key: cord-0760568-28khksh7
authors: Spyres, Meghan B.; Aldy, Kim; Farrugia, Lynn A; Kang, A. Min; Love, Jennifer S.; Campleman, Sharan L.; Li, Shao; Amaducci, Alexandra; Schwarz, Evan; Wax, Paul M.; Brent, Jeffery
title: The Toxicology Investigators Consortium 2020 Annual Report
date: 2021-09-17
journal: J Med Toxicol
DOI: 10.1007/s13181-021-00854-3
sha: aea6b4553a42ef336ce455404f055355f85f6f6f
doc_id: 760568
cord_uid: 28khksh7

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology in 2010. The registry collects data from participating sites with the agreement that all bedside and telehealth medical toxicology consultation will be entered. This eleventh annual report summarizes the Registry’s 2020 data and activity with its additional 6668 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from January 1 to December 31, 2020. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. Gender distribution included 50.6% cases in females, 48.4% in males, and 1.0% identifying as transgender. Non-opioid analgesics were the most commonly reported agent class, followed by opioid and antidepressant classes. Acetaminophen was once again the most common agent reported. There were 80 fatalities, comprising 1.2% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years’ reports. Sub-analyses were conducted to describe race and ethnicity demographics and exposures in the registry, telemedicine encounters, and cases related to the COVID-19 pandemic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13181-021-00854-3.

The year 2020 marked the beginning of the second decade of the Toxicology Investigators Consortium (ToxIC). It was a year marked by considerable expansion of ToxIC's activities. Our case accrual unabatedly continued, and we welcomed six new sites to the consortium.

Starting in 2020 ToxIC began a partnership with the US Centers for Disease Control and Prevention (CDC) Overdose Data to Action (OD2A) program. Through a data sharing agreement, ToxIC is working with our partners at OD2A to provide data on our experience with opioid and psychoactive substance toxicity. Given the uniqueness of our physician led data collection, ToxIC's patient-oriented database is Supervising Editor: Mark B. Mycyk, MD supplying a level of detail on adverse drug effects not generally available from alternate drug-toxicity databases. As our partnership with the CDC grows, we expect to collaborate with their overdose prevention efforts through our main Core Registry, our pediatric opioid and marijuana Sub-Registries, and our novel efforts on opioid and stimulant exposures.

In 2020 ToxIC embarked on two prospective multicenter projects in addition to the continuation of its Core Registry. These two projects are not based on bedside medical toxicology consultations and utilize their own unique data collection interface.

The first multicenter project started its initial year of a 5-year NIH-supported prospective clinical study of opioid overdoses presenting to the emergency department (NIH# 1RO1DA037317-02). Alex Manini, MD, Professor of Emergency Medicine at the Mt Sinai Icahn School of Medicine and a long time ToxIC collaborator, is the Principal Investigator of this project which characterizes the clinical course, patient characteristics, and in-depth toxicologic analysis of fentanyl analogs (or "fentalogs"). In the course of the Fentalog project, ToxIC is assessing the prevalence and role of fentalogs, novel psychoactive drugs, adulterants, and other substances in the clinical presentation and treatment of these patients. In a supplement to this grant, ToxIC is also partnering Mt Sinai on data collection specific to factors related to COVID-19 infections in patients with a history of opioid misuse. This is the first ToxIC project that has included comprehensive toxicological testing, utilizing liquid chromatography quadrupole time-of-flight mass spectrometry to elucidate the presence of psychoactive substances and their metabolites.

In 2020, the COVID-19 pandemic significantly altered human activity in a multitude of ways. The medical and public health communities vibrantly came to life in a way that had not been seen in a century. As these communities rose to the challenge and aggressively took action to deal with the evolving pandemic, ToxIC quickly mobilized. As we continued our data sharing agreement adopted in 2016 with the US Food and Drug Administration (FDA), new therapeutics were rapidly entering clinical practice via Emergency Use Authorizations employed in a time of unprecedented need. Simultaneously, measures taken by the lay community to prevent and combat COVID-19, such as taking hydroxychloroquine and drinking bleach, reached a concerning level. Because of our already existing data sharing agreement with the FDA and the need to expeditiously identify adverse drug events in this rapidly evolving environment, ToxIC and the FDA collaboratively implemented a real-time national toxicosurveillance project searching for adverse drug events associated with COVID-19 prophylaxis or treatment. The so-called FDA ACMT COVID-19 ToxIC (FACT) Pharmacovigilance Project was organized and swiftly pressed into action. Similar to the Fentalog project above, the FACT project is not based on the ToxIC Core Registry or bedside medical toxicology consults, and data is collected through a separate mechanism and database.

In addition to the summary Core Registry data, this year we are presenting additional data on the use of telemedicine by medical toxicologists, as well as taking a closer look at race and ethnicity, and COVID-19 positive cases since the start of the pandemic.

Twelve full ToxIC publications in six separate journals were published in 2020. This is the largest number of journal publications in any year since ToxIC's inception. Sixteen ToxIC abstracts were published from both national and international meetings. These full publications and abstracts are enumerated on the ToxIC website: www.ToxICRegistry.org.

In addition to the above, the following new ToxIC research projects were proposed and initiated by ToxIC investigators in 2020:

1. Effect of activated charcoal administration on clinical outcome 2. A comparison of clinical outcomes following benzodiazepine or Z-drug toxicity 3. A comparison of hydroxyzine and diphenhydramine poisonings 4. The effect or race and ethnicity on access to opioid treatment facilities 5. Organ donation after death from a toxic exposure 6. Fomepizole use in acetaminophen poisoning 7. Epidemiology of pediatric antiepileptic drug poisoning 8. Trends in gastrointestinal decontamination after acute poisoning 9. Trends in toxicity from household cleaners and sanitizing agents 10. Toxicity of chloroquine and hydroxychloroquine

In 2020 ToxIC was supported by the NIH, FDA, CDC, and BTG International. These collaborations have been enriching for ToxIC but more importantly have provided unique networking opportunities for ToxIC investigators.

ToxIC was started on January 1, 2010, as a Case Registry [1] . That Core Registry continues today and prospectively enrolls patients presenting to participating sites. All sites agree to enter all inpatients or outpatients presenting to their site on whom a formal medical toxicology consultation was completed. ToxIC staff periodically meet with all sites to review patient accrual, obstacles to achieving full compliance with patient entry, quality assurance efforts, and ongoing project opportunities. Deidentified case information is entered into an online data collection form using the REDCap (Research Electronic Data Capture) platform. REDCap is a secure, web-based software platform designed as an electronic data capture tool for research studies hosted at the Vanderbilt University Health Core. REDCap provides (1) an intuitive interface for validated data capture, (2) trail audits for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for data integration and interoperability with external sources.

In 2020, the Core Registry collected data in the following areas:

1. Names, sites, and specific facility of the entering medical toxicologist(s) 2. Specific focused data collections on areas of contemporary interest 3. Medication errors and adverse reactions associated with therapeutic use 4. Patient demographics 5. HIV status 6. Specific aspects of the patient's medical history 7. The source of the patient referral 8. The reasons for the patient requiring a medical toxicology consultation 9. The implicated substance(s) and their relationship, if any, to the patient's presentation 10. Patient signs and symptoms 11. Specific laboratory and electrocardiographic data 12. Treatments administered 13. Outcome ToxIC's data collection in 2020 included the addition of teletoxicology and COVID-19 status (defined as a positive SARS-CoV-2 test). A full enumeration of all fields collected in the Core Registry is provided in the supplemental materials.

In addition to the Core Registry data collected on every bedside medical toxicology consultation, there are five detailed Sub-Registries that are completed on relevant patients. These are:

1. North American Snakebite Registry 2. Pediatric Marijuana and Opioid Registry 3. Extracorporeal Therapies Registry 4. Lipid Emulsion Therapy Registry 5. Natural Toxins Registry: Mushrooms and Plants ToxIC has been reviewed by the Western Institutional Review Board (IRB) and operates in pursuant to the approval of the participating site IRBs. All data collected by ToxIC is deidentified and is compliant with the Health Insurance Portability and Accountability Act. All cases entered into the Core Registry, Sub-Registries, FACT Pharmacovigilance Project, and the Fentalog project are reviewed for quality assurance by the ToxIC staff. Any inconsistent or incomplete entries are queried back to the entering medical toxicologist for correction or clarification.

Additional information regarding ToxIC can be found at https://www.toxicregistry.org.

In 2020 there were a total of 6668 individual cases of toxicologic exposures reported to the ToxIC Registry from 37 sites comprised of 58 separate health care facilities. This is a decrease in total cases compared with 2019 [2] . Individual facilities contributing cases in 2020 are listed in Table 1 . Tables 2 and 3 summarize selective demographics for age and gender and race and ethnicity, respectively. Gender breakdown was similar to recent years [2] [3] [4] [5] . In 2020, 50.6% of cases involved female patients, and 1% involved transgender or gender non-conforming patients (37 female-to-male, 17 male-to-female, 8 gender non-conforming). Sixty-nine patients (1%) were pregnant. Age distribution was similar to recent years. Adults age 19-65 made up approximately half of the cases (55.5%) followed by adolescents age 13-18 (24.6%). Children (< 12 years of age) made up 9.5%; 5.9% of cases involved older adults (> 65 years of age).

The most commonly reported race was Caucasian (62.6%), followed by Black/African (15.1%) and Asian (2.3%). Hispanic ethnicity was reported in 12.4% of cases; however 15.7% of cases reported ethnicity as unknown/uncertain. Race and ethnicity are self-reported by patients, or in cases in which a patient is unable to report, it may be determined by the examining medical toxicologist to the best of their ability or abstracted from the medical record. Table 4 details the referral source of inpatient and outpatient medical toxicology encounters. The majority (53.5%) of inpatient cases were generated by the emergency department, and very few cases were referred from poison centers (0.2%) or outpatient physicians (0.2%). Outpatient encounters were primarily referred by primary care and other outpatient physicians (68.7%), followed by self-referrals (11.0%). These trends were similar to recent years.

Tables 5 and 6 describe the reason for the toxicology encounter and the details of intentional pharmaceutical exposures, respectively. Consistent with recent years, intentional pharmaceutical exposures were by far the most common reason for medical toxicology encounters (43.8%). Addiction medicine consult was a new reason for encounter in 2018 and has increased in frequency each year (2.7% to 6.6% to 7.1%) [2, 3] . Within the intentional pharmaceutical exposures, the majority of cases were again an attempt at self-harm (73.9%), primarily suicide attempts (87.5%). Tables 7 and 8 describe the top three primary reasons for encounter by race and ethnicity, respectively. Distribution of reasons for encounter was largely similar across races and ethnicities, with intentional pharmaceutical exposures being the most common reason for encounter across all groups. Of note, however snake envenomation was a top three encounter reason among Native American/Alaska Native (8.2%) and Asian (17.4%) race groups, but not among other race groups. Addiction medicine consultation was the primary reason for the encounter in 5.9% of non-Hispanic patients, but only 3.4% of Hispanic patients.

Agent class contributions to the Core Registry are described in Table 9 . In 2020, of the 6668 cases entered into the ToxIC Registry, 5987 included specific agents of exposure. Four thousand two hundred sixty-two (71.2%) cases involved single agents. Consistent with recent years, the non-opioid analgesic class was the most common (15.5%) class of drugs reported. Again in 2020, the opioid class was the second most common agent class reported (12.7%) [2] followed by the antidepressant (10.4%) and ethanol (8.4%) classes.

Tables 10 and 11 detail the top five agent classes broken down by race and ethnicity, respectively. The primary substance responsible for most encounters varied across racial groups: ethanol for Native Americans/Alaska Natives (13.7%); analgesics for Asians (10.3%), Caucasians (14.4%), and mixed-race patients (21.1%); opioids for Blacks (17.0%); and toxic alcohols for Pacific Islanders/ Native Hawaiians (28.6%). Primary substances associated with both Hispanic and non-Hispanic patient encounters were similar. Table 12 presents the non-opioid analgesics, the largest class in the Core Registry. Acetaminophen was again the most commonly reported agent (64.6%), reaching its claim as the highest reported drug of exposure every year since ToxIC was established. It is distantly followed by ibuprofen (12.3%), aspirin (6.7%), and gabapentin (6.5%). Aspirin and acetylsalicylic acid are listed separately in the registry; when combined they compose 11.0% of the non-opioid analgesic class. Table 13 describes the opioid class. Similar to recent years, heroin was again the most common agent in the class (32.1%) [2, 3] . The relative contribution of fentanyl increased again this year, now representing 25.4% of the opioid class (14.6% in 2019), and again was the second most common agent. [2] Oxycodone was the third most common agent reported again this year (13.9%) [2] . Other opioid agents remained fairly stable compared with prior years. Table 14 describes breakdown of analgesics by race. In comparing opioid and non-opioid analgesic agents, acetaminophen was associated with the highest percentage of encounters across most racial sub-groups. However, among a Percentage based on the total number of cases (N = 6505) seen by a medical toxicologist as consultant (ED or IP) or as attending (IP) b Percentage based on the total number of cases (N=163) seen by a medical toxicologist as outpatient, clinic visit, or office consultation. Sedative hypnotics Table 16 presents the sedative hypnotic/muscle relaxant class. Benzodiazepines (primarily alprazolam (25.8%) and clonazepam (12.2%)) and muscle relaxants (primarily baclofen (10.2%) and cyclobenzaprine (7.9%)) were the most common subtypes, similar to recent years. Other sedatives, Zdrugs, and barbiturates were again less common.

Table 17 describes data on ethanol and toxic alcohols. Ethanol was considered its own agent class, consistent with prior years and was the fourth most commonly reported agent class (up from fifth in 2019) [2] . The most commonly reported nonethanol alcohols and glycols were ethylene glycol (47.0%) and isopropanol (31.8%). Methanol and miscellaneous alcohols each made up 10.6% of the class. Table 18 presents the sympathomimetic class. This year, methamphetamine (40.3%) overtook cocaine (23.9%) as the most common agent in this class, followed again by amphetamine (10.1%). Table 19 describes the anticholinergic/antihistamine class. Consistent with recent years, diphenhydramine (58.6%), followed by hydroxyzine (18.1%), remains the most commonly reported agents in this class. Table 20 shows data on the cardiovascular class. Consistent with recent years, sympatholytics (32.5%) remain the most common subclass of cardiovascular drugs, followed by betablockers (23.5%) and calcium channel blockers (16.5%). a Percentages in bold based on the number of cases in a given race category in 2020 relative to the total number of Core Registry cases in 2020 (N = 6668) b Percentages based on number of cases for a primary encounter type relative to the number of cases in given race category in 2020 a Percentages in bold based on the number of cases in a given ethnicity category in 2020 relative to the total number of Core Registry cases in 2020 (N = 6668) b Percentages based on number of cases for a primary encounter type relative to the number of cases in given ethnicity category in 2020

Clonidine (24.0%) and metoprolol (10.0%) were again the most common sympatholytic and beta-blocker agents, respectively. Amlodipine (9.8%) remained the most common calcium channel blocker. a Counts include only the primary agent #1 selected for each Core Registry case b Percentages in bold based on the number of cases in a given race category in 2020 relative to the total number of Core Registry cases in 2020 (N = 6668) c Percentages based on number of cases for an agent type relative to the number of cases in given race category in 2020 Table 21 details the antipsychotic class. Trends in the antipsychotic class were similar to recent years. The atypicals, led by quetiapine (41.3%) and olanzapine (13.2%), represent the majority of cases reported.

Anticonvulsants, mood stabilizers, and lithium Table 22 presents data on anticonvulsants, mood stabilizers, and lithium. Consistent with past years, lithium was considered as its own agent class and made up just over 1% of reported agents in the Core Registry [2, 3] . Among anticonvulsants and mood stabilizers, lamotrigine (29.4%) and valproic acid (19.4%) were the most commonly reported agents followed by oxcarbazepine (10.7%) and phenytoin (9.5%).

Psychoactives Table 23 presents data on the psychoactive class including the a m p h e t a m i n e -l i k e h a l l u c i n o g e n methylenedioxymethamphetamine (Molly). Marijuana was again the most common agent in this class (25.5%) followed closely by tetrahydrocannabinol (20.3%). Synthetic cannabinoid cases continued to fall again this year (5.6% in 2020 vs 9.4% in 2019 and 12.3% in 2018) [2] [3] [4] . When combined, all non-synthetic cannabinoid product exposures represented 65.7% of the psychoactive class. Molly exposures remained low, with 7 cases reported. 2019, nearly approaching that of Crotalus envenomations. Again in 2020, Loxosceles exposures were the fourth most common exposure in this class (5.1%) [2] [3] [4] . Table 25 presents the diabetic medication agent class. Metformin was the most common agent at 39.4% of the agent class, followed by insulin (22.5%) and glipizide (21.7%). Table 26 presents the metal class. Lithium is its own agent class and is reported with the anticonvulsants and mood stabilizers.

Trends were similar to recent years with lead (37.6%) and iron (28.2%) composing the majority of reported cases [2] [3] [4] . Mercury and arsenic were reported each in 6 (7.1%) cases. a Counts include only cases for which an opioid or non-opioid analgesic was selected as primary agent #1 b Percentages in bold based on the number of cases in a given race category in 2020 relative to the total number of Core Registry cases in 2020 (N = 6668) c Percentages based on number of cases for an agent type relative to the number of cases in given race category in 2020 Gases, irritants, vapors, and dusts Table 29 presents data for the gases, irritants, vapors, and dusts class. Carbon monoxide again represented the large majority of this class (63.8%).

Table 30 details data on cough and cold preparations reported to the Core Registry. Dextromethorphan was again the most commonly reported agent, making up 77.5% of the class.

Caustics Table 31 presents the caustic agent class. Sodium hydroxide was the most common agent reported in this class (17.9%) followed by sodium hypochlorite concentration unknown (14.9%).

Antimicrobials Table 32 presents data on antimicrobial agents. Antibiotics were the most common subclass (57.2%), with amoxicillin representing 15.9% and miscellaneous antibiotics representing 41.3% of this class. Antivirals and other antimicrobials were less common. Hydrocarbons Table S2 presents the hydrocarbon agent class. The largest single contributor to the class was toluene (14.6%), however, infrequent miscellaneous agents represented the majority (73.2%) of the class. Insecticides, herbicides, rodenticides, and fungicides Table S4 presents the pesticide (insecticide, herbicide, rodenticide and fungicide) class. There were 13 herbicides reported (41.9%), with glyphosate being the most common. There were 11 (35.5%) insecticides and 9 (29.0%) rodenticides. No fungicides were reported. Other non-pharmaceuticals Table S10 describes the other non-pharmaceutical class. Water (13.0%), silicone (13.0%), and lactic acid (13.0%) were the three most common agents reported.

Table S11 describes reported pulmonary agents. Montelukast was the most common agent reported (66.7%).

Table S12 details the foreign object ingestions reported to the Core Registry. Batteries were the most common objects (42.9%).

Table S13 presents the anti-parkinsonism agent class, containing 5 entries. Reported agents included pramipexole, ropinirole, levodopa/carbidopa, and rasagiline.

Botulinum toxin (5 cases) was the only agent reported in the class of weapons of mass destruction, described in Table S14 . 

The categories of clinical signs and symptoms describe a diverse range of abnormal clinical findings. Predefined criteria must be met for each category in order for a sign or symptom to be reported as present. For example, tachycardia is defined as a heart rate greater than 140 beats per minute. Additionally, each case may report more than one abnormality within a a Includes ammonia ≤ 10%, aromatic or essential oils (carrier/solvent base unspecified), diaper rash ointment, dishwasher detergent, dishwasher detergent pod, drain cleaner (irritant), hair product, household product unspecified, mequinol (4-methoxyphenol), moisturizer/lotion, oven cleaner, soaps and detergents, windshield washer fluid group or across groups. For example, a single case entry may have multiple vital sign abnormalities or may have both a vital sign abnormality and a neurologic abnormality. The percentages for these categories and their individual signs and symptoms are calculated relative to the total number of Core Registry cases (N = 6668). It is therefore possible for the total to be more than 100%.

Toxidromes Table 33 reports the 1844 toxidromes reported to the Core Registry in 2020. Consistent with recent years, the sedativehypnotic toxidrome was the most common (8.3%). This year the opioid toxidrome (3.7%) overtook serotonin syndrome (3.0%) as the third most common toxidrome reported. Table 34 presents the 1738 vital sign abnormalities reported to the Core Registry in 2020. Trends were nearly identical to recent years. Tachycardia (11.2%), hypotension (6.2%), and bradycardia (3.4%) were the most common vital sign abnormalities reported. [2] . Clinical signs-other organ systems Table 37 presents the other organ system clinical signs which include metabolic, renal and musculoskeletal, hematological, gastrointestinal and hepatic, and dermatological. Metabolic abnormalities were again the most frequently reported (10.4%), and among these an elevated anion gap (4.0%) and metabolic acidosis (4.0%) were the most common [2, 3] . Renal and musculoskeletal abnormalities were the next most commonly reported (7.4%), with acute kidney injury (4.3%) being the most common sign in this subgroup. Hepatotoxicity was the most common gastrointestinal and hepatic abnormality (2.8%). Coagulopathy was the most commonly reported hematological abnormality (1.6%). Dermatological abnormalities were less frequently reported (3.4%), with rash being the most common (1.6%).

There were 81 fatalities in 2020, comprising 1.2% of Core Registry cases. Single-agent exposures were implicated in 34 cases (Table 38) , 26 cases involved multiple agents (Table 39) , and in 21 cases it was unknown if there was a toxicologic exposure (Table 40 ). There were 12 fatalities (14.8%) involving opioids, an decrease from 2019 and 2018 in which opioids were reported in 19.8% and 34.0% of Core Registry deaths, respectively [2, 3] . Fentanyl was reported in 2 deaths (2.5%) this year compared with 5.5% in 2019 and 9.4% in 2018 [2, 3] ; 3 deaths (3.7%) were reported as single opioid ingestions in 2020. HR heart rate, BP blood pressure, RR respiratory rate a Percentage based on the number of cases relative to the total number of Registry cases in 2020 (N = 6668). There were 1407 unique cases (21.1% of all Registry cases) reporting at least one major vital sign abnormality. Cases may be associated with more than one major vital sign abnormality Acetaminophen was the most common agent involved in both single and multiple agent fatalities; there were 11 fatalities (13.6%) involving acetaminophen, 5 as a single agent. A single death was reported after laundry pod exposure in a > 89-year-old that sustained a corrosive gastrointestinal injury. A single agent pancrelipase death in a 7-year-old after medication administering error due to the wrong medication (either wrong route or dilution technique) was reported. A single agent lactulose death in a 2-year-old also due to a medication dosing error after receiving 75 g chronically was reported with respir a t o r y d e p r e s s i o n , C N S d e p r e s s i o n , s e i z u r e s , hypernatremia, and hyperglycemia. A single agent paraquat death was reported in a 60-year-old who presented with hypotension, tachycardia, QRS and QTc prolongation, and gastrointestinal bleeding. He was treated with activated charcoal, NAC, steroids, vitamin C, and magnesium sulfate. A multi-agent death involving intentional verapamil exposure, with a subsequent lipid emulsion medication dosing error given intranasally, was reported in a 65-year-old. In addition to treatment for the verapamil exposure, she was treated with enhanced elimination and ECMO specifically related to the medication error.

In 2020 there were 13 pediatric (age 0-18 years) deaths due to a known toxicologic exposure (16.1%), compared with 20.0% in 2019 [2] . The age range was 13 months to 18 years. Nine were single agent exposures and 4 involved multiple agents. No pediatric exposures involved acetaminophen in 2020, whereas 35.7% of pediatric exposures in 2019 involved acetaminophen. Three deaths involved opioids in pediatric patients. One single agent methamphetamine death was reported in a 13-month old.

There were 46 fatality cases in which life support was withdrawn, representing 0.7% of Core Registry cases. It was unknown whether life support was withdrawn in an additional 7 cases. Brain death was declared in 19 cases. AST aspartate aminotransferase, PT prothrombin time, WBC white blood cells, Hgb hemoglobin, CPK creatine phosphokinase a Percentage equals the number of cases reporting specific clinical signs compared to the total number of Registry cases in 2020 (N = 6668) b Total reflects cases reporting at least one sign in the category. Cases may be associated with more than one symptom Table 41 presents the common drugs associated with adverse drug reactions reported to the Core Registry in 2020. One hundred seventy-seven ADRs (2.7% of cases) were reported in 2020. Lithium was again the most common drug reported (10.2%), similar to recent years.

Antidotal therapy Table 42 describes the 2777 antidotes reported to the Core Registry in 2020. Similar to last year, N-acetylcysteine (28.3%), followed by naloxone/nalmefene (15.5%), and thiamine (15.0%) were the three most common antidotes reported [2] . In 2020, 31.0% of Core Registry cases received at least one antidote compared with 26.3% in 2019 [2] . Pharmacologic supportive care Table 44 describes the 3260 pharmacologic supportive care treatments reported in 2020. Benzodiazepines were again the most commonly reported agents (47.1%), followed by opioids (12.8%) and vasopressors (8.1%).

Non-pharmacologic supportive care Table 45 presents non-pharmacologic supportive care treatments reported to the Core Registry in 2020. IV fluid resuscitation (76.1%) and intubation/ventilatory management (19.3%), remain the most common treatments in this category. Table 40 Decontamination interventions administered Although the Core Registry is not strictly population based, it represents a wide geographic distribution of cases evaluated by medical toxicologists. These data can be used in conjunction with data from other registries including the National Poison Data System to provide a more detailed picture of poisoning trends, novel exposures, and their public health implications.

This 11th annual report finds overall trends in agent classes, agents, demographics, types of encounters, clinical signs and symptoms, and treatments to be largely unchanged from recent years. Notable findings or trends in the Core Registry are discussed below.

In 2019, the opioid class jumped to the second most common agent class reported to the Core Registry; this trend [2, 3] and remains the second most common opioid reported in 2020. Oral opioids such as oxycodone, methadone, buprenorphine, tramadol, and hydrocodone remained relatively stable this year.

In 2020 ethanol became the 4th most common agent class reported, overtaking the sedative hypnotic/muscle relaxant class.

Marijuana and THC/CBD-related products continues to represent the majority of the psychoactive class (65.7%) and relative contribution of synthetic cannabinoid cases continued to fall.

With regards to envenomations, 2020 saw new trends including an increase in relative Agkistrodon cases (34.4% in 2020 vs 16.9% in 2019). Two of the six new sites added to the Core Registry in 2020 commonly report Agkistrodon cases, possibly driving this year's trend. In addition, the use of Crotalidae immune Fab2 (equine) antivenom continued to increase this year (31.0% in 2020 vs 19.9% 2019) [2] . Table 49 presents data on the 144 telemedicine encounters reported in 2020. This was the first year such data was collected in the Core Registry, prompted by the COVID-19 pandemic and national rise of telemedicine as a mode of patient care. Most evaluations were for patients physically located in the emergency department at the time of the encounter (n = 74; Only seven evaluations (4.9%) were primarily addiction medicine evaluations, five of which were for initiation of opioid agonist therapy. No telemedicine evaluations were for adverse drug reactions or medication errors. Toxicology therapeutic intervention was administered to 94 (65.3%) patients, but only 75 (52.1%) of telemedicine evaluations were billed.

A new set of COVID-19 specific questions were incorporated into the ToxIC Core Registry on August 1, 2020. After this implementation, a total of 3119 toxicological exposure cases were reported in 2020. Fifty-one cases (1.6%) were COVID-19 positive, 1397 (44.8%) were COVID-19 negative, and 1671 (53.6%) were unknown. Regarding the COVID-19 cases, males represented 54.9%; there were no transgender COVID-19-positive patients. Age and gender breakdown of COVID-19 cases are described in Table 50 . The toxic exposures in COVID-19 patients were largely unrelated to COVID-19; only 5 (9.8%) exposures were related to COVID-19 treatment or prophylaxis. Of the patients presenting with a toxic exposure, the four most common reasons for encounter include intentional pharmaceutical (50.9%), intentional non-pharmaceutical (15.7%) and unintentional pharmaceutical (9.8%) and withdrawal of ethanol or opioids (9.8%). Agent exposures related to COVID-19 treatment or prophylaxis are described in Table 51 . There were no children in this group. Only one case was related to a self-harm attempt. The remaining cases were intentional (3/4) or unintentional (1/4) supratherapeutic dosing. Acetaminophen was the most common agent (4 of 5 cases; 80.0%); all acetaminophen cases required NAC treatment and 3/4 developed a transaminitis.

The ToxIC Core Registry is a unique prospective database of cases in which bedside or telemedicine consultation is performed by medical toxicologists, enabling an informed relationship between exposures and clinical outcomes. Limitations, however, do exist for the Core Registry. One of these is a bias towards inclusion of more severe case presentations, as cases are only included if they undergo subspecialty consultation. Cases for which a medical toxicology consultation was not requested are not reported and may represent a group with less severe illness. Therefore, the Core Registry likely represents a different population from other data sources such as Poison Control Centers. Regional differences may lead to a disproportionate number of specific cases reported based on variations in drug use, abuse, and other toxic exposures. The ToxIC Core Registry includes sites from multiple, diverse locations, but the entire country is not uniformly represented. Larger academic medical centers with greater amounts of m edical toxicology faculty may be over-represented in the database.

At the level of the individual sites, there may be a reporting bias towards more complicated or interesting cases. Although the express intent of the Core Registry, as defined in written agreements with all sites, is to obtain a consecutive sample of all cases at a given site, individual cases may be missed. Data regarding substances of exposure or species of envenomation relies heavily on patient self-report and may be misclassified; this limitation is likely of most significance with regard to illicit drug exposure and patient hesitancy to disclose detailed information. Lastly, efforts are made to continually improve the quality of data collected. While member sites are instructed to complete all applicable data fields, there are still a number of cases and data fields with incomplete information. This remains an issue for collection of race and ethnicity, for example. Efforts continue to support quality data collection and follow up on missing data where applicable.

Supplementary Information The online version contains supplementary material

Funding sources The Toxicology Investigators Consortium received funding from the US National Institute of Drug Abuse (1RO1DA037317-02) and the American Academy of Addiction Psychiatry (1H79TI083343) and has data-sharing contracts with the U

Lo Table 51 Reasons for encounter and primary agent in toxic exposures related to COVID-19 treatment and prophylaxis

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On behalf of the Toxicology Investigators Consortium (ToxIC) Study Group. The Toxicology Investigators Consortium Case Registrythe 2017 Annual Report

On behalf of the Toxicology Investigators Consortium Study Group, et al. The Toxicology Investigators Consortium Case Registry-the 2016 Experience

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The ToxIC project continues to grow and evolve, including the Core Registry and additional surveillance projects. The Core Registry remains unique amongst databases in that it represents prospective data collected from cases evaluated by medical toxicologist specialists. Although this feature limits extrapolation to the population as a whole, it increases the potential for high-quality data and for increased correlation between exposure cases and clinical findings. Continued quality improvement and surveillance efforts remain areas of focus for the Core Registry and of ToxIC as a whole. Previous presentation of data This data has not been previously presented.