Predicting mortality from acetaminophen poisoning shortly after hospital presentation.

AIMS: Early identification of patients likely to die after acetaminophen (APAP) poisoning remains challenging. We sought to compare the sensitivity and time to fulfilment (latency) of established prognostic criteria. METHODS: Three physician toxicologists independently classified every in-hospital death associated with APAP overdose from eight large Canadian cities over three decades using the Relative Contribution to Fatality scale from the American Association of Poison Control Centres. The sensitivity and latency were calculated for each of the following criteria: King's College Hospital (KCH), Model for End Stage Liver Disease (MELD) ≥33, lactate ≥3.5 mmol/L, phosphate ≥1.2 mmol/L 48+ hours post-ingestion, as well as combinations thereof. RESULTS: A total of 162 in-hospital deaths were classified with respect to APAP as follows: 26 Undoubtedly, 40 Probably, 27 Contributory, 14 Probably not, 25 Clearly not, and 30 Unknown. Cases from the first three classes (combined into n = 93 "APAP deaths") typically presented with supratherapeutic APAP concentrations, hepatotoxicity, acidaemia, coagulopathy and/or encephalopathy, and began antidotal treatment a median of 12 hours (IQR 3.4-30 h) from the end of ingestion. Among all patients deemed "APAP deaths", meeting either KCH or lactate criteria demonstrated the highest sensitivity (94%; 95% CI 86-98%), and the shortest latency from hospital arrival to criterion fulfilment (median 4.2 h; IQR 1.0-16 h). In comparison, the MELD criterion demonstrated a substantially lower sensitivity (55%; 43-66%) and longer latency (52 h; 4.4-∞ h, where "∞" denotes death prior to criterion becoming positive). CONCLUSIONS: Meeting either KCH or serum lactate criteria identifies most patients who die from acetaminophen poisoning at or shortly after hospital presentation.

Outcomes of Patients With Premature Discontinuation of the 21-h Intravenous N-Acetylcysteine Protocol After Acute Acetaminophen Overdose.

BACKGROUND: The minimum recommended treatment duration for i.v. N-acetylcysteine (NAC) after an acute, single acetaminophen (APAP) overdose is 21 h. Some have questioned whether shorter courses may be sufficient in carefully selected cases. OBJECTIVE: We sought to describe the incidence of hepatotoxicity in a cohort of acute APAP overdose patients who received <21 h of i.v. NAC for any reason. METHODS: We performed a secondary analysis of a large multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected patients with a potentially toxic serum APAP concentration measured between 4 and 24 h post ingestion, in whom i.v. NAC was initiated but discontinued before completing the full 21-h course. We further characterized outcomes in these patients as a function of two novel risk-prediction tools, the psi (ψ) parameter and APAP × aminotransferase (AT) product. The ψ parameter is an estimate of the cellular burden of injury based on the area under the concentration-time curve before treatment, and calculated with respect to the APAP concentration and time to initiation of NAC. RESULTS: Fifty-nine patients met inclusion criteria. Intravenous NAC was initiated a median of 11.3 h post ingestion and administered for a median of 11.0 h. Hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 1,000 IU/L) occurred in one patient (1.7%; 95% confidence interval 0.04-9.1), and eight additional patients developed hepatic injury (AST or ALT > 100 IU/L). No fatalities occurred. A multiplication product of APAP and AT (APAP × AT) that falls below 10,000 µmol/L/IU-L, or pretreatment ψ < 5 mmol/L-h suggested a low risk of hepatic injury. CONCLUSIONS: In this retrospective analysis of patients treated with < 21 h of i.v. NAC for acute APAP overdose, the incidence of hepatotoxicity and coagulopathy was low, despite delays to NAC treatment.

Poisoning in the United States: 2012 emergency medicine report of the National Poison Data System.

Deaths from drug overdose have become the leading cause of injury death in the United States, where the poison center system is available to provide real-time advice and collect data about a variety of poisonings. In 2012, emergency medical providers were confronted with new poisonings, such as bath salts (substituted cathinones) and Spice (synthetic cannabinoid drugs), as well as continued trends in established poisonings such as from prescription opioids. This article addresses current trends in opioid poisonings; new substances implicated in poisoning cases, including unit-dose laundry detergents, bath salts, Spice, and energy drinks; and the role of poison centers in public health emergencies such as the Fukushima radiation incident.

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers.

OBJECTIVE: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). METHODS: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with ≥3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. RESULTS: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. CONCLUSIONS: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers.

OBJECTIVE: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). METHODS: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazettcorrected QT duration and QTcI outliers Pharmacokinetics and adverse events (AEs) were also assessed. RESULTS: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. CONCLUSIONS: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

Effect of smoking on the pharmacokinetics of inhaled loxapine.

BACKGROUND: Loxapine inhalation powder delivered by a hand-held device as a thermally generated aerosol (ADASUVE) was recently approved in the United States and European Union for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. As smokers comprise a large subpopulation of these patients, and many antipsychotic drugs require dose adjustments for smokers, the objective of this study was to compare the pharmacokinetics of inhaled loxapine administered to smokers and nonsmokers. METHODS: Pharmacokinetics and sedation pharmacodynamics using a visual analog scale were studied in 35 male and female adult subjects (18 nonsmokers and 17 smokers) following a single dose of 10 mg of inhaled loxapine. Blood samples were drawn at predose, 30 seconds, 1, 2, 3, 10, 30, and 60 minutes, and 2, 6, 12, and 24 hours after dosing. Loxapine and 8-OH-loxapine were analyzed using reverse-phase liquid chromatography coupled with a tandem mass spectrometer. Pharmacokinetic parameters assessed included Cmax, Tmax, AUCinf, and T1/2 for loxapine and 8-OH-loxapine. Geometric mean ratios (GMRs) were determined for smokers to nonsmokers. RESULTS: Loxapine Cmax was similar in smokers and nonsmokers with a GMR of 99.0%. The median loxapine Tmax was 1.88 and 1.01 minutes for nonsmokers and smokers, respectively. Loxapine AUCinf and AUClast values in nonsmokers were comparable with smokers (GMRs of 85.3% and 86.7%, respectively). A slight decrease in the observed mean terminal half-life values was observed for smokers (6.52 hours for smokers and 7.30 hours for nonsmokers). CONCLUSIONS: Sedation profiles and visual analog scale scores at each time point were similar for nonsmokers and smokers. It was concluded that inhaled loxapine does not require dosage adjustment based on smoking behavior.

2022 Annual Report of the National Poison Data System® (NPDS) from America's Poison Centers®: 40th Annual Report.

INTRODUCTION: This is the 40th Annual Report of America's Poison Centers National Poison Data System (NPDS). As of 1 January, 2022, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.72 [4.40, 9.27] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2022, 2,483,183 closed encounters were logged by NPDS: 2,064,875 human exposures, 50,381 animal exposures, 363,099 information requests, 4,790 human confirmed nonexposures, and 38 animal confirmed nonexposures. Total encounters showed a 12.9% decrease from 2021, and human exposure cases decreased by 0.771%, while health care facility (HCF) human exposure cases increased by 0.214%. All information requests decreased by 48.4%, medication identification (Drug ID) requests decreased by 21.2%, and medical information requests showed a 76.92% decrease, although these remain twice the median number before the COVID-19 pandemic. Drug Information requests showed a 52.4% decrease, due to declining COVID-19 vaccine calls to PCs but still comprised 5.55% of all information contacts. Human exposures with less serious outcomes have decreased 1.70% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.41% per year since 2000.Consistent with the previous year, the top 4 substance classes most frequently involved in all human exposures were analgesics (11.5%), household cleaning substances (7.23%), antidepressants (5.61%), and cosmetics/personal care products (5.23%). Antihistamines (4.81%) replaced sedatives/hypnotics/antipsychotics as the 5th substance class. As a class, analgesic exposures increased most rapidly, by 1,514 cases/year (3.26%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were household cleaning substances (10.3%), analgesics (9.54%), cosmetics/personal care products (9.49%), dietary supplements/herbals/homeopathic (6.65%), and foreign bodies/toys/miscellaneous (6.61%). NPDS documented 3,255 human exposures resulting in death; 2,622 (80.6%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage the increasing number of more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

OBJECTIVE: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. METHODS: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. RESULTS: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). CONCLUSIONS: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics.

BACKGROUND: Rapid delivery of potent opioid to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain. The delivery of different opioids by the pulmonary route has been inconsistent, usually resulting in low bioavailability of the drug. Staccato® Fentanyl for Inhalation is a handheld inhaler producing a single metered dose of aerosolized fentanyl during a single inspiration. The aerosol is of high purity (≥98%) at a particle size (1 to 3.5 microns) shown to be best for pulmonary absorption. METHODS: We conducted the study in healthy volunteers in 2 stages. In the crossover stage, 10 subjects received IV fentanyl 25 µg and inhaled fentanyl 25 µg on separate occasions. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl (50 to 300 µg). Serial blood sampling was performed over an 8-hour period after drug administration to determine the pharmacokinetic profile, and serial pupillometry was performed as a measure of pharmacodynamic effect. RESULTS: In the crossover stage the pharmacokinetic profiles of the inhaled and IV fentanyl showed similar peak arterial concentrations and areas under the curve. The time to maximum concentration was slightly shorter for the inhaled than IV fentanyl, 20.5 and 31.5 seconds, respectively. In the dose escalation stage the administration of repeated doses resulted in predictable, dose-dependent serum concentrations. CONCLUSIONS: This study has demonstrated that the pharmacokinetic profile of single doses of inhaled fentanyl is comparable to IV administration.

Making US poison centers a part of the solution to the COVID-19 pandemic.

OBJECTIVES: Our six goals are: 1) describe the relationship between the National Strategy for the COVID-19 Response and Pandemic Preparedness and the 55 US poison centers (PCs); 2) detail FDA emergency Use Authorization (EUA) COVID-19 vaccine-related regulatory procedures and associated acronyms; 3) list availability of specific vaccine clinical information to support PC staff COVID-19 vaccination and adverse event (AE) data collection; 4) describe required health care practitioner COVID-19 vaccine AE reporting to the Vaccine AE Reporting System (VAERS) and PC reporting options; 5) document public and health care professionals' use of PCs for COVID-19 vaccine information; and 6) propose strategy to maximize PCs contribution to the pandemic solution. METHODS: We reviewed 13-Feb-2020 through 15-Apr-2021 National Poison Data System (NPDS) COVID-19 records for changes over time. We examined NPDS cases and VAERS COVID-19 vaccine reports 1-Nov-2020 through 2-Apr-2021 for vaccine manufacturer, patient characteristics, state, and clinical effects. RESULTS: PCs reported 1,052,174 COVID-19 contacts; maximum (peak) contacts/day (12,163) on 16-Mar-2020. As of 5-Apr-2021 the US reported >167 million administrations of COVID-19 vaccines (Pfizer-BioNTech, Moderna or Janssen). US PCs reported 162,052 COVID-19 vaccine contacts. Most (61.1%) were medical information calls, 34.9% were drug information, and 2.58% were exposures. Over the same period VAERS reported 49,078 COVID-19 vaccine cases reporting 226,205 symptoms - headache most frequent, ranging from 20% to 40% across the 3 vaccines. CONCLUSIONS AND RECOMMENDATIONS: Although differences exist between the intent and content of the 2 data sets, NPDS volume is compelling. The PC nationwide 800 number facilitates data collection and suggests comingling the 2 data streams has merit. PC professionals received tens of thousands of calls and can: 1) support fact-based vaccine information; 2) contribute vaccine AE follow-up information: 3) advocate for best-case coding and reporting, especially for vaccine adverse experiences.

Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations.

OBJECTIVES: The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. METHODS: We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. RESULTS: The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower Cmax, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. CONCLUSIONS: Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower Cmax and later Tmax than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

2021 Annual Report of the National Poison Data System© (NPDS) from America's Poison Centers: 39th Annual Report.

ABSTRACTINTRODUCTION: This is the 39th Annual Report of America's Poison Centers' National Poison Data System (NPDS). As of 1 January, 2021, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.87 [4.38, 8.62] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2021, 2,851,166 closed encounters were logged by NPDS: 2,080,917 human exposures, 62,189 animal exposures, 703,086 information requests, 4,920 human confirmed nonexposures, and 54 animal confirmed nonexposures. Total encounters showed a 14.0% decrease from 2020, and human exposure cases decreased by 2.22%, while health care facility (HCF) human exposure cases increased by 7.20%. All information requests decreased by 37.0%, medication identification (Drug ID) requests decreased by 20.8%, and medical information requests showed a 61.1% decrease, although these remain about 13-fold higher than before the COVID-19 pandemic. Drug Information requests showed a 146% increase, reflecting COVID-19 vaccine calls to PCs. Human exposures with less serious outcomes have decreased 1.80% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.56% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.49%), cosmetics/personal care products (5.88%), antidepressants (5.61%), and sedatives/hypnotics/antipsychotics (4.73%). As a class, antidepressant exposures increased most rapidly, by 1,663 cases/year (5.30%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (10.8%), household cleaning substances (10.7%), analgesics (8.16%), dietary supplements/herbals/homeopathic (7.00%), and foreign bodies/toys/miscellaneous (6.51%). Drug identification requests comprised 3.64% of all information contacts. NPDS documented 4,497 human exposures resulting in death; 3,809 (84.7%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine.

BACKGROUND: There is a need for a rapid-acting, non-injection, acute treatment for agitation. AIMS: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia. METHOD: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one. RESULTS: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications. CONCLUSIONS: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

2020 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 38th Annual Report.

INTRODUCTION: This is the 38th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2020, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 6.15 [4.60, 8.62] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2020, 3,316,738 closed encounters were logged by NPDS: 2,128,198 human exposures, 66,745 animal exposures, 1,116,568 information requests, and 5,160 human confirmed nonexposures. Total encounters showed a 28.9% increase from 2019, while health care facility (HCF) human exposure cases decreased by 10.6%. While all information requests increased by 218.0%, medication identification (Drug ID) requests decreased by 31.5%, and human exposure cases decreased by 0.928%. Medical Information requests showed a 32.6-fold increase, reflecting COVID-19 pandemic calls to PCs. Human exposures with less serious outcomes have decreased 1.90% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.59% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.3%), household cleaning substances (8.37%), cosmetics/personal care products (6.53%), antidepressants (5.30%), and sedatives/hypnotics/antipsychotics (4.92%). As a class, antidepressant exposures increased most rapidly, by 1,793 cases/year (5.84%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.8%), household cleaning substances (11.3%), analgesics (7.57%), foreign bodies/toys/miscellaneous (6.71%), and dietary supplements/herbals/homeopathic (6.44%). Drug identification requests comprised 2.89% of all information contacts. NPDS documented 4,488 human exposures resulting in death; 3,869 (86.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Amlodipine toxicity in children less than 6 years of age: a dose-response analysis using national poison data system data.

BACKGROUND: Amlodipine is a long-acting calcium channel blocker capable of producing hypotension and dysrhythmia in overdose. The toxic doses of amlodipine in children are unclear. OBJECTIVES: The purposes of this study were to describe amlodipine poisoning in children and to determine whether a dose-response relationship could be detected in this population using standardized call data from United States (US) poison centers. PATIENTS AND METHODS: 1251 amlodipine-only ingestions in children < 6 years of age were reviewed. Cases with doses coded as "Exact" or "Estimated" and with dose, age, and medical outcome were analyzed (n = 678). Ingestions reported as a "taste or lick" (n = 53) were included as a dose of 1/10 of the dosage form involved. A clinically important response was defined as bradycardia, hypotension, dysrhythmia, conduction disturbance, or hyperglycemia. The risk of such responses was examined over four dosage intervals (< 2.5 mg, 2.5-5 mg, 5.1-10 mg, and > 10 mg). RESULTS: The median estimated dose ingested was 5 mg (range 0.25-200 mg). Clinically important responses developed in 27 patients (3.98%), and the prevalence of such response significantly increased from 0% for the lowest to 11.1% for the highest dose interval (p = 0.001). The smallest dose to produce a clinically important response was 2.5 mg (0.15 mg/kg). Children who ingested > 10 mg were 4.4 times more likely to develop clinically important responses than those ingesting < or = 5 mg. CONCLUSION: Hypotension may occur in children with amlodipine doses as low as 2.5 mg. The National Poison Data System might provide useful insights regarding dose-response.

2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report.

Introduction: This is the 37th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2019, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 6.52 [6.12, 8.68] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.Results: In 2019, 2,573,180 closed encounters were logged by NPDS: 2,148,141 human exposures, 68,711 animal exposures, 351,163 information requests, 5,078 human confirmed nonexposures. Total encounters showed a 1.70% increase from 2018, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.495%. All information requests decreased by 4.58%, medication identification (Drug ID) requests decreased by 29.7%, and human exposure cases increased by 2.30%. Human exposures with less serious outcomes have decreased 2.08% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.61% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.0%), household cleaning substances (7.13%), cosmetics/personal care products (6.16%), antidepressants (5.32%), and sedatives/hypnotics/antipsychotics (5.21%). As a class, antidepressant exposures increased most rapidly, by 1,957 cases/year (3.90%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.4%), household cleaning substances (10.5%), analgesics (8.97%), foreign bodies/toys/miscellaneous (7.17%), and dietary supplements/herbals/homeopathic (5.06%). Drug identification requests comprised 13.4% of all information contacts. NPDS documented 2,619 human exposures resulting in death; 2,048 (78.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning.

STUDY OBJECTIVE: To compare outcomes after acute acetaminophen poisoning in 2 large cohorts of patients treated with either the 20-hour intravenous or 72-hour oral acetylcysteine protocol. METHODS: We conducted a retrospective cohort study with historical control comparing patients treated with one of 2 acetylcysteine regimens. Data for the 20-hour group were obtained from a medical record review of patients on whom the 20-hour intravenous protocol was initiated in Canadian hospitals from 1980 to 2005. The 72-hour group consisted of a historical cohort of patients treated in US hospitals with the 72-hour oral protocol from 1976 to 1985. The primary outcome was hepatotoxicity (aminotransferase levels >1,000 IU/L). RESULTS: Of the 4,048 patients analyzed, 2,086 were in the 20-hour group and 1,962 were in the 72-hour group. The incidence of hepatotoxicity was 13.9% in the 20-hour group and 15.8% in the 72-hour group (-1.9% absolute difference; 95% confidence interval [CI] -4.2 to 0.3). The relative risk of hepatotoxicity was lower in the 20-hour group when acetylcysteine was initiated within 12 hours of ingestion. The relative risk was lower in the 72-hour group when acetylcysteine was initiated later than 18 hours after ingestion. There was no significant risk difference between groups when acetylcysteine treatment was started 12 to 18 hours after ingestion. One patient in the 20-hour group received a liver transplant and died because of acetaminophen toxicity compared with no liver transplants and 3 deaths in the 72-hour group. Anaphylactoid reactions to intravenous acetylcysteine were reported in 148 of 2,086 patients (7.1%; 95% CI 6.1% to 8.3%). This study is limited by comparison of 2 separate data sets from different countries and study years. CONCLUSION: The risk of hepatotoxicity differed between the 20-hour and 72-hour protocols according to the time to initiation of acetylcysteine. It favored the 20-hour protocol for patients presenting early and favored the 72-hour protocol for patients presenting late after acute acetaminophen overdose.

Exposures Through Breast Milk: An Analysis of Exposure and Information Calls to U.S. Poison Centers, 2001-2017.

Introduction: We described calls to U.S. poison centers (PCs) related to potential exposure to substances through breast milk. Materials and Methods: We analyzed National Poison Data System calls between 2001 and 2017 with "Exposure through breast milk" or "Drug use during breastfeeding" as the coded scenario. Data handling and descriptive statistics were carried out using SAS JMP 12.01. Results: U.S. PCs received 76,416 information calls and 2,319 exposure calls related to breast milk. Exposure calls were from a residence in 76% (n = 1,758), from health care facilities (HCFs) in 15.5% (n = 360), and from a workplace in 0.6% (n = 15). A total of 466 exposures (20.1%) were subsequently managed at a HCF: 269 were evaluated and released (58%), 38 were admitted to intensive care unit (8.2%), and 53 were admitted to hospital floor (11%). Medical outcomes included 1 death (0.04%), 8 major effect (0.3%), 43 moderate effect (1.9%), 170 minor effect (7.3%), and 390 no effect (16.8%). Exposure calls that reported major effects involved opioids, benzodiazepines, ethanol, cyclobenzaprine, insulin, and amphetamines. Exposure calls most commonly involved antibiotics, antifungals, benzodiazepines, opioids, and selective serotonin reuptake inhibitors (SSRIs). A total of 1,192 exposures (51.4%) had reported signs/symptoms including drowsiness, agitation, rash, and vomiting/diarrhea. Information calls most commonly involved systemic antibiotics, SSRIs, antihistamines, corticosteroids, and benzodiazepines. Conclusions: Substances common to both exposure and information calls included antibiotics, benzodiazepines, and SSRIs. Most cases of severe toxicity included potential exposures through breast milk to benzodiazepines and opioids. These data may help inform educational outreach, risk assessment, and bedside care for breastfeeding mothers.

Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis.

CONTEXT: The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold. METHODS AND MATERIALS: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones. RESULTS: Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24 h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150 µg/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing. CONCLUSIONS: Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.

2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 36th Annual Report.

Introduction: This is the 36th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2018, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.72 [6.90, 12.0] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.Results: In 2018, 2,530,238 closed encounters were logged by NPDS: 2,099,751 human exposures, 57,017 animal exposures, 368,025 information requests, 5,346 human confirmed nonexposures, and 99 animal confirmed nonexposures. United States PCs also made 2,621,242 follow-up calls in 2018. Total encounters showed a 2.96% decline from 2017, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.261%. All information requests decreased by 15.5%, medication identification (Drug ID) requests decreased by 30.2%, and human exposure cases decreased by 0.729%. Human exposures with less serious outcomes have decreased 2.33% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.45% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.8%), household cleaning substances (7.28%), cosmetics/personal care products (6.53%), sedatives/hypnotics/antipsychotics (5.53%), and antidepressants (5.22%). For cases with more serious outcomes, sedative/hypnotics/antipsychotics exposures were the class that increased most rapidly, by 1,828 cases/year (9.21%/year) over the past 18 years. Over just the past 10 years (for cases with the most serious outcomes) antidepressant exposures increased most rapidly, by 1,887 cases/year (7.02%/year).The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (12.1%), household cleaning substances (10.7%), analgesics (9.04%), foreign bodies/toys/miscellaneous (6.87%), and topical preparations (4.69%). Drug identification requests comprised 18.2% of all information requests. NPDS documented 3,111 human exposures resulting in death; 2,582 (83.0%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.