No-observed-adverse-effect-level (NOAEL) assessment as an optimized dose of cholinesterase reactivators for the treatment of exposure to warfare nerve agents in mice.

Despite the international convention on the prohibition of chemical weapons ratified in 1997, the threat of conflicts and terrorist attacks involving such weapons still exists. Among these, organophosphorus-nerve agents (OPs) inhibit cholinesterases (ChE) causing cholinergic syndrome. The reactivation of these enzymes is therefore essential to protect the poisoned people. However, these reactivating molecules, mainly named oximes, have major drawbacks with limited efficacy against some OPs and a non-negligible ChE inhibitor potential if administered at an inadequate dose, an effect that they are precisely supposed to mitigate. As a result, this project focused on assessing therapeutic efficacy, in mice, up to the NOAEL dose, the maximum dose of oxime that does not induce any observable toxic effect. NOAEL doses of HI-6 DMS, a reference oxime, and JDS364. HCl, a candidate reactivator, were assessed using dual-chamber plethysmography, with respiratory ventilation impairment as a toxicity criterion. Time-course modeling parameters and pharmacodynamic profiles, reflecting the interaction between the oxime and circulating ChE, were evaluated for treatments at their NOAEL and higher doses. Finally, the therapeutic potential against OPs poisoning was determined through the assessment of protective indices. For JDS364. HCl, the NOAEL dose corresponds to the smallest dose inducing the most significant therapeutic effect without causing any abnormality in ChE activity. In contrast, for HI-6 DMS, its therapeutic benefit was observed at doses higher than its NOAEL, leading to alterations in respiratory function. These alterations could not be directly correlated with ChE inhibition and had no adverse effects on survival. They are potentially attributed to the stimulation of non-enzymatic cholinergic targets by HI-6 DMS. Thus, the NOAEL appears to be an optimal dose for evaluating the efficacy of oximes, particularly when it can be linked to respiratory alterations effectively resulting from ChE inhibition.

Pharmaceutical Purchasing: a Review of the Landscape and Implications for Antidotal Therapies.

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.

Fifty years of paracetamol (acetaminophen) poisoning: the development of risk assessment and treatment 1973-2023 with particular focus on contributions published from Edinburgh and Denver.

INTRODUCTION: Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. METHODS: A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963-2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. DOSE AND CONCENTRATION RESPONSE: The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. MECHANISMS OF TOXICITY: A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. ANTIDOTE DEVELOPMENT AND EFFICACY IN PATIENTS: These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. RISK ASSESSMENT AT PRESENTATION: No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. CONCLUSION: Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters.

Pharmacological re-assessment of traditional medicinal plants-derived inhibitors as antidotes against snakebite envenoming: A critical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional healers have used medicinal plants to treat snakebite envenomation worldwide; however, mostly without scientific validation. There have been many studies on the therapeutic potential of the natural products against snake envenomation. AIM OF THE STUDY: This review has highlighted snake venom inhibitory activity of bioactive compounds and peptides from plants that have found a traditional use in treating snakebite envenomation. We have systematically reviewed the scenario of different phases of natural snake venom inhibitors characterization covering a period from 1994 until the present and critically analysed the lacuna of the studies if any, and further scope for their translation from bench to bedside. MATERIALS AND METHODS: The medicinal plant-derived compounds used against snakebite therapy were reviewed from the available literature in public databases (Scopus, MEDLINE) from 1994 till 2020. The search words used were 'natural inhibitors against snakebite,' 'natural products as therapeutics against snakebite,' 'natural products as antidote against snake envenomation,' ' snake venom toxin natural inhibitors,' 'snake venom herbal inhibitors'. However, the scope of this review does not include computational (in silico) predictions without any wet laboratory validation and snake venom inhibitory activity of the crude plant extracts. In addition, we have also predicted the ADMET properties of the identified snake venom inhibitors to highlight their valuable pharmacokinetics for future clinical studies. RESULTS: The therapeutic application of plant-derived natural inhibitors to treat snakebite envenomation as an auxiliary to antivenom therapy has been gaining significant momentum. Pharmacological reassessment of the natural compounds derived from traditional medicinal plants has demonstrated inhibition of the principal toxic enzymes of snake venoms at various extents to curb the lethal and/or deleterious effects of venomous snakebite. Nevertheless, such molecules are yet to be commercialized for clinical application in the treatment of snakebite. There are many obstacles in the marketability of the plant-derived natural products as snake envenomation antidote and strategies must be explored for the translation of these compounds from drug candidates to their clinical application. CONCLUSION: In order to minimize the adverse implications of snake envenomation, strategies must be developed for the smooth transition of these plant-derived small molecule inhibitors from bench to bedside. In this article we have presented an inclusive review and have critically analysed natural products for their therapeutic potential against snake envenomation, and have proposed a road map for use of natural products as antidote against snakebite.

Toxicity assessment of gelsenicine and the search for effective antidotes.

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.

Cost impact of hydroxocobalamin in the treatment of patients with known or suspected cyanide poisoning due to smoke inhalation from closed-space fires.

BACKGROUND & OBJECTIVES: Cyanide poisoning can occur due to exposure to smoke in closed-space fires. With no point of care cyanide test at the scene of a fire, first responders and clinicians base decisions to treat with cyanide antidote on patient history, clinical signs, and other indirect data points that have not been proven to correspond with actual systemic levels of cyanide. The aim of this exploratory study was to determine the economic implications of treating patients with known or suspected cyanide poisoning due to smoke inhalation with hydroxocobalamin. METHODS: A decision analysis model was developed from the US hospital perspective. Healthcare resource utilization was estimated from a retrospective evaluation of clinical outcomes in hydroxocobalamin-treated patients and in historical controls without hydroxocobalamin use (Nguyen, et al. 2017). Epidemiologic parameters and costs were estimated from the published literature, and publicly-available hospital charges were identified. Outcomes reported in the analysis included expected healthcare resource utilization in the US population and per-patient costs with and without the use of hydroxocobalamin. A cost-to-charge ratio was applied so that all costs would reflect hospital costs rather than hospital charges. Deterministic sensitivity analysis was performed to identify the most influential model parameters. All costs were reported in 2017 US dollars. RESULTS: Use of hydroxocobalamin reduces healthcare resource utilization and contributes to decreased per-patient hospital costs ($15,381 with hydroxocobalamin treatment versus $22,607 with no cyanide antidote). The most substantive cost-savings resulted from decreased hospital length of stay (i.e., intensive care unit [ICU] and non-ICU). Costs attributed to mechanical ventilation also decreased with use of hydroxocobalamin. A univariate sensitivity analysis demonstrated that the most impactful variables in the cost analysis were related to hospital length of stay (ICU followed by non-ICU stay), followed by the daily cost of ICU stay. CONCLUSIONS: Use of hydroxocobalamin in patients with known or suspected cyanide poisoning from closed-space fire smoke inhalation may decrease hospital costs and contribute to more efficient healthcare resource utilization.

Hospital referrals of patients with acute poisoning by the Belgian Poison Centre: analysis of characteristics, associated factors, compliance and costs.

OBJECTIVE: Aims were (1) to assess the characteristics, associated factors and compliance of patients with acute poisoning advised by the Belgian Poison Centre (BPC) to go (conditionally) to the hospital, (2) to assess the compliance and potential health-economic impact. METHODS: Three types of referrals to the hospital of patients who called the BPC between 1 January and 30 June 2018 were analysed: referrals in case of deterioration in the patient's condition (Hosp-watchful-wait), referrals (Hosp-referral) or urgent referrals (Hosp-urgent-referral). Factors associated with type of recommendation were registered. A survey was conducted on a second dataset of patients who called the BPC between 1 March and 15 May 2019 and referred (conditionally) to the hospital. RESULTS: 5476 referrals were included: 72.4% accidental poisoning, 25.3% intentional self-harm, 1.2% substance abuse and 1.1% unclear intentionality. There were 2368 (43.2%) Hosp-watchful-wait cases, 2677 (48.9%) Hosp-referrals and 431 (7.9%) Hosp-urgent-referrals. In Hosp-watchful-wait cases, soaps and detergents were represented most (20.5%). In Hosp-referrals and Hosp-urgent-referrals, benzodiazepines (12.7% and 15.1%, respectively) predominated. Factors associated with hospitalisation type were number of symptoms, intentionality, type of agent(s) involved and advising antidotes. The survey showed that 7.8% of Hosp-watchful-wait patients went to the hospital versus 57.3% of Hosp-referrals and 59.6% of Hosp-urgent-referrals. The mean cost for Hosp-watchful-wait patients, Hosp-referrals and Hosp-urgent-referrals was estimated at €127, €767 and €796, respectively. CONCLUSION: Only a small proportion of patients followed the advice of the BPC to go (conditionally) to the hospital. A systematic follow-up of cases is warranted to examine the appropriateness of referrals and the compliance of patients.

[Prehospital emergency care of patients exposed to poisoning: Assessment of epidemiological, clinical characteristics and quality of care]. / Atención prehospitalaria urgente de los pacientes pediátricos expuestos a tóxicos: características epidemiológico-clínicas y evaluación de la calidad asistencial.

OBJECTIVE: To describe the characteristics of paediatric patients with suspected poisoning treated by advanced life support (ALS) units, and to evaluate quality indicators (QI) for the prehospital emergency care of these patients. METHOD: A one-year observational study of patients under 18 years of age exposed to poisoning and treated by an ALS unit of the Medical Emergency System in Catalonia. Severe clinical criteria were defined, with 8 QI being evaluated for prehospital emergency care of poisoned paediatric patients. RESULTS: The study included a total of 254 patients, with a median age of 14 years-old (p25-75 = 7-16), with intentional poisoning in 50.8% of cases. The most frequently involved toxic agent was carbon monoxide (CO) (33.8%). Poisoning was found in 48.8% of those patients, being serious in 16.5%. Intentionally (OR 5.1; 95% CI: 1.9-13.8) and knowledge of the time of exposure (OD 3.1; 95% CI: 1.3-7.3) were independent risk factors associated with the appearance of severe clinical symptoms. Five QI did not reach the quality standard and included, availability of specific clinical guidelines, activated charcoal administration in selected patients, oxygen therapy administration at maximum possible concentration in carbon monoxide poisoning, electrocardiographic assessment in patients exposed to cardiotoxic substances, and recording of the minimum data set. CONCLUSIONS: Paediatric patients attended by ALS units showed specific characteristics, highlighting the involvement of CO and adolescents with voluntary poisoning. The QI assessment was useful to detect weak points in the quality of care of these patients and to develop strategies for improvement.

[Improved and harmonised laboratory analysis of paracetamol provides safer assessment of poisoning cases]. / Bättre labbanalys av paracetamol ger säkrare bedömning av förgiftningsfall - Bestämning av koncentrationen är grunden för rätt behandling.

Toxicological analysis is an important part of the acute treatment of various intoxications. Rapid laboratory responses are important for the patient to be assessed and treated correctly, and also to exclude poisoning and thus avoid unjustified and costly overtreatment. In Sweden, paracetamol (acetaminophen) is one of the most common pharmaceuticals in drug poisoning. Paracetamol overdose can cause severe liver damage unless treated early with the antidote acetylcysteine. A nation-wide initiative for improved laboratory measurement of paracetamol in plasma/serum samples has resulted in a marked reduction in the inter-laboratory coefficient of variation to generally below 10%. The introduction of a harmonized national reporting range for plasma/serum paracetamol covering at least 50-5 000 µmol/l was also recommended. This initiative will hopefully contribute to better healthcare from both a patient and health resource perspective in cases of paracetamol poisoning.

Target Population of Non-deferrable Surgery and Uncontrolled Severe Bleeding Related to Dabigatran.

PURPOSE: This observational study was aimed to identify patients who experienced non-deferrable surgery and/or uncontrolled severe bleeding following dabigatran administration and then are potentially eligible to the use of the specific antidote idarucizumab in a real-world setting. METHODS: From the big Italian real-world database ARCO, a cohort of adult patients treated with dabigatran and hospitalized due to diagnoses attributable to urgent interventions and/or major bleeding was selected in 2014. Baseline characteristics and all-cause hospitalizations, specialist/diagnostic outpatient services, and healthcare costs over the 1-year follow-up were described. RESULTS: Out of 16,756,843 Italian citizens, 271,540 (1.9%) were prescribed with oral anticoagulants, and specifically, 17,450 with dabigatran. Patients identified to be hospitalized for non-deferrable surgery (n = 106) and/or uncontrolled severe bleeding (n = 190) following dabigatran use were 289 (1.7%) [mean age (± SD) 79 ± 7, 50% of female sex]. On average, patients stayed in hospital 13.7 and 17.0 days, respectively. The per patient and per year cost to the Italian National Health System was on average 19,708€ (specifically 1487€ for drugs, of which 311€ for dabigatran, 17,353€ for all-cause hospitalizations, and 869€ for outpatient care), about four times more than the mean healthcare integrated cost of a single patient treated with dabigatran (4775€). CONCLUSIONS: This analysis of the ARCO database reliably describes the population potentially eligible to the dabigatran reversal agent, idarucizumab. These data may be useful for Healthcare Decision Makers to organize, define, and improve present and future emergency healthcare, mainly as starting point for cost-effectiveness analyses of new reversal agents.

Telemedicine Delivery and Successful Reimbursement in Toxicology.

INTRODUCTION: Telemedicine and its use in medical toxicology have existed for some time. There are varied definitions, but existing ones center on using currently available forms of audio, video, and internet communications to provide "real-time" patient care. Definitions have historically limited reimbursement but recently expanded CMS guidelines have improved this. Here we describe our experience with telemedicine and reimbursement. METHODS: A retrospective study was conducted of all toxicology and billing reimbursement for fiscal year 2016 for a solo Medical Toxicology service. Clinical identifiers were used to match telemedicine consults to hospital financial databases and then removed. Telemedicine consults were isolated, quantified, and described. RESULTS: A total of 16 telemedicine consults were conducted. Average age was 37.2 (range 2 months-82 years). Gender was evenly split at 8:8. Twenty-five percent were pediatric consultations. The main purposes of consultation were as follows: diagnosis and disease management in drug ingestion, triage assistance, clearance consults, antidote administration, and buprenorphine induction. At the time of the work, $1896.00 for 9.3 h of teletoxicology services was reimbursed equating to an hourly reimbursement rate of $203.90/h. LIMITATIONS: Our data was obtained from a toxicology practice with a surrounding infrastructure dedicated to telemedicine. All sites may not have this robust ancillary support. Furthermore, not all states have reimbursement mandates such as New York State. CONCLUSION: To our knowledge, this is the first published work describing pilot data in the successful reimbursement for Medical Toxicology services delivered via telemedicine. Toxicology via telemedicine represents a great opportunity for advancing the practice of toxicology in an economically feasible way, particularly in rural or underserved areas.

Cost-effectiveness of hospital treatment and outcomes of acute methanol poisoning during the Czech Republic mass poisoning outbreak.

PURPOSE: During an outbreak of mass methanol poisoning in the Czech Republic in 2012-2014, we compared the total hospital costs and one-year medical costs in the patients treated with different antidotes (fomepizole versus ethanol) and modalities of hemodialysis (intermittent hemodialysis, IHD, versus continuous renal replacement therapy, CRRT). METHODS: Cross-sectional study in 106 patients with confirmed diagnosis treated in 30 ICU settings. For each patient, the following data were analyzed: admission laboratory data, GCS, PSS, ICU length of stay, organ failures, treatment, outcome, and total hospital costs. Of 83 survivors, in 54 (65%) patients the follow-up examination, quality of life measurement with SF36 questionnaire two years after discharge, and one-year medical costs analysis were performed. RESULTS: The median total hospital costs were 7200 (IQR 1500-10,900) euros and the median one-year medical costs were 1447 (IQR 133-1163) euros in the study population. The total hospital costs were higher in the patients treated with fomepizole comparing to ethanol: 12,890 (IQR 6910-16,210) versus 5590 (IQR 1430-6940) euros (p<0.001). The hospital costs in the patients treated with IHD were 5400 (IQR 1520-6910) versus 12,410 (IQR 5380-16,960) euros in the patients with CRRT (p=0.317). The geometric mean ratio for increased hospital costs in the patients treated with fomepizole versus ethanol adjusted for the severity of poisoning was 3.30 (1.70-3.80 CI 95%), p<0.001, and in the patients treated with IHD versus CRRT - 0.70 (0.60-0.99 CI 95%), p=0.047. The patients with visual sequelae had higher total hospital costs than those without sequelae: 10,419 (IQR 2984-14,355) versus 4605 (IQR 1303-4505) euros (p=0.009). The patients with GCS≤13 on admission had higher one-year medical costs as well (p<0.001). No difference was found in physical and mental condition scores in the patients treated with different antidotes and modalities of hemodialysis two years after discharge (both p>0.05). CONCLUSION: The total hospital costs in the patients with acute methanol poisoning were more than three times higher in the patients treated with fomepizole than in the patients treated with ethanol after adjustment for the severity of poisoning. The dialysis modality did not affect the total hospital costs, but the trend to lower costs was present in IHD-group.

Trends in Emergency Department Resource Utilization for Poisoning-Related Visits, 2003-2011.

In recent years, there has been an increase in poisoning-related emergency department (ED) visits. This study examines trends in ED resource utilization for poisoning-related visits over time. A retrospective review of data from the National Hospital Ambulatory Medical Care Survey, 2003-2011, was conducted. All ED visits with a reason for visit or ICD-9 code related to poisoning were included. We examined the number of ED visits and resources used including diagnostic studies and procedures performed, medications provided, admission rates, and length of stay. The proportion of visits involving resource use was tabulated and trends analyzed using survey-weighted logistic regression, grouping into 2-year periods to ensure adequate sample size. Of an estimated 843 million ED visits between 2003 and 2011, 8 million (0.9 %) were related to poisoning. Visits increased from 1.8 million (0.8 %) visits in 2003-2004 to 2.9 million (1.1 %) visits in 2010-2011, p = 0.001. Use of laboratory studies, EKGs, plain radiographs, and procedures remained stable across the study period. CT use was more than doubled, increasing from 5.2 to 13.7 % of visits, p = 0.001. ED length of stay increased by 35.5 % from 254 to 344 min, p = 0.001. Admission rates increased by 45.3 %, from 15.0 to 21.8 %, p = 0.046. Over the entire study period, 52.0 % of poisoned patients arrived via ambulance, and 3.0 % of patients had been discharged from the hospital within the previous 7 days. Poisoning-related ED visits increased over the 8-year study period; poisonings are resource-intensive visits and require increasingly longer lengths of ED stay or hospital admission.

Digoxin Toxicity and Use of Digoxin Immune Fab: Insights From a National Hospital Database.

OBJECTIVES: This study was developed to determine contemporary management of digoxin toxicity and clinical outcomes. BACKGROUND: Although the use of digoxin in heart failure management has declined, toxicity remains a prevalent complication. METHODS: The Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) was used to retrospectively identify patients diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (2007 to 2011). DIF was evaluated using treatment date, number of vials administered, and total cost. Clinical outcomes included length of stay (total hospitalization; days after DIF), cost of hospitalization, and in-hospital mortality. Exploratory multivariate analyses were conducted to determine predictors of DIF and effect on length of stay, adjusting for patient characteristics and selection bias. RESULTS: Digoxin toxicity diagnosis without DIF treatment accounted for 19,543 cases; 5,004 patients received DIF of whom 3086 had a diagnosis of toxicity. Most patients were >65 years old (88%). The predictors of DIF use were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, or suicidal intent (odds ratios 1.7, 2.4, 3.6, 2.1, and 3.7, respectively; p < 0.0001 for all). The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received treatment after day 7. Digoxin was used after DIF administration in 14% of cases. Among patients who received DIF within 2 days of admission, there was no difference for in-hospital mortality or length of stay compared with patients not receiving DIF. CONCLUSIONS: Digoxin toxicity diagnoses are clustered in the elderly. One-fifth of cases receive treatment with DIF, most within 2 days of admission. Opportunities exist for improved diagnosis and post-DIF management. Prospective data may be required to assess the impact of DIF on length of stay.

Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote?

Cyanide toxicity is common after significant smoke inhalation. Two cases are presented that provide framework for the discussion of epidemiology, pathogenesis, presenting signs and symptoms, and treatment options of inhalational cyanide poisoning. An evidence-based algorithm is proposed that utilizes point-of-care testing to help physicians identify patients who benefit most from antidotal therapy.