The role of QRS complex prolongation in predicting severe toxicity in single-xenobiotic overdose.

OBJECTIVE: The QRS complex duration is commonly used to prognosticate severity, predict outcomes, and indicate treatment in overdose. However, literature to support this practice is mixed in tricyclic antidepressant overdoses and absent in non-tricyclic antidepressant overdoses. Our objective was to assess the validity of QRS complex duration as a prognostic marker in overdose. METHODS: This was a secondary analysis of cases reported to the Toxicology Investigators Consortium between January 1, 2010, and December 31, 2022. Cases were assessed to determine the six xenobiotics most associated with QRS complex prolongation. All cases involving these six xenobiotics, regardless of QRS complex duration, constituted the study cohort. Inclusion criteria were cases of patients older than 12 years old with single-xenobiotic exposures. Clinical outcomes evaluated were seizure, ventricular dysrhythmia, metabolic acidosis, and death. RESULTS: Of 94,939 total cases, diphenhydramine, amitriptyline, bupropion, quetiapine, nortriptyline, and cocaine were most associated with QRS complex prolongation. Inclusion criteria were met by 4,655 cases of exposure to these xenobiotics. QRS complex prolongation was associated with increased odds ratio of seizure in all included xenobiotics, of ventricular dysrhythmia in all included xenobiotics except nortriptyline, and of metabolic acidosis or death in all included xenobiotics except nortriptyline and quetiapine. A normal QRS complex duration had a negative predictive value of greater than or equal to 93.0 percent of developing metabolic acidosis and 98.0 percent of developing a ventricular dysrhythmia or death from the xenobiotics studied. DISCUSSION: This study demonstrates that patients with QRS complex prolongation from all six xenobiotics studied had an increased prevalence and odds of developing severe outcomes. Furthermore, patients who did not develop QRS complex prolongation were unlikely to develop a ventricular dysrhythmia, metabolic acidosis, or death. These findings were noted in six xenobiotics that mechanistically can cause QRS complex prolongation through sodium channel or gap junction inhibition. CONCLUSION: Identification of patients at risk for severe outcomes after overdose can be aided by measuring the QRS complex duration. If prospectively validated, these outcomes have implications on risk stratification, disposition level of care, and appropriateness of treatments.

Acute Medication Poisoning.

Poisoning is the leading cause of injury-related morbidity and mortality in the United States. The highest rates of exposure to poisons occur in children five years and younger, but opioid overdoses in young adults account for most deaths from poisonings in recent years. Intentional or accidental medication poisoning should be considered when evaluating patients with mental status changes, vital sign abnormalities, seizures, and gastrointestinal or cardiovascular problems. For all poisoned patients, a comprehensive history and physical examination are needed. Knowledge of toxidromes may help identify the cause in unknown ingestions; however, their usefulness may be limited when multiple toxins are ingested. Electrocardiography is indicated in patients reporting chest pain and dyspnea and in overdoses of beta blockers, tricyclic antidepressants, and antidysrhythmics. Measurement of electrolyte, serum creatinine, and serum bicarbonate levels and calculation of the anion gap may be helpful based on the clinical presentation. Treatment of a patient with acute poisoning is based on resuscitation and stabilization with a focus on airway, breathing, and circulation. When poisoning is suspected, the Poison Control provides health care workers and the public with access to a specialist 24 hours a day.

Creating and evaluating the score to assess overdose: the OD score.

BACKGROUND: During disasters (including epidemics such as coronavirus disease 2019), the capacity of emergency departments is exceeded, thereby hindering the administration of appropriate lifesaving measures. Furthermore, the number of overdose patients increases because of the stress overload during emergency situation. The fact that overdose patients are forced to be transported to medical facilities that do not typically treat them is becoming worrisome. Moreover, there is no definitive score for overdose. This study aimed to create a patient-specific scoring system to assess overdose. METHODS: This was a retrospective single-center study. The evidence-based OD score was evaluated on a scale of 0-15. Further, logistic analysis and receiver operating characteristic (ROC) curve analysis were performed to evaluate the score. RESULTS: Overall, 262 patients (including 118 overdose patients) receiving care at the intensive care unit of Japan's Teikyo University Hospital in 2021 were targeted. Regarding the total OD score, ROC analysis revealed a cutoff of 8 (area under the curve [AUC]: 0.99, 95% confidence interval [CI]: 0.980-0.997, sensitivity: 0.95, specificity: 0.95, p < 0.05), which was considered to indicate an overdose. Of the items evaluated in the OD score, the scenario at the location of the patient's discovery (adjusted odds ratio [AOR]: 16.8, 95% CI: 5.0-255.9, p = 0.002) and recent experience of mental anxiety (AOR: 55.7, 95% CI: 2.8-5399.5, p = 0.03) significantly predicted an overdose in multivariable logistic regression analysis. External validation revealed that the OD score could also identify overdose in patients treated in a cohort from 2022 (average cutoff: 8.6, average AUC: 1.0, p < 0.0001). CONCLUSIONS: The OD score could accurately assess overdose patients. Medical facilities that do not frequently address overdose patients will benefit from the use of this score.

An interpretable machine learning framework for opioid overdose surveillance from emergency medical services records.

The goal of this study is to develop and validate a lightweight, interpretable machine learning (ML) classifier to identify opioid overdoses in emergency medical services (EMS) records. We conducted a comparative assessment of three feature engineering approaches designed for use with unstructured narrative data. Opioid overdose annotations were provided by two harm reduction paramedics and two supporting annotators trained to reliably match expert annotations. Candidate feature engineering techniques included term frequency-inverse document frequency (TF-IDF), a highly performant approach to concept vectorization, and a custom approach based on the count of empirically-identified keywords. Each feature set was trained using four model architectures: generalized linear model (GLM), Naïve Bayes, neural network, and Extreme Gradient Boost (XGBoost). Ensembles of trained models were also evaluated. The custom feature models were also assessed for variable importance to aid interpretation. Models trained using TF-IDF feature engineering ranged from AUROC = 0.59 (95% CI: 0.53-0.66) for the Naïve Bayes to AUROC = 0.76 (95% CI: 0.71-0.81) for the neural network. Models trained using concept vectorization features ranged from AUROC = 0.83 (95% 0.78-0.88)for the Naïve Bayes to AUROC = 0.89 (95% CI: 0.85-0.94) for the ensemble. Models trained using custom features were the most performant, with benchmarks ranging from AUROC = 0.92 (95% CI: 0.88-0.95) with the GLM to 0.93 (95% CI: 0.90-0.96) for the ensemble. The custom features model achieved positive predictive values (PPV) ranging for 80 to 100%, which represent substantial improvements over previously published EMS encounter opioid overdose classifiers. The application of this approach to county EMS data can productively inform local and targeted harm reduction initiatives.

[Retrospective analysis of venlafaxine-induced hypoglycemia in patients with overdose]. / Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis.

INTRODUCTION: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose. PATIENTS AND METHODS: Retrospective study carried out in the Balearic Islands (2020-2023). INCLUSION CRITERIA: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared. RESULTS: Twenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459-17,976] in patients with hypoglycemia and 1,413 [930-1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05). CONCLUSIONS: The detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication.

Fentanyl Exposure and Detection Strategies Utilized by Clinical Trial Participants Seeking Linkage to Opioid Use Disorder Treatment at a Syringe Service Program.

INTRODUCTION: The USA continues to face a fentanyl-driven overdose epidemic. Prior research has demonstrated users of illicit opioids are concerned about fentanyl exposure and overdose, but the strategies they report using to detect fentanyl's presence lack empirical support. This study compares self-report and biologically detected fentanyl use and investigates overdose risk and risk reduction behaviors among a sample of high-risk people who use opioids. METHODS: Structured enrollment interviews conducted as part of a larger clinical trial assessed self-reported fentanyl exposure as well as strategies used to determine believed fentanyl exposure and prevent overdose among 240 participants enrolled at a Chicago, IL syringe service program. Urinalysis measured actual fentanyl exposure. RESULTS: Most participants identified as African American (66.7%) and had considerable overdose experience (76.7% lifetime and 48% in the past year). Most also tested positive for fentanyl (93.75%) despite reporting no past year use of fentanyl or fentanyl-adulterated drugs (64.17%). The most utilized approaches reported for identifying fentanyl exposure were stronger effects of the drug (60.7%), sight or taste (46.9%), and being told by someone using the same drugs (34.2%). Few participants (14%) reported using fentanyl test strips. No significant associations were identified between self-report and urinalysis measures or urinalysis results and risk reduction strategies. CONCLUSION: This study adds to prior fentanyl exposure risk research. The disconnect between participants' fentanyl detection methods and reported overdose experiences supports the need for more research to identify and understand factors driving access and use of overdose prevention resources and strategies.

What impacts the acceptability of wearable devices that detect opioid overdose in people who use opioids? A qualitative study.

INTRODUCTION: Drug-related deaths involving an opioid are at all-time highs across the United Kingdom. Current overdose antidotes (naloxone) require events to be witnessed and recognised for reversal. Wearable technologies have potential for remote overdose detection or response but their acceptability among people who use opioids (PWUO) is not well understood. This study explored facilitators and barriers to wearable technology acceptability to PWUO. METHODS: Twenty-four participants (79% male, average age 46 years) with current (n = 15) and past (n = 9) illicit heroin use and 54% (n = 13) who were engaged in opioid substitution therapy participated in semi-structured interviews (n = 7) and three focus groups (n = 17) in London and Nottingham from March to June 2022. Participants evaluated real devices, discussing characteristics, engagement factors, target populations, implementation strategies and preferences. Conversations were recorded, transcribed and thematically analysed. RESULTS: Three themes emerged: device-, person- and environment-specific factors impacting acceptability. Facilitators included inconspicuousness under the device theme and targeting subpopulations of PWUO at the individual theme. Barriers included affordability of devices and limited technology access within the environment theme. Trust in device accuracy for high and overdose differentiation was a crucial facilitator, while trust between technology and PWUO was a significant environmental barrier. DISCUSSION AND CONCLUSIONS: Determinants of acceptability can be categorised into device, person and environmental factors. PWUO, on the whole, require devices that are inconspicuous, comfortable, accessible, easy to use, controlled by trustworthy organisations and highly accurate. Device developers must consider how the type of end-user and their environment moderate acceptability of the device.

Qualitative and quantitative characteristics of xylazine-associated deaths detected using a post-mortem toxicology testing program.

INTRODUCTION: The United States drug overdose crisis continues to evolve. Xylazine has been increasingly identified as an adulterant in illicit opioid supplies. The incorporation of novel adulterants, like xylazine, into the illicit drug supply adds complexity to post-mortem toxicology testing, public health messaging, substance use mitigation, and the treatment of people who use drugs. METHODS: We assessed trends, decedent characteristics, drug co-detection, and blood concentrations of xylazine-positive post-mortem cases in Michigan. We utilized a toxicology testing program capable of detecting several opioids and non-opioids in post-mortem blood samples within 72 hours. RESULTS: A total of 279 deaths were xylazine-positive between October 2019 and June 2023, with 100 percent positive for fentanyl. Only 30 percent of xylazine-involved samples were positive for naloxone, while 21.2 percent of xylazine-negative and opioid-positive samples were positive for naloxone. The percentage of xylazine-positive deaths increased from 3.2 percent in 2021 to 4.7 percent in January-June 2023. A median of five total drug groups were present among xylazine-positive deaths. Post-mortem xylazine concentrations for 55 decedent blood samples ranged from 5.2 to 200 µg/L. DISCUSSION: Our study demonstrated increases in xylazine detection among post-mortem cases. Our findings are consistent with national trends of increasing xylazine presence among drug-involved deaths. Our range of detected post-mortem xylazine blood concentrations was consistent with what has been reported in previous literature. Fentanyl was detected in 100 percent of xylazine-positive overdose deaths. Naloxone detection was relatively low, highlighting the continued importance of increasing naloxone access and distribution. Deaths associated with xylazine often involved multiple other drugs. Limited human clinical xylazine research precludes accurate interpretation and attribution of causality from these data. CONCLUSIONS: Overdose-related deaths with xylazine detection are increasing in Michigan and across the United States. Further clinical and toxicological research can help contextualize the clinical significance of xylazine in opioid overdose, clarify epidemiologic and clinical research, and inform appropriate public health messaging.

Diphenhydramine overdose detected early by integration of toxidrome and electrocardiography and treated with venoarterial extracorporeal membrane oxygenation: a case report.

Drug overdose can lead to a range of symptoms, including potentially life-threatening cardiac arrhythmias. However, identifying the specific causative drug upon admission can be challenging in many cases. The toxidrome approach is a method that utilizes toxidromes, which are collections of findings obtained from physical examination and ancillary tests, that may be caused by a specific toxin. In this particular case, a man presented with an unknown drug overdose that caused symptoms indicative of anticholinergic effects and abnormal electrocardiogram (ECG) findings. The ECG revealed an R wave in lead aVR, S waves in leads I and aVL, and wide QRS tachycardia with a Brugada pattern. Shortly after arrival, the patient developed cardiac arrest due to a lethal arrhythmia. Prompt initiation of venoarterial extracorporeal cardiopulmonary membrane oxygenation (VA-ECMO) was performed. Fortunately, the patient achieved full neurological recovery, and the overdosed drug was identified as diphenhydramine. When diagnosing and treating drug overdose caused by an unidentified substance, diphenhydramine toxicity should be considered when an anticholinergic toxidrome is present and a Brugada pattern is observed on the ECG. VA-ECMO demonstrates potential as a viable treatment option when initial interventions prove ineffective.

Detection of thiocyanate in postmortem blood of a fatal potassium thiocyanate-poisoning patient using gas chromatography-mass spectrometry.

Thiocyanate is an inorganic compound used in industrial applications. Here, we report a case of suicidal death due to acute thiocyanate overdose. A 44-year-old man who consumed an unknown amount of thiocyanate solution was transferred to the emergency room and died 2 h after admission. An autopsy was performed 2 days after death. General toxicological analysis of blood using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry found no drug or alcohol. Quantification using GC-MS post-derivatization with pentafluorobenzyl bromide revealed 2,290 and 1,920 mg/L of thiocyanate in the heart and femoral blood samples, respectively. Thus, the cause of death was attributed to thiocyanate overdose. This study provides useful information for the interpretation of thiocyanate-related fatalities.

The Opioid Overdose Resuscitation Education for Addiction Counselors and Trainees (Opioid Overdose REACT) naloxone response education pilot project improved confidence and knowledge among addiction counselors and trainees.

INTRODUCTION: Community programs to teach nonmedical laypeople how to recognize an opioid overdose and effectively resuscitate the victim using naloxone have proliferated recently as a significant component of harm-reduction efforts. Although many such programs target laypeople like first responders or friends and family members of people who use drugs, there are currently no programs that specifically target addiction counselors, despite their work with a client population at high risk of an opioid overdose. METHODS: The four-hour curriculum designed by the authors covered opioid agonist and antagonist pharmacology; opioid toxidrome signs; legal implications and indications for using the naloxone kits; and hands-on training. Participants were two cohorts of addiction counselors and addiction counseling trainees at our institution and an affiliated Opioid Treatment Program methadone clinic. Surveys testing participant knowledge and confidence were conducted at baseline, immediately post-training, six months post-training, and 12 months post-training. RESULTS: Overall, opioid and naloxone pharmacology knowledge, as well as the confidence to intervene in an overdose emergency, improved among participants in both cohorts. Knowledge scores at baseline (n = 36, median 5/10) improved significantly immediately post-training (n = 31, median 7/10, P < 0.0001, Wilcoxon signed-rank test) and were sustained six (n = 19) and 12 months (n = 11) later. Two participants reported using their naloxone kits to successfully reverse a client overdose in the 12 months after taking the course. DISCUSSION: These results from our knowledge translation pilot project suggest that our educational program to train addiction counselors in opioid pharmacology and toxicology, allowing them to recognize and respond to an opioid overdose, is feasible and could be effective. Specific barriers to implementing such educational programs include cost, stigma, and unclear best practice for designing and conducting these programs. CONCLUSIONS: Further study of providing opioid pharmacology education and overdose and naloxone training to addiction counselors and counseling trainees appears to be warranted.

Reducing opioid related deaths for individuals who are at high risk of death from overdose: a co-production study with people housed within prison and hostel accommodation during Covid-19.

Background: A record number of Opioid-related deaths occurred in Northern Ireland in 2021 and it is acknowledged that the Covid-19 pandemic compounded drugs related deaths crisis. This co-production study set out to refine the design of a wearable device for Opioid users to detect and subsequently prevent a potential overdose situation. Method: Purposive sampling was used to recruit people who had substance use disorders and were living in a hostel and prison during the Covid-19 pandemic. Principles of co-production influenced the study, which encompassed a focus group phase and a wearable phase. The initial phase included three focus groups with participants who inject Opioids and one focus group with workers from a street injector support service. During the wearable phase, the participant group tested the feasibility of the wearable technology in a controlled environment. This included testing the transferability of data from the device to a backend server on the cloud. Results: All focus group participants expressed an interest in the wearable technology when it was presented to them and agreed, that in principle, such a device would be extremely beneficial to help reduce the risk of overdose within the active drug using community. Participants outlined factors which would help or hinder the design of this proposed device and their decision to wear it, if it were readily available to them. Findings from wearable phase indicated that it was feasible to use a wearable device for monitoring Opioid users' biomarkers remotely. The provision of information regarding the specific functionality of the device was considered key and could be disseminated via front line services. The data acquisition and transfer process would not be a barrier for future research. Conclusion: Understanding the benefit and disadvantages of technologies such as a wearable device to prevent Opioid-related deaths will be critical for mitigating the risk of overdose for people who use Heroin. It was also clear that this would be particularly relevant during Covid-19 lock-down periods, when the effects of the pandemic further exacerbated the isolation and solitude experienced by people who use Heroin.

Examination of the Accuracy of Existing Overdose Surveillance Systems.

Importance: Health departments have used a variety of methods for overdose surveillance, and the Centers for Disease Control and Prevention (CDC) is implementing a standardized case definition to improve overdose surveillance nationally. The comparative accuracy of the CDC opioid overdose case definition vs existing state opioid overdose surveillance systems is unknown. Objective: To evaluate the accuracy of the CDC opioid overdose case definition and existing Rhode Island Department of Health (RIDOH) state opioid overdose surveillance system. Design, Setting, and Participants: This cross-sectional study of ED opioid overdose visits was conducted at 2 EDs in Providence, Rhode Island, at the state's largest health system from January to May 2021. Electronic health records (EHRs) were reviewed for opioid overdoses identified by the CDC case definition and opioid overdoses reported to the RIDOH state surveillance system. Included patients were those at study EDs whose visit met the CDC case definition, was reported to the state surveillance system, or both. True overdose cases were confirmed by EHR review using a standard case definition; 61 of 460 EHRs (13.3%) were double reviewed to estimate classification accuracy. Data were analyzed from January through May 2021. Main Outcome and Measure: Accurate identification of an opioid overdose was assessed by estimating the positive predictive value of the CDC case definition and state surveillance system using results from the EHR review. Results: Among 460 ED visits that met the CDC opioid overdose case definition, were reported to the RIDOH opioid overdose surveillance system, or both (mean [SD] age, 39.7 [13.5] years; 313 males [68.0%]; 61 Black [13.3%], 308 White [67.0%], and 91 other race [19.8%]; and 97 Hispanic or Latinx [21.1%] among each patient visit), 359 visits (78.0%) were true opioid overdoses. For these visits, the CDC case definition and RIDOH surveillance system agreed that 169 visits (36.7%) were opioid overdoses. Of 318 visits meeting the CDC opioid overdose case definition, 289 visits (90.8%; 95% CI, 87.2%-93.8%) were true opioid overdoses. Of 311 visits reported to the RIDOH surveillance system, 235 visits (75.6%; 95% CI, 70.4%-80.2%) were true opioid overdoses. Conclusions and Relevance: This cross-sectional study found that the CDC opioid overdose case definition more often identified true opioid overdoses compared with the Rhode Island overdose surveillance system. This finding suggests that using the CDC case definition for opioid overdose surveillance may be associated with improved data efficiency and uniformity.

Metformin-associated lactic acidosis reported to the United Kingdom National Poisons Information Service (NPIS) between 2010 and 2019: a ten-year retrospective analysis.

INTRODUCTION: Metformin toxicity following therapeutic use or overdose may result in metabolic acidosis with hyperlactatemia. This study aims to assess the relationship between serum lactate concentration, arterial pH, and ingested dose with severity of poisoning, and to identify if serum lactate concentration is a useful marker of severity in metformin toxicity. METHODS: A retrospective study of telephone enquiries relating to metformin exposures to the National Poisons Information Service between 2010 and 2019 from hospitals in the United Kingdom. RESULTS: Six-hundred and thirty-seven cases were identified; 117 involved metformin only and 520 involved metformin with other drugs. The majority of cases involved acute (87%) and intentional (69%) exposures. There was a statistically significant difference in doses between the Poisoning Severity Scores, as well as between intentional and unintentional or therapeutic error doses (P < 0.0001). The distribution of cases for each Poisoning Severity Score differed between the metformin only and metformin with other drugs cases (P < 0.0001). Lactic acidosis was reported in 232 cases. Serum lactate concentration and arterial pH differed across Poisoning Severity Scores. Arterial pH inversely correlated with ingested dose (r=-0.3, P = 0.003), and serum lactate concentration positively correlated with ingested dose (r = 0.37, P < 0.0001). Serum lactate concentration and arterial pH did not correlate with each other. Twenty-five deaths were recorded, all following intentional overdoses. DISCUSSION: The dataset focuses mostly on acute, intentional overdoses. Increasing ingested metformin dose, a higher serum lactate concentration and worsening arterial pH were all associated with an unfavourable Poisoning Severity Score in patients in both metformin only and metformin with other drugs groups. As serum lactate concentration did not correlate with arterial pH, it represents an independent marker of poisoning severity. CONCLUSIONS: Data from the present study suggest that serum lactate concentration can be used to assess severity of poisoning in patients who have reportedly ingested metformin.

Sodium bicarbonate treatment for QRS widening in bupropion overdoses.

INTRODUCTION: Bupropion cardiotoxicity widens QRS complexes by inhibiting cardiac gap junctions. Sodium bicarbonate is the standard treatment for QRS widening from sodium channel blockade, but its effect on QRS widening in bupropion cardiotoxicity is not well-studied. METHODS: This is a retrospective cohort study of bupropion overdoses from 10 hospitals between January 2010 and June 2022. Patients with documented administration of sodium bicarbonate and QRS duration > 100 milliseconds on pre-bicarbonate electrocardiogram were included. Patients with no electrocardiogram within four hours of treatment or with baseline pre-overdose wide QRS and < 10 milliseconds widening from baseline were excluded. The primary outcome was a change in QRS duration between the pre-bicarbonate electrocardiogram and the first electrocardiogram after initial bicarbonate administration. Secondary outcomes included prevalence of post-bicarbonate QRS < 100 milliseconds, change in electrocardiogram intervals after total bicarbonate administration, and change in metabolic parameters and hemodynamics. Wilcoxon signed-rank testing was performed on the primary outcome. Linear regression modeling was performed to test for an association between change in QRS and bicarbonate dosing. RESULTS: Thirteen patients were included for final analysis. The median age was 32 years, and 54% were male. Six patients developed seizures; one developed ventricular tachycardia, and four received vasopressors. The median QRS and QTc pre-bicarbonate were 116 and 495 milliseconds, respectively. The median change in QRS duration was -2.0 milliseconds, which was not statistically significant (P = 0.42). The median bicarbonate dose administered before the first post-bicarbonate electrocardiogram was 100 milliequivalents. We did not identify an association between QRS change and bicarbonate dosing (P = 0.9, R-squared = 0.001). No patient had a QRS duration < 100 milliseconds after the initial bicarbonate dose. There was minimal change in QTc, electrolytes, heart rate, or blood pressure; alkalemia post-bicarbonate was achieved in eight patients. CONCLUSION: Sodium bicarbonate did not significantly decrease QRS duration in this small retrospective cohort of bupropion overdoses.

Fatal intoxication involving 2-methyl AP-237.

Novel synthetic opioids contribute considerably to the opioid epidemic, especially with the frequent emergence of structurally similar compounds. This case report describes a fatal intoxication involving 2-methyl AP-237. A 54-year-old Caucasian male was found deceased from an apparent drug overdose. A plastic container labeled "2MAP" and a cut straw were found in the decedent's backpack at the scene. A white substance found in the container tested positive for fentanyl by field testing. According to his medical history, the decedent was treated for a drug overdose 3 years prior to his death. With no diagnostic findings at autopsy, the case was submitted for toxicological analysis. An unknown substance was detected in peripheral blood and urine using gas chromatography with nitrogen phosphorous detection (GC-NPD). Further testing was conducted using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) which confirmed the presence of 2-methyl AP-237 and potential metabolites in blood and urine. Quantitation by GC-NPD revealed concentrations of 2-methyl AP-237 in blood and urine at 480 ng/mL and 4200 ng/mL, respectively. The toxicological analysis also identified and quantitated alprazolam in the blood at 55 ng/mL. Additionally, the metabolism of 2-methyl AP-237 was investigated and three hydroxylated metabolites were identified in peripheral blood and urine. Limited literature is available for the detection and quantitation of 2-methyl AP-237 in postmortem specimens. Given the toxicological findings with unremarkable autopsy findings, this case is an example of a fatal intoxication involving 2-methyl AP-237.

Integrated Imaging and Proteomic Sensors Resolve Proteome Aggregation in Liver Caused by Non-steroidal Anti-inflammatory Drug Overdose.

Given the extreme heterogeneity and the loss of defined protein structures, misfolded and aggregated proteins are technically challenging to visualize and analyze. Herein, we assembled an integrated sensor system to resolve aggregated proteome in live cells and animal liver tissues that are overdosed by non-steroidal anti-inflammatory drugs (NSAIDs). A fluorogenic protein aggregation sensor (AggStain) first discovered the presence of aggregated proteome upon overdosing liver cells with NSAIDs. A solvatochromic protein aggregation sensor (AggRetina) further quantified the compactness (polarity) inside these cellular aggregates. Importantly, we exploited a proteomic sensor (AggLink) to selectively capture aggregated proteins upon NSAID overdose and profile their composition, revealing global collapse of cellular protein homeostasis. Finally, we detected subtle proteome aggregation in mouse liver tissue without obvious acute injury at a low NSAID dosage. Overall, we demonstrated an integrated sensor toolset for proteome aggregation studies and unveiled for the first time that NSAID overdose can cause proteome aggregation in liver cells and tissues.

Opioid overdoses involving xylazine in emergency department patients: a multicenter study.

INTRODUCTION: Illicit opioids, consisting largely of fentanyl, novel synthetic opioids, and adulterants, are the primary cause of drug overdose fatality in the United States. Xylazine, an alpha-2 adrenergic agonist and veterinary tranquilizer, is being increasingly detected among decedents following illicit opioid overdose. Clinical outcomes in non-fatal overdose involving xylazine are unexplored. Therefore, among emergency department patients with illicit opioid overdose, we evaluated clinical outcome differences for patients with and without xylazine exposures. METHODS: This multicenter, prospective cohort study enrolled adult patients with opioid overdose who presented to one of nine United States emergency departments between 21 September 2020, and 17 August 2021. Patients with opioid overdose were screened and included if they tested positive for an illicit opioid (heroin, fentanyl, fentanyl analog, or novel synthetic opioid) or xylazine. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect current illicit opioids, novel synthetic opioids, xylazine and adulterants. Overdose severity surrogate outcomes were: (a) cardiac arrest requiring cardiopulmonary resuscitation (primary); and (b) coma within 4 h of arrival (secondary). RESULTS: Three hundred and twenty-one patients met inclusion criteria: 90 tested positive for xylazine and 231 were negative. The primary outcome occurred in 37 patients, and the secondary outcome occurred in 111 patients. Using multivariable regression analysis, patients positive for xylazine had significantly lower adjusted odds of cardiac arrest (adjusted OR 0.30, 95% CI 0.10-0.92) and coma (adjusted OR 0.52, 95% CI 0.29-0.94). CONCLUSIONS: In this large multicenter cohort, cardiac arrest and coma in emergency department patients with illicit opioid overdose were significantly less severe in those testing positive for xylazine.