal sepsis. PATIENTS AND METHODS: The study was conducted at mixed medical-surgical ICUs of two large teaching hospitals in the Netherlands. Consecutive patients who were treated on the ICUs between 2006 and 2019 for abdominal sepsis, with or without CCAB, were included. CCAB dosing was guided by TDM. Serum creatinine concentrations and renal failure scores of patients with CCAB treatment were compared with those without CCAB treatment. Excluded were: (i) patients treated with CCAB for less than 72 h; and (ii) patients with renal replacement therapy. RESULTS: A total of 319 patients were included (185 treated with CCAB and 134 controls). A multiple linear regression model showed that the serum creatinine concentration was independent of CCAB treatment (ß = -0.023; 95% CI = -12.2 to 7.2; P = 0.615). Propensity score matching resulted in 134 pairs of CCAB-treated and non-treated patients. Again, the analysis of these pairs showed that the cumulative CCAB dose was not associated with serum creatinine concentration during intensive care treatment (ß = 0.299; 95% CI = -0.38 to 0.98; P = 0.388). CONCLUSIONS: CCAB with TDM did not result in renal impairment over time in critically ill patients with abdominal sepsis.

First international quality control programme for laboratories measuring antimicrobial drugs to support dose individualization in critically ill patients.

OBJECTIVES: International quality control (proficiency testing) programmes are instituted to safeguard the analytical performance of laboratories and to aid these laboratories in identifying sources of error in their analytical methods. We describe the first international quality control programme for antimicrobial agents that are frequently used in critically ill patients. METHODS: Spiked plasma samples with ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim were shipped to 22 laboratories from eight different countries. Acceptable accuracy by the performing laboratory was defined if measurements were within 80%-120% limits of the true weighed-in concentrations. RESULTS: A total of 81% of the measurements (ranging between 56% and 100%, dependent on drug) were within the 80%-120% limits of the true weighed-in concentrations. CONCLUSIONS: We found a relatively good performance of the participating laboratories in measuring eight different antimicrobial drugs. Nevertheless, some of the antimicrobial drugs were not measured properly as up to 44% of the measurements was inaccurate depending on the drug. Our results emphasize the need for and utility of an ongoing quality control programme.

Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study.

PURPOSE: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. MATERIALS & METHODS: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. RESULTS: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. CONCLUSIONS: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients.

Acute onset heart failure due to reverse type Takotsubo cardiomyopathy caused by a single dose of 4-Fluoroamphetamine in a healthy young individual.

INTRODUCTION: 4-fluoroamphetamine (4-FA) is a novel psychoactive stimulant with a global presence on the drug market. Despite the popularity of 4-FA, data on severe adverse effects are scarce. We present a case of laboratory confirmed 4-FA mono intoxication causing acute heart failure due to a reverse type Takotsubo cardiomyopathy. CASE: A 20-year-old male with no previous medical history and no reported previous drug use, presented to the emergency department (ED) with complaints of headache, nausea and vomiting, approximately 4.5 h after the ingestion of a single 4-FA pill. After 30 min his condition deteriorated with severe hypertension, tachycardia and respiratory failure. Echocardiography showed a reverse type Takotsubo cardiomyopathy. The patient was successfully treated with mechanical ventilation, a phosphodiesterase-3-inhibitor (PDE3-inhibitor) and diuretics. Three months after hospital admission, the patient was free of complaints and his left ventricular function fully recovered. CONCLUSION: Recreational use of 4-FA may result in acute onset life-threatening cardiorespiratory toxicity, preceded by severe hypertension, even in drug-naïve patients without any medical history. Emergency physicians and cardiologists should be cautious not to underestimate life-threatening 4-FA complications.

Robotic compounding versus manual compounding of chemotherapy: Comparing dosing accuracy and precision.

BACKGROUND: Cytostatic drugs are increasingly being prepared with a cytostatic robot, though it is not known whether the dose of the final product is more accurate after automated or manual preparation. This study is the first to compare accuracy and precision of automated preparations with manual preparations by measuring volumes and drug concentrations. METHODS: The accuracy and precision of automated and manual preparations were compared by gravimetric and concentration measurements. During ten days 80 solutions were prepared; 40 robot preparations and 40 manual preparations. With both preparation methods, 20 methotrexate (MTX) and 20 cyclophosphamide (CP) bags were compounded. We simulated normal working conditions by performing the preparations on Monday till Friday. The MTX and CP concentrations were measured with validated ultra high performance liquid chromatography (UHPLC) methods on the last preparation day. RESULTS: With UHPLC analysis, dose accuracy (mean dose error) of robotic or manual preparation of MTX were 1.70% and 0,96% respectively. With gravimetric analysis, these values were 0.50% and 1.96%. Precision (standard error) of the robotic preparation for MTX was significantly smaller than that of manual preparation (p < 0.001). Dose accuracy (mean dose error) of robotic or manual preparation of CP, with UHPLC analysis, were 6.10% and 5.20% respectively. With gravimetric analysis, these values were 0,67% and 0,18%. CONCLUSION: We conclude that both robotic and manual compounding produce accurate cytostatic products in which the mean percentage of active substance differs by less than 10% from the prescribed amount. Both preparation methods are compliant with the Dutch Medicines Act and the European Pharmacopoeia.

Toxicological screening in the Amsterdam acute setting becomes more relevant if the standard panel of the drugs-of-abuse point-of-care test is expanded with GHB and ketamine.

OBJECTIVE: For diagnosis and treatment in the acute setting, it is crucial to know whether the clinical status of patients might be explained by the effects of drugs.The objective of this study was to determine how many drugs were detected by comprehensive toxicological screening, that could not be detected with a routine drugs-of-abuse point-of-care test (DOA-POCT) and which drugs of abuse (DOA) were relevant. A secondary objective was to determine in how many patients comprehensive toxicological screening provided additional clinically relevant information. METHODS: In this prospective study, patients were included in whom a DOA-POCT was performed and residual urine and serum samples were available.DOA-POCT were performed using the Triage® TOX Drug Screen. Comprehensive toxicological screening was performed using 1) the Toxtyper™ LC-MSN method and 2) two GC-FID methods for alcohols and GHB respectively.The clinical relevance of the comprehensive toxicological screening results regarding diagnosis and patient management was quantified. RESULTS: A total of 100 patients were included. In 91 of these patients, comprehensive toxicological screening identified 234 drugs that were not identified by DOA-POCT. However, DOA-POCT identified 34 DOA that were not identified by comprehensive toxicological screening.Seven percent of comprehensive toxicological screening results were found to be clinically relevant, all with regard to diagnosis. GHB and ketamine were the drugs involved. Another 38 % strengthened confidence in diagnosis and patient care decisions. CONCLUSION: GHB and ketamine should be added to the panel of drugs we screen at the point of care in the Amsterdam acute setting.

Stability of Furosemide 5 mg/mL in Polypropylene Syringes.

Furosemide parenteral solutions are routinely used in our hospital. However, the stability in transparent syringes is unknown. In this study, transparent polypropylene syringes were filled with 8 mL and 50 mL of furosemide 5-mg/mL solution. The furosemide was analyzed by high-performance liquid chromatography and assays were performed up to 35 days of storage of the syringes at 4°C protected from light, plus 24 hours at 20°C exposed to daylight. In addition, the appearance and pH of the solutions were determined. A microbiological assay using tryptic soy broth was also performed. Both types of syringes remained colorless, clear, and free from visible particles throughout the study period. The pH did not change, and concentrations remained between 95% and 105% of the stated concentration. None of the syringes filled with culture media exhibited bacterial or fungal growth. In conclusion, ready-to-administer furosemide 5-mg/mL, 8-mL, and 50-mL polypropylene syringes are stable for up to 35 days when stored in a refrigerator at 4°C protected from light, plus 24 hours at 20°C unprotected from light. These results allow maximum storage time in stock and the ability of 24-hour continuous infusion at ambient room temperature without protecting the syringe against light.

Microbiological performance of a robotic system for aseptic compounding of cytostatic drugs.

BACKGROUND: Compounding of cytostatic drugs requires strict aseptic procedures, while exposure to toxic drugs and repetitive manual movements should be minimized. Furthermore, reuse of vials is desirable to lower the costs. To assess if all this might be safely achieved with a robot, this study aimed at qualifying the aseptic preparation process with the robotic system APOTECAchemo. METHODS: The aseptic compounding of patient-individual cytostatic solutions was simulated with media fill simulation tests to qualify the performance according to European GMP Annex 1. The contamination in the environment was measured in critical places using settle plates, contact plates, active air sampling and particle counting. Media-fill simulation tests were prepared in 3 production batches. The second part of the study evaluated the microbiological shelf-life of commercial drug vials after repeated puncturing. On six days, fifty syringes of 15 ml media were prepared from the same 50 vials with the robot. After each preparation, vials were covered with an IVA seal upon unloading from the robot to protect them from microbiological contamination. RESULTS: No microbiological contamination was found in any of the 96 media fill preparations, nor in any of the 300 syringes that were prepared with repeated puncturing. The compounding area met class A limits, while class A criteria were not fulfilled by the contact plates and settle plates placed on the right side of the loading area. There, the average colony forming units (cfu) were 3 and 1.17, respectively, meeting class B criteria. CONCLUSIONS: Robotical compounding of cytostatic drugs with APOTECAchemo meets the microbiological requirements of the European GMP. In addition, the robot can reuse vials repeatedly and safely, thereby enabling extended usage.

Outcome effects of antiretroviral drug combinations in HIV-positive patients with chemotherapy for lymphoma: a retrospective analysis.

Background The combination of combined active antiretroviral therapy (cART) with chemotherapy in the treatment of lymphoma in human immunodeficiency virus (HIV)-positive patients has improved the overall survival of these patients. However, drug-drug interactions between antineoplastic agents and the antiretroviral agents non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) can occur by influencing the activity of the CYP3A4 enzyme. So far, little is known about the clinical relevance of this interaction: the effect on the efficacy and toxicity of the chemotherapy. Also, there is no general consensus which cART is preferable in combination with antineoplastic drugs. Objective To compare PI-based with NNRTI-based cART on the efficacy and toxicity of chemotherapy in lymphoma patients. Setting The Onze Lieve Vrouwe Gasthuis, located in Amsterdam, The Netherlands. Method A retrospective observational cohort study including all patients with HIV and lymphoma over a 10-year period. Clinical outcome (response to chemotherapy and survival) and toxicity of chemotherapy (renal, hepatic and bone marrow toxicity as well as dose reduction, treatment delay and discontinuation) was compared in patients with PI based and NNRTI-based cART. Main outcome measure: Response to chemotherapy and survival. Results Patients using PI-based cART (n = 22) had a significantly lower 1 year survival compared to NNRTI-based cART (n = 21). No significant differences were observed in reaching complete remission after chemotherapy. No overall significant differences in toxicity and discontinuation of the chemotherapy were observed. However, there was a trend towards more severe bone-marrow toxicity in patients with PI-based cART. In addition, patients with PI-based cART received earlier dose-reduction and treatment delay, indicating increased toxicity in PI-treated patients. Conclusion This retrospective study shows that PI-based cART is inferior in combination with chemotherapy to NNRTI-based cART: a lower 1 year survival is observed and dose-reduction and treatment delay occur earlier, possibly based on an earlier onset of toxicity.

Clinical value of drugs of abuse point of care testing in an emergency department setting.

OBJECTIVE: Toxicology screening tests for drugs-of-abuse and therapeutic drugs in urine (TST-U) are often used to assess whether a patient's clinical condition can be explained by the use of drugs-of-abuse (DOA) and/or therapeutic drugs. TST-U have clinical value when they support clinical decision making by influencing diagnosis and patient care. We aim to quantify the influence of TST-U results on diagnosis and patient care in an emergency department. Our secondary objective is to identify specific patients for which a TST-U is most warranted or mostly unhelpful. METHODS: This prospective observational study was performed at the emergency department of a middle-sized urban teaching hospital. A point of care TST-U has been used in this department for three years. When a TST-U is considered indicated by a physician, the influence of the TST-U result on diagnosis and patient care is quantified before and after the test results are available, by means of a questionnaire. Urgency and complaints upon admission have also been registered. RESULTS: Of 100 TST-U results 37% were reported having a substantial influence on diagnosis and 25% on patient care. TST-U had a substantial influence on diagnosis in 48% of patients with decreased consciousness, 47% of patients with psychiatric symptoms and in 47% of patients with "other" complaints. In this last category patients with neurological symptoms benefited most. In patients who were already suspected to be intoxicated, only 18% of the TST-U results had substantial influence on diagnosis. CONCLUSIONS: The use of point of care TST-U in an Emergency Department helps physicians to understand the clinical condition of a patient. They influence the way a patient is treated to a lesser extent. These tests are most helpful in patients with decreased consciousness, psychiatric or neurological symptoms and mostly unhelpful in patients who, upon admission, are already known to be intoxicated.

Pharmaceutical preparation of oxygen-15 labelled molecular oxygen and carbon monoxide gasses in a hospital setting.

BACKGROUND: Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [(15)O]O(2) and [(15)O]CO, respectively. In general, these oxygen-15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with (14)N(2) containing a trace of oxygen. In recent years, cyclotrons have been developed that only are capable of accelerating protons. The purpose of this study was to validate and assess such a cyclotron for production and administration of oxygen-15 labelled gasses in an hospital setting. METHODS: An RDS111 cyclotron (Siemens-CTI, Knoxville, USA) was validated for bolus production of [(15)O]O(2) and [(15)O]CO gasses. In addition, equipment was developed to administer these tracers to patients. RESULTS: Both [(15)O]O(2) and [(15)O]CO gasses could be produced in sufficient amounts, whilst meeting European Pharmacopeia requirements. Although produced oxygen-15 gasses contained a minor level of (11)C contamination, in clinical studies it was possible to correct for this contamination by delayed blood counting. CONCLUSION: An 11 MeV proton cyclotron combined with an in-house developed gas delivery system allows for the production and administration of sufficient amounts of [(15)O]-gasses for routine clinical PET studies in an hospital setting.

Toxicokinetics of dothiepin: 2 case reports.

In this article, 2 cases of intentional dothiepin intoxication are presented. Both patients survived after receiving appropriate supportive care. The dothiepin and metabolite levels were measured at different times after ingestion. The initial levels of dothiepin were 1900 microg/L in case 1 and 5500 microg/L in case 2. In case 1, a toxicokinetic model was fitted, suggesting a higher peak level, corresponding with the QRS duration and clinical symptoms. In case 2, a combined dothiepin-ethanol intoxication was seen, complicating the interpretation of clinical parameters, such as the QRS duration. In conclusion, the severity of dothiepin intoxication is poorly predicted by plasma levels alone, as time of ingestion can be critical for interpretation. However, especially in combined intoxications, interpretation of the QRS duration may also fail. Therefore, it is important to evaluate the whole range of clinical parameters, QRS duration, clinical symptoms, dothiepin concentration(s), and other possible intoxications.