Amaducci AM, Campleman SL, Li S
… +9 more, Karshenas DL, Spyres MB, Farrugia LA, Kang AM, Culbreth RE, Wax PM, Brent J, Aldy K, Toxicology Investigators Consortium Study Group
J Med Toxicol
· 2023 Oct · PMID 37644342
·
Full text
Since 2010, medical toxicology physicians from the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC) have provided reports on their in-hospital and clinic patient consultations to...Since 2010, medical toxicology physicians from the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC) have provided reports on their in-hospital and clinic patient consultations to a national case registry, known as the ToxIC Core Registry. De-identified patient data entered into the registry includes patient demographics, reason for medical toxicology evaluation, exposure agents, clinical signs and symptoms, treatments and antidotes administered, and mortality. This thirteenth annual report provides data from 7206 patients entered into the Core Registry in 2022 by 35 participating sites comprising 52 distinct healthcare facilities, bringing the total case count to 94,939. Opioid analgesics were the most commonly reported exposure agent class (15.9%), followed by ethanol (14.9%), non-opioid analgesic (12.8%), and antidepressants (8.0%). Opioids were the leading agent of exposure for the first time in 2022 since the Core Registry started. There were 118 fatalities (case fatality rate of 1.6%). Additional descriptive analyses in this annual report were conducted to describe the location of the patient during hospitalization, telemedicine consultations, and addiction medicine treatments.
Fox C, Ekaney ML, Runyon M
… +4 more, Nguyen HM, Turk PJ, McKillop IH, Murphy CM
J Med Toxicol
· 2023 Oct · PMID 37644341
·
Full text
INTRODUCTION: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated wit...INTRODUCTION: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity. METHODS: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation. RESULTS: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP. CONCLUSIONS: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC.
Keenan M, Titelbaum N, Suen K
… +3 more, Murray B, Wax P, Kiernan E
J Med Toxicol
· 2023 Oct · PMID 37639079
·
Full text
INTRODUCTION: Medical toxicology is a small but growing specialty. To ensure that the specialty continues to grow and attract strong candidates, it is important to understand what influences physicians to pursue medical...INTRODUCTION: Medical toxicology is a small but growing specialty. To ensure that the specialty continues to grow and attract strong candidates, it is important to understand what influences physicians to pursue medical toxicology training. This would allow for targeted interventions to recruit strong candidates to the field. METHODS: A cross-sectional survey was sent via email to current medical toxicology fellows and to medical toxicologists who completed fellowship in the last 5 years. ACMT listservs were utilized to target recipients. The survey was created through an iterative writing process among the study authors. Responses to the survey were recorded in REDCap. Descriptive statistics were obtained and analyzed. RESULTS: A total of 126 participants responded to the survey request (46 fellows and 80 recent graduates). Most were primarily trained in emergency medicine. Interest in medical toxicology usually started during residency when exposure to the field was highest. Most respondents cite a mentor as a primary influence in pursuing medical toxicology training. CONCLUSIONS: Among current fellows and recent graduates of medical toxicology, having a mentor in the field of medical toxicology, having exposure to medical toxicology during residency, and participating in a clinical rotation in medical toxicology were common shared experiences that led to the decision to subspecialize in the field. These results may guide targeted intervention to continue to recruit strong candidates to medical toxicology.
J Med Toxicol
· 2023 Oct · PMID 37624540
·
Full text
BACKGROUND: Clozapine is an anti-psychotic agent, reserved for treatment-resistant schizophrenia, with demonstrated efficacy in an otherwise therapeutically challenging patient population. We aimed to review the full spe...BACKGROUND: Clozapine is an anti-psychotic agent, reserved for treatment-resistant schizophrenia, with demonstrated efficacy in an otherwise therapeutically challenging patient population. We aimed to review the full spectrum casemix of clozapine presentations to our tertiary toxicology service. METHODS: In this retrospective study, we reviewed consecutive clozapine related toxicity presentations to a tertiary medical toxicology inpatient and consultation service-including deliberate self-poisoning (DSP), adverse drug reaction (ADR), recreational use, and therapeutic misadventure over a 10-year period from 2011 to 2021. Data were extracted for demographics, ingested dose, exposure characteristics, and patient outcome. RESULTS: We identified 83 patients with clozapine-related presentations over the 10-year period. Twenty-two patients were excluded. Of the remaining 61 patients, 28 patients presented with DSP, 20 patients with accidental overdose, and 13 patients with an ADR; no patients presented with recreational use. It was noted that ADRs were largely idiosyncratic reactions and not always related to dose adjustments. In the context of therapeutic misadventure and DSP, we noted that a lower mean dose achieved a higher poison severity score (PSS) in clozapine-naive patients when compared to those patients on regular clozapine. CONCLUSIONS: The presentation of clozapine-related toxicity differs depending on the modality of ingestion, whether DSP, accidental, or as a result of ADR. Patients naive to clozapine therapy tend to experience higher PSS with lower doses ingested either in a deliberate self-poisoning or accidental ingestion context. This is likely due to tolerance to the sedative properties of clozapine. No patients manifested clinical toxicity greater than 8 hours after ingestion, with an observation period of 6 hours accurately identifying toxicity in most patients.
Simon M, Buchanan J, Schimmel J
… +6 more, Brent J, Burkhart K, Wax P, Taylor N, Aldy K, Toxicology Investigators Consortium FACT Study Group
J Med Toxicol
· 2023 Oct · PMID 37581858
·
Full text
BACKGROUND: Pregnant patients are at high risk of maternal and fetal complications from Coronavirus Disease 2019 (COVID-19) infections. The COVID-19 pandemic prompted a surge in the development and repurposing of therapi...BACKGROUND: Pregnant patients are at high risk of maternal and fetal complications from Coronavirus Disease 2019 (COVID-19) infections. The COVID-19 pandemic prompted a surge in the development and repurposing of therapies for the SARS-CoV-2 virus. Evidence is sparse on the efficacy and safety of these therapies in pregnant patients. Our objective was to describe adverse events (AEs) to COVID-19 therapeutics in pregnant patients. METHODS: This was a case series of AEs reported to the FDA ACMT COVID-19 ToxIC (FACT) Pharmacovigilance Project between November 23, 2020, and June 28, 2022. FACT is an ongoing toxicosurveillance project at 17 sites to proactively identify and report AEs associated with COVID-19 therapeutics. Abstracted information includes demographics, case narratives, exposure details, clinical information, pregnancy details, treatments, and outcomes. RESULTS: Forty-six COVID-19-positive pregnant patients who developed AEs following COVID-19 therapeutics were reported to the FACT Pharmacovigilance Project over 19 months. The most reported medications were remdesivir in 22 patients (47.8%) and casirivimab/imdevimab in 8 patients (17.4%). Four patients (8.7%) had life-threatening clinical manifestation, and 16 patients (34.8%) required intervention to prevent permanent damage. The most common maternal and fetal events were elevated serum alanine aminotransferase (26.1%) and non-reassuring fetal heart patterns (20.0%), respectively. CONCLUSIONS: This case series reports AEs of elevated serum alanine aminotransferase, maternal bradycardia, maternal hypothermia, non-reassuring fetal heart patterns, and emergent or unplanned cesarean sections following administration of several COVID-19 therapeutics. This study was not designed to definitely identify causation, and further study is needed to evaluate the causal role of these therapeutics in AEs affecting pregnant COVID-19 patients.
Kao SH, Shofer FS, Greenwood JC
… +8 more, Alomaja O, Ranganathan A, Piel S, Mesaros C, Shin SS, Ehinger JK, Kilbaugh TJ, Jang DH
J Med Toxicol
· 2023 Oct · PMID 37523031
·
Full text
INTRODUCTION: Organophosphates (OPs) are a major public health problem worldwide due to ease of access and high toxicity lacking effective biomarkers and treatment. Cholinergic agents such as OPs and carbamates are respo...INTRODUCTION: Organophosphates (OPs) are a major public health problem worldwide due to ease of access and high toxicity lacking effective biomarkers and treatment. Cholinergic agents such as OPs and carbamates are responsible for many pesticide-related deaths. While the inhibition of AChE is thought to be the main mechanism of injury, there are other important pathways that contribute to the overall toxicity of OPs such as mitochondrial dysfunction. An existing gap in OP poisoning are biomarkers to gauge severity and prognosis. Cell-free DNA (cfDNA) are novel biomarkers that have gained increased attention as a sensitive biomarker of disease with novel use in acute poisoning. This study investigates alterations in cerebral mitochondrial function in a rodent model of chlorpyrifos poisoning with the use of cfDNA as a potential biomarker. METHODS: Twenty rodents were divided into two groups: Control (n = 10) and Chlorpyrifos (n = 10). Chlorpyrifos was administered through the venous femoral line with a Harvard Apparatus 11 Elite Syringe pump (Holliston, MA, USA) at 2 mg/kg. Animals were randomized to receive chlorpyrifos versus the vehicle (10% DMSO) for 60 min which would realistically present an acute exposure with continued absorption. At the end of the exposure (60 min), isolated mitochondria were measured for mitochondrial respiration along with measures of acetylcholinesterase activity, cfDNA, cytokines and western blot. RESULTS: The Chlorpyrifos group showed a significant decrease in heart rate but no change in the blood pressure. There was a significant increase in bulk cfDNA concentrations and overall decrease in mitochondrial respiration from brain tissue obtained from animals in the Chlorpyrifos group when compared to the Control group with no difference in acetylcholinesterase activity. In addition, there was a significant increase in both IL-2 and IL-12 in the Chlorpyrifos group. CONCLUSIONS: In our study, we found that the total cfDNA concentration may serve as a more accurate biomarker of OP exposure compared to acetylcholinesterase activity. In addition, there was an overall decrease in cerebral mitochondrial function in the Chlorpyrifos group when compared to the Control group.
Hodgman MJ, Marraffa JM, Wiener BG
… +4 more, Howland MA, Stork C, Mercurio-Zappala M, Su M
J Med Toxicol
· 2023 Oct · PMID 37495818
·
Full text
INTRODUCTION: Assays for ethylene glycol (EG) with a rapid turn-around time are not routinely available. Clinicians must rely on historical features and readily available clinical tests, combined with clinical acumen, to...INTRODUCTION: Assays for ethylene glycol (EG) with a rapid turn-around time are not routinely available. Clinicians must rely on historical features and readily available clinical tests, combined with clinical acumen, to guide the initial management of suspected EG poisoning. Hypocalcemia has been suggested as a clue supporting the diagnosis of EG poisoning in patients presenting with an unexplained high anion gap metabolic acidosis (HAGMA). A previous small study challenged this assumption. METHODS: This was a retrospective case series of one state's poison control system of confirmed EG-poisoned patients between September 2017 and April 2021. The definition of EG poisoning was based on suspected EG ingestion and a serum EG concentration > 5 mg/dL. Patients who were suspected to have EG toxicity but did not have a confirmed EG concentration or the EG concentration was less than 5 mg/dL were excluded. Routine laboratory studies were recorded for all patients. Comparisons between serum calcium on presentation to presenting blood pH, bicarbonate, anion gap, and creatinine were assessed for correlation. RESULTS: There was no correlation between the presenting calcium and either pH or creatinine. There was a weak positive correlation between the initial serum calcium and anion gap, a weak negative correlation between the initial serum calcium and bicarbonate. CONCLUSION: On hospital presentation, hypocalcemia was not associated with EG poisoning, even in patients with a HAGMA. A normal serum calcium on presentation does not exclude the diagnosis of EG poisoning.
Mohan S, Mahonski S, Koziatek C
… +3 more, Cohen ET, Smith S, Su MK
J Med Toxicol
· 2023 Oct · PMID 37365427
·
Full text
INTRODUCTION: Antenatal lead exposure is associated with multiple adverse maternal and fetal consequences. Maternal blood lead concentrations as low as 10 µg/dL have been associated with gestational hypertension, spontan...INTRODUCTION: Antenatal lead exposure is associated with multiple adverse maternal and fetal consequences. Maternal blood lead concentrations as low as 10 µg/dL have been associated with gestational hypertension, spontaneous abortion, growth retardation, and impaired neurobehavioral development. Current treatment recommendations for pregnant women with a blood lead level (BLL) ≥ 45 µg/dL include chelation. We report a successful case of a mother with severe gestational lead poisoning treated with induction of labor in a term infant. CASE REPORT: A 22-year-old G2P1001 female, at 38 weeks and 5 days gestation, was referred to the emergency department for an outpatient venous BLL of 53 µg/dL. The decision was made to limit ongoing prenatal lead exposure by emergent induction as opposed to chelation. Maternal BLL just prior to induction increased to 70 µg/dL. A 3510 g infant was delivered with APGAR scores of 9 and 9 at 1 and 5 min. Cord BLL at delivery returned at 41 µg/dL. The mother was instructed to avoid breastfeeding until her BLLs decreased to below 40 µg/dL, consistent with federal and local guidelines. The neonate was empirically chelated with dimercaptosuccinic acid. On postpartum day 2, maternal BLL decreased to 36 µg/dL, and the neonatal BLL was found to be 33 µg/mL. Both the mother and neonate were discharged to an alternative lead-free household on postpartum day 4.
J Med Toxicol
· 2023 Jul · PMID 37249803
·
Full text
The management of the poisoned patient often requires the utilization of uncommonly used pharmaceutical interventions. These interventions can be associated with significant costs to both the patient and treating institu...The management of the poisoned patient often requires the utilization of uncommonly used pharmaceutical interventions. These interventions can be associated with significant costs to both the patient and treating institution. Pharmaceutical supply shortages and issues with accessibility of antidotal therapies complicate the management of many toxic exposures. These challenges are an inherent property of the pharmaceutical purchasing infrastructure in the United States, which is a complicated network of public and private intra-institutional agreements. The cost and availability of any given therapy is dependent on the individual contracting agreements between the treating institution, payer, pharmacy benefit manager, manufacturer or wholesaler, and in some cases a specialty pharmacy. Small or remote hospitals may experience greater challenges related to insufficient patient volume to achieve predicable prescribing patterns of rare and expensive medications, necessitating consignment purchasing arrangements. Although pharmaceutical costs are the focus of recent legislative attention, these reforms are not expected to significantly alter the cost or availability of antidotal therapies.
Monte AA, Vest A, Reisz JA
… +7 more, Berninzoni D, Hart C, Dylla L, D'Alessandro A, Heard KJ, Wood C, Pattee J
J Med Toxicol
· 2023 Jul · PMID 37231244
·
Full text
BACKGROUND: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be pos...BACKGROUND: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration. METHODS: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test. RESULTS: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism. CONCLUSIONS: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.
Trebach J, Boyd M, Crane A
… +4 more, DiSalvo P, Biary R, Hoffman RS, Su MK
J Med Toxicol
· 2023 Jul · PMID 37222938
·
Full text
INTRODUCTION: Colchicine is commonly used to treat diseases like acute gouty arthritis. However, colchicine has a very narrow therapeutic index, and ingestions of > 0.5mg/kg can be deadly. We report a fatal acute colchic...INTRODUCTION: Colchicine is commonly used to treat diseases like acute gouty arthritis. However, colchicine has a very narrow therapeutic index, and ingestions of > 0.5mg/kg can be deadly. We report a fatal acute colchicine overdose in an adolescent. Blood and postmortem bile colchicine concentrations were obtained to better understand the degree of enterohepatic circulation of colchicine. CASE REPORT: A 13-year-old boy presented to the emergency department after acute colchicine poisoning. A single dose of activated charcoal was administered early but no other doses were attempted. Despite aggressive interventions such as exchange transfusion and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), the patient died 8 days later. Postmortem histology was notable for centrilobular necrosis of the liver and a cardiac septal microinfarct. The patient's blood colchicine concentration on hospital days 1 (~30 hours post-ingestion), 5, and 7 was 12ng/mL, 11ng/mL, and 9.5ng/mL, respectively. A postmortem bile concentration obtained during autopsy was 27ng/mL. DISCUSSION: Humans produce approximately 600mL of bile daily. Assuming that activated charcoal would be able to adsorb 100% of biliary colchicine, using the bile concentration obtained above, only 0.0162mg of colchicine per day would be able to be adsorbed and eliminated by activated charcoal in this patient. CONCLUSION: Despite supportive care, activated charcoal, VA-ECMO, and exchange transfusion, modern medicine may not be enough to prevent death in severely poisoned colchicine patients. Although targeting enterohepatic circulation with activated charcoal to enhance elimination of colchicine sounds attractive, the patient's low postmortem bile concentration of colchicine suggests a limited role of activated charcoal in enhancing elimination of a consequential amount of colchicine.